Effects Of Fetal Growth Restriction Research Articles

Genome-Wide Analysis in the Study of the Fetal Growth Restriction Pathogenetics

Fetal growth restriction is a complication of pregnancy that defined as the inability of the fetus to realize its genetically determined growth potential. Despite the high social and medical significance of this problem the exact pathogenesis of fetal growth restriction is not known by now. Therefore, the analysis of the molecular genetics mechanisms of this pathology within the framework of approaches using modern high-performance technologies of next generation sequencing is of undoubted interest. In this review we focused on the analysis of data obtained in studies of the fetal growth restriction genetics component. The authors of these researches used next generation sequencing technologies and carried out whole transcriptome profiling. The results of the genes expression genome-wide analysis in placental tissue allow us to identify 1430 differentially expressed genes between fetal growth restriction and normal pregnancy, of which only 1% were found in at least two studies. These differentially expressed genes are involved in the Wnt/β-catenin signaling pathway that plays an important role in cell migration, neural pattern formation and organogenesis during embryonic development. Common genes are associated with both obstetric and gynecological diseases, as well as with various somatic conditions from the groups of neurodegenerative, cardiovascular diseases and mental disorders, which probably reflects their involvement in the development of postnatal consequences of fetal growth restriction. The results of our work don‘t point only to potential molecular mechanisms and key genes underlying fetal growth restriction, but also indicate the important role of gene-gene communications in this pathology implementation: about 30% of all identified differentially expressed genes products interact with each other within the same gene network. In general, genome-wide RNA sequencing combined with the analysis of protein-protein interactions represents a promising direction in research on the development and functioning of the placenta, as well as the identification of placental insufficiency diseases genetics mechanisms, including fetal growth restriction.

Reduced in utero substrate supply decreases mitochondrial abundance and alters the expression of metabolic signalling molecules in the fetal sheep heart.

Babies born with fetal growth restriction (FGR) are at higher risk of developing cardiometabolic diseases across the life course. The reduction in substrate supply to the developing fetus that causes FGR not only alters cardiac growth and structure but may have deleterious effects on metabolism and function. Using a sheep model of placental restriction to induce FGR, we investigated key cardiac metabolic and functional markers that may be altered in FGR. We also employed phase-contrast magnetic resonance imaging MRI to assess left ventricular cardiac output (LVCO) as a measure of cardiac function. We hypothesized that signalling molecules involved in cardiac fatty acid utilisation and contractility would be impaired by FGR and that this would have a negative impact on LVCO in the late gestation fetus. Key glucose (GLUT4 protein) and fatty acid (FATP, CD36 gene expression) substrate transporters were significantly reduced in the hearts of FGR fetuses. We also found reduced mitochondrial numbers as well as abundance of electron transport chain complexes (complexes II and IV). These data suggest that FGR diminishes metabolic and mitochondrial capacity in the fetal heart; however, alterations were not correlated with fetal LVCO. Overall, these data show that FGR alters fetal cardiac metabolism in late gestation. If sustained ex utero, this altered metabolic profile may contribute to poor cardiac outcomes in FGR-born individuals after birth. KEY POINTS: Around the time of birth, substrate utilisation in the fetal heart switches from carbohydrates to fatty acids. However, the effect of fetal growth restriction (FGR) on this switch, and thus the ability of the fetal heart to effectively metabolise fatty acids, is not fully understood. Using a sheep model of early onset FGR, we observed significant downregulation in mRNA expression of fatty acid receptors CD36 and FABP in the fetal heart. FGR fetuses also had significantly lower cardiac mitochondrial abundance than controls. There was a reduction in abundance of complexes II and IV within the electron transport chain of the FGR fetal heart, suggesting altered ATP production. This indicates reduced fatty acid metabolism and mitochondrial function in the heart of the FGR fetus, which may have detrimental long-term implications and contribute to increased risk of cardiovascular disease later in life.

EP14.01: The effect of fetal growth restriction on maternal pre‐eclampsia in discordant dichorionic twin

EP14.01: The effect of fetal growth restriction on maternal pre‐eclampsia in discordant dichorionic twin

Effects of Fetal Growth Restriction on Postnatal Gut Microbiota in a Rat Model.

Fetal growth restriction (FGR) indicates increased risks of lifestyle-related diseases in adulthood. Previous studies showed the association between human gut dysbiosis and various diseases. However, reports examining the relationship between FGR and gut microbiota are scarce. Herein, we hypothesized that FGR may cause gut dysbiosis and analyzed the gut microbiota in a FGR rat model by restricting maternal protein intake during pregnancy. The FGR group was developed by feeding pregnant Sprague Dawley rats a diet containing 7% protein until birth. Control rats were fed 21% protein. Fecal samples of 2-11-week-old pups were collected weekly. DNA was extracted from each sample and subjected to polymerase chain reaction (PCR) amplification and sequencing. Additionally, short-chain fatty acids in the cecum were analyzed at 2 weeks of age, when there were differences in the occupancy of the gut microbiota. Comparative analysis of the gut microbiota showed differences only at 2 weeks of age. Verrucomicrobia was significantly more abundant in the control group ( q < 0.1), whereas pathogenic bacteria, including Enterococcus and Enterobacteriaceae , tended to increase in the FGR group. The abundance of acetic and butyric acid-producing bacteria also differed between groups. Acetic acid in the cecum was considerably decreased in the FGR group, while butyric acid was increased compared to that in the control group. Normalizing the alteration of FGR on postnatal gut microbiota may have beneficial effects for the host, since the FGR group caused gut dysbiosis.

Cardiac morphology in neonates with fetal growth restriction.

Assess effects of fetal growth restriction (FGR) on cardiac modelling in premature and term neonates. Prospective echocardiographic study of a cohort of FGR neonates (n = 21) and controls (n = 41) with normal prenatal growth and circulation. Unadjusted for gestational age, birth weight, sex, and twin/singleton, Late-FGR neonates had smaller hearts than controls, with globular left ventricles and symmetrical right ventricles. Adjusted estimates showed smaller left ventricles and similarly sized right ventricles, with symmetrical left and right ventricles. Early-FGR (compared with Late-FGR) had smaller hearts and globular left ventricles in unadjusted estimates, but after adjustment, sizes and shapes were similar. FGR had significant impact on cardiac modelling, seen in both statistical models unadjusted and adjusted for gestational age, birth weight, sex, and twin/singleton. The adjustments, however, refined the results and revealed more specific effects of FGR, thus underscoring the importance of statistical adjustments in such studies.

Divergent age patterns of under-5 mortality in south Asia and sub-Saharan Africa: a modelling study

Understanding the age pattern of under-5 mortality is essential for identifying the most vulnerable ages and underlying causes of death, and for assessing why the decline in child mortality is slower in some countries and subnational areas than others. The aim of this study is to detect age patterns of under-5 mortality that are specific to low-income and middle-income countries (LMICs). In this modelling study, we used data from 277 Demographic and Health Surveys (DHSs), 58 Health and Demographic Surveillance Systems (HDSSs), two cohort studies, and two sample-registration systems. From these sources, we collected child date of birth and date of death (or age at death) from LMICs between 1966 and 2020. We computed 22 deaths rates from each survey with the following age breakdowns: 0, 7, 14, 21, and 28 days; 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, and 21 months; and 2, 3, 4, and 5 years. We assessed how probabilities of dying estimated for the 22 age groups deviated from predictions generated by a vital registration model that reflects the historical mortality of 25 high-income countries. We calculated mortality rates of 81 LMICs between 1966 and 2020. In contrast with the other regions of the world, we found that under-5 mortality in south Asia and sub-Saharan Africa was characterised by increased mortality at both ends of the age range (ie, younger than 28 days and older than 6 months) at a given level of mortality. Observed mortality in these regions was up to 2 times higher than predicted by the vital registration model for the younger-than-28 days age bracket, and up to 10 times higher than predicted for the older-than-6 months age bracket. This age pattern of under-5 mortality is significant in 17 countries in south Asia and sub-Saharan Africa. Excess mortality in children older than 6 months without excess mortality in children younger than 28 days was found in 38 countries. In south Asia, results were consistent across data sources. In sub-Saharan Africa, excess mortality in children younger than 28 days was found mostly in DHSs; the majority of HDSSs did not show this excess mortality. We have attributed this difference in data sources mainly to omissions of early deaths in HDSSs. In countries with age patterns of under-5 mortality that diverge from predictions, evidence-based public health interventions should focus on the causes of excess of mortality; notably, the effect of fetal growth restriction and infectious diseases. The age pattern of under-5 mortality will be instrumental in assessing progress towards the decline of under-5 mortality and the Sustainable Development Goals. Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.

Maternal oral supplementation with citrulline increases plasma citrulline but not arginine in pregnant Merino ewes and neonatal lambs

Context Arginine supplementation can counter the negative effects of fetal growth restriction in ewes bearing multiple lambs by increasing birth weight and brown adipose fat stores in lambs; however ruminal degradation limits its bioavailability and necessitates ruminal protection. The arginine precursor citrulline increases circulating arginine after a single oral dose without ruminal protection, and bolus intravenous infusion of citrulline increases maternal and fetal circulating arginine for at least 4 h post infusion. Responses to oral and chronic citrulline have not, however, been evaluated in neonatal lambs. Aims This experiment sought to determine whether orally fed citrulline would increase circulating plasma concentrations of citrulline and arginine in pregnant Merino ewes. Methods Pregnant Merino ewes were fed citrulline (CIT, 8 g/day, n = 9) or no supplement (CON, n = 9) from Day 125 of gestation (DG 125) until parturition. Ewe (DG 125) and neonatal lamb serum (&lt;2 h old) was analysed for circulating plasma citrulline and arginine concentrations. Key results Circulating concentrations of citrulline were higher in CIT than CON ewes 4 h post feeding at DG 125, and in CIT compared to CON neonatal lambs. Despite higher citrulline concentrations, supplementation did not increase maternal or neonatal circulating arginine concentrations. Conclusions Maternal supplementation with this dose of citrulline was not effective in increasing circulating levels of arginine. Implications Further studies may be merited in pregnant sheep to determine whether higher doses of oral citrulline can increase arginine availability during gestation.

Subjective Well-Being and Self-Esteem in Preterm Born Adolescents: An Individual Participant Data Meta-Analysis.

To study self-reported well-being and self-esteem among adolescents born very preterm (VPT; <32 wk of gestation) and moderate to late preterm (MLPT; 32-36 wk of gestation) compared with those born full-term (FT) in an individual participant data (IPD) meta-analysis. We obtained IPD from the following 4 data sources: The Avon Longitudinal Study of Parents and Children (United Kingdom), the Millennium Cohort Study (United Kingdom), the Basel Study of Preterm Children (Switzerland), and the Bavarian Longitudinal Study (Germany) and conducted two-step random-effects IPD meta-analysis. A total of 986 MLPT, 412 VPT, and 12,719 FT born adolescents reported on subjective well-being and 927 MLPT, 175 VPT, and 13,312 FT born adolescents reported on global self-esteem. Adolescents born VPT or MLPT were not different from those born FT regarding general subjective well-being; family, school, and physical appearance-related well-being; and global self-esteem. However, adolescents born VPT reported lower well-being in peer relationships than those born FT (β = -0.209, 95% confidence interval = -0.336 to -0.082). There was no main effect of fetal growth restriction (FGR) and no moderation by FGR, sex, parental education, and ethnicity. No significant heterogeneity between cohorts was found, although some heterogeneity estimates were moderate. Adolescents born preterm mostly report no lower well-being and self-esteem than adolescents born FT. However, they perceive their peer relationships as poorer than those born FT.

412 Neurobehavioural and neuropathological consequences of fetal growth restriction in a rabbit model

To characterize the behavioural and neuropathological effects in a uteroplacental ligation FGR rabbit model. At gestational day (GD) 25, time mated does underwent partial uteroplacental vessel ligation (UPVL) in one randomly chosen horn, leaving the contralateral foetuses as internal controls. Does were delivered at GD 30 by C-section, and neurobehavioural assessment (NBA) was performed 24h after delivery. Thereafter neonates were transcardially perfused with heparinised saline and 4% paraformaldehyde. Brains were further immerse-fixated for 72 hrs, weighed, embedded and serial sectioned. Slides were stained with Cresyl violet, scanned, and neuron count was performed manually using QuPath software by an evaluator blinded to the specimen allocation. Brain slides from 12 cases and 12 controls were selected according to sample quality. Normal distribution was assessed by Shapiro-Wilk test and data presented as a mean with standard deviations or median and interquartile ranges. The comparison was done by unpaired students t-test or Mann Whitney test. A p-value < 0.05 was considered significant. Neonatal survival was 45% (27/60) in the ligated and 85% (44/52) in the non-ligated horn. UPVL resulted in lower birth weight (35.00±7.14 g vs. 39.05±9.94 g; p<0.05), and no difference in brain-to-body weight ratio (0.046±.005 vs. 0.044±.006; p=0.7). FGR resulted in significantly lower motor (19±4.25 vs. 20±2, p=0.007) and sensory scores (12±4 vs. 14±1.25, p=0.003) on early NBA, and was associated with lower neuron density in the prefrontal cortex (227.8±67 vs. 327±115 n/mm2; p<0.05), caudate nucleus (533.3±85 vs. 444.2±50 n/mm2; p<0.01), and dentate gyrus (222.5±34 vs. 292±49 n/mm2; p=0.001). FGR is associated with functional neurological impairment and structural alterations in the prefrontal cortex, basal ganglia and hippocampus in this rabbit model

Supplementing Merino ewes with melatonin during the last half of pregnancy improves tolerance of prolonged parturition and survival of second-born twin lambs.

High preweaning mortality rates continue to limit sheep production globally, constituting a major economic and welfare concern. Greater losses in twin lambs (≥30%) compared with singletons (≥10%) are attributed primarily to lower birth weight and increased risk of intrapartum hypoxia, leading to impairment of thermoregulation, neuromotor activity, and maternal bonding behavior. Previous intensive studies demonstrated that supplementing pregnant ewes with melatonin reduced the adverse effects of fetal growth restriction and perinatal hypoxia on the neonatal brain via increased umbilical blood flow, placental efficiency, and antioxidant actions. The current study examined the effects of supplementing pregnant ewes with melatonin on lamb survival, birth weight, and behavior under intensive conditions. From gestational day (gD) 80 until parturition, pregnant singleton and twin-bearing ewes were supplemented with melatonin via a 2-mg capsule fed daily (Mel-FED, n = 61) or 18 mg subcutaneous implant (Regulin), with one implant administered at gD80 and another at gD125 (Mel-IMP, n = 60). Control ewes received no supplementation (CTL, n = 60). Ewes and lambs were monitored via video throughout parturition. Postpartum measures were taken from lambs at 4 and 24 h (live weight [LW], rectal temperature, serum immunoglobulin G, and latency to stand and suck after birth) and LW at 72 h, 7 d, marking (49.7 ± 0.2 d), and weaning (124.2 ± 0.8 d). Chi-square analysis was used to compare lamb survival between treatment groups. There were no treatment effects on singleton lamb survival. Melatonin supplementation tended to increase the proportion of twin lambs surviving from birth to weaning (Mel-FED = 85.5%; Mel-IMP = 85.9%; CTL = 72.9%; each P < 0.1). Survival of first-born twins did not differ between treatment (each ~90%, P = 0.745) but within second-born twins, survival of Mel-FED was greater than CTL (81.6 vs. 57.1%, P = 0.023), and Mel-IMP (78.1%) tended to be greater than CTL (P = 0.068). Similarly, in second-born twins exposed to prolonged parturition (≥ 90 min), survival of lambs from Mel-FED ewes was greater than CTL (86.7% vs. 42.9%, P = 0.032), while Mel-IMP was intermediate (66.7%). These data suggest that the neuroprotective actions of melatonin may improve twin lamb survival by increasing tolerance of prolonged parturition and provide a sound basis for continued testing in extensively managed sheep flocks.

Maternal melatonin implants improve twin Merino lamb survival.

High preweaning mortality rates cost the Australian sheep industry an estimated $540 million annually in lost production, with losses significantly greater in twin (≥30%) compared with singleton lambs (≥10%). Previous intensive studies demonstrated that supplementing pregnant ewes with melatonin reduces adverse effects of fetal growth restriction and perinatal hypoxia on the neonatal brain via increased umbilical blood flow, placental efficiency, and antioxidant actions. The current study examined the effects of supplementing ewes with melatonin on the survival of twin Merino lambs under extensive grazing conditions. Pregnant mixed age ewes were implanted with 1 (M1, n = 50) or 2 (M2, n = 53) slow-release melatonin implants (18 mg, Regulin) at gestational days 70 to 90. Control ewes received no supplementation (CTL, n = 54). Ewes were monitored twice daily throughout the lambing period. Lamb survival, weight, and rectal temperature were recorded on the day of birth. Lamb blood samples were taken the following day for serum immunoglobulin G (IgG) analysis. Lamb survival and weight were recorded again at marking (30.6 ± 0.6 d postpartum) and weaning (70.7 ± 0.6 d postpartum). Lamb survival was increased in both melatonin treatments to 3 d postpartum (M1 = 98.0%; M2 = 95.3%; CTL = 83.3%; each P < 0.01), and this improvement was maintained to weaning (M1 = 94.0%; M2 = 92.5%; CTL = 79.6%; each P < 0.01). Melatonin did not affect lamb birthweight, rectal temperature, or growth rate. However, the rates of parturition-related death (dystocia, stillbirth, and birth injury) were greater in CTL lambs than M1 (P = 0.009) and M2 (P = 0.035). This suggests that improved survival is primarily due to melatonin-induced neuroprotection, although further studies are required to clarify the underlying mechanisms. These data provide evidence that supplementing pregnant twin-bearing Merino ewes with melatonin may be a practical strategy to reduce neonatal mortality and improve weaning rates in extensively managed sheep flocks. Although the present data are promising, this study is limited by small sample size and requires further replication.

Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation

ObjectiveThe importance of the placenta in mediating the pre- and post-natal consequences of fetal growth restriction has been increasingly recognized. However, the influence of placental sexual dimorphism on driving these outcomes has received little attention. The purpose of this study was to characterize how sex contributes to the relationship between placental metabolism and fetal programming utilizing a novel rodent model of growth restriction. MethodsFetal growth restriction was induced by maternal inhalation of 0.8 ppm ozone (4 h/day) during implantation receptivity (gestation days [GDs] 5 and 6) in Long-Evans rats. Control rats were exposed to filtered air. At GD 21, placental and fetal tissues were obtained for metabolic and genomic assessments. ResultsGrowth-restricted male placentae exhibited increased mitochondrial biogenesis, increased oxygen consumption, and reduced nutrient storage. Male growth-restricted fetuses also had evidence of reduced adiposity and downregulation of hepatic metabolic signaling. In contrast, placentae from growth-restricted females had elevated markers of autophagy accompanied by an observed protection against hepatic metabolic perturbations. Despite this, growth restriction in females induced a greater number of hypothalamic gene and pathway alterations compared to growth-restricted males. ConclusionsIncreases in mitochondrial metabolism in growth-restricted male placentae likely initiates a sequela of adaptations that promote poor nutrient availability and adiposity. Divergently, the female placenta expresses protective mechanisms that may serve to increase nutrient availability to support fetal metabolic development. Collectively, this work emphasizes the importance of sex in mediating alterations in placental metabolism and fetal programming.

Understanding the effects of being small for gestational age at birth.

Longitudinal neonatal outcome studies are becoming more exciting as we start to evaluate the trajectory of the well described sequelae of prematurity into the young adult effects of being born very preterm. In this issue of BJOG, Eves and colleagues use the Bavarian Longitudinal Study to evaluate the relative effects of being born small for gestational age (SGA) alongside important measures of social advantage and of parent infant relationship measures (BJOG 2020 xxxx). This is as it says - the effect of being small for dates at birth and not the effect of fetal growth restriction (FGR), an important distinction.

Effect of fetal growth restriction on urinary podocalyxin levels at birth in preterm neonates.

Small-for-gestational-age (SGA) neonates are at a higher risk of adult-onset metabolic disorders because of fetal programming in the presence of growth restriction. Nephrogenesis may also be affected in fetal growth restriction. This study hypothesized that urinary podocalyxin levels, a marker of nephrogenesis, would be lower among preterm SGA neonates as compared to appropriate-for-gestational-age (AGA) controls. This cross-sectional study enrolled gestation-matched SGA (n = 90) and AGA (n = 45) neonates born at 260-366 weeks of gestation. The SGA group comprised of 45 neonates with birth weight between 3rd and 10th centile and 45 neonates with birth weight <3rd centile. The primary outcome of the study was the difference in urinary podocalyxin levels between SGA and AGA neonates. Glomerular and tubular functions were also assessed. Urinary podocalyxin levels were similar in SGA and AGA neonates (ng/mg of creatinine; median [interquartile range]: 28.7 [4.8-70.2] vs. 18.7 [3.1-55.9]), P value 0.14). No correlation was observed between birth weight centile and urinary podocalyxin levels (r: -0.06). Glomerular filtration rate, fractional excretion of sodium, and serum β-2-microglobulin levels were comparable across the study groups. Glomerular development as assessed by urinary podocalyxin levels and renal functions are comparable in SGA and AGA preterm neonates. Neonates born with fetal growth restriction are at a higher risk of adult-onset metabolic disorders because of fetal programming. This cross-sectional study investigated the effect of presence and severity of fetal growth restriction on glomerular development by measuring urinary podocalyxin levels in preterm infants. This study did not observe any effect of the presence or severity of fetal growth restriction on urinary podocalyxin levels and other markers of glomerular and renal tubular functions.

PREPARE: protocol for a stepped wedge trial to evaluate whether a risk stratification model can reduce preterm deliveries among women with suspected or confirmed preterm pre-eclampsia

BackgroundPreeclampsia (PE) is a major cause of short and long-term morbidity for affected infants, including consequences of fetal growth restriction and iatrogenic prematurity. In Brazil, this is a special problem as PE accounts for 18% of preterm births (PTB). In the PREPARE (Prematurity REduction by Pre-eclampsia cARE) study, we will test a novel system of integrated care based on risk stratification and knowledge transfer, to safely reduce PTB.MethodsThis is a stepped wedge cluster randomised trial that will include women with suspected or confirmed PE between 20 + 0 and 36 + 6 gestational weeks. All pregnant women presenting with these findings at seven tertiary centres in geographically dispersed sites, throughout Brazil, will be considered eligible and evaluated in terms of risk stratification at admission. At randomly allocated time points, sites will transition to risk stratification performed according to sFlt-1/PlGF (Roche Diagnostics) measurement and fullPIERS score with both results will be revealed to care providers. The healthcare providers of women stratified as low risk for adverse outcomes (sFlt-1/PlGF ≤38 AND fullPIERS< 10% risk) will receive the recommendation to defer delivery. sFlt-1/PlGF will be repeated once and fullPIERS score twice a week. Rates of prematurity due to preeclampsia before and after the intervention will be compared. Additionally, providers will receive an active program of knowledge transfer about WHO recommendations for preeclampsia, including recommendations regarding antenatal corticosteroids for foetal benefits, antihypertensive therapy and magnesium sulphate for seizure prophylaxis. This study will have 90% power to detect a reduction in PTB associated with PE from a population estimate of 1.5 to 1.0%, representing a 33% risk reduction, and 80% power to detect a reduction from 2.0 to 1.5% (25% risk reduction). The necessary number of patients recruited to achieve these results is 750. Adverse events, serious adverse events, both anticipated and unanticipated will be recorded.DiscussionThe PREPARE intervention expects to reduce PTB and improve care of women with PE without significant adverse side effects. If successful, this novel pathway of care is designed for rapid translation to healthcare throughout Brazil and may be transferrable to other low and middle income countries.Trial registrationClinicalTrials.gov: NCT03073317.

Effect of fetal growth restriction on the biomechanical and structural properties in human umbilical and chorionic arteries

Effect of fetal growth restriction on the biomechanical and structural properties in human umbilical and chorionic arteries

The association between preterm labour, perinatal mortality and infant death (during the first year) in Bishop Lavis, Cape Town, South Africa.

We present further analyses from the Safe Passage Study, where the effect of alcohol exposure during pregnancy on sudden infant death syndrome and stillbirth was investigated. To describe pregnancy and neonatal outcome in a large prospective study where information on the outcome of pregnancy was known in &gt;98.3% of participants and ultrasound was used to determine gestational age (GA). As part of the Safe Passage Study of the PASS Network in Cape Town, South Africa, the outcomes of 6866 singleton pregnancies were prospectively followed from recruitment in early pregnancy until the infant was 12 months old to assess pregnancy outcome. Fetal growth was assessed by z-scores of the birth weight, and GA at birth was derived from early ultrasound assessments. The effects of fetal growth restriction and preterm delivery on pregnancy outcome were determined. There were 66 miscarriages, 107 stillbirths at ≥22 weeks' gestation, 66 stillbirths at ≥28 weeks' gestation, 29 and 18 neonatal deaths at ≥22 and ≥28 weeks' gestation, respectively, and 54 post-neonatal deaths (28 days - 12 months). The miscarriage rate was 9.6/1 000 and the infant mortality rate 12.4/1 000. Of the births, 13.8% were preterm. For deliveries at ≥22 and ≥28 weeks, the stillbirth rates were 15.7 and 9.8/1 000 deliveries, respectively. For deliveries at ≥22 and ≥28 weeks, the neonatal death rates were 4.3 and 2.7/1 000 live births, respectively. For these pregnancies the perinatal mortality rates were 20.0/1 000 (≥22 weeks) and 12.5/1 000 (≥28 weeks), respectively. Only 15.9% of stillbirths occurred during labour (in 15.9% of cases it was uncertain whether death had occurred during labour). In the majority of cases (68.2%) fetal death occurred before labour, and 82.2% of stillbirths and 62.1% of neonatal deaths occurred in deliveries before 37 weeks. Including the miscarriages, stillbirths and infant deaths, there were 256 pregnancy losses; 77.3% were associated with deliveries before 37weeks. Only 1.8% of all the women were HIV-positive, whereas the HIV-positive rate was 3.7% among those who had stillbirths. Birth weight was below the 10th centile in 25.6% of neonatal and post-neonatal deaths compared with 17.7% of survivors. Preterm birth and fetal growth restriction play significant roles in fetal, neonatal and infant losses.

Early onset of renal oxidative stress in small for gestational age newborn pigs

ABSTRACTObjective: Oxidative stress, a common feature in cardiovascular and renal disease is associated with the causes and consequences of fetal growth restriction. Hence, renal redox status is likely an early determinant of morbidity in small-for-gestational-age (SGA) infants. In this study, we examined renal oxidative stress in naturally-farrowed SGA newborn pigs.Methods: We studied SGA newborn pigs with 52% less body weight and 59% higher brain/liver weight ratio compared with their appropriate-for-gestational-age (AGA) counterparts.Results: The kidneys of the SGA newborn pigs weighed 56% less than the AGA group. The glomerular cross-sectional area was also smaller in the SGA group. SGA newborn pigs exhibited increased renal lipid peroxidation, reduced kidney and urine total antioxidant capacity, and increased renal nitrotyrosine immunostaining. Whereas the protein expression level of NADPH oxidase (NOX)2 was unchanged, NOX4 expression was significantly higher in SGA kidneys. The level of serum potassium was lower, but serum sodium and creatinine were similar in SGA compared with AGA newborn pigs. The serum concentrations of C‐reactive protein and NGAL, the biomarkers of inflammation and early acute kidney injury were significantly elevated in the SGA group.Conclusion: Early induction of oxidative stress may contribute to the onset of kidney injury in growth-restricted infants.

Neonatal and Long-Term Consequences of Fetal Growth Restriction.

Background: Fetal Growth Restriction (FGR) is one of the most common noxious ante-natal conditions in humans, inducing a substantial proportion of preterm delivery and leading to a si-gnificant increase in perinatal mortality, neurological handicaps and chronic diseases in adulthood. This review summarizes the current knowledge about the postnatal consequences of FGR, with a par-ticular emphasis on the long-term consequences on respiratory, cardiovascular and neurological struc-tures and functions.Result and Conclusion: FGR represents a global health challenge, and efforts are urgently needed to improve our understanding of the critical factors leading to FGR and subsequent insults to the deve-loping organs.

Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice.

Fetal growth restriction (FGR) causes a wide variety of defects in the neonate which can lead to increased risk of heart disease, diabetes, anxiety and other disorders later in life. However, the effect of FGR on the immune system, is poorly understood. We used a well-characterized mouse model of FGR in which placental Igf-2 production is lost due to deletion of the placental specific Igf-2 P0 promotor. The thymi in such animals were reduced in mass with a ~70% reduction in cellularity. We used single cell RNA sequencing (Drop-Seq) to analyze 7,264 thymus cells collected at postnatal day 6. We identified considerable heterogeneity among the Cd8/Cd4 double positive cells with one subcluster showing marked upregulation of transcripts encoding a sub-set of proteins that contribute to the surface of the ribosome. The cells from the FGR animals were underrepresented in this cluster. Furthermore, the distribution of cells from the FGR animals was skewed with a higher proportion of immature double negative cells and fewer mature T-cells. Cell cycle regulator transcripts also varied across clusters. The T-cell deficit in FGR mice persisted into adulthood, even when body and organ weights approached normal levels due to catch-up growth. This finding complements the altered immunity found in growth restricted human infants. This reduction in T-cellularity may have implications for adult immunity, adding to the list of adult conditions in which the in utero environment is a contributory factor.