Louise Bjørkholt Andersen

Parity and tanned white skin as novel predictors of vitamin D status in early pregnancy: a population-based cohort study.

In pregnancy, vitamin D insufficiency and deficiency, defined as serum 25‐hydroxyvitamin D (25(OH)D) <50 nM, and <25 nM, respectively, may have adverse effects for both mother and child. Prevalence estimates, and identification of subgroups at special risk, may be useful for the planning of preventive strategies.

Vitamin D insufficiency is associated with increased risk of first-trimester miscarriage in the Odense Child Cohort

BACKGROUND Miscarriage is the most common negative outcome of pregnancy, and identification of modifiable risk factors is potentially of great importance for public health. Low vitamin D concentrations in pregnancy are widespread worldwide, and vitamin D deficiency is implicated in immune cell regulation at the feto-maternal interface and several diseases of pregnancy. OBJECTIVE We investigated whether 25-hydroxyvitamin D serum concentration was a modifiable risk factor for early miscarriage. DESIGN In a prospective cohort study of 1683 pregnant women donating serum before gestational week 22, we investigated the association between maternal serum concentrations of serum 25-hydroxyvitamin D [25(OH)D] and the risk of subsequent miscarriage (n = 58). RESULTS The adjusted hazard of first-trimester miscarriage was lower with higher 25(OH)D concentrations (HR: 0.98; 95% CI: 0.96, 0.99). Concentrations of 25(OH)D <50 nmol/L were associated with a >2-fold increased adjusted HR for miscarriage (HR: 2.50; 95% CI: 1.10, 5.69). Concentrations of 25(OH)D were not associated with an increased risk of second-trimester miscarriage. CONCLUSIONS We found an association between 25(OH)D and first-trimester miscarriages, suggesting vitamin D as a modifiable risk factor for miscarriage. To test this hypothesis, randomized controlled trials should investigate the possible effect of vitamin D supplementation to increase 25(OH)D concentrations in early pregnancy, or before conception, to decrease risk of miscarriage. This trial was registered at clinicaltrials.gov as NCT02434900.

Infant Gut Microbiota Development Is Driven by Transition to Family Foods Independent of Maternal Obesity

The potential influence of maternal obesity on infant gut microbiota may occur either through vertically transmitted microbes or through the dietary habits of the family. Recent studies have suggested that the heritability of obesity may partly be caused by the transmission of “obesogenic” gut microbes. However, the findings presented here suggest that maternal obesity per se does not affect the overall composition of the gut microbiota and its development after introduction of complementary foods. Rather, progression in complementary feeding is found to be the major determinant for gut microbiota establishment. Expanding our understanding of the influence of complementary diet on the development and establishment of the gut microbiota will provide us with the knowledge to tailor a beneficial progression of our intestinal microbial community. ABSTRACT The first years of life are paramount in establishing our endogenous gut microbiota, which is strongly affected by diet and has repeatedly been linked with obesity. However, very few studies have addressed the influence of maternal obesity on infant gut microbiota, which may occur either through vertically transmitted microbes or through the dietary habits of the family. Additionally, very little is known about the effect of diet during the complementary feeding period, which is potentially important for gut microbiota development. Here, the gut microbiotas of two different cohorts of infants, born either of a random sample of healthy mothers (n = 114), or of obese mothers (n = 113), were profiled by 16S rRNA amplicon sequencing. Gut microbiota data were compared to breastfeeding patterns and detailed individual dietary recordings to assess effects of the complementary diet. We found that maternal obesity did not influence microbial diversity or specific taxon abundances during the complementary feeding period. Across cohorts, breastfeeding duration and composition of the complementary diet were found to be the major determinants of gut microbiota development. In both cohorts, gut microbial composition and alpha diversity were thus strongly affected by introduction of family foods with high protein and fiber contents. Specifically, intake of meats, cheeses, and Danish rye bread, rich in protein and fiber, were associated with increased alpha diversity. Our results reveal that the transition from early infant feeding to family foods is a major determinant for gut microbiota development. IMPORTANCE The potential influence of maternal obesity on infant gut microbiota may occur either through vertically transmitted microbes or through the dietary habits of the family. Recent studies have suggested that the heritability of obesity may partly be caused by the transmission of “obesogenic” gut microbes. However, the findings presented here suggest that maternal obesity per se does not affect the overall composition of the gut microbiota and its development after introduction of complementary foods. Rather, progression in complementary feeding is found to be the major determinant for gut microbiota establishment. Expanding our understanding of the influence of complementary diet on the development and establishment of the gut microbiota will provide us with the knowledge to tailor a beneficial progression of our intestinal microbial community.

Association between Perfluorinated Compound Exposure and Miscarriage in Danish Pregnant Women

Perfluorinated alkylated substances (PFAS) have been extensively used in consumer products and humans are widely exposed to these persistent compounds. A recent study found no association between exposure to perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) and miscarriage, but no studies have examined adverse effect of the more recently introduced PFASs. We therefore conducted a case-control study within a population-based, prospective cohort during 2010-2012. Newly pregnant women residing in the Municipality of Odense, Denmark were invited to enroll in the Odense Child Cohort at their first antenatal visit before pregnancy week 12. Among a total of 2,874 participating women, 88 suffered a miscarriage and 59 had stored serum samples, of which 56 occurred before gestational week 12. They were compared to a random sample (N=336) of delivering women, who had also donated serum samples before week 12. Using a case-control design, 51 of the women suffering a miscarriage were matched on parity and gestational day of serum sampling with 204 delivering women. In a multiple logistic regression with adjustment for age, BMI, parity and gestational age at serum sampling, women with the highest tertile of exposure to perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) in pregnancy had odds ratios for miscarriage of 16.5 (95% CI 7.4-36.6-36.5) and 2.67 (1.31-5.44), respectively, as compared to the lowest tertile. In the matched data set, the OR were 37.9 (9.9-145.2) and 3.71 (1.60-8.60), respectively. The association with perfluorohexane sulfonic acid (PFHxS) was in the same direction, but not statistically significant, while no association was found with PFOA and PFOS. Our findings require confirmation due to the possible public health importance, given that all pregnant women are exposed to these widely used compounds.

Vitamin D depletion aggravates hypertension and target-organ damage.

Background We tested the controversial hypothesis that vitamin D depletion aggravates hypertension and target‐organ damage by influencing renin. Methods and Results Four‐week‐old double‐transgenic rats (dTGR) with excess angiotensin (Ang) II production due to overexpression of the human renin (hREN) and angiotensinogen (hAGT) genes received vitamin D‐depleted (n=18) or standard chow (n=15) for 3 weeks. The depleted group had very low serum 25‐hydroxyvitamin D levels (mean±SEM; 3.8±0.29 versus 40.6±1.19 nmol/L) and had higher mean systolic BP at week 5 (158±3.5 versus 134.6±3.7 mm Hg, P<0.001), week 6 (176.6±3.3 versus 162.3±3.8 mm Hg, P<0.01), and week 7 (171.6±5.1 versus 155.9±4.3 mm Hg, P<0.05). Vitamin D depletion led to increased relative heart weights and increased serum creatinine concentrations. Furthermore, the mRNAs of natriuretic peptides, neutrophil gelatinase‐associated lipocalin, hREN, and rRen were increased by vitamin D depletion. Regulatory T cells in the spleen and in the circulation were not affected. Ang metabolites, including Ang II and the counter‐regulatory breakdown product Ang 1 to 7, were significantly up‐regulated in the vitamin D‐depleted groups, while ACE‐1 and ACE‐2 activities were not affected. Conclusions Short‐term severe vitamin D depletion aggravated hypertension and target‐organ damage in dTGR. Our data suggest that even short‐term severe vitamin D deficiency may directly promote hypertension and impacts on renin‐angiotensin system components that could contribute to target‐organ damage. The findings add to the evidence that vitamin D deficiency could also affect human hypertension.

Maternal 25‐hydroxyvitamin D level and fetal bone growth assessed by ultrasound: a systematic review

To assess systematically the role of maternal vitamin D levels in fetal bone growth.

Prediction of preeclampsia with angiogenic biomarkers. Results from the prospective Odense Child Cohort.

ABSTRACT Objective: We aimed to investigate how maternal serum soluble Fms-like kinase 1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio prospectively associate to preeclampsia (PE) and clinical subtypes. Methods: In an unselected cohort of 1909 pregnant women, sFlt-1 and PlGF were measured with KRYPTOR assays in gestational weeks (GW) 8–14 and 20–34. Associations to PE were assessed by receiver operating characteristics and logistic regression. Results: Concentrations of sFlt-1, PlGF, and sFlt-1/PlGF in GW20-34 were predictive of PE development, but not in GW8-14. PlGF outperformed sFlt-1/PlGF ratio with an area under curve (AUC) of 0.755 vs. 0.704, p = 0.002. The highest AUC values for PlGF and sFlt-1/PlGF ratio were seen for severe early-onset PE (0.901 and 0.883). Negative predictive values were high for all PE types, but positive predictive values were low. Conclusion: PlGF and sFlt-1/PlGF had good predictive value for PE at GW20-34 in a population-based unselected cohort, however with low positive predictive value.

Usability, Acceptability, and Adherence to an Electronic Self-Monitoring System in Patients With Major Depression Discharged From Inpatient Wards

Background Patients suffering from depression have a high risk of relapse and readmission in the weeks following discharge from inpatient wards. Electronic self-monitoring systems that offer patient-communication features are now available to offer daily support to patients, but the usability, acceptability, and adherence to these systems has only been sparsely investigated. Objective We aim to test the usability, acceptability, adherence, and clinical outcome of a newly developed computer-based electronic self-assessment system (the Daybuilder system) in patients suffering from depression, in the period from discharge until commencing outpatient treatment in the Intensive Outpatient Unit for Affective Disorders. Methods Patients suffering from unipolar major depression that were referred from inpatient wards to an intensive outpatient unit were included in this study before their discharge, and were followed for four weeks. User satisfaction was assessed using semiqualitative questionnaires and the System Usability Scale (SUS). Patients were interviewed at baseline and at endpoint with the Hamilton depression rating scale (HAM-D17), the Major Depression Inventory (MDI), and the 5-item World Health Organization Well-Being Index (WHO-5). In this four-week period patients used the Daybuilder system to self-monitor mood, sleep, activity, and medication adherence on a daily basis. The system displayed a graphical representation of the data that was simultaneously displayed to patients and clinicians. Patients were phoned weekly to discuss their data entries. The primary outcomes were usability, acceptability, and adherence to the system. The secondary outcomes were changes in: the electronically self-assessed mood, sleep, and activity scores; and scores from the HAM-D17, MDI, and WHO-5 scales. Results In total, 76% of enrolled patients (34/45) completed the four-week study. Five patients were readmitted due to relapse. The 34 patients that completed the study entered data for mood on 93.8% of the days (872/930), sleep on 89.8% of the days (835/930), activity on 85.6% of the days (796/930), and medication on 88.0 % of the days (818/930). SUS scores were 86.2 (standard deviation [SD] 9.7) and 79% of the patients (27/34) found that the system lived up to their expectations. A significant improvement in depression severity was found on the HAM-D17 from 18.0 (SD 6.5) to 13.3 (SD 7.3; P<.01), on the MDI from 27.1 (SD 13.1) to 22.1 (SD 12.7; P=.006), and in quality of life on the WHO-5 from 31.3 (SD 22.9) to 43.4 (SD 22.1; P<.001) scales, but not on self-assessed mood (P=.08). Mood and sleep parameters were highly variable from day-to-day. Sleep-offset was significantly delayed from baseline, averaging 48 minutes (standard error 12 minutes; P<.001). Furthermore, when estimating delay of sleep-onset (with sleep quality included in the model) during the study period, this showed a significant negative effect on mood (P=.03) Conclusions The Daybuilder systems performed well technically, and patients were satisfied with the system and had high adherence to self-assessments. The dropout rate and the gradual delay in sleep emphasize the need for continued clinical support for these patients, especially when considering sleep guidance.

The association between angiogenic markers and fetal sex: implications for preeclampsia research

OBJECTIVE Current research suggests sexual dimorphism between the male and female fetoplacental units, but with unknown relevance for preeclampsia. We investigated the association between fetal sex and concentrations of the angiogenic markers soluble Fms-like kinase 1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in first and second-third trimester in women with/without preeclampsia, and the impact of fetal sex on the prognostic value of angiogenic markers for preeclampsia. STUDY DESIGN Observational study in a prospective, population-based cohort of 2110 singleton pregnancies with 150 preeclampsia cases. RESULTS Higher sFlt-1 concentrations were observed for women carrying female fetuses in first trimester (all, 1107.65 vs. 992.27pg/ml; preeclampsia cases, 1118.79 vs. 934.49pg/ml, p<0.05) and in second-third trimester (all, 1130.03 vs. 1043.15pg/ml; preeclampsia, 1480.30 vs. 1152.86pg/ml, p<0.05), with similar findings for the sFlt-1/PlGF ratio concentrations in first (29.67 vs. 27.39 p<0.05) and second-third trimester (3.56 vs. 3.22, p<0.05). In first trimester, log transformed concentrations of PlGF, sFlt-1 and sFlt-1/PlGF (all participants) and sFlt-1 (preeclampsia cases) associated with fetal sex in adjusted analyses (p<0.05). In second-third trimester, only log(sFlt-1) associated with fetal sex (all, p=0.028; preeclampsia, p=0.067) In receiver operating curve analysis, prediction of early-onset preeclampsia by sFlt-1/PlGF tended to be superior in pregnancies with female vs. male fetuses (p=0.06). CONCLUSION Sexual dimorphism was observed for concentrations of angiogenic markers. Female fetal sex was associated to higher sFlt-1 and sFlt-1/PlGF ratio concentrations in both healthy pregnancies and women developing preeclampsia. Fetal sex should be considered in research and clinical use of angiogenic markers.

Prostasin and matriptase (ST14) in placenta from preeclamptic and healthy pregnant women.

Objective: Preeclampsia is characterized by disturbed placentation, hypertension, proteinuria, and suppression of plasma renin, angiotensin II, and aldosterone. Regulated activity of tissue serine proteases, prostasin, and matriptase is necessary for normal placental development in mice. Prostasin activates the renal epithelial sodium channel. We hypothesized that preeclampsia is associated with low prostasin expression in placenta and spillover of prostasin into urine across the defect glomerular barrier. Methods: In a cross-sectional study, 20 healthy pregnant women and 20 patients suspected of preeclampsia were included. Plasma and urine was obtained before delivery, and placental biopsies were taken immediately after delivery (mean gestational age: control 39 and preeclampsia 38 weeks). Results: Patients with preeclampsia displayed lower levels of aldosterone in plasma and in spot urine normalized for creatinine (P = 0.0001). Prostasin, matriptase, hepatocyte growth factor activator inhibitor type 1 (HAI-1) and 2, and nexin-1 mRNA abundances were not different in placental tissue between groups. Prostasin mRNA in placenta correlated directly with nexin-1 and HAI-1 mRNA, but not with matriptase mRNA. Plasma prostasin and placental homogenate prostasin and nexin-1 protein levels did not differ between groups. Activated, arginine 614 (Arg614)-cleaved matriptase was not detectable in placentas. Western blotting showed significant elevated levels of prostasin in urine from preeclamptic patients that correlated with urine albumin. Placenta and plasma prostasin did not correlate to aldosterone or placental weight. Conclusion: Preeclampsia is not associated with altered prostasin in placenta or plasma at term, but with increased prostasin in urine. An impact of prostasin–matriptase on placental development is likely to be at the level of activity and not protein abundance.