Angiogenic factors assessment in pre-eclampsia high-risk population for the prediction of small-for-gestational age neonates: A prospective longitudinal study.

OBJECTIVE: The authors aimed to compare cross-sectional versus longitudinal models for prediction of small-for-gestational age (SGA) neonates among pregnancies with high risk of early pre-eclampsia (PE). METHODS: A prospective longitudinal study was performed in Hospital Universitari Dexeus, Barcelona. The study population included 390 pregnancies with a high risk of early PE according to the first trimester algorithm. Cross-sectional models combining first trimester risk plus placental growth factor and FMS-like tyrosine kinase 1/placental growth factor ratio, respectively, were created at 19-22, 24-26, and 27-30 weeks and compared with a model assessing longitudinal changes of these parameters. Models adding mean uterine artery pulsatility index and abdominal circumference were evaluated. SGA neonates were defined as having a birth weight less than the tenth centile. RESULTS: The predictive performance of a model assessing longitudinal changes of angiogenic factors was similar to that of single evaluations at the second and early third trimesters. The performance of the models combining angiogenic factors with mean uterine artery pulsatility index and abdominal circumference was better than those using only biochemical markers. However, the longitudinal evaluation of biochemical and biophysical parameters did not perform better than cross-sectional evaluations. CONCLUSIONS: Evaluation of angiogenic factors are useful for prediction of SGA neonates in a high-risk population for early PE. However, longitudinal models do not increase their predictive capacity.

Sex-dependent differential transcript expression in the placenta of growth restricted infants.

INTRODUCTION: The pathological decrease of fetal growth during gestation can lead to subsequent poor health outcomes for the fetus. This process is commonly controlled by the placenta, the interface between mother and baby during gestation. Sex-specific gene expression has been implicated in placental function, therefore, there is a need to determine if it is important during reduced fetal growth. We therefore aimed to characterise placental gene expression at term to evaluate sex-specific genetic changes that occur in small for gestational age (SGA) infants. METHODS: RNA-sequencing of twelve human placental tissue samples collected from pregnancies yielding either term appropriate for gestational age (AGA) or SGA infants identified at delivery. Candidate genes associated with fetal size and fetal sex were identified using differential gene expression and weighted gene co-expression network analyses. Single-cell sequencing data was used for candidate validation and to estimate candidate transcript expression in specific placental cell populations. RESULTS: Differential gene expression and weighted gene co-expression network analyses identified 403 candidate transcripts associated with SGA infants. One hundred and three of these transcripts showed sex-specific expression. . Published placental sequencing datasets were used to validate the key expression results from the twelve placental samples initially studied; the sex-independent transcript expression for genes involved in cell cycle processes in males (7 transcripts) and endoplasmic reticulum stress in females (17 transcripts). DISCUSSION: This study identified the activation of multiple molecular mechanisms involved in the placental response to an adverse environmental stressor. Mechanisms such as disrupted protein synthesis were shared between infant biological sex when comparing AGA to SGA, whilst other pathways such as cell cycle and endoplasmic reticulum stress appear as independent/specific to either males or females when investigating reduced fetal growth. This data suggests that sexual dimorphism is an important consideration when examining placental dysfunction and poor fetal growth.

Exosomal miRNA Profile in Small-for-Gestational-Age Children: A Potential Biomarker for Catch-Up Growth.

Objective: The mechanism underlying postnatal growth failure and catch-up growth in small-for-gestational-age (SGA) children is poorly understood. This study investigated the exosomal miRNA signature associated with catch-up growth in SGA children. Methods: In total, 16 SGA and 10 appropriate-for-gestational-age (AGA) children were included. Serum exosomal miRNA was analyzed using next-generation sequencing (NGS). Exosomal miRNA was profiled for five SGA children with catch-up growth (SGA-CU), six SGA children without CU growth (SGA-nCU), and five AGA children. Results: Exosomal miRNA profiles were clustered into three clear groups. The exosomal miRNA expression profiles of the SGA-nCU group differed from those of the SGA-CU and AGA groups. In all, 22 miRNAs were differentially expressed between SGA-nCU and AGA, 19 between SGA-nCU and SGA-CU, and only 6 between SGA-CU and AGA. In both SGA-nCU and SGA-CU, miR-874-3p was upregulated and miR-6126 was downregulated. Therefore, these two miRNAs could serve as biomarkers for SGA. Compared with SGA-CU and AGA, miR-30c-5p, miR-363-3p, miR-29a-3p, and miR-29c-3p were upregulated in SGA-nCU, while miR-629-5p and miR-23a-5p were downregulated. These six miRNAs could be associated with growth failure in SGA-nCU children. Conclusions: SGA children without CU have a distinct exosomal miRNA expression profile compared with AGA and SGA children with CU. Exosomal miRNAs could serve as novel biomarkers for CU.

Serum spexin levels are not associated with size at birth but are associated with metabolic syndrome components in prepubertal children born at term.

BACKGROUND: Babies born small for gestational age (SGA) are at risk of obesity and metabolic syndrome (MetS). Spexin (SPX) is a novel peptide implicated in food intake and obesity. Spexin levels are lower in obese subjects. This study investigated the potential association of SPX and some obesity related peptides such as leptin and active ghrelin with size at birth and MetS components in prepubertal children born term and either SGA or appropriate for GA (AGA). Secondary aim was to identify whether any of the investigated peptides were associated with MetS components. METHODS: We conducted a cross-sectional study of 37 consecutive (median age: 5.6 y) SGA- and 50 (median age: 5.9 y) AGA-born children. Clinical evaluations were performed using standard methods. Several biochemical variables (SPX, total leptin, and active ghrelin levels) were analyzed. Age-dependent cut-off values were used to define MetS components, including excess adiposity, hypertension, insulin resistance, and dyslipidemia. The associations between the assessed clinical and laboratory variables and MetS components were investigated. RESULTS: Children born SGA had higher frequencies of MetS components than AGA-born peers (p < 0.01). None of the investigated peptides were different between children born SGA and AGA after correcting for body mass index (p > 0.05 for all). Serum SPX levels were lower in children with at least one metS component than those without MetS components (p = 0.018). CONCLUSIONS: Size at birth had no association with serum SPX. Serum SPX levels are decreased in prepubertal children with MetS components.

High Maternal Serum Estradiol in First Trimester of Multiple Pregnancy Contributes to Small for Gestational Age via DNMT1-Mediated CDKN1C Upregulation.

High maternal serum estradiol (E2) levels in the first trimester of pregnancy are associated with a high incidence of low birth weight (LBW) and small for gestational age (SGA). This study aimed to investigate the effect of first-trimester high maternal serum E2 levels on fetal growth and the underlying mechanisms in multiple pregnancies. Maternal serum E2 levels of women at 8 weeks of gestation were measured. The expression levels of imprinted genes and DNMT1 were determined by RT-qPCR, and KvDMR1 methylation in embryo tissue, placenta, and newborn cord blood samples was examined by bisulfite sequencing PCR. The effect of E2 on CDKN1C expression was investigated in HTR8 cells. The incidence of SGA was significantly higher in multiple pregnancies reduced to singleton than that in primary singleton pregnancies (11.4% vs. 2.9%) (P < 0.01) and multiple pregnancies reduced to twins than primary twins (38.5% vs. 27.3%) (P < 0.01). The maternal serum E2 level at 8 weeks of gestation increased with the number of fetuses and was negatively correlated with offspring birth weight. CDKN1C and DNMT1 expression was significantly upregulated in embryo tissue, placenta, and cord blood from multiple pregnancies. Furthermore, there was a positive correlation between CDKN1C mRNA expression and KvDMR1 methylation levels. In HTR8 cells, DNMT1 mediated the estrogen-induced upregulation of CDKN1C, which might contribute to SGA. To minimize the risks of LBW and SGA, our findings suggest that abnormally high maternal serum E2 levels should be avoided during the first trimester of multiple pregnancies from assisted reproductive technology (ART).

Fatty acids in the placenta of appropiate- versus small-for-gestational-age infants at term birth.

INTRODUCTION: Fatty acids are essential nutrients for the fetus and are supplied by the mother through the placenta. Desaturase and elongase enzymes play an important role in modulating the fatty acid composition of body tissues. We aimed to compare the fatty acid profile and the estimated desaturase and elongase activities in the placenta of appropriate (AGA) versus small-for-gestational-age (SGA), and to determine their relationship with the offspring size at birth. METHODS: The placental fatty acid profile was analyzed by gas chromatography in 84 infants (45 AGA and 30 SGA) from a prenatal cohort study. The estimated desaturase and elongase activities were calculated from product-precursor fatty acid ratios. Results were associated with maternal (age, body mass index and weight gain during gestation) and neonatal (gestational age, sex, birth weight and birth length) parameters. RESULTS: Differences in placental fatty acid composition between AGA and SGA infants rather than correlations thereof with neonatal parameters were observed. Placentas from SGA infants contained lower levels of omega-3 (ALA, EPA, DPA, and DHA) and high omega-6/omega-3 ratios (AA/DHA and LA/ALA), as well as low elongase (Elovl5) and high desaturase (D9Dn7 and D5Dn6) activity as compared to AGA infants (all p < 0.0001). DISCUSSION: Placentas of AGA and SGA infants differed in fatty acids profile as well as in estimated desaturase and elongase activities. A striking feature of SGA placentas was the low availability of omega-3. Hence, omega-3 fatty acid status deserves further attention, as a potential target of prenatal interventions.

Assessing the relationship between pregravid body mass index and risk of adverse maternal pregnancy and neonatal outcomes: prospective data in Southwest China.

The relevance of pregestational body mass index (BMI) on adverse pregnancy outcomes remained unclear in Southwest China. This study aimed to investigate the overall and age-category specific association between pre-gestational BMI and gestational diabetes mellitus (GDM), preeclampsia, cesarean delivery, preterm delivery, stillbirth, macrosomia, and small-for-gestational age (SGA) or large-for-gestational age (LGA) neonates in Southwest China. Furthermore, it explores the relative importance of influence of pregravid BMI and maternal age on pregnancy outcomes. 51,125 Chinese singleton pregnant women were recruited as study subjects. Multiple logistic regression models were used to examine the influence of pre-pregnancy BMI on adverse pregnancy outcomes. Gradient boosting machine was used to evaluate the relative importance of influence of pregravid BMI and maternal age on pregnancy outcomes. It is found that women who were overweight or obese before pregnancy are at higher risk of adverse pregnancy outcomes except for SGA neonates, while pre-pregnancy underweight is a protective factor for GDM, preeclampsia, cesarean delivery, macrosomia and LGA, but not SGA. Younger mothers are more susceptible to GDM and macrosomia neonates, while older mothers are more prone to preeclampsia. Pre-pregnancy BMI has more influence on various pregnancy outcomes than maternal age. To improve pregnancy outcomes, normal BMI weight as well as relatively young maternal ages are recommended for women in child-bearing age.

Associations of early pregnancy BMI with adverse pregnancy outcomes and infant neurocognitive development.

The prevalence of overweight and obesity amongst reproductive women has been increasing worldwide. Our aim was to compare pregnancy outcomes and infant neurocognitive development by different BMI classifications and investigate whether early pregnancy BMI was associated with risks of adverse outcomes in a Southwest Chinese population. We analysed data from 1273 women enrolled in the Complex Lipids in Mothers and Babies (CLIMB) randomized controlled trial in Chongqing, China. Maternal BMI was classified as underweight, normal weight and overweight/obese according to the Chinese, WHO Asian, and WHO European standards. For the adverse pregnancy outcomes, after adjustment for potential confounders, an underweight BMI was associated with increased risk of small for gestational age (SGA) babies, and an overweight/obese BMI was associated with increased risk of maternal gestational diabetes mellitus (GDM), caesarean section (C-section), macrosomia and large for gestational age (LGA) babies. For infant neurocognitive development, 1017 mothers and their children participated; no significant differences were seen in the Mental Development Index (MDI) or the Psychomotor Development Index (PDI) between the three BMI groups. Our findings demonstrate that abnormal early pregnancy BMI were associated with increased risks of adverse pregnancy outcomes in Chinese women, while early pregnancy BMI had no significant influence on the infant neurocognitive development at 12 months of age.

Cardiometabolic evaluation of small for gestational age children: protective effect of breast milk / Evaluación cardiometabólica de niños pequeños para su edad gestacional: efecto protector de la leche materna

INTRODUCTION: human growth is the result of an interaction between genetic, hormonal, nutritional, and environmental factors. It is not yet fully understood what is predominant and decisive in determining an individual's weight and height. OBJECTIVE: the aim of this study was to evaluate the cardiometabolic profile of exclusively breastfed children born small for gestational age (SGA). METHODS: this is a prospective cohort study of children born at term who were classified as SGA, and as appropiate for gestational age (AGA), who were followed up to pre-school age. Anthropometric measures and body composition parameters were obtained. Breastfeeding duration was calculated in days, and achievement of catch up of weight was considered an increase in Z-score ≥ 0.67. The cardiometabolic profile was evaluated in the first month of life and repeated at pre-school age. At pre-school age, fasting blood glucose, insulin, HOMA-IR, and blood pressure were measured. RESULTS: twenty SGA and 12 AGA children were studied. The mean duration of exclusive breastfeeding (EBF) was 180 days in both groups. Of SGA children, 85 % had recovery anthropometric parameters for age within the first six months, with a speed of weight gain significantly higher than the that of AGAs (p < 0.001). SGAs continued to be thinner and smaller than AGAs at pre-school age. There was no diagnosis of overweight or obesity in the studied sample, and no differences were foun between groups in laboratory tests. CONCLUSION: these findings suggest that EBF may confer protection until pre-school age in children born SGA, who are considered at higher risk for chronic non-communicable diseases

INTRODUCCIÓN: el crecimiento humano es el resultado de la interacción de factores genéticos, hormonales, nutricionales y ambientales. Todavía no se comprende completamente lo que es predominante y decisivo para determinar el peso y la altura del individuo. OBJETIVO: el objetivo de este estudio fue evaluar el perfil cardiometabólico de niños alimentados con lactancia materna exclusivamente y que nacieron pequeños para la edad gestacional (PEG). MÉTODOS: este es un estudio de cohortes prospectivo con niños nacidos a término, unos clasificados como PEG y otros como apropiados para la edad gestacional (AEG). Se hizo un seguimiento de estos niños hasta la edad preescolar. Se realizaron medidas antropométricas y de la composición corporal. La duración de la lactancia materna se calculó en días y el éxito en la recuperación del peso se consideró como un aumento de la puntuación Z ≥ 0,67. El perfil cardiometabólico se evaluó en el primer mes de vida y se repitió en la edad preescolar. En la edad preescolar se midieron la glucosa en sangre en ayunas, la insulina, el HOMA-IR y la presión arterial. RESULTADOS: el grupo del estudio estaba formado por veinte niños PEG y doce niños AEG. La duración media de la lactancia materna exclusiva (LME) fue de 180 días en ambos grupos. De los niños PEG, el 85 % tenían parámetros antropométricos de recuperación para la edad en los primeros seis meses, siendo la velocidad del aumento de peso significativamente mayor que en los AEG (p < 0,001). Aun así, los niños PEG continuaron siendo más delgados y pequeños que los AEG en la edad preescolar. No hubo diagnóstico de sobrepeso u obesidad en la muestra estudiada, y no hay diferencia entre los grupos relativos a las pruebas de laboratorio. CONCLUSIÓN: estos hallazgos sugieren que la LME puede conferir protección hasta la edad preescolar en los niños nacidos PEG, que se consideran en mayor riesgo de contraer enfermedades crónicas no transmisibles

Glycerophospholipid and detoxification pathways associated with small for gestation age pathophysiology: discovery metabolomics analysis in the SCOPE cohort.

INTRODUCTION: Small for gestational age (SGA) may be associated with neonatal morbidity and mortality. Our understanding of the molecular pathways implicated is poor. OBJECTIVES: Our aim was to determine the metabolic pathways involved in the pathophysiology of SGA and examine their variation between maternal biofluid samples. METHODS: Plasma (Cork) and urine (Cork, Auckland) samples were collected at 20 weeks' gestation from nulliparous low-risk pregnant women participating in the SCOPE study. Women who delivered an SGA infant (birthweight < 10th percentile) were matched to controls (uncomplicated pregnancies). Metabolomics (urine) and lipidomics (plasma) analyses were performed using ultra performance liquid chromatography-mass spectrometry. Features were ranked based on FDR adjusted p-values from empirical Bayes analysis, and significant features putatively identified. RESULTS: Lipidomics plasma analysis revealed that 22 out of the 33 significantly altered lipids annotated were glycerophospholipids; all were detected in higher levels in SGA. Metabolomic analysis identified reduced expression of metabolites associated with detoxification (D-Glucuronic acid, Estriol-16-glucuronide), nutrient absorption and transport (Sulfolithocholic acid) pathways. CONCLUSIONS: This study suggests higher levels of glycerophospholipids, and lower levels of specific urine metabolites are implicated in the pathophysiology of SGA. Further research is needed to confirm these findings in independent samples.

Associations of umbilical cord fatty acid profiles and desaturase enzyme indices with birth weight for gestational age in Japanese infants.

Long-chain polyunsaturated fatty acids (LCPUFAs) required for infant development are produced by Δ6 desaturase (D6D) and Δ5 desaturase (D5D). The D6D index and D5D index are calculated based on their respective precursor/product ratios. The D5D and D6D indices are related to obesity and lifestyle-related diseases. The aim of the present study was to examine the associations of umbilical cord fatty acid profiles, D6D index, and D5D index in appropriate for gestational age (AGA), small for gestational age (SGA), and large for gestational age (LGA) infants. This was a nested case-control study, and the relationship between case and control maternal blood and umbilical cord blood fatty acid compositions was examined. Cases were small for gestational age (SGA; n = 55) and large for gestational age (LGA; n = 149) infants, whereas controls were appropriate for gestational age (AGA; n = 204) infants. Fatty acid profiles in maternal blood and umbilical cord plasma were analyzed by gas-liquid chromatography. The D6D index was calculated as dihomo-γ-linolenic acid (DGLA 20: 3 n-6) / linoleic acid (18: 2 n - 6), and the D5D index was calculated as arachidonic acid (20: 4 n - 6) / DGLA (20: 3 n - 6). Statistical analysis of umbilical cord blood fatty acids was performed with multiple comparisons. SGA infants showed high umbilical cord values for α-linolenic acid and DHA and lower values for DGLA compared to AGA infants. SGA infants showed a higher D5D index but a lower D6D index than AGA infants. LGA infants showed high values for α-linolenic acid and DGLA and lower values for arachidonic acid than AGA infants. LGA infants showed a high D6D index and a low D5D index relative to AGA infants. No significant differences in maternal blood fatty acid profiles, the D6D index, and D5D index desaturase activities were found among the three groups. There were differences in umbilical cord fatty acid profiles and D6D and D5D indices among AGA, SGA, and LGA infants, but further study is needed.

Methylation Status of GLP2R, LEP and IRS2 in Small for Gestational Age Children with and without Catch-up Growth

Objective: In small for gestational age (SGA) children, catch-up growth could be influenced by methylation of several genes involved in metabolism. Epigenetics may influence the development of metabolic diseases in adulthood. To compare the methylation of leptin (LEP), glucagon-like peptide-2 receptor (GLP2R), insulin receptor substrate-2 (IRS2) in SGA patients with and without catch-up growth. Methods: Observational prospective study of SGA children. Demographical and clinical variables were collected from clinical records and parents' questionnaire. Methylation status of LEP, IRS2, and GLP2R promoters was evaluated in DNA extracted from patient and one parent saliva samples. Results: Forty-eight SGA patients were included. Twenty-six (54.2%) had catch-up growth phenotype and 22 (45.8%) did not. The median age was 5.2 years [RIC 4.1-6.8] without difference between groups (p=0.306). The catch-up group had increased appetite (42.3% vs 9.1%, p=0.008), family history of dyslipidemia (42.3% vs 27.3%) and diabetes (34.6% vs 22.7%) compared to non-catch-up group. Catch-up patients had significantly larger waist circumference compared to non-catch-up group (median 55 cm [RIC 52-58] versus median 49.5 cm [RIC46-52]; p<0.001). LEP and GLP2R were methylated in all samples. IRS2 was methylated in 60% of SGA patients without difference between groups (p=0.520). Conclusion: There is no association between IRS2 methylation and catch-up growth among SGA patients. LEP and GLP2R were methylated in all SGA patients. Gene methylation may be implicated in metabolic disease later in life. More studies should be performed to confirm this hypothesis.

The intra-hepatic umbilical-Porto-systemic venous shunt and fetal growth.

OBJECTIVE: The fetal liver circulation has an important role in fetal growth. The intra-hepatic Umbilical-Porto-Systemic Venous Shunt (IHUPSVS) causes a reduction of the umbilical blood flow to the liver and has been reported to have a restrictive effect on fetal growth. The aim of this study was to evaluate the effect of IHUPSVS on fetal growth. METHODS: We conducted a retrospective cohort study of IHUPSVS diagnosed between 2001 and 2019. IHUPSVS was defined as any abnormal communication between any branch of the portal vein and hepatic vein. Pre- and postnatal characteristics were collected from medical files and compared between cases with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). RESULTS: Twenty-five fetuses were included in the study. Eighteen (72%) had last estimated fetal weight and birth weight below the 10th centile, four (16%) of them between the third and fifth centile, and 11 (44%) below the third centile. Median gestational age at delivery was lower for FGR than AGA fetuses (37 vs. 38 weeks, p = 0.034) and rate of preterm delivery was higher (38.9 vs. 14.3, P = 0.24). Four cases had associated structural anomalies (2 in each group), and two had minor genetic aberrations (1 in each group). CONCLUSIONS: Growth restriction is prevalent in fetuses with IHUPSVS, suggesting that fetal growth should be monitored. In equal measure, in cases with growth restriction, especially without other apparent cause, an intrahepatic shunt should be looked for.

Human placental uptake of glutamine and glutamate is reduced in fetal growth restriction.

Fetal growth restriction (FGR) is a significant risk factor for stillbirth, neonatal complications and adulthood morbidity. Compared with those of appropriate weight for gestational age (AGA), FGR babies have smaller placentas with reduced activity of amino acid transporter systems A and L, thought to contribute to poor fetal growth. The amino acids glutamine and glutamate are essential for normal placental function and fetal development; whether transport of these is altered in FGR is unknown. We hypothesised that FGR is associated with reduced placental glutamine and glutamate transporter activity and expression, and propose the mammalian target of rapamycin (mTOR) signaling pathway as a candidate mechanism. FGR infants [individualised birth weight ratio (IBR) < 5th centile] had lighter placentas, reduced initial rate uptake of 14C-glutamine and 14C-glutamate (per mg placental protein) but higher expression of key transporter proteins (glutamine: LAT1, LAT2, SNAT5, glutamate: EAAT1) versus AGA [IBR 20th-80th]. In further experiments, in vitro exposure to rapamycin inhibited placental glutamine and glutamate uptake (24 h, uncomplicated pregnancies) indicating a role of mTOR in regulating placental transport of these amino acids. These data support our hypothesis and suggest that abnormal glutamine and glutamate transporter activity is part of the spectrum of placental dysfunction in FGR.

Usefulness of the sFlt-1/PlGF (Soluble fms-Like Tyrosine Kinase-1/Placental Growth Factor) Ratio in Diagnosis or Misdiagnosis in Women With Clinical Diagnosis of Preeclampsia.

Preeclampsia is characterized by angiogenic imbalance (AI), sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) is useful for its diagnosis and prediction of adverse outcomes, but the relationship among the degrees of AI as assessed by this ratio with the correct diagnosis, clinical characteristics, and outcomes in women with clinical diagnosis of preeclampsia are unclear. We studied 810 women with clinical diagnosis of preeclampsia. Patients were divided into 3 groups based on their degree of AI, evaluated by the sFlt-1/PlGF ratio: no AI (≤38), mild AI (>38-<85), and severe AI (≥85). Patients with no AI were more likely to have comorbidities and false significant proteinuria compared with patients with mild and severe AI (P<0.001). The rates of preterm delivery, delivery within 14 days, and small-for-gestational-age infant were higher among patients with severe AI than in patients with no and mild AI (P<0.001) and in patients with mild AI that in those with no AI (P≤0.01). The occurrence of any adverse maternal outcome (HELLP syndrome, elevated liver enzymes, thrombocytopenia, placental abruption, acute kidney injury) was only present in patients with severe AI. Interestingly, the frequency of misdiagnosis of preeclampsia was progressively lower as the degrees of AI increased (no AI: 100%, mild AI: 88.2%, and severe AI: 15.6%). We concluded that in women with clinical diagnosis of preeclampsia, severe AI is characterized by high frequency of true preeclampsia and preeclampsia-related adverse outcomes, in contrast, no and mild AI, are characterized by unnecessary early deliveries, often due to misdiagnosis.

Growth and metabolic effects of long-term recombinant human growth hormone (rhGH) treatment in short children born small for gestational age: GH-RAST study.

Objectives To study the efficacy and influence on metabolism of recombinant human growth hormone (rhGH) treatment in short children born small for gestational age (SGA). Methods Retrospective, observational, multicenter study in 305 short children born SGA, treated with rhGH during a mean ± SD of 5.03 ± 1.73 years at a mean ± SD dose of 37 ± 8 µg/kg/day. Auxological and metabolic assessment including glucose and lipids profile were collected. Results Mean ± SD age at the start of treatment was 7.11 ± 2.78 years. Height and weight improved significantly until the end of treatment from mean -2.72 (CI95%: -2.81 to -2.63) standard deviation score (SDS) to -1.16 (CI95%: -1.44 to -0.88) SDS and from -1.62 (CI95%: -1.69 to -1.55) SDS to -0.94 (CI95%: -1.14 to -0.74) SDS respectively. Mean height gain was 1.27 (CI95%: 0.99-1.54) SDS. Prepubertal patients showed higher height gain than pubertal children (mean [CI95%] = 1.44 [CI95%: 1.14-1.74] vs. 0.73 [CI95%: 0.22-1.24], p=0.02). Height gain SDS during treatment negatively correlated with chronological age (CA) and bone age (BA) delay and positively correlated with duration of treatment, height gain during first year of treatment, years on prepubertal treatment and height SDS from target height (TH). Glucose, insulin, and triglycerides increased significantly but remained within the normal range. Total and LDL-cholesterol decreased significantly, and HDL-cholesterol remained unchanged. Conclusions rhGH treatment in short SGA children effectively normalized height in most of the patients and showed a safe metabolic profile. Children who benefit the most are those with greater height SDS distance from TH, BA delay, longer duration of treatment and prepubertal treatment initiation.

Non-targeted urinary metabolomics in pregnancy and associations with fetal growth restriction.

Our objective was to identify metabolites associated with fetal growth restriction (FGR) by examining early and late pregnancy differences in non-targeted urinary metabolites among FGR cases and non-FGR controls. An exploratory case-control study within LIFECODES birth cohort was performed. FGR cases (N = 30), defined as birthweight below the 10th percentile, were matched with controls (N = 30) based on maternal age, race, pre-pregnancy body mass index, and gestational age at delivery. Gas chromatography/electron-ionization mass spectrometry was performed on urine samples collected at 10 and 26 weeks of gestation. Differences in urinary metabolite levels in cases and controls at each time point and between the two time points were calculated and then changes compared across pregnancy. 137 unique urinary metabolites were annotated, and several identified that were higher in cases compared to controls. For example, urinary concentrations of benzoic acid were higher in cases compared to controls at both study visits (3.01-fold higher in cases at visit 1, p < 0.01; 3.10-fold higher in cases at visit 3, p = 0.05). However, these findings from our exploratory analysis were not robust to false-discovery-rate adjustment. In conclusion, using a high-resolution, non-targeted approach, we found specific urinary organic acids differed over pregnancy by FGR case status.

Association among placental 11ß-HSD2, PPAR-γ, and NF-κB p65 in small-for-gestational-age infants: A nested case-control study.

PROBLEM: 11ß-Hydroxysteroid dehydrogenase 2 (11ß-HSD2) catalyzes active glucocorticoids into their inactive products, preventing the passage of glucocorticoids into the fetus from maternal circulation. Peroxisome proliferator-activated receptor (PPAR)γ is a member of the nuclear receptor superfamily that regulates the expression of placental 11ß-HSD2. Nuclear factor-kappa B (NF-κB) is a transcription factor that regulates inflammatory signaling. This study aimed to investigate the association among 11ß-HSD2, PPAR-γ, and NF-κB p65 in small-for-gestational-age (SGA) infants. METHOD OF STUDY: Forty-six SGA and 46 appropriate-for-gestational-age (AGA) infants were enrolled in this study. Both newborns and placentas were weighed. Placental 11ß-HSD2 levels were measured using Western blotting. Placental PPAR-γ and NF-κB p65 were detected by immunohistochemistry. Placental inflammatory cytokines were evaluated by real-time RT-PCR. RESULTS: 11ß-HSD2 levels were lower in SGA placentas than those in AGA placentas. Placental PPAR-γ-positive nuclei were less in SGA than those in AGA. By contrast, placental NF-κB p65-positive nuclei were more in SGA than those in AGA. The levels of CRP, TNF-α, IL-8, and IL-1ß, several inflammatory cytokines, were higher in SGA placentas. Correlation analysis showed that neonatal weight was positively associated with PPAR-γ and 11ß-HSD2 in SGA placentas. By contrast, neonatal weight was inversely correlated with NF-κB p65 in SGA placentas. 11ß-HSD2 was positively correlated with PPAR-γ in SGA placentas. CONCLUSIONS: Inflammation-associated downregulation of placental PPAR-γ and 11ß-HSD2 may be involved in SGA.

The presence of coexisting sleep-disordered breathing among women with hypertensive disorders of pregnancy does not worsen perinatal outcome.

OBJECTIVE: To determine whether the presence of co-existing sleep-disordered breathing (SDB) is associated with worse perinatal outcomes among women diagnosed with a hypertensive disorder of pregnancy (HDP), compared with normotensive controls. STUDY DESIGN: Women diagnosed with HDP (gestational hypertension or preeclampsia) and BMI- and gestation-matched controls underwent polysomnography in late pregnancy to determine if they had coexisting SDB. Fetal heart rate (FHR) monitoring accompanied the sleep study, and third trimester fetal growth velocity was assessed using ultrasound. Cord blood was taken at delivery to measure key regulators of fetal growth. RESULTS: SDB was diagnosed in 52.5% of the HDP group (n = 40) and 38.1% of the control group (n = 42); p = .19. FHR decelerations were commonly observed during sleep, but the presence of SDB did not increase this risk in either the HDP or control group (HDP group-SDB = 35.3% vs. No SDB = 40.0%, p = 1.0; control group-SDB = 41.7% vs. No SDB = 25.0%, p = .44), nor did SDB affect the total number of decelerations overnight (HDP group-SDB = 2.7 ± 1.0 vs. No SDB = 2.8 ± 2.1, p = .94; control group-SDB = 2.0 ± 0.8 vs. No SDB = 2.0 ± 0.7, p = 1.0). Fetal growth restriction was the strongest predictor of fetal heart rate events during sleep (aOR 5.31 (95% CI 1.26-22.26), p = .02). The presence of SDB also did not adversely affect fetal growth; in fact among women with HDP, SDB was associated with significantly larger customised birthweight centiles (43.2% ± 38.3 vs. 16.2% ± 27.0, p = .015) and fewer growth restricted babies at birth (30% vs. 68.4%, p = .026) compared to HDP women without SDB. There was no impact of SDB on measures of fetal growth for the control group. Cord blood measures of fetal growth did not show any adverse effect among women with SDB, either in the HDP or control group. CONCLUSION: We did not find that the presence of mild SDB worsened fetal acute or longitudinal outcomes, either among women with HDP or BMI-matched normotensive controls. Unexpectedly, we found the presence of SDB conferred a better prognosis in HDP in terms of fetal growth. The fetus has considerable adaptive capacity to withstand in utero hypoxia, which may explain our mostly negative findings. In addition, SDB in this cohort was mostly mild. It may be that fetal sequelae will only be unmasked in the setting of more severe degrees of SDB and/or underlying placental disease.

Modulation of Placental Gene Expression in Small-for-Gestational-Age Infants.

Small-for-gestational-age (SGA) infants are fetuses that have not reached their genetically programmed growth potential. Low birth weight predisposes these infants to an increased risk of developing cardiovascular, metabolic and neurodevelopmental conditions in later life. However, our understanding of how this pathology occurs is currently incomplete. Previous research has focused on understanding the transcriptome, epigenome and bacterial signatures separately. However, we hypothesise that interactions between moderators of gene expression are critical to understanding fetal growth restriction. Through a review of the current literature, we identify that there is evidence of modulated expression/methylation of the placental genome and the presence of bacterial DNA in the placental tissue of SGA infants. We also identify that despite limited evidence of the interactions between the above results, there are promising suggestions of a relationship between bacterial signatures and placental function. This review aims to summarise the current literature concerning fetal growth from multiple avenues and propose a novel relationship between the placental transcriptome, methylome and bacterial signature that, if characterised, may be able to improve our current understanding of the placental response to stress and the aetiology of growth restriction.