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Objective: To determine whether abnormal global, transverse, and longitudinal ventricular contractility of the heart in fetuses with an estimated fetal weight <10th centile is present, irrespective of Doppler studies of the umbilical artery and cerebroplacental ratio., Study Design: This was a retrospective study of 50 fetuses with an estimated fetal weight <10th centile that were classified based on Doppler results from the pulsatility indices of the umbilical artery and middle cerebral artery, and the calculated cerebroplacental ratio (pulsatility indices of the umbilical artery/middle cerebral artery). Right and left ventricular measurements were categorized into 3 groups: (1) global ventricular contractility (fractional area change), (2) transverse ventricular contractility (24-segment transverse fractional shortening), and (3) basal-apical longitudinal contractility (longitudinal strain, longitudinal displacement fractional shortening, and basal lateral and septal wall annular plane systolic excursion). Z scores for the above measurements were computed for fetuses with an estimated fetal weight <10th centile using the mean and standard deviation derived from normal controls. Ventricular contractility measurements were considered abnormal if their Z score values were <5th centile (z score <-1.65) or >95th centile (Z score >1.65), depending on the specific ventricular measurement., Results: The average gestational age at the time of the examination was 32 weeks 4 days (standard deviation 3 weeks 4 days). None of the 50 study fetuses demonstrated absent or reverse flow of the umbilical artery Doppler waveform. Eighty-eight percent (44/50) of fetuses had one or more abnormal measurements of cardiac contractility of 1 or both ventricles. Analysis of right ventricular contractility demonstrated 78% (39/50) to have 1 or more abnormal measurements, which were grouped as follows: global contractility 38% (19/50), transverse contractility 66% (33/50); and longitudinal contractility 48% (24/50). Analysis of left ventricular contractility demonstrated 1 or more abnormal measurements in 58% (29/50) that were grouped as follows: global contractility 38% (19/50); transverse contractility 40% (20/50); and longitudinal contractility 40% (20/50). Of the 50 study fetuses, 25 had normal pulsatility index of the umbilical artery and cerebroplacental ratios, 80% of whom had 1 or more abnormalities of right ventricular contractility and 56% of whom had 1 or more abnormalities of left ventricular contractility. Abnormal ventricular contractility for these fetuses was present in all 3 groups of measurements; global, transverse, and longitudinal. Those with an isolated abnormal pulsatility index of the umbilical artery (n=11) had abnormalities of transverse contractility of the right ventricular and global contractility in the left ventricle. When an isolated cerebroplacental ratio abnormality was present, the right ventricle demonstrated abnormal global, transverse, and longitudinal contractility, with the left ventricle only demonstrating abnormalities in transverse contractility. When both the pulsatility index of the umbilical artery and cerebroplacental ratio were abnormal (3/50), transverse and longitudinal contractility measurements were abnormal for both ventricles, as well as abnormal global contractility of the left ventricle., Conclusions: High rates of abnormal ventricular contractility were present in fetuses with an estimated fetal weight <10th centile, irrespective of the Doppler findings of the pulsatility index of the umbilical artery, and/or cerebroplacental ratio. Abnormalities of ventricular contractility were more prevalent in transverse measurements than global or longitudinal measurements. Abnormal transverse contractility was more common in the right than the left ventricle. Fetuses with estimated fetal weight less than the 10th centile may be considered to undergo assessment of ventricular contractility, even when Doppler measurements of the pulsatility index of the umbilical artery, and cerebroplacental ratio are normal., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To asses the occurrence of discrepancies between the Doppler waveforms of the left and right umbilical arteries in their paravesical part in fetuses with absent or reversed end-diastolic flow in the free-floating umbilical cord., Methods: This prospective observational study included pregnant women with fetal growth restriction or twin-to-twin transfusion syndrome. Umbilical arterial Doppler waveforms were obtained from both umbilical arteries in their intra-abdominal paravesical part. Doppler findings were recorded as present end-diastolic flow (PEDF)/absent end-diastolic flow (AEDF); AEDF/AEDF; AEDF/reversed end-diastolic flow (REDF); or REDF/REDF pattern., Results: There were 49 fetuses with AEDF or REDF at the free-floating umbilical cord. Of these, 20 (40.8%) had a discrepancy in Doppler waveforms between the two umbilical arteries, with 14 (28.6%) showing PEDF/AEDF, 17 (34.7%) AEDF/AEDF, 6 (12.2%) AEDF/REDF, and 12 (24.5%) REDF/REDF pattern., Conclusion: Doppler waveforms showed discrepancies between the two umbilical arteries in 40.8% of pregnant women with AEDF or REDF in the free-floating umbilical cord. The presence of end-diastolic flow in one umbilical artery cannot exclude the possibility of AEDF in the other., (© 2019 Wiley Periodicals, Inc.)

Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension-like pathophysiological features in adulthood.

Pregnancy complications of preeclampsia and intrauterine growth restriction (IUGR) are major causes of maternal and perinatal/neonatal morbidity and mortality. Although their etiologies remain elusive, it is generally accepted that they are secondary to placental insufficiency conferred by both failure in spiral artery remodeling and uteroplacental vascular malfunction. MicroRNAs (miRNAs) are small no-coding RNA molecules that regulate gene expression at the post-transcriptional level. Increasing evidence suggests that miRNAs participate in virtually all biological processes and are involved in numerous human diseases. Differentially expressed miRNAs in the placenta are typical features of both preeclampsia and IUGR. Dysregulated miRNAs target genes of various signaling pathways in uteroplacental tissues, contributing to the development of both complications. In this review, we provide an overview of how aberrant miRNA expression in preeclampsia and IUGR impacts the expression of genes involved in trophoblast invasion and uteroplacental vascular adaptation., Competing Interests: The authors declare no conflict of interest.

Background This study aimed to investigate fetal cardiac functions by spectral tissue Doppler imaging (s-TDI) in pregnancies complicated with late-onset fetal growth restriction (LO-FGR) and small-for-gestational age (SGA). Methods Forty pregnancies complicated with late-onset FGR and 40 pregnancies complicated with SGA between the 34th and 37th weeks of gestation were enrolled in this study. Forty gestational age-matched pregnant women with no obstetrics complication were randomly selected as a control group. Small fetuses were classified as fetal growth restriction or SGA according to estimated fetal weight (EFW), umbilical artery pulsatility index (PI), cerebroplacental ratio (CPR) and uterine artery PI. s-TDI measurements were obtained at the right atrioventricular valve annulus. Results SGA and LO-FGR fetuses had significantly lower A' and S' values, and higher E'/A' ratio than the control group (P < 0.001). In comparison to controls, significantly prolonged isovolumetric contraction time (ICT') and isovolumetric relaxation time (IRT') and, significantly shortened ejection time (ET') were observed in fetuses with SGA and LO-FGR. Increased myocardial performance index (MPI') values were also found in fetuses with SGA and LO-FGR compared to controls. Conclusion The signs of cardiac dysfunction were observed both in fetuses with SGA and LO-FGR. The fetal cardiac function assessment with s-TDI could be a valuable method in the diagnosis of true growth restricted fetuses and in the management of these fetuses.

Chorioamnionitis and intrauterine growth retardation (IUGR) are risk factors for cerebral palsy (CP). Common bacteria isolated in chorioamnionitis include group B Streptococcus (GBS) serotypes Ia and III. Little is known about the impact of placental inflammation induced by different bacteria, including different GBS strains. We aimed to test the impact of chorioamnionitis induced by two common GBS serotypes (GBSIa and GBSIII) on growth and neuromotor outcomes in the progeny. Dams were exposed at the end of gestation to either saline, inactivated GBSIa or GBSIII. Inactivated GBS bacteria invaded placentas and triggered a chorioamnionitis featured by massive polymorphonuclear cell infiltrations. Offspring exposed to GBSIII - but not to GBSIa - developed IUGR, persisting beyond adolescent age. Male rats in utero exposed to GBSIII traveled a lower distance in the Open Field test, which was correlating with their level of IUGR. GBSIII-exposed rats presented decreased startle responses to acoustic stimuli beyond adolescent age. GBS-exposed rats displayed a dysmyelinated white matter in the corpus callosum adjacent to thinner primary motor cortices. A decreased density of microglial cells was detected in the mature corpus callosum of GBSIII-exposed males - but not females - which was correlating positively with the primary motor cortex thickness. Altogether, our results demonstrate a causal link between pathogen-induced acute chorioamnionitis and (1) IUGR, (2) serotype- and sex-specific neuromotor impairments and (3) abnormal development of primary motor cortices, dysmyelinated white matter and decreased density of microglial cells.

Background: The Polyvagal theory argues that behavioral modulation is a fundamental neurodevelopmental process that depends on autonomic regulation., Objective: The present study aimed to assess sleep architecture in newborns with fetal growth restriction (FGR) using polysomnography as an indicator of Polyvagal theory., Methods: We studied polysomnography recordings from 68 preterm infants, 34 with FGR and 34 born with appropriate growth for gestational age (AGA), who were matched according to the corrected age for prematurity (CA). Total sleep time, arousals, the percentage of quiet sleep, active sleep, indeterminate sleep, and heart rate were compared between the groups. Linear multiple regression analyses were used to evaluate polysomnography data for the FGR and AGA groups., Results: Average heart rate was significantly lower in most FGR groups compared with AGA groups, and small to large effect sizes were observed in several sleep responses when comparing these groups. In the lineal regression model the CA explains significantly the differences in heart rate, controlled by FGR (p = .012). Additionally, there was evidence that sleeping states show similar trends, that is, increases in quiet and indeterminate sleep, as well as decreases in active sleep when CA was controlled by FGR., Conclusion: FGR probably intensifies the unfavorable effect of preterm birth in the responses evaluated by polysomnography. It seems that FGR is associated with alteration in sleep regulation and with differences in heart rate modulation, which may serve as a strategy to preserve energy and such differences likely underlie neurodevelopmental impairments in affected newborns., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The dynamic field of perinatology entails ever-increasing search for molecular mechanisms of neonatal diseases, especially in the domain of fetal growth and neurodevelopmental outcome. There is an urgent need for new molecular biomarkers, to early identify newborn at high risk for developing diseases and to provide new treatment targets. The interest in biomarkers of oxidative stress in perinatal period have begun to grow in the last century, when it was evidenced the importance of the free radicals generation underlying the various disease conditions. To date, interesting researches have been carried out, representing milestones for implementation of oxidative stress biomarkers in perinatal medicine. Use of a panel of "oxidative stress biomarkers", particularly non protein bound iron, advanced oxidative protein products and isoprostanes, may provide valuable information regarding functional pathways underlying free radical mediated diseases of newborns and their early identification and prevention. Here, we will review recent advances and the current knowledge on the application of biomarkers of oxidative stress in neonatal/perinatal medicine including novel biomarker discovery, defining yet unrecognized biologic therapeutic targets, and linking of oxidative stress biomarkers to relevant standard indices and long-term outcomes., (Copyright © 2019. Published by Elsevier Inc.)

The scientific background of perinatal pathology, regarding both mother and offspring, from the lipidomic perspective, has highlighted the possibility of identifying new, promising clinical markers of oxidative stress and inflammation, closely related to the normal development of unborn and newborn children, together with their application. In this regard, in recent years, significant advances have been achieved, assisted by both newly developed analytical tools and basic knowledge on the biological implications of oxylipins. Hence, in the light of this recent progress, this review aims to provide an update on the relevance of human oxylipins during pregnancy and in the unborn and newborn child, covering two fundamental aspects. Firstly, the evidence from human clinical studies and dietary intervention trials will be used to shed light on the extent to which dietary supplementation can modulate the lipidomic markers of oxidative stress and inflammation in the perinatal state, emphasizing the role of the placenta and metabolic disturbances in the mother and fetus. The second part of this article comprises a review of existing data on specific pathophysiological aspects of human reproduction, in relation to lipidomic markers in pregnant women, unborn children, and newborn children. The information reviewed here evidences the current opportunity to correct reproductive disturbances, in the framework of lipidomics, by fine-tuning dietary interventions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Oxidative stress is responsible for microvascular complications (hypertension, nephropathy, retinopathy, peripheral neuropathy) of diabetes, which during pregnancy increase both maternal and fetal complications. Chronic hypoxia and hyperglycemia result in increased oxidative stress and decreased antioxidant enzyme activity. However, oxidative stress induces also anti-oxidative reactions both in pregnant diabetes patients and in their fetuses. Not all type 1 diabetes patients with long-lasting disease develop microvascular complications, which suggests that some of these patients have protective mechanisms against these complications. Fetal erythropoietin (EPO) is the main regulator of red cell production in the mother and in the fetus, but it has also protective effects in various maternal and fetal tissues. This dual effect of EPO is based on EPO receptor (EPO-R) isoforms, which differ structurally and functionally from the hematopoietic EPO-R isoform. The tissue protective effects of EPO are based on its anti-apoptotic, anti-oxidative, anti-inflammatory, cell proliferative and angiogenic properties. Recent experimental and clinical studies have shown that EPO has also positive metabolic effects on hyperglycemia and diabetes, although these have not yet been fully delineated. Whether the tissue protective and metabolic effects of EPO could have clinical benefits, are important topics for future research in diabetic pregnancies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aim of the present study was to evaluate the effects of maternal exposure to triclosan (TCS) during pregnancy and lactation on the uterine morphology of rat offspring. For this, 32 Wistar rat dams were distributed into four dose groups (eight mothers per group), and gavage daily, throughout pregnancy and lactation, as follows: Group I-control (GI): corn oil; Group II (GII): TCS diluted in corn oil at a dose of 75 mg/kg/d; Group III (GIII): TCS diluted in corn oil at a dose of 150 mg/kg/d; Group IV (GIV): TCS diluted in corn oil at a dose of 300 mg/kg/d. A female pup of each mother was selected, and at 90 days the pups were euthanized for weighing and collection of the uterus for histomorphometric analysis. The results showed that the mean litter weight was minor in all the groups treated with TCS, when compared with control. The levels thyroid hormones thyroxine (T4) and triiodothyronine (T3) in TCS mother rats were reduced; however the levels of thyroid stimulating hormone (TSH) were increases. The offspring of all groups exposed to TCS presented deregulation of the estrous cycle, compared with control. Analysis of the uterine histological structure demonstrated that all layers of the uterus were affected by the administration of TCS, and the morphometric analysis showed increased uterine layers thickness in the treated groups. We concluded that maternal exposure to TCS during pregnancy and lactation causes intrauterine development restriction, deregulation of the oestrous cycle, and alters uterine tissue in rat offspring., (© 2019 Wiley Periodicals, Inc.)

The aim of the study was to investigate any association between extrauterine growth restriction (EUGR) and intestinal flora of <30-week-old preterm infants. A total of 59 preterm infants were assigned to EUGR (n=23) and non-EUGR (n=36) groups. Intestinal bacteria were compared by using high-throughput sequencing of bacterial rRNA. The total abundance of bacteria in 344 genera (7568 v. 13,760; P<0.0001) and 456 species (10,032 v. 18,240; P<0.0001) was significantly decreased in the EUGR group compared with the non-EUGR group. After application of a multivariate logistic model and adjusting for potential confounding factors, as well as false-discovery rate corrections, we found four bacterial genera with higher and one bacterial genus with lower abundance in the EUGR group compared with the control group. In addition, the EUGR group showed significantly increased abundances of six species (Streptococcus parasanguinis, Bacterium RB5FF6, two Klebsiella species and Microbacterium), but decreased frequencies of three species (one Acinetobacter species, Endosymbiont&#95;of&#95;Sphenophorus&#95;lev and one Enterobacter&#95;species) compared with the non-EUGR group. Taken together, there were significant changes in the intestinal microflora of preterm infants with EUGR compared to preterm infants without EUGR.

Key Points: Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health. A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus. Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR. Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid-pregnancy, but this adaptation was insufficient in late pregnancy. Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR., Abstract: Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild-type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin-like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (K mf ) of 14 C-glutamine and 14 C-glutamate ( glutamine K mf and glutamate K mf ) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamine K mf and glutamate K mf were higher (P0 versus wild-type littermates, WTL) at E15.5. At E18.5, glutamine K mf remained elevated whereas glutamate K mf was similar between groups. In summary, we provide evidence that glutamine K mf and glutamate K mf adapt according to placental size in WT mice. The placenta of the growth-restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth., (© 2019 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Low birth weight is associated with a greater prevalence of hypertension in women by age 60; yet, the mechanisms involved are unknown. We previously reported that hypertension in female growth-restricted offspring that is associated with early reproductive senescence and a shift in the testosterone-to-estradiol ratio at 12 months of age is abolished by AR (androgen receptor) blockade in conjunction with downregulation of renal AT1aR (angiotensin type 1a receptor) mRNA expression. These data suggest androgen-mediated activation of the renin-angiotensin system contributes to the pathogenesis of hypertension that develops in female growth-restricted offspring with aging. Thus, this study tested the hypothesis that androgen-mediated increased blood pressure is specific to female growth-restricted offspring. Control and growth-restricted rats underwent sham or ovariectomy at 10 months of age. Vehicle or flutamide (8 mg/kg/day; subcutaneous), an AR antagonist, was administered at 11.5 months of age for 2 weeks followed by measurement of blood pressure. Loss of ovarian hormones was associated with a 10 mm Hg increase in blood pressure in control compared with intact counterparts accompanied by a 1.8-fold increase in renal AT1aR mRNA expression. Treatment with flutamide had no effect on blood pressure or renal AT1aR mRNA expression in ovariectomized controls. Although blood pressure was significantly decreased in flutamide-treated ovariectomized growth-restricted, flutamide had no effect on the increase in renal AT1aR mRNA expression. Therefore, these findings suggest the effect of AR blockade on blood pressure is specific to intact growth-restricted offspring and that mechanisms of postmenopausal hypertension may differ between normal and low birth weight women.

Thirty years ago, there was an emerging appreciation for the significance of oxidative stress in newborn disease. This prompted a renewed interest in the impact of oxygen therapy for the newborn in the delivery room and beyond, especially in premature infants. Today, the complexity of oxidative stress both in normal regulation and pathology is better understood, especially as it relates to neonatal mitochondrial oxidative stress responses to hyperoxia. Mitochondria are recipients of oxidative damage and have a propensity for oxidative self-injury that has been implicated in the pathogenesis of neonatal lung diseases. Similarly, both intrauterine growth restriction (IUGR) and macrosomia are associated with mitochondrial dysfunction and oxidative stress. Additionally, reoxygenation with 100% O 2 in a hypoxic-ischemic newborn lamb model increased the production of pro-inflammatory cytokines in the brain. Moreover, the interplay between inflammation and oxidative stress in the newborn is better understood because of animal studies. Transcriptomic analyses have found a number of genes to be differentially expressed in murine models of bronchopulmonary dysplasia (BPD). Epigenetic changes have also been detected both in animal models of BPD and premature infants exposed to oxygen. Antioxidant therapy to prevent newborn disease has not been very successful; however, new therapeutic principles, like melatonin, are under investigation., (Copyright © 2019. Published by Elsevier Inc.)

Preeclampsia is a prevalent pregnancy complication characterized by new-onset maternal hypertension and inflammation, with placental ischemia as the initiating event. Studies of others have provided evidence for the importance of lymphocytes in placental ischemia-induced hypertension; however, the contributions of B1 versus B2 lymphocytes are unknown. We hypothesized that peritoneal B1 lymphocytes are important for placental ischemia-induced hypertension. As an initial test of this hypothesis, the effect of anti-CD20 depletion on both B-cell populations was determined in a reduced utero-placental perfusion pressure (RUPP) model of preeclampsia. Anti-murine CD20 monoclonal antibody (5 mg/kg, Clone 5D2) or corresponding mu IgG2a isotype control was administered intraperitoneally to timed pregnant Sprague-Dawley rats on gestation day (GD)10 and 13. RUPP or sham control surgeries were performed on GD14, and mean arterial pressure (MAP) was measured on GD19 from a carotid catheter. As anticipated, RUPP surgery increased MAP and heart rate and decreased mean fetal and placental weight. However, anti-CD20 treatment did not affect these responses. On GD19, B-cell populations were enumerated in the blood, peritoneal cavity, spleen, and placenta with flow cytometry. B1 and B2 cells were not significantly increased following RUPP. Anti-CD20 depleted B1 and B2 cells in peritoneum and circulation but depleted only B2 lymphocytes in spleen and placenta, with no effect on circulating or peritoneal IgM. Overall, these data do not exclude a role for antibodies produced by B cells before depletion but indicate the presence of B lymphocytes in the last trimester of pregnancy is not critical for placental ischemia-induced hypertension. NEW & NOTEWORTHY The adaptive and innate immune systems are implicated in hypertension, including the pregnancy-specific hypertensive condition preeclampsia. However, the mechanism of immune system dysfunction leading to pregnancy-induced hypertension is unresolved. In contrast to previous reports, this study reveals that the presence of classic B2 lymphocytes and peritoneal and circulating B1 lymphocytes is not required for development of hypertension following third trimester placental ischemia in a rat model of pregnancy-induced hypertension.

Objectives: The modified myocardial performance index (Mod-MPI) can be used to assess myocardial function. Fetal growth restriction can affect fetal myocardial function, thereby altering the Mod-MPI. The results of previous studies on the utility of the Mod-MPI in growth-restricted fetuses are conflicting. The aim of this study was to calculate the left modified-MPI in growth-restricted fetuses and to compare the results with those of healthy fetuses., Methods: This was a prospective cross-sectional case-control study. In total, 40 women with growth-restricted fetuses and 40 women with fetuses of normal weight (controls) at 29-39 gestational weeks were enrolled in the study. An experienced obstetrician calculated the Mod-MPI for each fetus. Women with systemic diseases or fetuses with chromosomal/structural abnormalities were excluded from the study. The results of Mod-MPI measurements of the two groups were compared., Results: The mean single deepest vertical pocket (SDVP) of amniotic fluid, estimated fetal weight (EFW), and isovolumetric relaxation time (IRT) was significantly lower in the fetal growth restriction (FGR) group as compared with these parameters in the control group (P < .05). The uterine artery (UtA) pulsatility index (PI) was significantly higher in the FGR group as compared with that in the control group (P < .05). There were six cases of absent end-diastolic flow (AED) in the FGR group. There were no statistically significant between-group differences in the Mod-MPI, isovolumetric contraction time (ICT), and ejection time (ET) (P > .05). There was also no statistically significant correlation between the Mod-MPI in the fetuses with AED and the control group for Mod-MPI (P > .05)., Conclusion: The utility of the Mod-MPI in FGR remains unclear. Future studies with larger populations are needed to determine the utility of the Mod-MPI as a predictor of cardiac compromise in FGR., (© 2019 Wiley Periodicals, Inc.)

Background Altered cardiac geometry affects a proportion of fetuses with growth restriction (FGR). The aim of this study was to explore the hemodynamic factors associated with cardiac remodeling in late FGR. Methods This was a prospective study of singleton pregnancies complicated by late-onset FGR undergoing assessment of left (LV) and right (RV) ventricular sphericity-index (SI). The study population was divided in two groups according to the presence of cardiac remodelling, defined as LVSI <5th centile. The following outcomes were explored: gestational age at birth, birthweight, caesarean section (CS) for fetal distress, umbilical artery (UA) pH and neonatal admission to special care unit. The differences between the 2 groups in UA pulsatility index (PI), middle cerebral artery (MCA) PI, uterine artery PI, cerebroplacental ratio (CPR) and umbilical vein (UV) flow corrected for fetal abdominal circumference (UVBF/AC) were tested. Results In total, 212 pregnancies with late FGR were enrolled in the study. An abnormal LV SI was detected in 119 fetuses (56.1%). Late FGR fetuses with cardiac remodeling had a lower birthweight (2390 g vs. 2490; P = 0.04) and umbilical artery pH (7.21 vs. 7.24; P = 0.04) and were more likely to have emergency CS (42.8% vs. 26.9%; P = 0.023) and admission to special care unit (13.4% vs. 4.3%; P = 0.03) compared to those with normal LVSI. No difference in either UA PI (p = 0.904), MCA PI (P = 0.575), CPR (P = 0.607) and mean uterine artery PI (P = 0.756) were present between fetuses with or without an abnormal LV SI. Conversely, UVBF/AC z-score was lower (-1.84 vs. -0.99; P ≤ 0.001) in fetuses with cardiac remodeling and correlated with LV (P ≤ 0.01) and RV SI (P ≤ 0.02). Conclusion Fetal cardiac remodelling occurs in a significant proportion of pregnancies complicated by late FGR and is affected by a high burden of short-term perinatal compromise. The occurrence of LV SI is independent from fetal arterial Dopplers while it is positively associated with umbilical vein blood flow.

Objective: Fetal growth restriction (FGR) is a major risk factor for stillbirth and most commonly arises from uteroplacental insufficiency. Despite clinical examination and third-trimester fetal biometry, cases of FGR often remain undetected antenatally. Placental insufficiency is known to be associated with altered blood flow resistance in maternal, placental and fetal vessels. The aim of this study was to evaluate the performance of individual and combined Doppler blood flow resistance measurements in the prediction of term small-for-gestational age and FGR., Methods: This was a prospective study of 347 nulliparous women with a singleton pregnancy at 36 weeks' gestation in which fetal growth and Doppler measurements were obtained. Pulsatility indices (PI) of the uterine arteries (UtA), umbilical artery (UA) and fetal vessels were analyzed, individually and in combination, for prediction of birth weight < 10 th , < 5 th and < 3 rd centiles. Doppler values were converted into centiles or multiples of the median (MoM) for gestational age. The sensitivities, positive and negative predictive values and odds ratios (OR) of the Doppler parameters for these birth weights at ∼ 90% specificity were assessed. Additionally, the correlations between Doppler measurements and other measures of placental insufficiency, namely fetal growth velocity and neonatal body fat measures, were analyzed., Results: The Doppler combination most strongly associated with placental insufficiency was a newly generated parameter, which we have named the cerebral-placental-uterine ratio (CPUR). CPUR is the cerebroplacental ratio (CPR) (middle cerebral artery PI/UA-PI) divided by mean UtA-PI. CPUR MoM detected FGR better than did mean UtA-PI MoM or CPR MoM alone. At ∼ 90% specificity, low CPUR MoM had sensitivities of 50% for birth weight < 10 th centile, 68% for < 5 th centile and 89% for < 3 rd centile. The respective sensitivities of low CPR MoM were 26%, 37% and 44% and those of high UtA-PI MoM were 34%, 47% and 67%. Low CPUR MoM was associated with birth weight < 10 th centile with an OR of 9.1, < 5 th centile with an OR of 17.3 and < 3 rd centile with an OR of 57.0 (P < 0.0001 for all). CPUR MoM was also correlated most strongly with fetal growth velocity and neonatal body fat measures, as compared with CPR MoM or UtA-PI MoM alone., Conclusions: In this cohort, a novel Doppler variable combination, the CPUR (CPR/UtA-PI), had the strongest association with indicators of placental insufficiency. CPUR detected more cases of FGR than did any other Doppler parameter measured. If these results are replicated independently, this new parameter may lead to better identification of fetuses at increased risk of stillbirth that may benefit from obstetric intervention. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Fetal growth restriction (FGR) is a major risk factor for bronchopulmonary dysplasia (BPD). Maternal stress and poor diet are linked to FGR. Effect of perinatal stress on lung development remains unknown., Objective: Using a murine model of adverse early life environment (AELE), we hypothesized that maternal exposure to perinatal environmental stress and high-fat diet (Western diet) lead to impaired lung development in the offspring., Methods: Female mice were placed on either control diet or Western diet before conception. Those exposed to Western diet were also exposed to perinatal environmental stress, the combination referred to as AELE. Pups were either euthanized at postnatal day 21 (P21) or weaned to control diet and environment until adulthood (8-14 wk old). Lungs were harvested for histology, gene expression by quantitative RT-PCR, microRNA profiling, and immunoblotting., Results: AELE increased the mean linear intercept and decreased the radial alveolar count and secondary septation in P21 and adult mice. Capillary count was also decreased in P21 and adult mice. AELE lungs had decreased vascular endothelial growth factor A (VEGFA), VEGF receptor 2, endothelial nitric oxide synthase, and hypoxia inducible factor-1α protein levels and increased expression of genes that regulate DNA methylation and upregulation of microRNAs that target genes involved in lung development at P21., Conclusion: AELE leads to impaired lung alveolar and vascular growth, which persists into adult age despite normalizing the diet and environment at P21. AELE also alters the expression of genes involved in lung remodeling.

Background: Fetal growth restriction accounts for a significant proportion of perinatal morbidity and death. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the "at-risk" fetus in both fetal growth restriction and appropriate-for-gestational-age pregnancies. The Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction group has demonstrated previously that the presence of this "brain-sparing" effect is associated significantly with adverse perinatal outcomes in the fetal growth restriction cohort. However, data about neurodevelopment in children from pregnancies that are complicated by fetal growth restriction are sparse and conflicting., Objective: The aim of the Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction NeuroDevelopmental Assessment Study was to determine whether children born after fetal growth-restricted pregnancies are at additional risk of adverse early childhood developmental outcomes compared with children born small for gestational age. The objective of this secondary analysis was to describe the role of cerebroplacental ratio in the prediction of adverse early childhood neurodevelopmental outcome., Study Design: Participants were recruited prospectively from the Perinatal Ireland multicenter observational Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction study cohort. Fetal growth restriction was defined as birthweight <10th percentile with abnormal antenatal umbilical artery Doppler indices. Small for gestational age was defined similarly in the absence of abnormal Doppler indices. Cerebroplacental ratio was calculated with the pulsatility indices of the middle cerebral artery and divided by umbilical artery with an abnormal value <1. Children (n=375) were assessed at 3 years with the use of the Ages and Stages Questionnaire and the Bayley Scales of Infant and Toddler Development, 3rd edition. Small-for-gestational-age pregnancies with normal Doppler indices were compared with (1) fetal growth-restricted cases with abnormal umbilical artery Doppler and normal cerebroplacental ratio or (2) fetal growth restriction cases with both abnormal umbilical artery and cerebroplacental ratio. Statistical analysis was performed with statistical software via 2-sample t-test with Bonferroni adjustment, and a probability value of .00625 was considered significant., Results: Assessments were performed on 198 small-for-gestational-age children, 136 fetal growth-restricted children with abnormal umbilical artery Doppler images and normal cerebroplacental ratio, and 41 fetal growth-restricted children with both abnormal umbilical artery Doppler and cerebroplacental ratio. At 3 years of age, although there were no differences in head circumference, children who also had an abnormal cerebroplacental ratio had persistently shorter stature (P=.005) and lower weight (P=.18). Children from fetal growth restriction-affected pregnancies demonstrated poorer neurodevelopmental outcome than their small-for-gestational-age counterparts. Fetal growth-restricted pregnancies with an abnormal cerebroplacental ratio had significantly poorer neurologic outcome at 3 years of age across all measured variables., Conclusion: We have demonstrated that growth-restricted pregnancies with a cerebroplacental ratio <1 have a significantly increased risk of delayed neurodevelopment at 3 years of age when compared with pregnancies with abnormal umbilical artery Doppler evidence alone. This study further substantiates the benefit of routine assessment of cerebroplacental ratio in fetal growth-restricted pregnancies and for counseling parents regarding the long-term outcome of affected infants., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To investigate the effect of fetal growth restriction (FGR) on cerebrovascular autoregulation in preterm neonates during the first 3 days of life., Design: Case-control study., Setting: Neonatal intensive care unit of the Wilhelmina Children's Hospital, The Netherlands., Patients: 57 FGR (birth weight <10th percentile) and 57 appropriate for gestational age (AGA) (birth weight 20th-80th percentiles) preterm neonates, matched for gender, gestational age, respiratory and blood pressure support., Methods: The correlation between continuously measured mean arterial blood pressure and regional cerebral oxygen saturation was calculated to generate the cerebral oximetry index (COx). Mean COx was calculated for each patient for each postnatal day. The percentage of time with impaired autoregulation (COx>0.5) was also calculated., Results: FGR neonates had higher mean COx values than their AGA peers on day 2 (0.15 (95% CI 0.11 to 0.18) vs 0.09 (95% CI 0.06 to 0.13), p=0.029) and day 3 (0.17 (95% CI 0.13 to 0.20) vs 0.09 (95% CI 0.06 to 0.12), p=0.003) of life. FGR neonates spent more time with impaired autoregulation (COx value >0.5) than controls on postnatal day 2 (19% (95% CI 16% to 22%) vs 14% (95% CI 12% to 17%), p=0.035) and day 3 (20% (95% CI 17% to 24%) vs 15% (95% CI 12% to 18%), p=0.016)., Conclusion: FGR preterm neonates more frequently display impaired cerebrovascular autoregulation compared with AGA peers on days 2 and 3 of life which may predispose them to brain injury. Further studies are required to investigate whether this impairment persists beyond the first few days of life and whether this impairment is linked to poor neurodevelopmental outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Capillarization plays a key role in the growth of the developing heart. We therefore hypothesized that impaired heart development following intrauterine growth restriction (IUGR) may arise from inadequate myocardial capillary growth. The aims of the study were to examine the effect of IUGR on the growth and diffusion radius of intramyocardial capillaries in rats at postnatal day 1. Uteroplacental insufficiency was induced in rats in late gestation (E18, term = E22) by bilateral uterine artery and vein ligation (restricted offspring N = 12; six males and six females); offspring from sham-operated dams were used as controls (N = 10; five males and five females). At postnatal day 1, the hearts were immersion-fixed and heart volume, capillary length density, capillary diffusion radius, and total capillary length were stereologically determined. Restricted offspring were significantly smaller at birth, with a concomitant reduction in heart volume and total myocardial capillary length compared to controls. Capillary growth was not impaired relative to heart size, with no significant differences in capillary length density or diffusion radius in the myocardium of restricted and control offspring. There were no sex differences in any of the parameters examined. In conclusion, there was no evidence to indicate that microvascular development is compromised in the heart of IUGR offspring at 1 day after birth. Total myocardial capillary length, however, was significantly reduced in the growth restricted offspring and further longitudinal studies are required to elucidate the long-term impact, particularly following hypertrophic cardiac growth. Anat Rec, 302:1580-1586, 2019. © 2018 American Association for Anatomy., (© 2018 American Association for Anatomy.)

Polyphenol-rich pomegranate juice has been shown to have benefit as a neuroprotectant in animal models of neonatal hypoxic-ischemia. No published studies have investigated maternal polyphenol administration as a potential neuroprotectant in at-risk newborns, such as those with intrauterine growth restriction (IUGR). This was a randomized, placebo-controlled, double-blind pilot study to investigate the impact of maternal pomegranate juice intake in pregnancies with IUGR, on newborn brain structure and function at term-equivalent age (TEA). Mothers with IUGR at 24-34 weeks' gestation were recruited from Barnes-Jewish Hospital obstetrical clinic. Consented mothers were randomized to treatment (8 oz. pomegranate juice) or placebo (8 oz. polyphenol-free juice) and continued to take juice daily from enrollment until delivery (mean 20.1 and 27.1 days, respectively). Infants underwent brain MRI at TEA (36-41 weeks' gestation). Brain measures were compared between groups including: brain injury score, brain metrics, brain volumes, diffusion tensor imaging and resting state functional connectivity. Statistical analyses were undertaken as modified intention-to-treat (including randomized participants who received their allocated intervention and whose infants received brain MRI) and per-protocol (including participants who strictly adhered to the protocol, based on metabolite status). Seventy-seven mothers were randomized to treatment (n = 40) or placebo (n = 37). Of these, 28 and 27 infants, respectively, underwent term-equivalent MRI. There were no group differences in brain injury, metrics or volumes. However, treatment subjects displayed reduced diffusivity within the anterior and posterior limbs of the internal capsule compared with placebo. Resting state functional connectivity demonstrated increased correlation and covariance within several networks in treatment subjects, with alterations most apparent in the visual network in per-protocol analyses. Direct effects on health were not found. In conclusion, maternal pomegranate juice intake in pregnancies with known IUGR was associated with altered white matter organization and functional connectivity in the infant brain, suggesting differences in brain structure and function following in utero pomegranate juice exposure, warranting continued investigation. Clinical trial registration. NCT00788866, registered November 11, 2008, initial participant enrollment August 21, 2012., Competing Interests: The authors have declared that no competing interests exist.

Small-for-gestational age (SGA) human newborns have an increased risk of hyperphagia and obesity, as well as a spectrum of neurologic and neurobehavioral abnormalities. We have shown that the SGA hypothalamic (appetite regulatory site) neuroprogenitor cells (NPCs) exhibit reduced proliferation and neuronal differentiation. DNA methylation (DNA methyltransferase; DNMT1) regulates neurogenesis by maintaining NPC proliferation and suppressing premature differentiation. Once differentiation ensues, DNMT1 preferentially promotes neuronal and inhibits astroglial fate. We hypothesized that the programmed dysfunction of NPC proliferation and differentiation in SGA offspring is epigenetically mediated via DNMT1. Pregnant rats received either ad libitum food (Control) or were 50% food-restricted to create SGA offspring. Primary hypothalamic NPCs from 1 day old SGA and Controls newborns were cultured and transfected with nonspecific or DNMT1-specific siRNA. NPC proliferation and protein expression of specific markers of NPC (nestin), neuroproliferative transcription factor (Hes1), neurons (Tuj1) and astrocytes (GFAP) were determined. Under basal conditions, SGA NPCs exhibited decreased DNMT1 and reduced proliferation and differentiation, as compared to Controls. In both SGA and Controls, DNMT1 siRNA in complete media inhibited NPC proliferation, consistent with reduced expression of nestin and Hes1. In differentiation media, DNMT1 siRNA decreased expression of Tuj1 but increased GFAP. In vivo data replicated these findings. In SGA offspring, impaired neurogenesis is epigenetically mediated, in part, via reduction in DNMT1 expression and suppression of Hes1 resulting in NPC differentiation. It is likely that the maturation of regions beyond the hypothalamus (e.g., cerebral cortex, hippocampus) may be impacted, contributing to poor cognitive and neurobehavioral competency in SGA offspring., (Copyright © 2019. Published by Elsevier Ltd.)

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.

Objective: Maternal hemodynamics in pregnancy is associated with fetal growth and birth weight, which in turn are associated with offspring cardiovascular disease later in life. The aim of this study was to quantify the extent to which birth weight is associated with cardiac structure and function in adolescence., Methods: A subset of offspring (n = 1964; 55% female) of the Avon Longitudinal Study of Parents and Children were examined with echocardiography at a mean age of 17.7 (SD, 0.3) years. The associations of birth-weight Z-score for sex and gestational age with cardiac structure (assessed by relative wall thickness, left ventricular mass index (LVMI) and left atrial diameter index), systolic function (assessed by ejection fraction and left ventricular wall velocity) and diastolic function (assessed by early/late mitral inflow velocity (E/A) and early mitral inflow velocity/mitral annular early diastolic velocity (E/e')) were evaluated. Linear regression models were adjusted for several potential confounders, including maternal prepregnancy body mass index, age, level of education and smoking during pregnancy., Results: Higher birth-weight Z-score was associated with lower E/A (mean difference, -0.024; 95% CI, -0.043 to -0.005) and E/e' (mean difference, -0.05; 95% CI, -0.10 to -0.001) and higher LVMI (mean difference, 0.38 g/m 2.7 ; 95% CI, 0.09 to 0.67). There was no or inconsistent evidence of associations of birth-weight Z-score with relative wall thickness, left atrial diameter and measurements of systolic function. Further analyses suggested that the association between birth-weight Z-score and LVMI was driven mainly by an association observed in participants born small-for-gestational age and it did not persist when risk factors in adolescence were accounted for., Conclusions: Higher birth weight adjusted for sex and gestational age was associated with differences in measures of diastolic function in adolescence, but the observed associations were small. It remains to be determined the extent to which these associations translate into increased susceptibility to cardiovascular disease later in life. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology., (© 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.)

Intrauterine growth restriction (IUGR) and maternal high-fat diet (HFD) independently predispose offspring to hypertension. In a rat model, IUGR more so than maternal HFD increases arterial stiffness with vascular remodeling as early as postnatal day (PND) 21 . The trajectory of such early vascular changes remains unknown. We hypothesized that IUGR would increase blood pressure (BP), arterial stiffness, and markers of ongoing detrimental vascular remodeling in adult rats exposed to a maternal HFD regardless of weaning diet. Adult female rats were fed either a regular diet (RD) or an HFD before mating through lactation. IUGR was induced by uterine artery ligation. Offspring were weaned to either a RD or HFD through PND 60. For both control and IUGR rats, this design resulted in the following three diet groups: offspring from RD dams weaned to a RD and offspring from HFD dams weaned to a RD or to an HFD (IHH). In both males and females, only IHH increased systolic BP, but IUGR and HFD both alone and in combination increased arterial stiffness. Aortas contained fewer but thicker elastin bands in IHH rats and IUGR offspring from dams fed an HFD and weaned to a regular diet. IHH increased aortic lysl oxidase protein. In summary, the PND 21 rat mediators of vascular remodeling from IUGR and maternal HFD normalize by PND 60 while changes in elastin and arterial stiffness persist. We speculate that the longer-term risk of hypertension from dietary mediators is augmented by underlying IUGR-induced structural changes to the extracellular matrix. NEW & NOTEWORTHY We report that a combined insult of intrauterine growth restriction and maternal high-fat diet increases the risk of early cardiovascular pathology both independently and in conjunction with a continued high-fat diet in offspring.

We previously showed that prenatal caffeine exposure (PCE) induces intrauterine growth retardation (IUGR) and high susceptibility to nonalcoholic fatty liver disease in offspring rats, and the underlying mechanisms are associated with fetal overexposure to maternal glucocorticoids. Herein, we aimed to verify whether PCE disrupts liver development before and after birth and explore its possible programming mechanism. In vivo, reduced fetal weights and increased IUGR rates were accompanied by fetal liver developmental dysfunction in PCE rats. Increased fetal serum corticosterone and decreased insulin-like growth factor 1 (IGF1) levels were observed. Both male and female fetal livers exhibited increased glucocorticoid function-related gene (GR/C/EBPα) expression and inhibited IGF1 signaling pathway (IGF1/IGF1R/Akt2) expression. At PW6, the levels of serum corticosterone and glucocorticoid function-related genes in PCE offspring livers were decreased, while serum IGF1 and liver IGF1 signaling pathway expression were increased, accompanied by obvious catch-up growth and enhanced liver function. Furthermore, in PCE adult offspring under chronic stress, serum corticosterone and liver GR/C/EBPα expression levels were elevated, while the serum IGF1 and liver IGF1 signaling pathway levels were decreased. In vitro, cortisol (not caffeine) upregulated GR and C/EBPα expression and downregulated IGF1R expression. The IGF1R expression downregulated by cortisol was partially reversed by GR or C/EBPα knockdown. In conclusion, PCE induced liver developmental dysfunction in fetal rats and catch-up growth in IUGR offspring. The mechanisms may be closely associated with GR/C/EBPα upregulation and IGF1/IGF1R signaling pathway downregulation in the fetal liver, caused by intrauterine programming of the liver glucocorticoid-IGF1 axis induced by glucocorticoid overexposure.

Background: Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region., Case Presentation: A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient., Conclusions: Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.

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: Non-invasive electrophysiological assessment (NIEA) is an evolving area in fetal surveillance and is attracting increasing research interest. There is however, limited data outlining its utility in evaluating intra uterine growth restriction (IUGR). The objective of this study was to carry out a systematic review to outline the utility of NIEA parameters in evaluating IUGR., Methods: A systematic review of peer reviewed literature was performed, searching PUBMED, Ovid MEDLINE and EMBASE. The outcomes of interest included NIEA parameters [P wave duration, PR interval, QRS duration, QT interval, T/QRS ratio, short term variability (STV) and long term variability (LTV)] and a descriptive summary of relevant studies as well., Results: Sixteen studies were identified as suitable for inclusion. The utility of NIEA parameters were investigated in tabular form. In particular, QRS and QT duration, T/QRS ratio, STV and PRSA analysis displayed utility and merit further consideration in evaluating for IUGR. Issues identified in the review were in relation to variances in definition of IUGR, small sample sizes and the lack of technological consistency across studies., Conclusion: NIEA shows promise as an adjunct surveillance tool in fetal diagnostics for IUGR. Larger prospective studies should be directed towards establishing reliable parameters with a focus on uniformity of IUGR definition, technological consistency and the individualisation of NIEA parameters.

Maternal supplementation with hydroxytyrosol, a polyphenol present in olive leaves and fruits, is a highly promising strategy to improve the oxidative and metabolic status of fetuses at risk of intrauterine growth restriction, which may diminish the appearance of low-birth-weight neonates. The present study aimed to determine whether hydroxytyrosol, by preventing lipid peroxidation, may influence the fat accretion and energy homeostasis in the liver, as well as the fatty acid composition in the liver and muscle. The results indicate that hydroxytyrosol treatment significantly decreased the energy content of the fetal liver, without affecting fat accretion, and caused significant changes in the availability of fatty acids. There were significant increases in the amount of total polyunsaturated fatty acids, omega-3 and omega-6, which are highly important for adequate fetal tissue development. However, there were increases in the omega-6/omega-3 ratio and the desaturation index, which make further studies necessary to determine possible effects on the pro/anti-inflammatory status of the fetuses., Competing Interests: The authors declare no conflict of interest.

Background: Young maternal age is associated with poorer birth outcomes, but the mechanisms are incompletely understood. Using data from a prospective cohort of pregnant women living in Mumbai slums, India, we tested whether lower maternal age was associated with adverse fetal growth., Methods: Fetal crown-rump length (CRL) was recorded at a median (interquartile range, IQR) of 10 weeks' gestation (9-10 weeks). Head circumference (HC), biparietal diameter (BPD), femur length (FL), and abdominal circumference (AC) were recorded at 19 (19-20) and 29 (28-30) weeks. Newborns were measured at a median (IQR) of 2 days (1-3 days) from delivery. Gestation was assessed using prospectively collected menstrual period dates., Results: The sample comprised 1653 singleton fetuses without major congenital abnormalities, of whom 1360 had newborn measurements. Fetuses of younger mothers had smaller CRL (0.01 standard deviation [SD] per year of maternal age; 95% confidence interval CI: 0.00-0.02 1 ; P = .04), and smaller HC, FL, and AC at subsequent visits. Fetal growth of HC (0.04 cm; 95% CI: 0.02-0.05; P < .001), BPD (0.01 cm; 95% CI: 0.00-0.01; P = .009), FL (0.04 cm; 95% CI: 0.02-0.06; P < .001), and AC (0.01 cm; 95% CI: 0.00-0.01; P = .003) up to the third trimester increased with maternal age. Skinfolds, head, and mid-upper arm circumferences were smaller in newborns of younger mothers. Adjusting for maternal prepregnancy socioeconomic status, body mass index, height, and parity attenuated the associations between maternal age and newborn size but did not change those with fetal biometry., Conclusion: Fetuses of younger mothers were smaller from the first trimester onward and grew slower, independently of known confounding factors.

Objective: To compare maternal hemodynamics and perinatal outcome, in pregnancies that do not develop pre-eclampsia (PE) or deliver a small-for-gestational-age (SGA) neonate, between those identified at 11-13 weeks' gestation as being screen positive or negative for preterm PE, by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, serum placental growth factor and pregnancy associated plasma protein-A., Methods: This was a prospective longitudinal cohort study of maternal cardiovascular function, assessed using a bioreactance method, in women undergoing first-trimester screening for PE. Maternal hemodynamics and perinatal outcome were compared between screen-positive and screen-negative women who did not have a medical comorbidity, did not develop PE or pregnancy-induced hypertension and delivered at term a live neonate with birth weight between the 5 th and 95 th percentiles. A multilevel linear mixed-effects model was used to compare the repeated measures of cardiac variables, controlling for maternal characteristics., Results: The screen-negative group (n = 926) had normal cardiac function changes across gestation, whereas the screen-positive group (n = 170) demonstrated static or reduced cardiac output and stroke volume and higher mean arterial pressure and peripheral vascular resistance with advancing gestation. In the screen-positive group, compared with screen-negative women, birth-weight Z-score was shifted toward lower values, with prevalence of delivery of a neonate below the 35 th , 30 th or 25 th percentile being about 70% higher, and the rate of operative delivery for fetal distress in labor also being higher., Conclusion: Women who were screen positive for impaired placentation, even though they did not develop PE or deliver a SGA neonate, had pathological cardiac adaptation in pregnancy and increased risk of adverse perinatal outcome. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

The ductus venosus plays a critical role in circulatory adaptation to hypoxia in fetal growth restriction but the mechanisms still remain controversial. Increased shunting of blood through the ductus venosus under hypoxic conditions has been shown in animal and human studies. The hemodynamic laws governing the accelerated flow in this vessel suggest that any dilation at its isthmus, which increases the blood flow shunting to the heart, is associated with a low, absent or reversed a-wave and a high pulsatility index. Cardiac dysfunction associated with increased atrial pressure as well as reduced ventricular compliance might be predominant mechanisms determining the profile of ductus venosus velocity waveforms in severe fetal growth restriction with signs of hypoxic compromise. Understanding the pathophysiology of the ductus venosus will underpin translation of the hypotheses developed through biostatistics toward explaining with more confidence Doppler changes in the fetal circulation in predicting clinical outcomes., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

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.

Aim: Long-term follow-up studies on children born with fetal growth restriction (FGR) have revealed a specific profile of neurocognitive difficulties, including problems with speech, language and literacy skills. We hypothesized that problems with communication skills, including language use and literacy skills of FGR children at primary school age are associated with prenatal circulatory changes., Methods: Ultrasonographic assessment of fetoplacental hemodynamics was performed prenatally in 77 fetuses. After a follow-up period of 8-10 years, assessment of reading and spelling skills using standardized tests and the Children's Communication Questionnaire (CCC-2) was performed to measure different language skills in 37 FGR children and 31 appropriately grown (AGA) controls, matched for gestational age., Results: Increased blood flow resistance in the umbilical artery (UA PI >2 SD) during fetal life showed odds ratios of 3.5-19.1 for poor literacy and communication skills and need for speech and language therapy. Furthermore, FGR children with prenatal cerebral vasodilatation (cerebroplacental ratio (CPR) < -2 SD) had significantly poorer literacy and communication skills, at primary school age compared to the AGA controls. Abnormal CPR demonstrated odds ratios of 4.2-28.1 for poor literacy and communication skills and need for speech and language therapy., Conclusion: Increased blood flow resistance in the umbilical artery and cerebral vasodilatation are associated with poor communication, language, and literacy skills at early school age in children born with FGR. These findings indicate the need for continuous follow-up of this group and timely targeted support to ensure optimal academic outcomes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Stillbirth, defined as foetal death ≥20 weeks' gestation, is associated with poor foetal growth and is often attributed to placental abnormalities, which are also associated with poor foetal growth. Evaluating inter-relationships between placental abnormalities, poor foetal growth, and stillbirth may improve our understanding of the underlying mechanisms for some causes of stillbirth., Objective: Our primary objective was to determine whether poor foetal growth, operationalised as small for gestational age (SGA), mediates the relationship between placental abnormalities and stillbirth., Methods: We used data from the Stillbirth Collaborative Research Network study, a population-based case-control study conducted from 2006-2008. Our analysis included 266 stillbirths and 1135 livebirths. We evaluated associations of stillbirth with five types of placental characteristics (developmental disorders, maternal and foetal inflammatory responses, and maternal and foetal circulatory disorders) and examined mediation of these relationships by SGA. We also assessed exposure-mediator interaction. Models were adjusted for maternal age, race/ethnicity, education, body mass index, parity, and smoking status., Results: All five placental abnormalities were more prevalent in cases than controls. After adjustment for potential confounders, maternal inflammatory response (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.77, 3.75), maternal circulatory disorders OR 4.14, 95% CI 2.93, 5.84, and foetal circulatory disorders OR 4.58, 95% CI 3.11, 6.74 were strongly associated with stillbirth, and the relationships did not appear to be mediated by SGA status. Associations for developmental disorders and foetal inflammatory response diverged for SGA and non-SGA births, and strong associations were only observed when SGA was not present., Conclusions: Foetal growth did not mediate the relationships between placental abnormalities and stillbirth. The relationships of stillbirth with maternal and foetal circulatory disorders and maternal inflammatory response appear to be independent of poor foetal growth, while developmental disorders and foetal inflammatory response likely interact with foetal growth to affect stillbirth risk., (© 2019 John Wiley & Sons Ltd.)

Aim: The early-onset intrauterine growth restriction (IUGR) is associated with severe placental insufficiency and Doppler abnormalities. The late-onset IUGR is associated with mild placental insufficiency and normal Doppler velocimetry. The computerized cardiotocographic (cCTG) monitoring is used to evaluate the fetal well-being in pregnancies complicated by IUGR. Our aim was to investigate the cardiotocographic characteristics of IUGR fetuses and to identify every cCTG difference between Healthy and IUGR fetuses., Methods: Four hundred thirty pregnant women were enrolled starting from the 28th week of gestation until the time of delivery: 200 healthy and 230 IUGR fetuses. Fetal heart rate (FHR) baseline (FHR), short-term variability (STV), long-term irregularity (LTI), delta, interval index (II), approximate entropy (ApEn), high frequency (HF), low frequency (LF), movement frequency (MF), LF/(HF + MF) ratio (LF/(HF + MF)) and number of decelerations were examined. Newborn baby data were also collected., Results: The parameters of short- and medium-term variability discriminate between IUGR and healthy fetuses before 36 weeks including FHR, STV, LTI and delta discriminate between each subgroup of IUGR were compared to each one of the other two (P < 0.05)., Conclusion: cCTG is a useful tool for the evaluation of chronic hypoxemia, which causes a delay in the maturation of all components of the autonomic and central nervous system. However, cCTG requires integration with fetal ultrasound and Doppler vessels evaluation to improve the ability to predict the neonatal outcome., (© 2019 Japan Society of Obstetrics and Gynecology.)

Background: Small for gestational age (SGA) is frequently used to define fetal growth restriction (FGR). However, FGR describes a slowdown in fetal growth and is not synonymous with SGA, which may introduce misclassification. We investigated the effect of both on delivery and childhood outcomes., Methods: From a prospective population-based cohort study we included 7959 live singleton births with data available on second trimester estimated fetal weight (EFW) and birth weight. We used a decrease in growth of > 40 percentiles between second trimester EFW and birthweight to define a deceleration in growth. SGA was defined as birthweight

Background: A normally developed placenta is integral to a successful pregnancy. Preeclampsia (PE) and intrauterine growth restriction (IUGR) are two common pregnancy related complications that maybe a result of abnormal placental development. Placental microRNAs (miRNAs) have been investigated as potential biomarkers for these complications, as they may play a role in placental development and pathophysiology by influencing gene expression. The purpose of this study is to utilize next-generation sequencing to determine miRNA and gene expression in human placental (chorionic villous) samples from three distinct patient groups with early-onset (EO) PE, IUGR, or PE + IUGR., Methods: Placental tissues were collected from four patient groups (control [N = 21], EO-PE [N = 20], EO-IUGR [N = 18], and EO-PE + IUGR [N = 20]), and total RNA was used for miRNA and RNA sequencing on the Illumina Hiseq2000 platform. For stringent differential expression analysis multiple analysis programs were used to analyze both expression datasets in each patient group compared to gestational age-matched controls., Results: Analysis revealed miRNAs and genes that are disease-specific, as well as others that were common between disease groups, which suggests common underlying placental pathologies in EO-PE and EO-IUGR. More specifically, 6 miRNAs and 22 genes were identified to be differentially expressed in all three patient groups. In addition, integrative analysis between the miRNA and gene expression datasets revealed candidate gene targets for miRNAs of interest., Conclusions: Integration of miRNA and RNA profiling in the same three subgroups of pregnancy complications, provides an alternate level of molecular information, in addition it can be used to better understand both unique and common molecular mechanisms involved in the pathophysiology of these diseases.

Intrauterine growth restriction (IUGR) is a fetal condition that affects up to 10% of all pregnancies and is associated with cardiovascular structural and functional remodelling that persists postnatally. Some studies have reported an increase in myocardial coronary blood flow in severe IUGR fetuses which has been directly associated to the dilatation of the coronary arteries. However, a direct measurement of the coronaries' lumen diameter in IUGR has not been reported before. The aim of this paper is to perform, for the first time, a quantitative analysis of the effects of IUGR in cardiac geometry and coronary vessel size in a well-known rabbit model of IUGR using synchrotron-based X-ray Phase Contrast Tomography Imaging (X-PCI). Eight rabbit fetal hearts were imaged non-destructively with X-PCI. 3D reconstructions of the coronary arterial tree were obtained after semi-automatic image segmentation. Different morphometric features including vessel lumen diameter of the three main coronaries were automatically quantified. IUGR fetuses had more globular hearts and dilated coronary arteries as compared to controls. We have quantitatively shown that IUGR leads to structural coronary vascular tree remodelling and enlargement as an adaptation mechanism in response to an adverse environment of restricted oxygen and nutrients and increased perfusion pressure., Competing Interests: The authors have declared that no competing interests exist.

Pregnancies complicated by severe fetal growth restriction with a bnormal umbilical artery D oppler v elocimetry (FGRadv) are at substantial risk for adverse perinatal and long-term outcomes. Impaired angiogenesis of the placental vasculature in these pregnancies results in a sparse, poorly branched vascular tree, which structurally contributes to the abnormally elevated fetoplacental vascular resistance that is clinically manifested by absent or reversed umbilical artery Doppler indices. Previous studies have shown that aryl hydrocarbon receptor nuclear translocator (ARNT) is a key mediator of proper placental angiogenesis, and within placental endothelial cells (ECs) from human FGRadv pregnancies, low expression of ARNT leads to decreased vascular endothelial growth factor A (VEGFA) expression and deficient tube formation. Thus, the aim of the present study was to determine the effect of VEGFA administration or ARNT overexpression on angiogenic potential of FGRadv ECs. ECs were isolated and cultured from FGRadv or gestational age-matched control placentas and subjected to either vehicle vs VEGFA treatment or transduction with adenoviral-CMV (ad-CMV) vs adenoviral-ARNT (ad-ARNT) constructs. They were then assessed via wound scratch and tube formation assays. We found that VEGFA administration nominally improved FGRadv EC migration ( P <0.01) and tube formation ( P <0.05). ARNT overexpression led to significantly enhanced ARNT expression in FGRadv ECs ( P <0.01), to a level similar to control ECs. Despite this, FGRadv EC migration ( P <0.05) and tube formation ( P <0.05) were still only partially rescued. This suggests that although ARNT does play a role in fetoplacental EC migration, other factors in addition to ARNT are likely also important in placental angiogenesis., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The development of pathologies during pregnancy, including pre-eclampsia, hypertension and fetal growth restriction (FGR), often originates from poor functioning of the placenta. In vivo models of maternal stressors, such as nutrient deficiency, and placental insufficiency often focus on inadequate growth of the fetus and placenta in late gestation. These studies rarely investigate the origins of poor placental formation in early gestation, including those affecting the pre-implantation embryo and/or the uterine environment. The current study characterises the impact on blastocyst, uterine and placental outcomes in a rat model of periconceptional alcohol exposure, in which 12.5% ethanol is administered in a liquid diet from 4 days before until 4 days after conception. We show female-specific effects on trophoblast differentiation, embryo-uterine communication, and formation of the placental vasculature, resulting in markedly reduced placental volume at embryonic day 15. Both sexes exhibited reduced trophectoderm pluripotency and global hypermethylation, suggestive of inappropriate epigenetic reprogramming. Furthermore, evidence of reduced placental nutrient exchange and reduced pre-implantation maternal plasma choline levels offers significant mechanistic insight into the origins of FGR in this model., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Fetal growth restriction (FGR) is a complex disorder of human pregnancy that leads to poor health outcomes in offspring. These range from immediate risks such as perinatal morbidity and stillbirths, to long-term complications including severe neurodevelopmental problems. Despite its relatively high global prevalence, the aetiology of FGR and its complications is not currently well understood. We now know that serotonin (5-HT) is synthesised in the placenta and is crucial for early fetal forebrain development in mice. However, the contribution of a disrupted placental 5-HT synthetic pathway to the pathophysiology of placental insufficiency in FGR and its significant fetal neurodevelopmental complications are unclear., (Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Aim: To investigate the changes of modified myocardial performance index (Mod-MPI) in early-onset and late-onset fetal growth restriction (FGR) cases, and its association with adverse perinatal outcome., Methods: This was a prospective study on 77 early-onset and 100 late-onset FGR cases. Hundred normal fetuses were matched as control groups for early-onset and late-onset FGR groups, respectively. Mod-MPI and vessel Doppler parameters including umbilical artery (UA), ductus venosus (DV), and middle cerebral artery (MCA) were measured. Perinatal outcomes were followed up. Mod-MPI of FGR cases were compared in normal Doppler, abnormal Doppler, and control groups. The association of Mod-MPI and perinatal outcome was investigated, and further efficacy of Mod-MPI predicting adverse outcome was studied., Results: Compared with control groups, both abnormal and normal Doppler groups showed increased Mod-MPI in early-onset and late-onset FGR, respectively. Mod-MPI had no significant difference between abnormal and normal Doppler groups. Mod-MPI was associated with adverse outcome in early-onset FGR (OR = 3.307) and late-onset FGR (OR = 3.412). The sensitivity and specificity of Mod-MPI predicting adverse outcome were 60% and 80% when cutoff value was 0.47 in early-onset FGR. And they were 65% and 70% when cutoff value was 0.50 in late-onset FGR., Conclusion: Fetal growth restriction fetuses had increased Mod-MPI. Mod-MPI could be used to predict adverse perinatal outcome of FGR fetuses. Mod-MPI was an effective parameter to supplement vessels' Doppler parameters in monitoring FGR., (© 2019 The Authors. Echocardiography Published by Wiley Periodicals, Inc.)

There is a lack of knowledge of factors preventing an adequate response to moderate hypothermia after hypoxic ischemic (HI) brain injury. We hypothesized that growth restriction from reduced intrauterine perfusion would predispose neonatal rats to have a worse outcome with HI brain injury. IUGR was induced by placental insufficiency in dams at 14 days of gestation. HI was induced at postnatal day (P) 10 by permanent right carotid artery ligation followed by 90 min of hypoxia (8% oxygen). Tests for early brain injury and neurobehavioral outcomes were subsequently done. All statistical analysis was done using Two-way ANOVA; post hoc Holm-Sidak test. HI in control and IUGR groups decreased the success rate of the contralateral vibrissa-elicited forelimb test, increased response latency in movement initiation test and increased the time to finish elevated beam walk test at P40 and P60. IUGR augmented HI-induced abnormality in vibrissa-elicited forelimb test at P40 but showed higher success rate when compared to HI only group at P60. IUGR's negative effect on HI-induced changes on the elevated beam walk test was sex-specific and exaggerated in P60 males. Increased TUNEL positive cells in the cortex were noted at 72 h after in HI in control but not in IUGR groups. In conclusion, the consequences of IUGR on subsequent neonatal HI varied based on age, sex and outcomes examined, and overall, male sex and IUGR had worse effects on the long-term neurobehavioral outcomes following HI., (© 2019 Wiley Periodicals, Inc.)

Objective: We investigated whether the extent of fetal growth restriction (FGR) in terms of not only birth weight but length and head circumference at birth is correlated with an increased risk of bronchopulmonary dysplasia (BPD) in preterm infants., Study Design: A total of 4,940 very low birth weight (VLBW) infants born between 23 and 31 weeks of gestation from 2013 to 2015 who were registered in the Korean Neonatal Network (KNN) database were enrolled. Infants with major congenital malformations and those with incomplete data were excluded. Z-scores for weight, length, and head circumference at birth were calculated from the Fenton 2013 growth curve. Multivariable logistic regression analysis was performed to determine whether the z-score for length at birth was associated with BPD or death before 36 postmenstrual weeks., Results: A total of 4,662 VLBW infants were analyzed: 518 infants died before 36 postmenstrual weeks; 1,388 infants developed BPD. Decreased length at birth z-scores were significantly associated with an increased risk of BPD or death when adjusted for covariates (odds ratio (OR) 1.25 per 1-point decrease of length at birth z-score, 95% confidence interval (CI) 1.14-1.37). The association was particularly evident in infants born earlier than 29 weeks of gestation (OR 1.57, 95% CI 1.31-1.89 in infants born at 23-25 weeks; OR 1.24, 95% CI 1.09-1.42 in infants born at 26-28 weeks)., Conclusion: Length at birth was inversely associated with an increased risk of BPD or death in VLBW infants born earlier than 32 weeks of gestation., Competing Interests: The authors have declared that no competing interests exist.