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.

Dietary behaviors and attitudes among Norwegian medical students.

BACKGROUND: Dietary patterns and beliefs are influenced by socioeconomic status, cultural influences, as well as medical advice, social media and marketing. Medical doctors are expected to provide correct, updated and non-biased nutritional advice to their patients, but their own dietary behaviors and attitudes may influence nutritional counselling. METHODS: We have investigated dietary habits and food attitudes among medical students by using an anonymous survey distributed to all students at the Medical Faculty, University of Bergen, Norway. The survey included a 36-item questionnaire covering information about demographics, former and current diet, use of nutritional supplements, tobacco and alcohol, in addition to food attitudes and nutritional knowledge. Descriptive statistics were calculated for each survey item. RESULTS: Of the 880 students, 394 responded to the survey. Although 90% of the students were omnivores, the majority had a negative attitude towards meat, and considered fish to be healthier than meat. Significantly more women than men reported use of a special diet and excluded meat from their diet, even if they were omnivores. The most frequently used supplement was cod liver oil or omega 3 fatty acids. CONCLUSION: The medical students' diet and food attitudes not only reflect current health recommendations, but also popular beliefs and marketing in Norway. Curriculum planners should make the students capable of recognizing the influence of social media, marketing and medicine-food industry interactions, to ensure relevant nutrition knowledge for future doctors.

Folate - a scoping review for Nordic Nutrition Recommendations 2023.

Folate is an essential micronutrient for normal development and metabolic function, and folate deficiency is associated with an increased risk of cancer, cardiovascular disease, mental dysfuntion and negative pregnancy outcomes. When estimating folate requirements, one must consider different bioavailability and functionality between synthetic folic acid and dietary folate, together with increased needs of folate in women of fertile age, pregnant and lactating women, preterm and small for gestational age weight infants and individuals who are homozygote for the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism. In order to achieve an adequate metabolic status based on the metabolic marker total homocysteine, and not merely the absence of clinical signs of folate deficiency, the recommended intake of folate differs according to age, pregnancy and lactation. According to the World Health Organization, a decision limit for folate deficiency in adults is serum folate level below 10 nmol/L, and in women of fertile age a red blood cell folate level below 906 nmol/L in order to prevent neural tube defects. Qualified systematic reviews along with identified relevant literature have been used for this scoping review prepared for the Nordic Nutrition Recommendations 2023.

A novel case of impaired C-reactive protein response following open-heart surgery: A case report and review of the literature.

BACKGROUND: C-reactive protein (CRP) is expected to increase in response to a range of inflammatory stimuli such as infections or extensive tissue trauma. CASE REPORT: We present a novel case of severely impaired CRP response following NSTEMI, influenza A infection and open-heart surgery in which serum CRP concentrations remained < 1 mg/L during an observational period of 28 days. CONCLUSION: To our knowledge, no previous publications exists describing patients with a lack of CRP response following cardiothoracic surgery. We believe this to be a novel finding warranting further investigations regarding the etiology and prevalence of this phenomenon.

Low serum sodium concentrations in patients with obesity normalizes with weight loss.

BACKGROUND & AIMS: Obesity is associated with higher extracellular fluid (ECF) compared to intracellular fluid (ICF) volume and this dysregulation is associated with hypertension and abdominal obesity, associated with metabolic syndrome. As sodium is predominantly an extracellular cation, a higher ECF/ICF ratio will lower serum sodium concentration. The aim of the study was to see whether weight loss, due to dieting and bariatric surgery, had any impact on serum sodium concentrations in patients with severe obesity. METHODS: Patients with a BMI ≥35 kg/m2 admitted for bariatric surgery at Innlandet Hospital Trust, Norway during 2012-14 were included in the study (n = 119). Clinical data and blood samples were recorded at inclusion, after mean six months of dieting, as well as six and 12 months after bariatric surgery. RESULTS: At inclusion, mean serum sodium was in the lower normal range, 138.3 (SD 2.4) mmol/L, but increased to 141.8 (SD 1.9) mmol/L after weight loss. The increase was significantly correlated to total weight loss (rho: 0.29, p = 0.007). Twelve months after surgery, serum sodium was significantly higher in patients with a normal BMI (<25 kg/m2) compared to patients with overweight. CONCLUSION: Obesity and hypertension are associated with body fluid dysregulation affecting serum sodium concentrations. As mild hyponatremia, even within the normal sodium range, is associated with increased total mortality and major cardiovascular disease events, serum sodium might be a potential risk marker in patients with obesity.

Essential trace elements in Norwegian obese patients before and 12 months after Roux-en-Y gastric bypass surgery: Copper, manganese, selenium and zinc.

OBJECTIVES: The objective of the present study was to assess trace element status in morbidly obese subjects before and one year after Roux-en-Y gastric bypass (RYGB) in order to identify possible deficiencies. METHODS: The study population included 46 patients in the age range 27-59 years, the majority (85 %) were women. The enrolled patients attended an eight week course on lifestyle changes before bariatric surgery. After RYGB they were recommended daily micronutrient supplements with a commonly used multivitamin-mineral tablet in addition to intramuscular vitamin B12 injections (1 mg) every third month for 12 months. Whole blood concentrations of Cu, Mn, Se and Zn were determined using high resolution inductively coupled plasma mass spectrometry. RESULTS: During the 12 months follow up after bariatric surgery, the patients had lost mean 32.3 kg and median whole blood concentrations of Cu (-16 %) were reduced, Mn (+14 %) and Zn (+6%) were increased, while the Se values were essentially unchanged. Compared with reference ranges, median postoperative concentrations of all essential trace elements were either below (Zn) or in the lower reference range (Cu, Mn, Se). CONCLUSION: Essential trace elements were below or in the lower reference range twelve months after RYGB. Our results indicate a need for updated guidelines in Nordic countries for trace metal monitoring and supplements in patients after bariatric surgery, especially when gastric bypass surgery is used. Further studies are required to explore and prevent trace element deficiency related to obesity and bariatric surgery.

Cadmium, lead and mercury in Norwegian obese patients before and 12 months after bariatric surgery.

PURPOSE: Previous studies have suggested a role for the toxic elements lead (Pb), mercury (Hg) and cadmium (Cd) in the development of insulin resistance and hypertension. Increased blood Pb levels have been reported after bariatric surgery and weight loss. As about 80% of patients undergoing bariatric surgery are women, most of them of childbearing age, there are concerns regarding fetal exposure to toxic trace elements. We measured whole blood Hg, Pb and Cd concentrations in morbidly obese patients before and 12 months after Roux-en-Y gastric bypass (RYGB). PATIENTS AND METHODS: Forty-six patients eligible for bariatric surgery were recruited at Innlandet Hospital Trust, Norway (2012-2014). The majority were women and 54% were of reproductive age. Whole blood samples were collected prior to and 12 months after surgery. Trace element concentrations were measured using mass spectrometry (HR-ICP-MS). RESULTS: Median whole blood Pb concentrations increased by 73% during the 12 months study period while Hg and Cd decreased by 31% and 27%, respectively. We found a negative correlation between Pb levels before surgery and BMI (p = 0.02). Before surgery patients with hypertension had significantly higher median whole blood Hg levels compared to patients with normal blood pressure (p < 0.001). CONCLUSION: One year after bariatric surgery, the median whole blood Pb concentration was increased, while Hg and Cd concentrations were decreased. The majority of bariatric surgery patients are women of reproductive age and weight loss is associated with improved fertility. As even low dose Pb exposure during fetal life is associated with negative effects on the central nervous system, the observed increase in whole blood Pb after weight loss causes concern. Further studies are needed to elucidate these observations.

Improved Magnesium Levels in Morbidly Obese Diabetic and Non-diabetic Patients After Modest Weight Loss.

Serum magnesium (Mg) is reported to be reduced in individuals with obesity, hypertension, and diabetes mellitus and has been suggested as a marker for metabolic syndrome. We have studied changes in serum Mg concentrations in a group of obese patients (n = 92) with and without diabetes mellitus after weight loss induced by dieting and bariatric surgery. At inclusion, 11% (10/92) of the population had severe Mg deficiency (< 0.75 mmol/L) and median serum Mg was lower in diabetic (n = 20) compared to non-diabetic (n = 72) patients (p = 0.002). A weight loss of 10 kg after 8 weeks of lifestyle interventions was accompanied by increased serum Mg of about 5% in both diabetic and non-diabetic patients. Serum Mg remained stable thereafter in the non-diabetic patients, while it continued to increase in the diabetic patients after bariatric surgery. Six months after bariatric surgery, there was no significant difference in serum Mg concentration between the groups (p = 0.08). The optimal range of circulating Mg concentration is not known, but as even small increments in serum Mg are reported to lower the risk of cardiovascular and ischemic heart disease, our results are interesting in a public health perspective.

Renal function and blood pressure in 11 year old children born extremely preterm or small for gestational age.

BACKGROUND: Preterm birth and low birth weight are associated with reduced nephron numbers and increased risk of hypertension and kidney disease in later life. AIMS: We tested the hypothesis that extremely preterm birth and intrauterine growth restriction is associated with decreased renal function in mid childhood. METHODS: At 11 years of age the following measures were obtained in a regional cohort of children born extremely premature (EP, i.e. < 28 weeks gestational age-GA) or with extremely low birth weight (ELBW, i.e. BW < 1000 grams) and in matched controls born at term with appropriate BW (AGA): Height, weight, abdominal circumference, triceps and subscapular skin fold thicknesses, blood pressure, plasma levels of creatinine, cystatin C and symmetric dimethyl arginine (SDMA). Small for gestational age (SGA) was defined as a BW < 10th percentile for GA. Glomerular filtration rate (GFR) was estimated according to the equations by Schwartz, Zappitelli and Gao. RESULTS: Fifty-seven of 61 eligible EP/ELBW children, 20 (35%) born SGA, and 54 controls, were assessed. Estimated GFR decreased while plasma SDMA increased from the children born AGA at term through those born preterm AGA to preterm SGA. Systolic BP was correlated to fat mass indices (p<0.03), but not to renal function (p>0.2) and did not differ between the groups. CONCLUSIONS: Children born EP/ELBW, particularly those born SGA, had impaired renal function at age 11 years as judged from estimated GFRs and plasma levels of SDMA. Since reduced renal function is associated with an increased risk of later disease, these children should be followed in order to minimize additional risk factors.

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.

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.

Increased Bronchial Hyperresponsiveness and Higher Asymmetric Dimethylarginine Levels after Fetal Growth Restriction.

Bronchial hyperresponsiveness (BHR), a feature of asthma, is observed in preterm-born children and has been linked to intrauterine growth restriction. BHR is mediated via airway smooth muscle tone and is modulated by the autonomic nervous system, nitric oxide, and airway inflammation. Interactions among these factors are insufficiently understood. Methacholine-induced BHR (Met-BHR), fractional exhaled NO, and systemic soluble markers of nitric oxide metabolism and inflammation were determined in a population-based sample of 57 eleven-year-old children born extremely preterm (gestational age [GA] < 28 wk) or with extremely low birth weight (<1,000 g), and in a matched normal-birth weight term-born control group (n = 54). Bronchopulmonary dysplasia (BPD) was defined as the need for oxygen treatment at a GA of 36 weeks. In preterm-born children, birth weight below the 10th percentile for GA was associated with increased Met-BHR and higher plasma levels of asymmetric dimethylarginine (ADMA), with an increased odds ratio for being in the upper tertile of Met-BHR (11.8; 95% confidence interval, 3.3-42.4) and of ADMA (5.2; 95% confidence interval, 1.3-20.3). Met-BHR was correlated to ADMA level (r = 0.27, P = 0.007). There were no significant differences in Met-BHR, fractional exhaled NO, or z-FEV1 according to BPD status. No associations with systemic soluble markers of inflammation were observed for Met-BHR, birth, or BPD status. Intrauterine growth restriction in preterm-born children was associated with substantially increased Met-BHR and higher ADMA levels, suggesting altered nitric oxide regulation. These findings contribute to the understanding of the consequences from an adverse fetal environment; they should also be tested in term-born children.

Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying mechanisms of protection. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

Folic acid supplementation and interpregnancy interval.

BACKGROUND: Maternal folic acid supplementation between subsequent pregnancies may be important to reduce the risk of low folate status associated with short interpregnancy intervals. We examined how the prevalence of preconception folic acid use for a given pregnancy in Norwegian women varied according to the time interval from the previous pregnancy. METHODS: Analysis was based on 48 855 pairs of pregnancies with the second pregnancy included in the Norwegian Mother and Child Cohort Study (birth years 1999-2009). Interpregnancy interval was defined as the time from birth of a child to the conception of the subsequent sibling. Preconception folic acid use was defined as any use of folic acid-containing supplements within the last 4 weeks before the second pregnancy. RESULTS: The prevalence of preconception folic acid use was 31%. Among women with a term birth (≥37 weeks) in the previous pregnancy (92%), those with interpregnancy intervals ≤12 and ≥49 months were associated with up to 35% lower prevalence of preconception folic acid use for the second pregnancy, relative to the reference group (13-24 months). The low use in short intervals was mainly attributable to lower proportion of planned pregnancies and fewer women with higher education. Among women with a preterm birth (<37 weeks) in the previous pregnancy (8%), preconception folic acid use significantly decreased with increasing pregnancy spacing. CONCLUSIONS: Our finding of a lower preconception folic acid use in women with both short and long interpregnancy intervals might help identifying those with higher risk of folate deficiency and preventing unwanted pregnancy outcomes.

Evaluating iron status and the risk of anemia in young infants using erythrocyte parameters.

BACKGROUND: Correct evaluation of iron status is important in young infants because both iron deficiency and excess may have negative effects on development, growth, and morbidity. METHODS: We evaluated iron status using erythrocyte parameters, including reticulocyte hemoglobin content (CHr) in infants with birth weight <3,000 g (n = 80). Blood samples and infant characteristics were recorded at 6 wk and at 4 and 6 months. Infants with a birth weight ≤2,500 g (n = 36) were recommended for iron supplementation. RESULTS: Despite a significantly poorer status at 6 wk, iron-supplemented infants had significantly higher hemoglobin level (Hb): 12.2 (SD = 0.8) g/dl and CHr: 28.3 (SD = 1.4) pg at 6 mo, as compared with nonsupplemented infants, Hb: 11.7 (SD = 1.0) g/dl, P = 0.02 and CHr: 26.5 (SD = 2.5) pg, P < 0.001. Prolonged exclusive breastfeeding, high weight gain, and male gender were the predisposing factors for a low iron status at 6 mo. A CHr cutoff level of 26.9 pg at 4 mo proved to be a sensitive predictor for anemia at 6 mo. CONCLUSION: Signs of an iron-restricted erythropoiesis were observed in nonsupplemented infants (birth weight 2,501-3,000 g), and CHr was a useful tool for evaluating iron status. The need for iron supplementation in certain infant risk populations should be further evaluated.

Increased yet iron-restricted erythropoiesis in postpartum mothers.

Iron deficiency in the postpartum period is common and associated with impaired quality of life. Interpretation of ordinary laboratory parameters is considered to be simple in postpartum women, as normalization of pregnancy induced physiological changes is assumed to take place in the early postpartum period. We have studied changes in erythrocyte and iron parameters during the first 11 postpartum months. Erythrocyte parameters and iron markers, serum ferritin, and soluble transferrin receptor (sTfR), and an inflammation marker, neopterin, were investigated in healthy mothers 6 weeks (n = 104), 4 months (n = 100), and 11 months (n = 43) after giving birth to a term infant. Healthy nonpregnant and nonlactating women (n = 61) were included as controls. The hemoglobin level increased throughout the first 11 postpartum months and was significantly higher from 4 months on, compared to control women. At all time points, the mothers had significantly lower mean corpuscular volume (MCV) and higher erythrocyte count and percentage of hypochromic erythrocytes. sTfR levels were significantly higher over the whole serum ferritin distribution during the first 4 postpartum months compared to the controls, indicative of an increased cell production. At 6 weeks, postpartum mothers had higher neopterin levels and this was associated with markers of a low iron status, not including sTfR. Substantial changes in erythrocyte and iron parameters were observed in the postpartum period, consistent with an increased, but iron restricted erythropoiesis. The increased erythropoietic activity was reflected in higher sTfR concentrations. Given the vital role for iron in both mothers and infants, further studies are warranted for establishing proper cut off levels for sTfR as an iron marker in postpartum women.

Common metabolic profile in infants indicating impaired cobalamin status responds to cobalamin supplementation.

OBJECTIVE: A metabolic profile consistent with impaired cobalamin status is prevalent in breastfed infants. We investigated whether this profile reflects immature organ systems or impaired cobalamin status. METHODS: In a single-center, randomized, placebo-controlled trial, we studied 107 six-week-old infants. The infants were randomly assigned to receive either an intramuscular injection of 400 mug of cobalamin or no intervention. Concentrations of cobalamin and folate in serum and total homocysteine, methylmalonic acid, and cystathionine in plasma were determined at enrollment and at the age of 4 months. RESULTS: There were no significant differences between the intervention group (n = 54) and the control group (n = 53) in the concentrations of any vitamin marker at baseline (6 weeks). At 4 months, the supplement-treated infants had a 75% higher median serum cobalamin level and remarkable reductions in median plasma total homocysteine (from 7.46 to 4.57 micromol/L) and methylmalonic acid (from 0.58 to 0.20 micromol/L) levels, whereas levels of both metabolites were essentially unchanged during the follow-up period in the control group. CONCLUSIONS: Cobalamin supplementation changed all markers of impaired cobalamin status (low cobalamin, high total homocysteine, and high methylmalonic acid levels) toward a profile observed in cobalamin-replete older children and adults. Therefore, the high total homocysteine and methylmalonic acid levels reported for a large fraction of infants reflect not immature metabolism but rather insufficient cobalamin levels to fully sustain cobalamin-dependent reactions fully.

Hematological parameters and cobalamin status in infants born to smoking mothers.

Hematological parameters, serum cobalamin and folate levels, and the concentrations of the functional markers plasma methylmalonic acid and total homocysteine were determined in 173 newborns and 46 infants at 6 weeks to see whether maternal smoking influences the hematological parameters and the vitamin status of the newborn. At birth, there was a strong inverse correlation between the number of cigarettes smoked per day during pregnancy and red blood cell count (r = -0.56, p = 0.001) and hemoglobin level (r = -0.52, p = 0.003) in the newborns. Neonates born to smoking mothers had lower red blood cell counts and lower hemoglobin and serum cobalamin levels as compared with infants born to nonsmoking mothers. At 6 weeks, maternal smoking significantly predicted the methylmalonic acid and total homocysteine levels, suggesting an influence from smoking on the cobalamin function in these infants.