An SMS chatbot digital educational program to increase healthy eating behaviors in adolescence: A multifactorial randomized controlled trial among 7,890 participants in the Danish National Birth Cohort.

BACKGROUND: Few cost-effective strategies to shift dietary habits of populations in a healthier direction have been identified. We examined if participating in a chatbot health education program transmitted by Short Messages Service ("SMS-program") could improve adolescent dietary behaviors and body weight trajectories. We also explored possible added effects of maternal or peer involvement. METHODS AND FINDINGS: We conducted a randomized controlled trial (RCT) among adolescents from the Danish National Birth Cohort (DNBC). Eligible were adolescents who during 2015 to 2016 at age 14 years had completed a questionnaire assessing height, weight, and dietary habits. Two thirds were offered participation in an SMS-program, whereas 1/3 ("non-SMS group") received no offer. The SMS program aimed to improve 3 key dietary intake behaviors: sugar-sweetened beverages (SSBs), fruit and vegetables (FV), and fish. The offered programs had 3 factorially randomized schemes; the aims of these were to test effect of asking the mother or a friend to also participate in the health promotion program, and to test the effect of a 4-week individually tailored SMS program against the full 12-week SMS program targeting all 3 dietary factors. Height and weight and intakes of SSB, FV, and fish were assessed twice by a smartphone-based abbreviated dietary questionnaire completed at 6 months (m) and 18 m follow-up. Main outcome measures were (1) body mass index (BMI) z-score; and (2) an abbreviated Healthy Eating Index (mini-HEI, 1 m window, as mean of z-scores for SSB, FV, and fish). Among the 7,890 randomized adolescents, 5,260 were assigned to any SMS program; 63% (3,338) joined the offered program. Among the 7,890 randomized, 74% (5,853) and 68% (5,370) responded to follow-ups at 6 m and 18 m, respectively. Effects were estimated by intention-to-treat (ITT) analyses and inverse probability weighted per-protocol (IPW-PP) analyses excluding adolescents who did not join the program. Mean (standard deviation (SD)) mini-HEI at baseline, 6 m and 18 m was -0.01 (0.64), 0.01 (0.59), and -0.01 (0.59), respectively. In ITT-analyses, no effects were observed, at any time point, in those who had received any SMS program compared to the non-SMS group, on BMI z-score (6 m: -0.010 [95% confidence interval (CI) -0.035, 0.015]; p = 0.442, 18 m: 0.002 [95% CI -0.029, 0.033]; p = 0.901) or mini-HEI (6 m: 0.016 [95% CI -0.011, 0.043]; p = 0.253, 18m: -0.016 [95% CI -0.045, 0.013]; p = 0.286). In IPW-PP analyses, at 6 m, a small decrease in BMI z-score (-0.030 [95% CI -0.057, -0.003]; p = 0.032) was observed, whereas no significant effect was observed in mini-HEI (0.027 [95% CI -0.002, 0.056]; p = 0.072), among those who had received any SMS program compared to the non-SMS group. At 18 m, no associations were observed (BMI z-score: -0.006 [95% CI -0.039, 0.027]; p = 0.724, and mini-HEI: -0.005 [95% CI -0.036, 0.026]; p = 0.755). The main limitations of the study were that DNBC participants, though derived from the general population, tend to have higher socioeconomic status than average, and that outcome measures were self-reported. CONCLUSIONS: In this study, a chatbot health education program delivered through an SMS program had no effect on dietary habits or weight trajectories in ITT analyses. However, IPW-PP-analyses, based on those 63% who had joined the offered SMS program, suggested modest improvements in weight development at 6 m, which had faded at 18 m. Future research should focus on developing gender-specific messaging programs including "booster" messages to obtain sustained engagement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02809196 https://clinicaltrials.gov/study/NCT02809196.

Early-life exposure to perfluoroalkyl substances and serum antibody concentrations towards common childhood vaccines in 18-month-old children in the Odense Child Cohort.

Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with reduced antibody response to childhood vaccinations. Previous studies have mostly focused on antibodies against diphtheria or tetanus, while fewer studies have assessed antibodies toward attenuated viruses, such as measles, mumps or rubella (MMR). Therefore, we set out to determine associations between prenatal and early postnatal PFAS exposure and vaccine-specific Immunoglobulin G (IgG) in the background-exposed Odense Child Cohort. Blood samples were drawn in pregnancy at gestation weeks 8-16 and from the offspring at age 18 months. In the maternal serum samples we quantified perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA). In the offspring serum samples we quantified the same five PFAS compounds and IgG towards diphtheria, tetanus and MMR. A total of 880 and 841 children were included in the analyses of diphtheria and tetanus or MMR, respectively. Multiple linear regression models were used for estimation of difference in virus-specific IgG per doubling of PFAS concentrations. Maternal PFAS concentrations were non-significantly inversely associated with most vaccine-specific antibody concentrations. Likewise, child PFAS concentrations were associated with non-significant reductions of antibodies towards tetanus and MMR. A significant reduction in the percent difference in mumps antibody concentration per doubling of child PFNA (-9.2% (95% confidence interval: -17.4;-0.2)), PFHxS (-8.3% (-15.0;-1.0) and PFOS (-7.9% (-14.8;-0.4) was found. These findings are of public health concern, as inadequate response towards childhood vaccines may represent a more general immune dysfunction.

[Gastrointestinal symptoms and dietary intake of patients with irritable bowel syndrome following a low FODMAP diet].

INTRODUCTION: High FODMAP (fermentable oligo-, di, monosaccharides and polyols) foods have been linked with worsening symptoms of IBS patients. The aim was to compare gastrointestinal symptoms and dietary intake of patients with irritable bowel syndrome following a low FODMAP diet, with or without individual nutrition therapy. MATERIALS AND METHODS: A total of 54 patients that met Rome IV criteria for IBS were randomized into two groups, guided group (individual nutrition therapy, n=28) and self-management group (learned about low FODMAP diet online, n=26). Both groups followed low FODMAP diet for 4 weeks. Four-day food records were used to assess dietary intake. Symptoms were assessed by the IBS-severity scoring system (ISB-SSS). RESULTS: The number of subjects who did not complete the study was 13, thereof five in the nutrition therapy and eight in the self-management group, leaving 23 and 18 subjects available for analysis, respectively. Symptoms declined from baseline to endpoint in both groups, by 183±101 points on average in the group receiving nutrition therapy (p< 0.001) and 132±110 points in the self-management group (p< 0.001), with no difference between groups. At baseline, about 80% of meals in both groups contained food high in FODMAP's. The corresponding proportion was 9% and 36% in week 3 in the nutrition therapy and self-management group, respectively (p< 0.001). CONCLUSION: Both groups experienced relieve of symptoms, but compliance to the low FODMAP diet was better in the group receiving individual nutrition therapy compared with the group who only received instructions on how to learn about low FODMAP diet online.

[Prevalence and Trends in Prepregnancy Overweight and Obesity in Northern Iceland 2004-2022].

INTRODUCTION: Prepregnancy overweight and obesity is an increasing public health issue worldwide, including Iceland, and has been associated with higher risk of adverse maternal and birth outcomes. The aim of this study was to investigate trends in prepregnancy weight amongst women in North Iceland from 2004 to 2022, and the prevalence of overweight and obesity in this population. MATERIAL AND METHODS: This retrospective cross-sectional study included all women who gave birth at Akureyri Hospital in North Iceland between 2004 and 2022 (N = 7410). Information on age, parity, height, and prepregnancy weight was obtained from an electronic labour audit database. Body mass index (BMI) was calculated from self-reported height and weight, and the median BMI and proportions in each of the six BMI categories were calculated for four time periods. RESULTS: Median BMI increased significantly from 24.5 kg/m2 in 2004-2008 to 26.2 kg/m2 in 2019-2022. On average, BMI increased by 0.15 kg/m2 with each passing year (p<0.001). The prevalence of normal weight decreased from 53% to 40% and the entire BMI distribution shifted towards a higher BMI. The proportion of women in obesity class I (BMI 30.0 - 34.9) increased from 12.8% to 17.3%, the proportion of women in obesity class II (BMI 35.0 - 39.9) doubled (3.7% to 8.1%) and tripled in obesity class III (BMI ≥ 40.0; 1.6% to 4.8%). CONCLUSION: Prepregnancy weight of women in Northern Iceland has gradually increased over the last 19 years and 30% of pregnant women are now classified as obese. Further studies on the subsequent effects on maternal and birth outcomes are needed, with a focus on strategies to decrease adverse effects and reverse this trend.

Association Between Prenatal and Early Postnatal Exposure to Perfluoroalkyl Substances and IQ Score in 7-Year-Old Children From the Odense Child Cohort.

Perfluoroalkyl substances (PFAS) are persistent chemicals capable of crossing the placenta and passing into breast milk. Evidence suggests that PFAS exposure may affect brain development. We investigated whether prenatal or early postnatal PFAS exposure was associated with intelligence quotient (IQ) scores in schoolchildren from the Odense Child Cohort (Denmark, 2010-2020). We assessed concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) in maternal serum collected during the first trimester of pregnancy and in child serum at age 18 months. At 7 years of age, children completed an abbreviated version of the Wechsler Intelligence Scale for Children, Fifth Edition, from which Full Scale Intelligence Quotient (FSIQ) and Verbal Comprehension Index scores were estimated. In multiple linear regression analyses conducted among 967 mother-child pairs, a doubling in maternal PFOS and PFNA concentrations was associated with a lower FSIQ score, while no significant associations were observed for PFOA, PFHxS, or PFDA. PFAS concentrations at age 18 months and duration of breastfeeding were strongly correlated, and even in structural equation models it was not possible to differentiate between the opposite effects of PFAS exposure and duration of breastfeeding on FSIQ. PFAS exposure is ubiquitous; therefore, an association with even a small reduction in IQ is of public health concern.

[Levels of mercury in hair among pregnant women in Iceland].

INTRODUCTION: To limit exposure to methylmercury several countries have implimented specific advice on fish intake to pregnant women as well a measuring compliance through regular human biomonitoring. Despite fish intake being relatively high in Iceland, human biomonitoring data on mercury is scarce. MATERIALS AND MEHODS: We measured mercury in hair from 120 pregnant women recruited in 2021 from the the Reykjavik Capital area. At recruitment, information on fish intake during the past four months was recorded. Hair mercury concentrations were compared to existing health based guidance values and associatons with fish intake was explored. RESULTS: Mean (standard deviation) mercury concentration in hair was 0.48 µg/g (0.33). All participants had concentrations in hair below 1.8 µg/g, which corresponds to the hair value that the tolerable daily intake set by the European Food Safety Authority is derived from, while 5% had concentrations above 1.1 µg/g, which corresponds to the hair value that the US-EPA reference dose is derived from. Mean mercury concentrations in hair increased in a dose dependent manner (p for trend p<0.001) from 0.25 µg/g among women who consumed fish ≤ 3/month (n=24) and up to 0.80 mg/g among those consuming fish 3-4/ week (n=16). The few (n=3) women who reported to have eaten shark (p<1/month) were all at the higher end of the exposure distribution. CONCLUSION: Our results suggest that exposure is generally below the tolerable daily intake set by EFSA but may in some women exceed the reference dose established by the US-EPA.

Comprehensive Evaluation of Blood Plasma and Serum Sample Preparations for HRMS-Based Chemical Exposomics: Overlaps and Specificities.

Sample preparation of biological samples can have a substantial impact on the coverage of small molecules detectable using liquid chromatography-high-resolution mass spectrometry (LC-HRMS). This initial step is particularly critical for the detection of externally derived chemicals and their metabolites (internal chemical exposome) generally present at trace levels. Hence, our objective was to investigate how blood sample preparation methods affect the detection of low-abundant chemicals and to propose alternative methods to improve the coverage of the internal chemical exposome. We performed a comprehensive evaluation of 12 sample preparation methods (SPM) using phospholipid and protein removal plates (PLR), solid phase extraction plates (SPE), supported liquid extraction cartridge (SLE), and conventionally used protein precipitation (PPT). We implemented new quantitative and qualitative criteria for nontargeted analyses (detection frequency, recoveries, repeatability, matrix effect, low-level spiking significance, method detection limits, throughput, and ease of use) to amply characterize these SPM in a step-by-step-type approach. As a final step, PPT and one PLR plate were applied to cohort plasma and serum samples injected in triplicate to monitor batch repeatability, and annotation was performed on the related data sets to compare the respective impacts of these SPM. We demonstrate that sample preparation significantly affects both the range of observable compounds and the level at which they can be observed (only 43%-54% of total features are overlapping between the two SPM). We propose to use PPT and PLR on the same samples by implementing a simple analytical workflow as their complementarity would allow the broadening of the visible chemical space.

Does metabolomic profile differ with regard to birth weight?

BACKGROUND: Macrosomia and child obesity are growing health-care issues worldwide. The purpose of the study was to evaluate how extremely high or low birth weight affects metabolic markers evaluated in newborn screening. METHODS: The study was register-based and included full-term singletons born in Iceland from 2009 to 2012 with newborn screening samples taken 72-96 h after birth. Three groups based on birth weight were compared: low birth weight (<2500 g), appropriate-for-gestational age, and extreme macrosomia (≥5000 g). The comparison was adjusted for possible confounding factors. RESULTS: Compared to appropriate-for-gestational age neonates, both low birth weight and extreme macrosomia were associated with higher levels of glutamic acid. The amino acids alanine and threonine were increased in low birth weight neonates. Free carnitine and some medium- and long-chain acylcarnitines were higher in low birth weight infants. Hydroxybutyrylcarnitine was lower in low birth weight infants, but higher in extremely macrosomic neonates. Acetylcarnitine was higher in low birth weight and extremely macrosomic neonates. Succinylcarnitine was lower and hexadecenoylcarnitine higher in macrosomic newborns. CONCLUSION: Low birth weight and extremely macrosomic neonates show distinctive differences in their metabolomic profile compared to appropriate-for-gestational age newborns. The differences are not explained by gestational age. IMPACT: The key message of this article is that both low birth weight and extremely macrosomic newborns show dissimilar metabolomic profiles compared to appropriate-for-gestational age neonates. The article contributes to knowledge on what affects evaluation of results in newborn screening. The impact of this article is to provide information on metabolism at both ends of the birth weight range after accounting for confounding factors including gestational age.

Mode of delivery was associated with transient changes in the metabolomic profile of neonates.

AIMS: To estimate potential differences in neonatal metabolomic profiles at birth and at the time of newborn screening by delivery mode. METHODS: A prospective study at Women's Clinic at Landspitali-The National University Hospital of Iceland. Women having normal vaginal birth or elective caesarean section from November 2013 to April 2014 were offered participation. Blood samples from mothers before birth and umbilical cord at birth were collected and amino acids and acylcarnitines measured by tandem mass spectrometry. Results from the Newborn screening programme in Iceland were collected. Amino acids and acylcarnitines from different samples were compared by delivery mode. RESULTS: Eighty three normal vaginal births and 32 elective caesarean sections were included. Mean differences at birth were higher for numerous amino acids, and some acylcarnitines in neonates born vaginally compared to elective caesarean section. Maternal blood samples and newborn screening results showed small differences that lost significance after correction for multiple testing. Many amino acids and some acylcarnitines were numerically higher in cord blood compared to maternal. Many amino acids and most acylcarnitines were numerically higher in newborn screening results compared to cord blood. CONCLUSION: We observed transient yet distinct differences in metabolomic profiles between neonates by delivery mode.

Correction: Mother's dietary quality during pregnancy and offspring's dietary quality in adolescence: Follow-up from a national birth cohort study of 19,582 mother-offspring pairs.

[This corrects the article DOI: 10.1371/journal.pmed.1002911.].

Mother's dietary quality during pregnancy and offspring's dietary quality in adolescence: Follow-up from a national birth cohort study of 19,582 mother-offspring pairs.

BACKGROUND: The Developmental Origins of Health and Disease (DOHaD) hypothesis postulates that exposures during early life, such as maternal dietary intake during pregnancy, may have a lifelong impact on the individual's susceptibility to diseases. The individual's own lifestyle habits are obviously an additional factor, but we have only limited knowledge regarding how it may interact with prenatal exposures in determining later disease. To gain further insight into these potentially complex relationships, we examined the longitudinal association between maternal diet quality during pregnancy and diet quality in early adolescence in a contemporary cohort. METHODS AND FINDINGS: From 1996 to 2003, the Danish National Birth Cohort (DNBC) was established. Women from across the country were enrolled, and dietary intake in midpregnancy was assessed concurrently with a 360-item food frequency questionnaire (FFQ) (https://www.dnbc.dk/-/media/arkiv/projekt-sites/dnbc/kodeboeger/dnbc-food-frequency-questionnaire/dnbc-food-frequency-questionnaire-pdf.pdf?la=en). During 2013-2018, dietary intake was assessed at age 14 years with a 150-item FFQ (https://www.dnbc.dk/-/media/arkiv/projekt-sites/dnbc/kodeboeger/ffq-14/dnbc-ffq-14-english-translation.pdf?la=en) in the DNBC children. Among the 19,582 mother-offspring pairs included in the analyses, the mean age (±standard deviation [SD]) was 30.7 (±4.1) years and 14.0 (±0.0) years for mothers and offspring, respectively. The majority of both mothers (67%) and offspring (76%) were classified as normal weight. For both questionnaires, a Healthy Eating Index (HEI) was developed as an indicator for diet quality based on current Danish Food-Based Dietary Guidelines (FBDG) including eight components: fruits and vegetables, fish, dietary fibres, red meat, saturated fatty acids (SFAs), sodium, sugar-sweetened beverages (SSBs), and added sugar. The HEI score was divided into quartiles; individuals in the highest quartile represented those with the most optimal diet. The maternal HEI score was correlated positively with offspring HEI score (Pearson r = 0.22, p < 0.001). A log-linear binomial model was used to estimate the relative risk of the offspring being in the highest quartile of HEI at age 14 years if the mother was ranked in quartile 4 during pregnancy. Results showed that offspring born to mothers who were in the highest HEI quartile during pregnancy were more likely themselves to be located in the highest HEI quartile at age 14 years (risk ratio [RR]: 2.1, 95% confidence interval [CI]: 2.0, 2.3, p < 0.001). Adjusting for maternal prepregnancy body mass index (BMI), parity, education, alcohol intake, physical activity, smoking, and breastfeeding, as well as offspring total energy intake and sex, did not influence the effect estimates. The limitations of our study include that some attrition bias towards more healthy participants was observed when comparing participants with nonparticipants. Bias in the FFQ method may also have resulted in underrepresentation of adolescents with poorer diet quality. CONCLUSIONS: In this study using data from a large national birth cohort, we observed that maternal diet quality during pregnancy was associated with diet quality of the offspring at age 14 years. These findings indicate the importance of separating early dietary exposures from later dietary exposures when studying dietary aetiologies of diseases postulated to have developmental origins such as, for instance, obesity or asthma in observational settings.

Do female elite athletes experience more complicated childbirth than non-athletes? A case-control study.

OBJECTIVE: Previous studies have suggested that female athletes might be at higher risk of experiencing complications such as caesarean sections and perineal tears during labour than non-athletes. Our aim was to study delivery outcomes, including emergency caesarean section rates, length of the first and second stages of labour and severe perineal tears, in first-time pregnant elite athletes compared with non-athletes. METHODS: This is a retrospective case-control study comparing birth outcomes of primiparous female elite athletes engaging in high-impact and low-impact sports compared with non-athletic controls. The athletes had prior to birth competed at a national team level or equivalent. Participant characteristics and frequency of training for at least 3 years before a first pregnancy were collected via a self-administered questionnaire. Information on delivery outcome was retrieved from the Icelandic Medical Birth Registry. RESULTS: In total, 248 participated, 118 controls, 41 low-impact and 89 high-impact elite athletes. No significant differences were found between the groups with regard to incidence of emergency caesarean section or length of the first and second stages of labour. The incidence of third-degree to fourth-degree perineal tears was significantly higher (23.7%) among low-impact athletes than in the high-impact group (5.1%, p=0.01), but no significant differences were seen when the athletes were compared with the controls (12%; p=0.09 for low-impact and p=0.12 for high-impact athletes). CONCLUSION: Participation in competitive sports at the elite level was not related to adverse delivery outcome, including length of labour, the need for caesarean section during delivery and severe perineal tears.

Vitamin D measured in maternal serum and offspring neurodevelopmental outcomes: a prospective study with long-term follow-up.

BACKGROUND: Vitamin D is obtained from dietary sources and synthesized in the skin during exposure to ultraviolet B radiation in sunlight. During pregnancy, vitamin D is transported from mother to fetus through the placenta in the form of 25-hydroxyvitamin D [25(OH)D]. There is evidence that vitamin D influences neuronal differentiation, endocrine functions, and fetal brain growth. Animal studies indicate alterations in the offspring brain as a consequence of vitamin D deficiency during pregnancy. In humans, maternal vitamin D insufficiency has been linked to impaired child language development. Using data from a prebirth cohort with up to 22 years of follow-up, we examined the association of vitamin D status with proxies of offspring neurodevelopmental outcomes. During 1988-1989, pregnant women were recruited for the DaFO88 cohort (n = 965) in Aarhus, Denmark. Maternal concentrations of 25(OH)D were quantified in serum from week 30 of gestation via the LC-MS/MS method (n = 850). Offspring were followed up through national registries until the age of 22 years. We evaluated the association of the maternal concentration of 25(OH)D with offspring neurodevelopmental outcomes defined as first admission diagnosis or prescription of medication for (1) ADHD, (2) depression, and (3) scholastic achievement based on the mean grade on standardized written examinations in the 9th grade (final exams after 10 years of compulsory school in Denmark). KEY MESSAGES: Maternal concentrations of 25(OH)D were higher compared to current levels (median 76 nmol/l; 5th to 95th percentiles 23-152). There was a direct association between maternal vitamin D status and offspring depression (p(trend) = 0.01); for ADHD there was no association. Scholastic achievement was slightly higher for offspring of mothers with a vitamin D status in the range of >50-125 nmol/l, but this nonlinear association was not statistically significant. CONCLUSIONS: Our analyses based on biomarker measurement of 25(OH)D from a cohort of 850 pregnant women combined with long-term follow-up showed no support for a beneficial fetal programming effect of vitamin D status with regard to behavioral and affective disorders and scholastic achievement.

Animal protein intake at 12 months is associated with growth factors at the age of six.

AIM: To study the associations between protein intake from different sources with anthropometry and serum insulin-like growth factor 1 (IGF-1) in infancy and childhood. METHODS: Children (n = 199) born in Iceland were followed up to six years of age. Their intake of various animal proteins and vegetable protein was calculated from weighed food records at 12 months and 6 years. Information about their weight and height at birth, 12 and 18 months, and 6 years was gathered. Serum IGF-1 was measured at 12 months and 6 years. RESULTS: At the age of six, children in the highest quartile for animal protein intake at 12 months (≥12.2% of total energy) had 0.8 kg/m(2) (95% CI = 0.1, 1.5) higher body mass index (BMI) than children in the lowest quartile (<7.6% of total energy). They were also heavier and longer in infancy and childhood. At 12 months, dairy protein intake as a percentage of total energy was associated with IGF-1 in six-year-old girls, ß = 5.4 µg/L (95% CI = 2.5, 8.2). CONCLUSION: High animal protein intake in infancy, but not vegetable protein intake, was associated with accelerated growth and higher BMI in childhood. Dairy protein intake in infancy may be positively associated with linear growth and also with IGF-1 in six-year-old girls.

Maternal use of nitrosatable drugs during pregnancy and adult male reproductive health: A population-based cohort study.

BACKGROUND: Prenatal exposures to xenobiotics during the masculinization programming window are suggested to impact male fecundity later in life. Frequently used nitrosatable drugs, such as penicillins and beta2-agonists, contain amines or amides that may form teratogenic compounds in reaction with nitrite. OBJECTIVES: We explored whether maternal nitrosatable drug use during gestation was associated with biomarkers of male fecundity in adulthood; moreover, the potential modifiable effect of nitrate and vitamin intake was investigated. METHOD: We performed a cohort study in the Fetal Programming of Semen Quality cohort that includes semen characteristics, reproductive hormone concentrations, and measures of testis size on 1058 young adult sons in the Danish National Birth Cohort. Information on maternal use of nitrosatable drugs was obtained from questionnaires and interviews around gestational weeks 11 and 16. A multivariable negative binomial regression model was used to obtain relative differences in biomarkers of male fecundity for those whose mothers used nitrosatable drugs compared to those without such maternal use. In sub-analyses, the exposure was categorized according to nitrosatable drug type: secondary amine, tertiary amine, or amide. We investigated dose dependency by examining the number of weeks with intake and explored potential effect modification by low versus high maternal nitrate and vitamin intake from diet and nitrate concentration in drinking water. We added selection weights and imputed values of missing covariates to limit the risk of selection bias. RESULTS: In total, 19.6% of the study population were born of mothers with an intake of nitrosatable drugs at least once during early pregnancy. Relative differences in biomarkers related to male fecundity between exposed and unexposed participants were negligible. Imputation of missing covariates did not fundamentally alter the results. Furthermore, no sensitive subpopulations were detected. CONCLUSIONS: The results suggest that maternal use of nitrosatable drugs does not have a harmful influence on the male fecundity of the offspring.

Guidance on risk-benefit assessment of foods.

The EFSA Scientific Committee has updated its 2010 Guidance on risk-benefit assessment (RBA) of foods. The update addresses methodological developments and regulatory needs. While it retains the stepwise RBA approach, it provides additional methods for complex assessments, such as multiple chemical hazards and all relevant health effects impacting different population subgroups. The updated guidance includes approaches for systematic identification, prioritisation and selection of hazardous and beneficial food components. It also offers updates relevant to characterising adverse and beneficial effects, such as measures of effect size and dose-response modelling. The guidance expands options for characterising risks and benefits, incorporating variability, uncertainty, severity categorisation and ranking of different (beneficial or adverse) effects. The impact of different types of health effects is assessed qualitatively or quantitatively, depending on the problem formulation, scope of the RBA question and data availability. The integration of risks and benefits often involves value-based judgements and should ideally be performed with the risk-benefit manager. Metrics such as Disability-Adjusted Life Years (DALYs) and Quality-Adjusted Life Years (QALYs) can be used. Additional approaches are presented, such as probability of all relevant effects and/or effects of given severities and their integration using severity weight functions. The update includes practical guidance on reporting results, interpreting outcomes and communicating the outcome of an RBA, considering consumer perspectives and responses to advice.

Nutrient intake in infancy and body mass index at six years in two population-based cohorts recruited before and after revision of infant dietary recommendations.

BACKGROUND/AIMS: The dietary intake in infancy can affect growth and the risk of childhood overweight. The aim of this study was to compare the nutrient intake in infancy and the body mass index (BMI) at age 6 years in two population-based cohorts recruited before and after the revision of infant dietary recommendations. METHODS: Two randomly selected population-based cohorts were recruited at birth and studied until 12 months of age and again at 6 years of age. Subjects were 90 and 170 children born in 1995-1996 and 2005, respectively. The dietary intake at 9 and 12 months was assessed via weighed food records. The height and weight from birth to age 12 months and at age 6 years were measured. RESULTS: The contribution of protein to the total energy intake (E%) was significantly lower in the 2005 cohort than in the 1995-1996 cohort [11.9 vs. 14.4 E% (p < 0.001) at 9 months and 14.6 vs. 15.6 E% (p = 0.016) at 12 months]. Relatively fewer children were classified as being overweight (including obese) in the 2005 cohort, i.e. 12 versus 21% (p = 0.045). CONCLUSION: The emphasis placed on the revised infant dietary recommendations resulted in a lower protein intake in the latter half of the first year. Changes in the infants' diets on the population level might have contributed to the lower overweight prevalence seen in the 2005 cohort.

Internal relative potency factors based on immunotoxicity for the risk assessment of mixtures of per- and polyfluoroalkyl substances (PFAS) in human biomonitoring.

Relative potency factors (RPFs) for per- and polyfluoroalkyl substances (PFAS) have previously been derived based on liver effects in rodents for the purpose of performing mixture risk assessment with primary input from biomonitoring studies. However, in 2020, EFSA established a tolerable weekly intake for four PFAS assuming equal toxic potency for immune suppressive effects in humans. In this study we explored the possibility of deriving RPFs for immune suppressive effects using available data in rodents and humans. Lymphoid organ weights, differential blood cell counts, and clinical chemistry from 28-day studies in male rats from the National Toxicology Program (NTP) were combined with modeled serum PFAS concentrations to derive internal RPFs by applying dose-response modelling. Identified functional studies used diverse protocols and were not suitable for derivation of RPFs but were used to support immunotoxicity of PFAS in a qualitative manner. Furthermore, a novel approach was used to estimate internal RPFs based on epidemiological data by dose-response curve fitting optimization, looking at serum antibody concentrations and key cell populations from the National Health and Nutrition Examination Survey (NHANES). Internal RPFs were successfully derived for PFAS based on rat thymus weight, spleen weight, and globulin concentration. The available dose-response information for blood cell counts did not show a significant trend. Immunotoxic potency in serum was determined in the order PFDA > PFNA > PFHxA > PFOS > PFBS > PFOA > PFHxS. The epidemiological data showed inverse associations for the sum of PFOA, PFNA, PFHxS, and PFOS with serum antibody concentrations to mumps and rubella, but the data did not allow for deduction of reliable internal RPF estimates. The internal RPFs for PFAS based on decreased rat lymphoid organ weights are similar to those previously established for increased rat liver weight, strengthening the confidence in the overall applicability of these RPFs.

Exposure to persistent organic pollutants in Danish pregnant women: Hormone levels and fetal growth indices.

This study examines possible associations of maternal Persistent Organic Pollutants (POP) exposure during pregnancy, maternal hormone levels and fetal growth indices (FGI). During 1st trimester, we measured maternal thyroids, androgens and estrogens, lipophilic POP and perfluorinated-alkyl-acid (PFAA) levels in serum from nulliparous women. Adjusted multivariate-linear regression models assessed associations between exposure and outcomes. Maternal characteristics and POP exposures associated with maternal hormone levels. Lipophilic POP elicited inverse association with androgen and estrogen levels but no strong association with thyroids. Higher level of PFAA was associated with higher thyroid and androgen levels. The PFAA did not associate with estrogens. Higher thyroid-peroxidase-antibody (TPO-Ab) and estradiol level associated with higher birth weight and length in sons. For daughters, the TPO-Ab associations were the opposite being inversely associated with birth weight and length, and higher TPO-Ab and estradiol associated with lower gestational age. Mediation analyses suggested that TPO-Ab mediates the association of PFAA with FGI.

Prenatal exposure to nitrosatable drugs and timing of puberty in sons and daughters: A nationwide cohort study.

BACKGROUND: N-nitroso compounds (NOCs) can be formed by endogenous reactions between nitrosatable drugs and nitrite. Animal studies have found that several NOCs are teratogenic, and epidemiological studies report associations between prenatal exposure to nitrosatable drugs and adverse birth outcomes. It is unknown whether prenatal exposure to nitrosatable drugs is harmful to the child's reproductive health, including pubertal development. OBJECTIVES: We investigated whether prenatal exposure to nitrosatable drugs was associated with timing of puberty and whether nitrate, nitrite and antioxidant intake modified any association. METHODS: The population-based Danish National Birth Cohort (DNBC) Puberty Cohort, which includes 15,819 children, was used to investigate the association between prenatal exposure to nitrosatable drugs and timing of puberty. Around gestational week 11 and gestational week 18, mothers provided information about drug use during pregnancy. The children's self-reported information on onset of pubertal milestones was collected every six months from 11 years of age and throughout puberty. To investigate potential effect modification by nitrite, nitrate and antioxidant intake, information on these factors was obtained from a food frequency questionnaire completed by the mothers in gestational week 25, and information on nitrate concentration in maternal drinking water at her residential address was obtained from monitoring data from public waterworks. Data were analysed using a multivariable regression model for interval-censored data estimating difference in months in timing of puberty between exposure groups. RESULTS: A total of 2,715 children were prenatally exposed to nitrosatable drugs. We did not find an association between prenatal exposure to nitrosatable drugs and timing of puberty. This finding was supported by null-findings in the following sub-analyses investigating: 1. subtypes of nitrosatable drugs (secondary and tertiary amines and amides), 2. dose-dependency (duration of drug intake), 3. effect modification by maternal intake of nitrate, nitrite, and antioxidants. 4. confounding by indication. CONCLUSIONS: Prenatal exposure to nitrosatable drugs was not associated with timing of puberty. Nitrosatable drugs are commonly used drugs in pregnancy, and further research is needed to allow firm conclusions on the potential effect of prenatal exposure to nitrosatable drugs on the child's reproductive health.