Lower levels of the neuroprotective tryptophan metabolite, kynurenic acid, in users of estrogen contraceptives.

Changes in kynurenine metabolites are reported in users of estrogen containing contraception. We have assessed kynurenines, vitamin B6, vitamin B2 and the inflammation markers, C-reactive protein (CRP) and neopterin, in healthy, never-pregnant women between 18 and 40 years (n = 123) and related this to their use of hormonal contraception. The population included 58 women, who did not use hormonal contraceptives (non-users), 51 users of estrogen-containing contraceptives (EC-users), and 14 users of progestin only contraceptives (PC-users). EC-users had significantly lower plasma kynurenic acid (KA) and higher xanthurenic acid (XA) levels compared to non-users. Serum CRP was significantly higher and negatively associated with both vitamin B6 and B2 status in EC-user compared to non-users. No significant differences in any parameters were seen between PC-users and non-users (p > 0.1). The low KA and high XA concentration in users of estrogen containing contraception resemble the biochemical profile observed in vitamin B6 deficiency. The hormonal effect may result from interference with the coenzyme function of vitamin B6 and B2 for particular enzymes in the kynurenine metabolism. KA has been suggested to be neuroprotective and the significantly reduced concentration in EC-users may be of importance in the observed increased risk of mood disorders among users of oral contraceptives.

A Vegetarian Diet Significantly Changes Plasma Kynurenine Concentrations.

Tryptophan is an essential amino acid and a precursor of a number of physiologically important metabolites, including serotonin, melatonin, tryptamine, and kynurenines. We assessed tryptophan, kynurenines, and vitamin B2 and B6, as well as biomarkers of liver function and inflammation, in a group of 158 female omnivores and vegetarians aged 18-40 years. The majority of women were omnivores, and 22% were vegetarians. Vegetarians had 25% lower serum ALT, significantly higher pyridoxal concentrations, and significantly lower plasma concentrations of most kynurenines, varying from 8% lower concentrations of median plasma kynurenine to 42% lower concentrations of plasma xanthurenic acid, compared to omnivores. No significant differences were observed in vitamin B2 status or in inflammation markers, C-reactive protein and neopterin between the groups. Vegetarians had lower levels of several plasma kynurenines compared to omnivores. The reason for this is unknown; however, lower ALT concentrations, suggesting a better liver status, and a more favourable vitamin B6 status might be contributing factors.

Assessment of vitamin B6 status in never-pregnant, pregnant and postpartum women and their infants.

PURPOSE: Pyridoxal 5´-phosphate (PLP) is the main form of vitamin B6 in humans and functions a coenzyme for more than 160 different enzymatic reactions. The purpose of the study was to find plasma PLP concentrations, which ensure an optimal vitamin B6 status determined by a metabolic marker, in never-pregnant, pregnant and lactating women and their infants. METHODS: In an observational, prospective study, plasma PLP and the metabolic marker, HKr (hydroxykynurenine/(kynurenic acid + anthranilic acid + xanthurenic acid + hydroxyanthranilic acid) were assessed in women (n = 114) from pregnancy week 18 to 6 months postpartum and related to infant status. Never-pregnant women 18-40 years (n = 127) were included as controls. RESULTS: Compared to controls, plasma PLP decreased during pregnancy and increased postpartum, while HKr increased from week 18 to 6 weeks postpartum, indicating maternal vitamin B6 insufficiency during this period. In never-pregnant women, HKr increased gradually with plasma PLP < 100 nmol/L, and in pregnancy week 28 a sharp increase in HKr was seen at plasma PLP < 30 nmol/L. Despite correcting for maternal vitamin B6 status, infant median plasma PLP decreased with months of exclusive breastfeeding. CONCLUSIONS: Plasma PLP and kynurenine concentrations differ substantially between never-pregnant, pregnant and postpartum women and infants. A plasma PLP concentration in the range of 50-100 nmol/L seems to ensure an optimal vitamin B6 status for never-pregnant women, whereas a plasma PLP > 30 nmol/L in pregnancy week 28 ensures an adequate vitamin B6 status during pregnancy and lactation. Infant vitamin B6 status at age 6 months is inversely correlated to number of months of exclusive breastfeeding.

Impaired gross motor development in infants with higher PFAS concentrations.

Industrial produced perfluoroalkyl substances (PFAS) are environmentally persistent and found in humans around the globe. PFAS is transferred from mother to child during pregnancy and lactation and PFAS concentrations are high in infants. PFAS exposure in early life has been linked to a range of negative health effects. In the present study we have investigated PFAS concentrations in mothers (pregnancy week 18, 28 and 36 and six weeks, four and six months postpartum, n = 114) and in infants at six months age (n = 94), and studied the effects of PFAS status on infant gross motor development by Alberta Infant Motor Scale (AIMS) at age six months. PFAS concentrations declined in the mothers during pregnancy and postpartum period, and the highest concentrations were seen in infants aged six months. Parity was a strong negative predictor and fish intake a strong positive predictor of maternal PFAS status, while maternal concentrations of PFAS in pregnancy week 18 and months of exclusive breastfeeding determined the PFAS concentrations in infants at six months. Infants who scored below the median on gross motor development had higher PFAS concentrations than infants with a better gross motor development. Ninety percent of the women reported having fish for dinner at least once a week, with fatty fish as the most popular choice (72%). A higher maternal fish intake in pregnancy week 18 was associated with a poorer gross motor development in the infants at six months. Infant gross motor development is a marker of later cognitive outcome and our findings indicate that higher PFAS concentrations in young infants and maternal fatty fish intake may impair neurodevelopment.

Quantitation of linear and branched perfluoroalkane sulfonic acids (PFSAs) in women and infants during pregnancy and lactation.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are associated with negative health effects, and exposure during fetal life and infancy are of concern. A subgroup of PFAS, linear and branched perfluoroalkane sulfonic acids (PFSA), have significant differences in biochemical reactions, bioaccumulation and potential toxic exposure effects, and data on transfer of PFSA isomers from mother to baby through placenta or in breastmilk are scarce. OBJECTIVES: The objective was to investigate differences in branched and linear PFSA isomers in never-pregnant, pregnant and postpartum women and infants. METHODS: Serum concentrations of branched and linear, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS) and perfluorooctane sulfonate (PFOS) were measured in never-pregnant women (n = 158), pregnant and postpartum women (n = 114) and their infants (n = 94) at age six months. RESULTS: There was a linear relation between maternal PFSA concentrations in pregnancy week 18 and the infant at age six months. The PFSA concentrations in maternal and infant serum varied with a factor up to 20. The maternal branched/ linear PFHxS ratio increased in the latter part of pregnancy (+45%) and remained high postpartum, and was substantially lower in the infants. Branched/linear PFHpS ratio increased during pregnancy and was highest in the infants, while the branched/linear PFOS ratio decreased in the mothers and was high in the infants. DISCUSSION: The linear relations between PFSA concentrations in infants aged six months and mothers in pregnancy week 18 confirm that pregnancy and lactation are major excretion routes for PFSA, but accumulate in the infant. The observed great variability in PFSA burden among mothers and infants, as well as the reduced maternal transfer of branched PFHxS isoforms and increased transfer of branched PFOS isoforms compared to the respective linear isoforms to the infant, might impact adverse health effects associated with PFSA exposure, but this should be confirmed in future studies.

Perfluoroalkyl substances (PFASs) and mercury in never-pregnant women of fertile age: association with fish consumption and unfavorable lipid profile.

OBJECTIVES: To examine concentrations of perfluoroalkyl substances (PFASs) and lifestyle factors that may contribute to higher levels of pollutants in never-pregnant women of fertile age. DESIGN: Observational cross-sectional study. SETTING: Participants were recruited among employees and students at Haukeland University Hospital and the University of Bergen, Norway. PARTICIPANTS: Healthy, never-pregnant Norwegian women (n=158) of fertile age (18-39 years). OUTCOMES: Concentrations of 20 different PFASs, mercury (Hg), lead, cadmium, total, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol, in addition to self-reported data on dietary intake. RESULTS: Seven PFASs were detected in more than 95% of the women. Women aged 30-39 years had higher concentrations of sum PFAS compared with younger women. Serum PFASs were significantly intercorrelated (rho: 0.34-0.98, p<0.001) and six of them were significantly correlated to whole blood Hg (rho: 0.21-0.74, p<0.01). Fish consumption was the strongest predictor for most serum PFASs and for whole blood Hg. Fish consumption and serum perfluorooctanesulfonic acid (PFOS) concentrations were both positively associated with serum total and LDL cholesterol, established risk factors for cardiovascular disease. CONCLUSIONS: The majority of Norwegian never-pregnant women of fertile age had a mixture of seven different PFASs and Hg detected in their blood. PFAS concentrations were higher in older women and associated with fish intake. As the mean age of women at first birth is increasing, several factors require further consideration including diet, as this may influence the burden of PFAS to the next generation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: NCT03272022, Unique Protocol ID: 2011/2447, Regional Committee for Medical Research Ethics West (2011/2447), 12 January 2012.

Plasma Homoarginine Concentrations According to Use of Hormonal Contraception.

Estrogen is a potent vasodilator through activation of endothelial nitric oxide synthase (eNOS). Arginine and its homologue homoarginine are substrates for NOS, while asymmetric dimethylarginine (ADMA) is a NOS inhibitor. Healthy, never-pregnant women aged 18 to 40 years (n = 158) were categorized according to use of hormonal contraception into non-users (n = 76), users of estrogen contraceptives (EC-users, n = 58) and users of progestins-only contraceptives (PC-users, n = 24). Plasma homoarginine, arginine, ADMA and SDMA concentrations were assayed using a LC-MS/MS method. Compared to non-users, EC users had higher plasma homoarginine (median (interquartile range) 1.63 (1.24, 2.04) vs. 2.39 (2.05, 2.85) µmol/L, p < 0.001), lower arginine (80.8 (72.4, 94.3) vs. 72.1 (62.9, 85.1) µmol/L, p = 0.008) and ADMA (0.52 (0.46, 0.59) vs. 0.48 (0.42, 0.54) µmol/L, p = 0.003) concentrations. The lowest median plasma homoarginine concentration (1.34 (0.92, 1.75) µmol) was seen in PC-users. No differences were seen in SDMA concentrations according to use of hormonal contraception. In healthy, never-pregnant women aged 18 to 40 years, use of estrogen containing contraception was associated with significantly higher plasma concentrations of homoarginine and lower plasma concentrations of arginine and ADMA as compared to non-users, while the lowest plasma homoarginine concentrations were seen in progestin-only users. Whether the observed changes in relation to use of hormonal contraception have an impact on cardiovascular status, should be evaluated in an intervention study.

Maternal Serum Cobalamin at 18 Weeks of Pregnancy Predicts Infant Cobalamin Status at 6 Months-A Prospective, Observational Study.

Background: An adequate maternal cobalamin status is crucial for fetal and infant neurodevelopment. Pregnancy-induced physiologic changes make evaluation of maternal cobalamin status in pregnancy difficult. Objective: We have investigated maternal cobalamin status during pregnancy in order to establish a maternal cobalamin concentration which secures an optimal infant cobalamin status during the first 6 mo of life. Methods: In an observational, prospective study, markers of cobalamin status including serum cobalamin, plasma total homocysteine (tHcy), and plasma methylmalonic acid (MMA) were assessed in healthy pregnant women (n = 114) from week 18 of pregnancy through 6 mo postpartum and related to infant cobalamin status at 6 mo. Healthy, never-pregnant women aged 18-40 y (n = 123) were included as controls. Results: Compared to controls, all markers of cobalamin status were lower in pregnant women. Median serum cobalamin concentration progressively decreased from week 18 to week 36 of pregnancy (356 to 302 pmol/L, P < 0.001) and increased by >40% by 6 wk postpartum (518 pmol/L). The metabolic markers increased from week 18 of pregnancy to 6 wk postpartum: median plasma tHcy 3.9 to 7.7 µmol/L (P < 0.001), and MMA 0.13 to 0.17 µmol/L (P < 0.001). The serum cobalamin concentration of infants at age 6 mo correlated with maternal serum cobalamin concentration during pregnancy and postpartum (rho = 0.36-0.55, P < 0.001). A maternal serum cobalamin concentration <394 pmol/L during week 18 of pregnancy was associated with an increased risk (OR: 4.2; 95% CI: 1.5, 11.5) of infant biochemical cobalamin deficiency at 6 mo (defined as tHcy ≥6.5 µmol/L). Conclusions: The maternal serum cobalamin concentration in early pregnancy is a strong predictor for later maternal and infant cobalamin status. To secure an optimal infant cobalamin status during the first 6 mo of life, we recommend a maternal serum cobalamin concentration >394 pmol/L at week 18 of pregnancy. This should be confirmed in an intervention study. This trial was registered at clinicaltrials.gov as NCT03272022.

Predictors of mercury, lead, cadmium and antimony status in Norwegian never-pregnant women of fertile age.

BACKGROUND: The toxic trace elements mercury (Hg), lead (Pb), cadmium (Cd) and antimony (Sb) are transferred over the placenta to the fetus and secreted into the breastmilk. All four elements bioaccumulate in the body and as maternal age at delivery is increasing in industrialized countries, the burden of toxic trace elements in never-pregnant women of fertile age is of concern. METHODS: Healthy, never-pregnant women aged 18 to 40 years (n = 158) were recruited between June 2012 and March 2015 in Bergen, Norway. Clinical data were collected and non-fasting venous blood samples were analyzed for whole blood Hg, Pb and Cd and serum Sb by ICP-MS and related to diet and life style factors. RESULTS: In a multiple linear regression model, increasing age was associated with higher levels of Hg and Sb, but diet and life style factors were more important predictors. Median whole blood Hg was increased by a factor of 70 in women who had fish for dinner ≥1/week, compared to women who rarely or never ate fish (p<0.001). Alcohol intake was the strongest predictor for whole blood Pb, while use of tobacco was the strongest predictor for whole blood Cd. Being a vegetarian was associated with lower levels of both Hg and Sb. CONCLUSIONS: As toxic trace elements tend to bioaccumulate in the body, increasing maternal age at delivery may represent a threat to the next generation. In a group of healthy Norwegian never-pregnant women, age contributed to Hg and Sb levels, but diet and life style factors were stronger determinants of whole blood Hg, Pb, Cd and serum Sb levels. Continuous public actions are needed to reduce modifiable and preventable sources of potentially deleterious toxins to minimize the exposure in children and fertile women.

Impact of Maternal Selenium Status on Infant Outcome during the First 6 Months of Life.

Pregnant women and infants are at risk for selenium deficiency, which is known to have negative effects on immune and brain function. We have investigated selenium levels in 158 healthy never-pregnant women and in 114 pregnant and lactating women and their infants at age 6 months and related this to clinical outcomes during the first 6 months of life. Neurodevelopment was assessed with the parental questionnaire Ages and Stages (ASQ) at 6 months. A maternal selenium level ≤0.90 µmol/L in pregnancy week 18 was negatively related to infant neurodevelopment at 6 months (B = -20, p = 0.01), whereas a selenium level ≤0.78 µmol/L in pregnancy week 36 was associated with an increased risk (odds ratio 4.8) of having an infant infection during the first 6 weeks of life. A low maternal selenium status in pregnancy was found to be associated with an increased risk of infant infection during the first 6 weeks of life and a lower psychomotor score at 6 months. We suggest a cutoff for maternal serum selenium deficiency of 0.90 µmol/L in pregnancy week 18 and 0.78 µmol/L in pregnancy week 36. This should be reevaluated in an intervention study.

The Accu-Chek Mobile blood glucose monitoring system used under controlled conditions meets ISO 15197 standards in the hands of diabetes patients.

BACKGROUND: Self-monitoring of blood glucose is a cornerstone of diabetes management. The aim of this study was to evaluate the analytical quality and the ease of use of the Accu-Chek Mobile, a new glucose monitoring system designed for capillary blood testing by diabetic patients. MATERIALS AND METHODS: The performance of the Accu-Chek Mobile was evaluated both in the hands of a scientist and of diabetes patients. The designated comparative method was a hexokinase-based laboratory method (Architect ci8200). Diabetics (N = 88) with previous experience of self-testing were recruited for the study. Patient samples, containing glucose in concentrations mainly between ˜4 and ˜20 mmol/L, were analyzed in duplicates both on the Accu-Chek Mobile and with the comparative method. The patients answered a questionnaire about the ease of use of the meter. RESULTS: The meter yields reproducible readings, with an imprecision CV <5% as required by the American Diabetes Association (ADA). Of the glucose concentrations obtained by both the scientist and the patients, more than 95% of the individual results were within ± 20% of the comparative method, meeting the ISO 15197 accuracy goal, but not the stricter ± 10% ADA goal. CONCLUSION: Accu-Chek Mobile is a user-friendly glucometer that in a normo- and hyperglycemic range fulfils the ISO 15197 accuracy requirement, also in the hands of diabetes patients.