Associations of maternal bisphenol urine concentrations during pregnancy with neonatal metabolomic profiles.

BACKGROUND: Fetal exposure to bisphenols is associated with altered fetal growth, adverse birth outcomes and childhood cardio-metabolic risk factors. Metabolomics may serve as a tool to identify the mechanisms underlying these associations. We examined the associations of maternal bisphenol urinary concentrations in pregnancy with neonatal metabolite profiles from cord blood. METHODS: In a population-based prospective cohort study among 225 mother-child pairs, maternal urinary bisphenol A, S and F concentrations in first, second and third trimester were measured. LC-MS/MS was used to determine neonatal concentrations of amino acids, non-esterified fatty acids (NEFA), phospholipids (PL), and carnitines in cord blood. RESULTS: No associations of maternal total bisphenol concentrations with neonatal metabolite profiles were present. Higher maternal average BPA concentrations were associated with higher neonatal mono-unsaturated alkyl-lysophosphatidylcholine concentrations, whereas higher maternal average BPS was associated with lower neonatal overall and saturated alkyl-lysophosphatidylcholine (p-values < 0.05).Trimester-specific analyses showed that higher maternal BPA, BPS and BPF were associated with alterations in neonatal NEFA, diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholine, sphingomyelines and acyl-carnitines, with the strongest effects for third trimester maternal bisphenol and neonatal diacyl-phosphatidylcholine, sphingomyeline and acyl-carnitine metabolites (p-values < 0.05). Associations were not explained by maternal socio-demographic and lifestyle characteristics or birth characteristics. DISCUSSION: Higher maternal bisphenol A, F and S concentrations in pregnancy are associated with alterations in neonatal metabolite profile, mainly in NEFA, PL and carnitines concentrations. These findings provide novel insight into potential mechanisms underlying associations of maternal bisphenol exposure during pregnancy with adverse offspring outcomes but need to be replicated among larger, diverse populations.

How short is too short? A randomised controlled trial evaluating short-term existential behavioural therapy for informal caregivers of palliative patients.

BACKGROUND: Informal caregivers of palliative patients show higher levels of depression and distress compared with the general population. Fegg's (2013) existential behavioural therapy was shortened to two individual 1-h sessions (short-term existential behavioural therapy). AIM: Testing the effectiveness of sEBT on psychological symptoms of informal caregivers in comparison with active control. DESIGN: Randomised controlled trial. SETTING/PARTICIPANTS: Informal caregivers of palliative in-patients. METHODS: The primary outcome was depression; secondary outcomes were anxiety, subjective distress and minor mental disorders, positive and negative affect, satisfaction with life, quality of life and direct health care costs. General linear mixed models allow several measurements per participant and change over time. Reasons for declining the intervention were investigated by Rosenstock's Health Belief Model. RESULTS: Overall inclusion rate was 41.0%. Data of 157 caregivers were available (63.1% females; mean age: 54.6 years, standard deviation (SD): 14.1); 127 participants were included in the main analysis. Participation in sEBT or active control was not significantly associated with post-treatment depression. Outcomes showed prevailingly significant association with time of investigation. Self-efficacy, scepticism of benefit of the intervention, belief of better coping alone and support by family and friends were significant factors in declining participation in the randomised controlled trial. CONCLUSION: Inclusion rate was tripled compared with a previously evaluated longer EBT group intervention. By shortening the intervention, inclusion rate was traded for effectiveness and the intervention could not impact caregivers' psychological state. Early integration of sEBT and combination of individual and group setting and further study of the optimal length for caregiver interventions are suggested.

Investigation of the impact of birth by cesarean section on fetal and maternal metabolism.

PURPOSE: Elective cesarean section (CS) was related to long-term adverse health effects in the offspring, but little is known about underlying mechanisms. Our study investigates the metabolic changes in both maternal and cord blood associated with CS in comparison to vaginal delivery (VD) to explore potential causal pathways. METHODS: Samples obtained from PREOBE study participants were subjected to LC-MS/MS-targeted metabolomics comprising > 200 metabolites. RESULTS: Elective CS showed an impact on both maternal and cord blood metabolomes. In maternal blood, the CS group showed lower levels of phospholipids (PL), principally ether-linked phosphatidylcholines (aaPC), pyruvic acid, branched chain keto-acids (BCKA), and other gluconeogenic substrates, but since the CS group showed different HDL levels in comparison to the VD group, we could not exclude contribution of the latter in the findings. In cord blood, the most remarkable finding in the CS group was the high levels of Cys; conversely, the lower levels of non-esterified fatty acids (NEFA), some tricarboxylic acid (TCA) cycle metabolites, gluconeogenic substrates, markers of ß-oxidation, and the sum of hexoses were lower in CS-born babies in addition to tendentially lower levels of PL. CONCLUSIONS: We speculate that lower levels of maternal and fetal corticosteroids in CS, due to less stressful condition, cause metabolic perturbations at birth initiating future negative health outcomes. This further supports the early programming hypothesis.

Early Programming of Obesity Throughout the Life Course: A Metabolomics Perspective.

BACKGROUND: Over the last decades, research on early life risk factors for obesity and its comorbidities in early life has gained attention within the field of developmental origins of health and diseases. Metabolomics studies that are trying to find early life biomarker and intervention targets for the early development of obesity and associated cardiovascular diseases could help break the inter-generational cycle of obesity. SUMMARY: Metabolomics studies in the field of early programming are scarce and causality is lacking at this stage, as most of the studies are cross-sectional. The main metabolites in the focus of obesity are branched-chain and aromatic amino acids, long-chain polyunsaturated fatty acids, lysophosphatidylcholines, and sphingomyelins. Sex and puberty have not been considered in most of the biomarker studies, but show differences in the metabolite associations to obesity. Key Messages: There is still a lot unknown about the associations between early programming exposures, metabolite concentrations, and the development of obesity. The few studies focusing on this topic find similar metabolite classes in the same age groups being associated with rapid early growth or obesity; but due to differences in the methodological and statistical approaches, the single species often differ. Therefore, more research, preferably with standardized approaches, is needed.

Maternal Body Mass Index, Early-Pregnancy Metabolite Profile, and Birthweight.

CONTEXT: Maternal prepregnancy body mass index (BMI) has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown. OBJECTIVE: First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations. DESIGN, SETTING, AND PARTICIPANTS: Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study. MAIN OUTCOME MEASURES: Maternal nonfasting targeted amino acids, nonesterified fatty acid, phospholipid, and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight was obtained from medical records. RESULTS: A higher prepregnancy BMI was associated with 72 altered amino acids, nonesterified fatty acid, phospholipid and carnitine concentrations, and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress, and lipid metabolic processes (P-values < 0.05). Using penalized regression models, a metabolite profile was selected including 15 metabolites and 4 metabolite ratios based on its association with birthweight in addition to prepregnancy BMI. The adjusted R2 of birthweight was 6.1% for prepregnancy BMI alone, 6.2% after addition of glucose and lipid concentrations, and 12.9% after addition of the metabolite profile. CONCLUSIONS: A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, nonesterified fatty acids, phospholipids, and carnitines. Using these metabolites, we identified a maternal metabolite profile that improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.

Associations of maternal and fetal SCD-1 markers with infant anthropometry and maternal diet: Findings from the ROLO study.

BACKGROUND: Elevated stearoyl-CoA desaturase 1 (SCD-1) activity showed associations with obesity in cross-sectional studies. In non-pregnant populations, nutrition regulates SCD-1 transcription and activity. OBJECTIVE: To investigate the longitudinal associations of maternal and fetal SCD-1 activity markers with infant anthropometry up to 2 years of age, and to explore how selected dietary intakes modulate SCD-1 activity in pregnancy. METHODS: As a secondary analysis from the ROLO intervention study, which was conducted in a population at risk for macrosomia, non-esterified fatty acids (NEFA) from maternal plasma at 13 and 28 weeks' gestation and in cord blood were measured via liquid-chromatography-mass-spectrometry. Fatty acid ratios 18:1/18:0 and 16:1/16:0 were used as markers for SCD-1 activity ('desaturation indices', DIs). Relationships of DIs with infant anthropometry up to 2 years of age and maternal dietary parameters during pregnancy were investigated using adjusted linear regression models and p-values correction for multiple testing. RESULTS: 18:1/18:0, but not 16:1/16:0, was associated with measures of infant anthropometry at birth (maternal and fetal markers) and up to 2 years of age (maternal markers only). Dietary intakes did not show strong associations with 18:1/18:0, but 16:1/16:0 was associated with absolute and relative dietary intakes. CONCLUSIONS: In a population at risk for macrosomia, maternal SCD-1 activity measured via 18:1/18:0 was involved in the fetal programming of infant obesity, but could not be substantially modulated by short-term diet in pregnancy. CLINICAL TRIAL REGISTRATION: ISRCTN Registration number: ISRCTN54392969 (http://www.isrctn.com/ISRCTN54392969).

Effect of a low glycaemic index diet during pregnancy on maternal and cord blood metabolomic profiles: results from the ROLO randomized controlled trial.

BACKGROUND: Elevated post-prandial blood glucose during pregnancy has been associated with adverse pregnancy and offspring outcomes, such as maternal gestational diabetes and excessive foetal growth. The ROLO Study is a randomized controlled trial (RCT) investigating the effect of a low glycaemic index (GI) diet in pregnancy to prevent foetal macrosomia (birth weight > 4000 g). We described the impact of a low-GI diet on the maternal and feto-placental unit metabolism by studying how the ROLO intervention affected maternal and cord blood metabolomes. METHODS: Fasting maternal plasma samples pre- and post-intervention of 51 pregnant women and 132 cord blood samples were measured with a targeted metabolomics approach using liquid-chromatography coupled to tandem mass spectrometry. The differences between RCT groups were explored via multivariate models with covariates correction. Significance was set at Bonferroni-corrected level of 0.05. RESULTS: A total of 262 metabolites species, sums and ratios were investigated. While no metabolite reached statistical significance after Bonferroni correction, many maternal phospholipids and acylcarnitines were elevated in the intervention group at uncorrected 0.05 alpha level. Most species contained saturated and monounsaturated fatty acid chains with 16 or 18 carbon atoms. In cord blood, no differences were identified between RCT groups. CONCLUSIONS: A low-GI diet in pregnancy was associated with a trend to modest but consistent changes in maternal lipid and fatty acid metabolism. The intervention seemed not to affect foetal metabolism. Our exploratory findings may be used to direct further investigations about low GI diets before and during pregnancy, to improve patient care for pre-conceptional and pregnant women with lipid dysregulations and potentially modulate the offspring's risk for future metabolic diseases. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54392969.

Caesarean section, but not induction of labour, is associated with major changes in cord blood metabolome.

The physiology of how prelabour caesarean section (PCS) and induction of labour (IOL) in comparison to spontaneous vaginal delivery (SVD) has not been fully clarified yet. We measured 201 cord blood (CB) phospholipids and energy metabolites via LC/MS-MS in 109 newborns from the ROLO Kids study; metabolites were compared across the three parturition groups via linear mixed models with correction for multiple testing. In comparison to SVD, PCS babies had lower non-esterified fatty acids (NEFA), including sum of NEFA (p < 0.001), and trends for lower acylcarnitines. The lack of hormonal stimuli, especially catecholamines and cortisol, may underlie the metabolic changes involving gluconeogenesis from fatty acid oxidation (FAO) in PCS born infants. IOL and SVD infants showed no significant differences in metabolites, but ratios estimating carnitine palmitoyltrasferase 1 activity (precursor for FAO) were slightly higher in IOL than in SVD. Thus, IOL does not induce metabolic disadvantage when compared to SVD, though post-natal gluconeogenesis might start earlier due to the artificial solicitation in IOL. These data shed light on the physiology of parturition and may contribute to understand how mode of delivery might modulate future metabolic risks.

Transgenerational cycle of obesity and diabetes: investigating possible metabolic precursors in cord blood from the PREOBE study.

AIMS: Offspring of mothers suffering from obesity and/or gestational diabetes mellitus (GDM) were reported to be at risk of higher birth weight (BW), later obesity and diabetes. We hypothesize that infant anthropometry changes related to maternal pathological status are due to dysregulated infant metabolism. METHODS: First, we inspected differences in BMI z-scores (z-BMI) between three infant groups: born to normal weight (NW; n = 49), overweight/obese (OV/OB; n = 40) and GDM mothers (n = 27) at birth and 1 year. Then, we inspected associations between cord blood metabolites and 1-year Δ z-BMI in the three infant groups at birth and 1 year. RESULTS: No statistically significant difference was detected in z-BMI between the study groups at birth; however, GDM was associated with heavier infants at 1 year. Regarding the associations between the metabolites and z-BMI, phospholipids, especially those containing polyunsaturated fatty acids, were the species most impacted by the maternal metabolic status, since numerous phosphatidylcholines-PUFA were positively associated with z-BMI in NW but negatively in OV/OB and GDM groups at birth. Conversely, the sum of lysophosphatidylcholines was only positively associated with z-BMI in NW at birth but of no relation in the other two groups. At 1 year, most of the associations seen at birth were reversed in NW and lost in OV/OB and GDM groups. In the NW group, PC-PUFA were found to be negatively associated with Δ z-BMI at 1 year in addition to some medium-chain acylcarnitines, tricarboxylic acid metabolites, Asp and Asn-to-Asp ratio. In OV/OB and GDM groups, the non-esterified fatty acid (NEFA26:0) and His correlated with Δ z-BMI at 1 year in negative and positive directions, respectively. CONCLUSIONS: GDM was associated with overweight in offspring at 1 year, independent of the BW with lack of evidence on existing correlation of this finding with metabolic alterations detected in cord blood metabolome. Associations were found between cord blood metabolites and infant anthropometry at birth and were influenced by maternal OB and GDM. However, an extension of the findings monitored at birth among the three groups was not detected longitudinally showing a lack of predictive power of cord blood metabolome for later development at least 1 year.

Impact of maternal BMI and gestational diabetes mellitus on maternal and cord blood metabolome: results from the PREOBE cohort study.

AIMS: Maternal obesity and gestational diabetes mellitus (GDM) were frequently reported to be risk factors for obesity and diabetes in offspring. Our goal was to study the impact of maternal prepregnancy BMI (pBMI) and GDM on both maternal and cord blood metabolic profiles. METHODS: We used LC-MS/MS to measure 201 metabolites comprising phospholipids (PL), amino acids, non-esterified fatty acids (NEFA), organic acids, acyl carnitines (AC), and Krebs cycle metabolites in maternal plasma at delivery and cord plasma obtained from 325 PREOBE study participants. RESULTS: Several metabolites were associated with pBMI/GDM in both maternal and cord blood (p < 0.05), while others were specific to either blood sources. BMI was positively associated with leucine, isoleucine, and inflammation markers in both mother and offspring, while ß-hydroxybutyric acid was positively associated only in cord blood. GDM showed elevated levels of sum of hexoses, a characteristic finding in both maternal and cord blood. Uniquely in cord blood of offspring born to GDM mothers, free carnitine was significantly lower with the same tendency observed for AC, long-chain NEFA, PL, specific Krebs cycle metabolites, and ß-oxidation markers. CONCLUSIONS: Maternal BMI and GDM are associated with maternal and cord blood metabolites supporting the hypothesis of transgenerational cycle of obesity and diabetes.