Investigation of the 1H-NMR based urine metabolomic profiles of IUGR,LGA and AGA newborns on the first day of life

Abstract

¹H-NMR spectroscopy coupled with multivariate statistical analysis was used for the first time to compare the urinary NMR metabolic profiles of neonates with intrauterine growth retardation (IUGR) and large for gestational age (LGA). For the sake of comparison, infants who were adequate for gestational age (AGA) were also analyzed. Pattern recognition methods, including Principal Component Analyses (PCA), Partial Least Squares Discriminant Analysis (PLS-DA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA), were used to analyze NMR data. Clear differences among the metabolic profiles of AGA, IUGR and LGA were observed. The main metabolites responsible for these differentiations were identified as myo-inositol, creatinine, creatine, citrate, urea and glycine. In particular, among these, myo-inositol may be a potential biomarker of an altered glucose metabolism during fetal development both in IUGR and LGA. This study highlights the applicability of NMR-based metabolomics for improving the understanding of the relations among nutrition, integrated metabolism and health in neonatology.     

The effect of intrauterine growth on leukocyte telomere length at birth

Abstract

Objective: Telomeres are specialized nucleoprotein structures located at the ends of chromosomes, which play a crucial role in genomic stability. Telomere shortening has been proposed as a biomarker for the onset of age-related diseases. This study aimed to determine whether restricted or increased intrauterine growth affects leukocyte telomere length (LTL) at birth.

Materials and methods: One hundred sixty-five (n?=?165) full-term neonates participated in the study. Fetuses were classified as intrauterine growth restriction (IUGR, n?=?21), large-for-gestational-age (LGA, n?=?15), or appropriate-for-gestational-age (AGA, n?=?129), based on customized birth-weight standards. Mixed arteriovenous cord blood samples were collected for isolation of leukocyte DNA. The LTL was measured using multiplex monochrome quantitative real-time PCR and telomeric restriction fragments through Southern blot analysis (terminal restriction fragment [TRF]).

Results: Despite differences among groups in birth weight, length and head circumference, LTL did not differ among AGA (6.78?±?0.58), IUGR (10.54?±?1.80), and LGA (11.95?±?2.42) neonates (p?=?.098). Cord blood IGF-1 and IGFBP-3 concentrations were higher in the LGA group. LTL positively correlated with birth length (r?=?0.176, p?=?.032).

Conclusions: Intrauterine growth does not seem to affect LTL at birth. Further studies, comprising a larger sample size of IUGR, LGA, and AGA neonates, are required to determine whether growth at birth influences LTL.     

Differential expression of cord blood neurotrophins in gestational diabetes: the impact of fetal growth abnormalities

Objective: Gestational diabetes mellitus (GDM) may induce fetal macrosomia or growth restriction and is associated with later offspring neurodevelopmental disorders. We aimed to determine whether neurotrophins brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-4 (NT-4) are differentially expressed in cord blood samples at birth in large-for-gestational-age (LGA), intrauterine-growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) offspring of diabetic mothers, as compared to AGA controls from non-diabetic mothers.

Methods: BDNF, NGF and NT-4 concentrations were prospectively determined in 80?cord blood samples from LGA (n?=?15), IUGR (n?=?12) and AGA (n?=?33) diabetic, as well as from AGA normal (controls, n?=?20) singleton full-term pregnancies.

Results: Fetal BDNF concentrations considerably decreased in GDM, as compared with normal pregnancies [(b?=??2.836, 95%CI ?5.067 to (?0.604), p?=?0.013)] and were higher in females (b?=?2.298, 95%CI 0.357–4.238, p?=?0.021). Cord blood NGF concentrations were lower in IUGR than AGA infants (p?=?0.038).

Conclusions: BDNF is down-regulated in the fetus exposed to GDM, independently of the fetal growth pattern, probably representing a candidate mechanism underlying the association between maternal diabetes and later psychopathology. IUGR fetuses born to diabetic mothers present with NGF deficiency, which may contribute to their long-term neurodevelopmental sequelae. Gender-dependent differences in fetal BDNF may partly explain the higher prevalence of adverse neurodevelopmental outcomes following brain insults in male infants.     

Urinary metabolomics of bronchopulmonary dysplasia (BPD): preliminary data at birth suggest it is a congenital disease

Abstract

Objective: Bronchopulmonary dysplasia (BPD) or chronic lung disease is one of the principal causes of mortality and morbidity in preterm infants. Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications. The trigger cause of the disease comprehends the impairment of the alveolar development and the increased angiogenesis. Nevertheless, the molecular pathways characterizing the disease are still unclear. Therefore, the use of the metabolomics technique, due to the capability of identifying instantaneous metabolic perturbation, might help to recognize metabolic patterns associated with the condition.

Methods: The purpose of this study is to compare urinary metabolomics at birth in 36 newborns with a gestational age below 29 weeks and birth weight <1500?g (very low birth weight – VLBW), admitted in Neonatal Intensive Care Unit (NICU) divided into two groups: the first group (18 cases) consisting of newborns who have not yet developed the disease, but who will subsequently develop it and the second group (18 controls) consisting of newborns not affected by BPD. Urine samples were collected within 24–36?h of life and immediately frozen at ?80?°C.

Results: The ¹H-NMR spectra were analyzed using a partial least squares discriminant analysis (PLS-DA) model coupled with orthogonal Signal Correction. Using this approach it was possible with urine at birth to discriminate newborns that will be later have a diagnosis of BPD with a high statistics power. In particular, we found five important discriminant metabolites in urine in BPD newborns: lactate, taurine, TMAO, myoinositol (which increased) and gluconate (which decreased).

Conclusion: These preliminary results seem to be promising for the identification of predictor’s biomarkers characterizing the BPD condition. These data may suggest that BPD is probably the result of an abnormal development (respiratory bud, vascular tree, hypodysplasia of pneumocytes) and could be considered a congenital disease (genetics plus intrauterine epigenetics). Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications.     

Cord blood netrin-1 and -4 concentrations in term pregnancies with normal,restricted and increased fetal growth

Abstract

Objective: To determine levels of the possible angioregulatory molecules netrin-1 and -4, in intrauterine-growth-restricted (IUGR), large for gestational age (LGA) (both groups characterized by altered angiogenic mechanisms) and appropriate-for-gestational-age (AGA) pregnancies.

Methods: Cord blood (UC) netrin-1 and -4 concentrations were measured in 30 IUGR, 30 LGA and 20 AGA infants and their mothers (MS).

Results: Netrin-1 and -4 concentrations did not differ in all groups. UC netrin-4 increased with gestational age (b?=?0.075, 95% CI 0.029–0.121, p?=?0.002). In the IUGR group, MS netrin-4 decreased as birth-weight centiles increased [b?=??0.058, 95% CI ?0.112 to ?0.004, p?=?0.036]. In the LGA group, MS netrin-1 decreased with advanced gestational age [b?=??0.063, 95% CI ?0.105 to ?0.022, p?=?0.004]. In all cases, MS netrin-1 positively correlated with MS netrin-4 (r?=?0.299, p?=?0.007), while UC netrin-1 negatively correlated with UC netrin-4 (r?=??0.239, p?=?0.033).

Conclusions: Increased UC netrin-4 levels with advancing gestational age may reflect its effect on fetal development. Decreased maternal netrin-1 levels in the LGA group possibly represent a negative feedback mechanism against increased angiogenesis. Increased maternal netrin-4 levels in IUGR neonates may reflect in utero hypoxia, while the negative correlations between fetal netrin-1 and -4 levels may exert the dynamic balance between their angio- and anti-angiogenic properties.     

The relationship between serum visfatin,adiponectin, and insulin sensitivity markers in neonates after birth

Aim.?The aim of this study was to assess the adiponectin and visfatin concentrations in small-for-gestational age (SGA), appropriate-for-gestational age (AGA), and large-for-gestational age (LGA) newborns and their mothers. Sixty parturients giving birth to 20 term AGA singleton infants, 20 term singleton SGA infants, and 20 term singleton LGA infants were included into the study.

Results.?Mean visfatin levels were found significantly higher in the SGA (p?<?0.001) and LGA (p?<?0.001) groups, and adiponectin levels were found significantly lower in the SGA group (p?<?0.001) when compared with the AGA group. The SGA and LGA groups had higher insulin concentrations and HOMA-IR in comparison with the AGA group. The visfatin, glucose levels, and HOMA-IR (p?<?0.001, p?<?0.001, and p: 0.002, respectively) were higher in the LGA group than SGA group.

Conclusion.?We found significantly higher insulin and visfatin levels in LGA neonates and lower adiponectin levels in SGA neonates. We concluded that the relationship between adiponectin and visfatin and insulin sensitivity (metabolic disturbances) is very complex with little evidence of correlation in SGA and LGA neonates.     

Perinatal sclerostin concentrations in abnormal fetal growth: the impact of gestational diabetes

Objective: To prospectively evaluate maternal and cord blood concentrations of sclerostin – an osteocyte-secreted factor, inhibiting osteoblast differentiation and bone formation and associated with adverse metabolism – in pregnancies with normal and abnormal fetal growth.

Methods: Plasma sclerostin concentrations were determined by ELISA in 80 maternal and 80?cord blood samples from asymmetric intrauterine-growth-restricted (IUGR, n?=?30), large-for-gestational-age (LGA, n?=?30), and appropriate-for-gestational-age (AGA, n?=?20) singleton full-term pregnancies. Fourteen out of 30 mothers with LGA offspring presented with gestational diabetes mellitus (GDM).

Results: Maternal and fetal sclerostin concentrations did not differ among LGA, IUGR, and AGA groups. Fetal concentrations were higher than maternal. In LGA group, maternal concentrations were elevated in cases of GDM (b?=?13.009, 95%CI 1.425–24.593, p?=?.029). In a combined group and the IUGR group, maternal concentrations were elevated in older mothers (b?=?0.788, 95%CI 0.190–1.385, p?=?.010, and b?=?0.740, 95%CI 0.042–1.438, p?=?.039, respectively).

Conclusions: Maternal and fetal sclerostin concentrations may not be differentially regulated in pregnancies complicated by abnormal fetal growth. Circulating maternal levels are higher in cases of GDM, probably implying reduced bone formation. Sclerostin up-regulation with aging may be one of the molecular pathways responsible for the observed age-related decline in bone synthesis, leading to accelerated bone loss in humans.     

Adropin concentrations in term pregnancies with normal,restricted and increased fetal growth

Objective: To determine levels of adropin (implicated in insulin resistance and endothelial dysfunction) in intrauterine growth restricted (IUGR), large (LGA) and appropriate for gestational age (AGA) pregnancies.

Methods: Cord-blood (UC) adropin and insulin concentrations were measured in 30 IUGR, 30 LGA and 20 AGA full-term infants and their mothers (MS).

Results: No significant differences in adropin concentrations were observed between the three groups. In the IUGR group MS adropin was significantly decreased when neonates had higher birth weights [b?= ?0.003, 95% CI??0.006 to 0.0, p?=?0.043]. In all groups, MS adropin levels were positively correlated with UC ones (r?=?0.282, p?=?0.011) and were significantly increased in female neonates [b?=?0.977, 95% CI 0.122–1.832, p?=?0.026]. In the LGA group, MS insulin was negatively correlated with UC adropin (r?= ?0.362 p?=?0.049).

Conclusions: Increased maternal adropin levels in severe IUGR cases might represent a regulatory feedback mechanism against endothelial placental dysfunction. The positive correlation between maternal and umbilical cord adropin levels implies its transplacental transfer. Increased maternal adropin levels in female neonates could be attributed to interaction of adropin with fetal estrogens through vascular endothelial growth factor (VEGF). The negative correlation between maternal insulin and fetal adropin levels in the LGA group is probably attributed to their respective insulin resistance.     

Implication of the myokine irisin in maternal energy homeostasis in pregnancies with abnormal fetal growth

Objective: To prospectively investigate maternal concentrations of the myokine irisin in large for gestational age (LGA) and intrauterine growth restricted (IUGR) versus appropriate for gestational age (AGA) normal pregnancies and associate them with various perinatal parameters.

Methods: Plasma irisin and insulin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and immunoradiometric assay (IRMA), respectively, in a cohort of 80 mothers delivering LGA (n?=?30), IUGR (n?=?30) and AGA (n?=?20) singleton full-term infants.

Results: Maternal irisin concentrations were similar among LGA, IUGR and AGA groups and did not correlate with respective insulin ones or maternal body mass index. In a combined group, maternal irisin concentrations decreased with advancing gestational age (p?<?0.001) and were lower in multi-, compared to nulliparous women (p?=?0.004). In the IUGR group, maternal irisin concentrations were higher in cases of smoking (p?=?0.006).

Conclusions: Irisin may not be differentially regulated in insulin resistance-associated pregnancy disorders resulting in fetal macrosomia and IUGR. Maternal irisin down-regulation with advancing gestation could possibly contribute to the observed maternal fat accumulation and progressive insulin resistance towards term. Similarly, lower maternal irisin concentrations in multiparous women may reflect the documented positive association between parity and fat deposition. Irisin up-regulation in cases of smoking may indicate the need for enhanced oxygen consumption to maintain energy production under conditions of hypoxia.     

The association between birth weight at term and long-term endocrine morbidity of the offspring*

Objective: To investigate whether small-for-gestational-age (SGA) and large-for-gestational-age (LGA) birth weight at-term poses an increased risk for long-term pediatric endocrine morbidity.

Study design: A retrospective population-based cohort study compared the incidence of long-term pediatric hospitalizations due to endocrine morbidity of singleton children born SGA, appropriate-for-gestational-age (AGA), and LGA at-term. A multivariate generalized estimating equation (GEE) logistic regression model analysis was used to control for confounders.

Results: During the study period, 235,614 deliveries met the inclusion criteria; of which 4.7% were SGA (n?=?11,062), 91% were AGA (n?=?214,249), and 4.3% were LGA neonates (n?=?10,303). During the follow-up period, children born SGA or LGA at-term had a significantly higher rate of long-term endocrine morbidity. Using a multivariable GEE logistic regression model, controlling for confounders, being delivered SGA or LGA at-term was found to be an independent risk factor for long-term pediatric endocrine morbidity (Adjusted OR?=?1.4; 95%CI?=?1.1–1.8; p?=?.015 and aOR?=?1.4; 95%CI?=?1.1–1.8; p?=?.005, respectively). Specifically, LGA was found an independent risk factor for overweight and obesity (aOR?=?1.7; 95%CI?=?1.2–2.5; p?=?.001), while SGA was found an independent risk factor for childhood hypothyroidism (aOR?=?3.2; 95%CI?=?1.8–5.8; p?=?.001).

Conclusions: Birth weight either SGA or LGA at-term is an independent risk factor for long-term pediatric endocrine morbidity.     

Serum levels and ApaI polymorphism of insulin-like growth factor 2 on intrauterine growth restriction infants

Purpose: The aim of our study was to evaluate the IGF2 and IGF2R plasmatic level and IGF2-ApaI polymorphism on infants with intrauterine growth restriction (IUGR).

Materials and methods: A transversal study was conducted at the Neonatology Ward of the Gynecology Clinic I, Emergency Hospital Cluj-Napoca on neonates with IUGR who were discharged during June 2014 and June 2015. The serum levels of IGF2 and IGF2R were obtained by using ELISA method and IGF2-ApaI polymorphism by taking PCR-RFLP analysis.

Results: Forty infants with IUGR and 21 infants of appropriate gestational age (AGA) were evaluated. The serum levels of IGF2 proved higher on the A/G genotype when the IUGR group was compared with AGA (p value?=?.048). The G allele proved significantly more frequent in both the IUGR and the AGA group compared with the A allele (p?p value?>?.3). The A/G genotype proved significantly more frequent on term infants compared with preterm infants (p value?=?.039).

Conclusions: The infant with IUGR has a higher serum level of IGF2 if has A/G IGF2-ApaI genotype and higher values of IGF2R if it has the A/A genotype.     

Metabolomics technology and their application to the study of the viral infection

Abstract

Objective: In the present review article we have summarized the use of the metabolomics approach to study the metabolic modifications occurring in several bio-fluids due to viral infections. The aim is to highlight the ability of metabolomics to find early fingerprints, which are related to the infections.

Methods: The ¹H-NMR, UHPLC/MS/MS², UPLC/ESI-SYNAPT-HDMS, UPLC-Q-TOF-HDMS analyses were used for the determination of several metabolites representative of the viral infections. The data were analyzed by Principal Component Analysis (PCA), Partial Least Square Discriminant Analysis (PLS-DA) and by regression techniques.

Results: The major changes were related to nucleotide, carbohydrates, lipids and amino acid metabolisms.

Conclusions: The metabolomics approach could be considered a viable option for characterization of the viral infection and for detecting on going differences in the bio-fluids composition.     

Perinatal outcome of pregnancies complicated with extreme birth weights at term

Objective: The objective of this study is to investigate whether an abnormal birthweight at term, either small for gestational age (SGA,??95th centile for gestational age), is a risk factor for perinatal complications as compared with birthweight appropriate for gestational age (AGA).

Methods: A population-based retrospective cohort analysis of all singleton pregnancies delivered between 1991 and 2014 at Soroka Medical Center. Congenital malformations and multiple pregnancies were excluded. A multivariable generalized estimating equation regression model was used to control for maternal clusters and other confounders.

Results: During the study period, 228,242 births met the inclusion criteria, of them 91% were AGA (n?=?207,652), 4.7% SGA, and 4.3% LGA. SGA significantly increased the risk for perinatal mortality (aOR 5.6, 95%CI 4.5–6.8) and low 5-min Apgar scores (aOR 2.2, 95%CI 2.0–2.4), while LGA did not. SGA and LGA were both significant risk factors for cesarean delivery. LGA was significantly associated with shoulder dystocia and post-partum hemorrhage (aOR =13.6, 95%CI 10.9–17.0, and aOR 1.7, 95%CI 1.2–2.6, respectively).

Conclusions: Extreme birthweights at term are significantly associated with adverse maternal and neonatal outcomes. As opposed to SGA, LGA is not independently associated with perinatal mortality.     

Impact of transient period of metabolic adaptation on perinatal asphyxia in neonates with intrauterine growth retardation

Introduction: Temperature, glycemia and respiration make neonatal energy triangle (NET). In growth retardation (IUGR) neonates pathological metabolic adaptation exists in transient neonatal period.

Aim: The of this study was to examine the occurrence of pathological NET and check its impact on perinatal asphyxia during the transient period in IUGR neonates.

Material and methods: One hundred and fifty-nine neonates with IUGR were classified into – early preterm, late preterm and term neonates. By the presence of hypothermia, hypoglycemia and hypoxia in the first hour after birth neonates were classified into: group of pathological NET, group of unstable NET and group of stable NET. We analyzed distribution per body mass, gestational age, type of IUGR, gender and the frequency of perinatal asphyxia between the groups.

Results: The late preterm neonates were the most frequent in the group of pathological NET. Perinatal asphyxia was diagnosed in 52 (32.7%) neonates, with highest frequency in the group of pathological NET. Univariate binary logistic regression analysis showed that pathological NET in neonates with IUGR is significant predictor for perinatal asphyxia occurrence (OR?=?8.57; CI?=?4.05–18.12; p?R²?=?0.27).

Conclusion: Poor metabolic adaptation in neonates with IUGR in the first hour after birth is significant risk factor for the perinatal asphyxia.     

Assessment of bone health in preterm infants through quantitative ultrasound and biochemical markers

Abstract

Objective: To assess bone status in preterm infants with quantitative ultrasound and to search for biochemical markers of bone health.

Methods: Metacarpus bone transmission time (mcBTT) was prospectively performed during hospitalization, together with biochemical and clinical outcomes analysis.

Results: 154 patients were studied. At 3rd week of life mcBTT positively correlated with serum phosphate. Urinary excretion of calcium and phosphate were assessed in a subgroup of 55 patients: on day 21 mcBTT positively correlated with phosphaturia, negatively with calciuria. Gestational age (GA), weight and length at 3rd week and at 36 weeks of GA correlated positively with mcBTT. We found negative correlation between mcBTT at 3rd week and days of parenteral nutrition, mechanical ventilation period and days to reach 1800?g.

Conclusions: Serum phosphate, phosphaturia and calciuria correlate most with mcBTT. Further studies are necessary to verify the possible influence of early bone status on future bone health.     

Urinary metabolomics of pregnant women at term: a combined GC/MS and NMR approach

Abstract

Background: Physiological changes leading to parturition are not completely understood while clinical diagnosis of labour is still retrospective. Gas chromatography mass spectrometry (GC/MS) and nuclear magnetic resonance spectroscopy (NMR) represent two of the main analytical platforms used in clinical metabolomics. Metabolomics might help us to improve our knowledge about the biochemical mechanisms underlying labour.

Methods: Urine samples (n?=?59), collected from pregnant women at term of gestation before and/or after the onset of labour, were analysed by GC/MS and NMR techniques in order to identify the metabolic profile. Both GC/MS and NMR data matrices containing the identified metabolites were analysed by multivariate statistical techniques in order to characterise the discriminant variables between labour (L) and not labour (NL) status.

Results: 18 potential metabolites (11 with ¹H-NMR, eight with GC-MS: glycine was relevant in both) were found discriminant in urine of women during labour. Taken together, the identified metabolites produced a composite biomarker pattern, a sort of barcode, capable of differentiating between labour and not labour conditions. Major discriminant metabolites for NMR and GC/MS analysis were: alanine, glycine, acetone, 3-hydroxybutiyric acid, 2,3,4-trihydroxybutyric acid and succinic acid, giving a urine metabolite signature on the late phase of labour.

Conclusions: The metabolomics analysis evidenced clusters of metabolites involved in labour condition able to discriminate between urine samples collected before the onset and during labour, potentially offering the promise of a robust screening test.     

Assessment of interleukin-6, interleukin-8 and interleukin-18 count in the serum of IUGR newborns

Abstract

Aim: Aim of this study was to assess concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-18 (IL-18) in the serum of newborns with diagnosed intrauterine growth restriction (IUGR) in comparison to concentrations in serum of newborns with weight appropriate for gestational age (AGA).

Materials: Research was conducted at the Lodz Medical University Clinic of Neonatology during 2010–2011. Surveyed group consisted of 50 hypotrophic full-term infants of single pregnancies (average weight: 2329?±?287?g); control group, enclosing 50 infants AGA (average weight: 3544?±?2161?g). Both groups received average Apgar score of 9 points. Concentrations of analysed cytokines were marked between 4–6 hours after birth. The enzyme-linked immunosorbent assay (ELISA) test was used to determine interleukins concentrations. Study was prospective. Statistics on the data were conducted with the Kolmogorov–Smirnov test. Significance level: p?<?0.05.

Results: Concentrations of IL-6 and IL-18 were elevated in the IUGR group in a statistically significant manner in comparison to the control group.

Conclusions: An elevated level of IL-6 and IL-18 in the IUGR group, comparing to control group, signifies the existence of inflammation in the process of developing IUGR, therefore, screening tests estimating levels of interleukins as IL-6 and IL-18 might be clinically useful in predicting the occurrence of IUGR and help preventing it.     

Perinatal risk factors and mode of delivery associated with mortality in very low birth weight infants

Objective: To investigate the association of perinatal risk factors including delivery mode with mortality in very low birthweight (VLBW) in a tertiary hospital setting.

Methods: Medical records of 241 live-born VLBW infants (≤1500?g) were retrospectively reviewed. Details of maternal, obstetrical, perinatal risk factors and their associations with infant mortality were evaluated.

Results: The overall infant mortality rate was 23.2%. Mortality was significantly higher for infants born at ≤27 gestational weeks and with a birthweight of ≤750?g (p?=?0.000 and p?=?0.000, respectively), showing a steep decrease thereafter. On ROC analysis, a cut off of 26.5 weeks was determined for mortality with a sensitivity of 57.1% and a specificity of 90.3% (area under the curve?=?0.792, 95% CI: 0.719–0.866). On multivariate regression analysis, gestational week at birth, birthweight, antenatal steroid treatment and pathologic Doppler ultrasound findings were found as independent risk factors for mortality.

Conclusions: Gestational week at birth, birthweight and antenatal steroid treatment remain the most important perinatal risk factors for infant mortality in VLBW infants. Mode of delivery does not seem to be associated with mortality when adjusted for other perinatal risk factors.     

The influence of maternal disease on metabolites measured as part of newborn screening

Abstract

Objective: Measurements of neonatal metabolites are commonly used in newborn screening (NBS) programs to detect inborn errors of metabolism. Variation in these metabolites, particularly in infants born preterm (<37 weeks gestation), can result from multiple etiologies. We sought to evaluate the impact of maternal complications of pregnancy and environmental stressors on NBS metabolites.

Methods: We examined 49 metabolic biomarkers obtained from routine NBS in 452 infants born preterm for association with maternal environmental stressors and complications of pregnancy.

Results: Neonatal free carnitine (C0, p?=?1.4?×?10^?7), acetylcarnitine (C2, p?=?2.7?×?10^?7), octenoylcarnitine (C8:1, p?=?5.2?×?10^?11) and linoleoylcarnitine (C18:2, p?=?9.1?×?10^?7) were elevated in infants born to preeclamptic mothers. Similar elevations were observed in small for gestational age infants and in infants where labor was not initiated prior to delivery. When accounting for all three factors, associations remained strongest between acylcarnitines and preeclampsia.

Conclusion: We observed that maternal conditions, particularly preeclampsia, influence NBS biomarkers. This is important for identifying maternal conditions that influence metabolites measured during routine NBS that are also markers of fetal growth and overall health.     

Plasma amino acid concentrations throughout normal pregnancy and early stages of intrauterine growth restricted pregnancy

Objectives: Assessment of maternal plasma amino acids during normal gestation and in early stages of intrauterine growth restriction (IUGR).

Study design: Plasma amino acid concentrations were measured in: (1) non-pregnant women (n?=?7); (2) normal pregnant women in the first (n?=?13), second (n?=?17) and third (n?=?12) trimester; and (3) pregnant women in the first trimester with later development of IUGR (n?=?8). Amino acid levels were quantified by electrochemical detection in a reversed-phase high-performance liquid chromatography (HPLC) system.

Results: The levels of most essential and non-essential amino acids changed markedly in the first trimester during normal pregnancy and thereafter remained almost constant. In the first trimester of IUGR, a number of both essential and non-essential amino acids were significantly different from those observed in normal pregnancies, with values more similar to those observed in non-pregnant women.

Conclusions: Levels of most maternal amino acids decrease and some increase during early gestation reflecting a metabolic adaptation that occurs in normal pregnancies. Pregnancies that later develop IUGR show a lack of these adaptations for a significant number of both essential and non-essential amino acids, suggesting a lack of adaptation.