[Show abstract][Hide abstract] ABSTRACT: Context: Adequate thyroid hormone availability during fetal and early life is crucial for normal child growth and development. Fetal growth heavily depends on angiogenesis. Placental growth factor (PlGF) is a proangiogenic factor sharing high homology with vascular endothelial growth factor, whereas soluble FMS-like tyrosine kinase-1 (sFlt1) is a potent antagonist of vascular endothelial growth factor and PlGF signaling. Because the thyroid is a highly vascularized organ, we hypothesized that fetal angiogenic factors influence in utero thyrogenesis and impair newborn thyroid function. Therefore, we investigated the association between sFlt1 and PlGF on newborn thyroid function. Design, Setting, and Participants: sFlt1, PlGF, TSH, and free T4 (FT4) were determined in cord serum of 3525 newborns from a large prospective cohort study. Analyses were adjusted for relevant maternal and child covariates. Results: sFlt1 levels were positively associated with TSH (β, 0.07 ± 0.02 mU/L; P< .001) and inversely with FT4 (β, -0.58 ± 0.11; P< .001). PlGF showed a positive association with FT4 (β, 0.19 ± 0.02; P< .001). Elevated levels of sFlt1 were associated with a 2.8-fold increased risk of hypothyroxinemia (P= .04). Decreased levels of PlGF were associated with a 6.7-fold increased risk of hypothyroxinemia (P< .001). Within the normal range, a dose-dependent effect of sFlt1 on thyroid dysfunction was observed: high-normal sFlt1 levels were associated with a 17.7-fold increased risk of hypothyroxinemia (P< .001) and a 2.7-fold increased risk of hyperthyrotropinemia (P= .01). Conclusion: Fetal angiogenic factors sFlt1 and PlGF are associated with newborn thyroid function. Possible effects are most likely mediated through effects on in utero thyrogenesis. Abnormal as well as normal-range fetal sFlt1 and PlGF levels influence the risk of impaired newborn thyroid function, which has been associated with adverse neurodevelopmental effects. These data provide important novel insights into the physiology of thyrogenesis and into the etiology of newborn thyroid (dys)function.
The Journal of clinical endocrinology and metabolism. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Fetal growth is dependent on adequate development of the placenta. Impaired angiogenesis and vasculogenesis in early pregnancy compromises placental and embryonic development. The proteins soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and plasminogen activator inhibitor type 2 (PAI-2), and the B-vitamin folate are determinants of placental development. This study aims to identify associations between these maternal biomarkers and early fetal size. STUDY DESIGN: From a prospective birth cohort study in the Netherlands, 1,491 pregnant women were selected for this study. At a mean gestational age of 12.4 weeks (SD 0.8) maternal venous blood samples were obtained to determine the concentrations of sFlt-1, PlGF, PAI-2 and folate. Early fetal size was assessed with the measurement of the crown-to-rump length (CRL) at a mean of 12.4 weeks GA (SD 0.8). Analyses were performed using multivariable linear regression analyses with the biomarkers (continuous, quintiles) as regressors and CRL as main outcome measure. RESULTS: Linear trend analysis showed positive associations between maternal sFlt-1 (p<0.001), PlGF (p=0.042), PAI-2 (p<0.001) and folate (p=0.039) and CRL. These associations were independent of gestational age, maternal age, height, body mass index, ethnicity, fetal gender, parity, educational level, smoking and folic acid supplement use (folate not adjusted). CONCLUSION: sFlt-1, PlGF, PAI-2 and folate are positively associated with first trimester fetal size.
American journal of obstetrics and gynecology 04/2013; · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To identify periconceptional maternal dietary patterns associated with crown-rump length (CRL), estimated fetal weight (EFW) and birthweight. DESIGN: Population-based prospective birth cohort study. SETTING: Rotterdam, the Netherlands. PARTICIPANTS: For this study, 847 pregnant Dutch women were eligible. Women were included between 2001 and 2005. METHODS: Information on nutritional intake was collected by a semiquantitative food frequency questionnaire. For extracting dietary patterns, principal component factor analysis was used. Fetal growth was assessed using ultrasound measurements. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used. MAIN OUTCOME MEASURES: Crown-to-rump length, estimated fetal weight in second and third trimester and birthweight. RESULTS: An 'energy-rich dietary pattern' was identified, characterised by high intakes of bread, margarine and nuts. A significant association was shown between a high adherence to this dietary pattern (difference, mm: 2.15, 95% confidence interval 0.79-3.50) and CRL (linear trend analyses P = 0.015). No association was revealed between increasing adherence to this dietary pattern and EFW in second or third trimester, or birthweight. CONCLUSION: This study suggests that increasing adherence to an energy-rich dietary pattern is associated with increased CRL in the first trimester.
BJOG An International Journal of Obstetrics & Gynaecology 11/2012; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Air pollution exposure during pregnancy might affect placental growth and function, which may lead to pregnancy complications. Objective: We prospectively evaluated the associations of maternal air pollution exposure with markers of placental growth and function among 7801 pregnant women in the Netherlands. Methods: PM10 and NO2 levels were estimated at the home address for different periods during pregnancy using dispersion modelling techniques. Pro- and anti-angiogenic factors [placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), respectively] were measured in first and second trimester maternal blood and in fetal cord blood samples at delivery. Pulsatility index of the uterine and umbilical arteries was measured by Doppler ultrasound in second and third trimester and notching was assessed in third trimester. Placenta weight and birth weight were obtained from medical records. Results: Higher PM10 and NO2 exposure levels were associated with lower second trimester maternal sFlt-1 and PlGF levels. PM10 and NO2 exposures averaged over total pregnancy were associated with higher sFlt-1 and lower PlGF levels in fetal cord blood, consistent with an anti-angiogenic state. PM10 and NO2 exposures were not consistently associated with second or third trimester placental resistance indices. NO2 exposure was associated with third trimester notching (odds ratio 1.33; 95% CI: 0.99, 1.78 per 10 μg/m3 increase in the prior two months). PM10 and NO2 exposures were associated with lower placenta weight (-11.8g; 95% CI: -20.9, -2.7 and -10.7; 95% CI: -19.0, -2.4, respectively, per 10 μg/m3 increase in the prior two months), but not with placenta to birth weight ratio. Conclusions: Our results suggest that maternal air pollution exposure may influence markers of placental growth and function. Future studies are needed to confirm these findings and explore the maternal and fetal consequences.
Environmental Health Perspectives 08/2012; · 7.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To estimate whether the imbalance of angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor) and fibrinolytic factors (plasminogen activator inhibitor-2 [PAI-2]) might affect placentation in early pregnancy.
We studied the associations of maternal soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 concentrations in the first trimester (before 18 weeks of gestation) and soluble fms-like tyrosine kinase-1 and placental growth factor concentrations in the second trimester (18-25 weeks of gestation) with placental function and adverse pregnancy outcomes. This study was embedded in a population-based prospective cohort study. Data were used from 7,519 women. Biomarker concentrations were divided into deciles and evaluated in multivariable linear and logistic regression models.
First-trimester high soluble fms-like tyrosine kinase-1 was associated with a 5.2% lower uterine artery index in the second-trimester and a 1.6% higher birth weight (55 g, confidence interval [CI] 15-95). Neither in the first nor in the second trimester were soluble fms-like tyrosine kinase-1 concentrations significantly associated with preeclampsia. First-trimester low placental growth factor was associated with a 6.1% higher uterine artery index and a 3.4% lower birth weight (-115 g, CI -157 to -74). First-trimester low placental growth factor was associated with fetal growth restriction (odds ratio [OR] 2.62, CI 1.68-4.08) and preeclampsia (OR 2.46, CI 1.49-4.08). First-trimester low PAI-2 was associated with a 1.9% higher uterine artery index and a 2.7% lower birth weight (-94 g, CI -136 to -51). First-trimester low PAI-2 was associated with a higher risk of fetal growth restriction (OR 2.22, CI 1.39-3.55).
First-half-of-pregnancy concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 are associated with uteroplacental vascular resistance, placental weight, and birth weight. Moreover, first-trimester placental growth factor and PAI-2 are associated with an increased risk of adverse pregnancy outcomes.
Obstetrics and Gynecology 06/2012; 119(6):1190-200. · 4.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate associations between early pregnancy homocysteine, folate and vitamin B12 concentrations and placental weight, birthweight and adverse pregnancy outcomes.
Population-based birth cohort study.
Rotterdam, the Netherlands.
Cohort of 5805 pregnant women.
To analyse homocysteine, folate and vitamin B12 concentrations, blood was drawn in early pregnancy. These concentrations were divided into quintiles. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used.
Placental weight, birthweight, small for gestational age at birth (SGA) (<5th centile), prematurity and pre-eclampsia.
High homocysteine concentrations (highest quintile) were associated with lower placental weight (difference 30 g; P < 0.001) and birthweight (difference 110 g; P < 0.001), and increased risk of SGA [odds ratio (OR) 1.7; P = 0.006] compared with lowest quintile (reference). Low folate concentrations (lowest quintile) were associated with lower placental weight (difference 26 g; P = 0.001) and birthweight (difference 125 g; P < 0.001), and increased risks of SGA (OR 1.9; P = 0.002), prematurity (OR 2.2; P = 0.002) and pre-eclampsia (OR 2.1; P = 0.04) compared with highest quintile (reference). The risk of developing SGA and pre-eclampsia was substantially higher in women who had higher homocysteine and lower folate concentrations. No associations were found with vitamin B12.
Higher homocysteine and lower folate concentrations in early pregnancy are associated with lower placental weight and birthweight, and higher risk of adverse pregnancy outcomes. These findings suggest that high homocysteine and low folate concentrations in early pregnancy may adversely influence placentation and subsequently affect the success of pregnancy and birth outcomes.
BJOG An International Journal of Obstetrics & Gynaecology 05/2012; 119(6):739-51. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Developmental adaptations due to early nutritional exposures may have permanent health consequences. Studies of diet and fetal size have mainly focused on individual nutrients despite evidence that the pattern of food consumption may be of significance. Hence, we evaluated the associations of dietary habits in early pregnancy (gestational age < 18 weeks) with fetal size, uteroplacental vascular resistance, placental weight and birth weight in a prospective observational study of 3207 Caucasian pregnant mothers in Rotterdam, the Netherlands. Participants completed a semiquantitative FFQ during early pregnancy. Logistic regression analysis was used to predict the occurrence of intra-uterine growth retardation at birth as a function of food intake. The derived solution was considered as the dietary pattern. As it was characterised by higher intakes of fruit, vegetables, vegetable oil, fish, pasta and rice, and lower intakes of meat, potatoes and fatty sauces, it was labelled the 'Mediterranean' diet. The degree of adherence to the diet was positively associated with plasma folate and serum vitamin B12 concentrations and showed an inverse relationship with homocysteine and high-sensitivity C-reactive protein plasma concentrations (P <0·05). Important fetal size and placental parameters were associated with the degree of adherence to the diet, revealing a 72 g lower birth weight (95 % CI - 110·8, - 33·3) and a 15 g lower placental weight (95 % CI - 29·8, - 0·2) for women with low adherence to the diet. To conclude, low adherence to a Mediterranean diet in early pregnancy seems associated with decreased intra-uterine size with a lower placental and a lower birth weight.
The British journal of nutrition 02/2012; 108(8):1399-409. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to air pollution has been associated with higher C-reactive protein (CRP) levels, suggesting an inflammatory response. Not much is known about this association in pregnancy.
We investigated the associations of air pollution exposure during pregnancy with maternal and fetal CRP levels in a population-based cohort study in the Netherlands.
Particulate matter (PM) with an aerodynamic diameter ≤ 10 μm (PM10) and nitrogen dioxide (NO2) levels were estimated at the home address using dispersion modeling for different averaging periods preceding the blood sampling (1 week, 2 weeks, 4 weeks, and total pregnancy). High-sensitivity CRP levels were measured in maternal blood samples in early pregnancy (n = 5,067) and in fetal cord blood samples at birth (n = 4,450).
Compared with the lowest quartile, higher PM10 exposure levels for the prior 1 and 2 weeks were associated with elevated maternal CRP levels (> 8 mg/L) in the first trimester [fourth PM10 quartile for the prior week: odds ratio (OR), 1.32; 95% confidence interval (CI): 1.08, 1.61; third PM10 quartile for the prior 2 weeks: OR, 1.28; 95% CI: 1.06, 1.56]; however, no clear dose-response relationships were observed. PM10 and NO2 exposure levels for 1, 2, and 4 weeks preceding delivery were not consistently associated with fetal CRP levels at delivery. Higher long-term PM10 and NO2 exposure levels (total pregnancy) were associated with elevated fetal CRP levels (> 1 mg/L) at delivery (fourth quartile PM10: OR, 2.18; 95% CI: 1.08, 4.38; fourth quartile NO2: OR, 3.42; 95% CI: 1.36, 8.58; p-values for trend < 0.05).
Our results suggest that exposure to air pollution during pregnancy may lead to maternal and fetal inflammatory responses.
Environmental Health Perspectives 02/2012; 120(5):746-51. · 7.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 28-year-old female vegetarian was referred to a specialist in internal medicine with persistent iron deficiency. Laboratory analysis revealed microcytic anaemia with low ferritin levels but normal total vitamin B12 levels. The red blood cell distribution width, however, showed a very wide variation in red blood cell sizes, indicating a coexisting vitamin B12 deficiency, which was confirmed by the low concentration of active vitamin B12. Another patient, a 69-year-old woman with a history of previous gastric surgery and renal insufficiency as a complication of diabetes mellitus, was suspected to be deficient in vitamin B12, as she had low total vitamin B12 levels and an accumulation of methylmalonic acid and homocysteine in her blood. Testing the total concentration of vitamin B12 alone has insufficient diagnostic accuracy and no accepted gold standard is available for diagnosing vitamin B12 deficiency. With the development of newer tests, such as measuring holotranscobalamin II (concentration of active vitamin B12), atypical and subclinical deficiency states can be recognized. A new approach to diagnosing vitamin B12 deficiency is presented, based upon these 2 case descriptions.
Nederlands tijdschrift voor geneeskunde 01/2012; 156(1):A3595.
[Show abstract][Hide abstract] ABSTRACT: Aim of this study was to investigate the associations of C-reactive protein levels, as marker of low-grade inflammation, with blood pressure development during pregnancy and the risks of gestational hypertensive complications. We also explored the role of maternal BMI in these associations.
High-sensitivity C-reactive protein levels were measured in early pregnancy (median 13.2 weeks, 95% range 9.6-17.6) in 5816 mothers participating in a population-based prospective cohort study in the Netherlands. Blood pressure measurements were performed in each trimester. Information about pregnancy-induced hypertension and preeclampsia was retrieved from hospital charts of the women.
Longitudinal analyses showed that C-reactive protein levels were not associated with SBP and DBP patterns throughout pregnancy. Trimester-specific multivariate linear regression models showed that as compared to low C-reactive protein levels (<5.0 mg/l), elevated levels (≥20.0 mg/l) were associated with maternal SBP and DBP. Elevated C-reactive protein levels in early pregnancy were associated with the risks of pregnancy-induced hypertension [odds ratio (OR) 2.78, 95% confidence interval (CI) 1.66-4.66]. After adjustment for maternal BMI, all associations attenuated.
Our results suggest that first-trimester C-reactive protein levels are associated with SBP and DBP levels throughout pregnancy and with gestational hypertensive complications, but these associations are largely explained by maternal BMI.
Journal of Hypertension 12/2011; 29(12):2413-21. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to evaluate associations between dietary patterns and systolic blood pressure (SBP) and diastolic blood pressure during pregnancy.
This was a prospective study of 3187 pregnant women. Participants completed a food-frequency questionnaire in early pregnancy. The Mediterranean dietary pattern, comprising high intake of vegetables, vegetable oils, pasta, fish, and legumes, and the Traditional dietary pattern, comprising high intake of meat and potatoes, were identified using factor analysis.
A higher SBP was observed among mothers with high Traditional pattern adherence. Low adherence to the Mediterranean pattern was also associated with higher SBP but only in early and mid pregnancy. A higher diastolic blood pressure throughout pregnancy was observed in mothers with high adherence to the Traditional pattern and low adherence to the Mediterranean pattern. These effect estimates were most pronounced in mid pregnancy.
Low adherence to a Mediterranean and high adherence to a Traditional dietary pattern is associated with a higher blood pressure in pregnancy.
American journal of obstetrics and gynecology 05/2011; 205(4):337.e1-12. · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to examine the associations of maternal C-reactive protein (CRP) levels with fetal growth and the risks of neonatal complications.
CRP levels were measured in early pregnancy in 6016 women. Main outcome measures were fetal growth in each trimester and neonatal complications.
As compared to the reference group (CRP levels<5 mg/L), elevated maternal CRP levels (≥25 mg/L) were associated with lower estimated fetal weight in third trimester and lower weight at birth (differences: -29 g, 95% confidence interval [CI], -58 to 0 and -128 g, 95% CI, -195 to -60, respectively). Elevated maternal CRP levels were also associated with an increased risk of a small size for gestational age in the offspring (adjusted odds ratio, 2.94; 95% CI, 1.61-5.36).
Maternal CRP levels in early pregnancy are associated with fetal growth restriction and increased risks of neonatal complications.
American journal of obstetrics and gynecology 04/2011; 205(2):132.e1-12. · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the cell content and purity of Ficoll-separated peripheral blood mononuclear cells and granulocyte isolates in sepsis patients compared to healthy controls.
Prospective study in the adult and pediatric intensive care departments of the Erasmus University Medical Center in the Netherlands.
Three sepsis patients (two adults, one child) and four healthy controls.
Blood leukocytes were separated by Ficoll into an interface and a bottom fraction. The cell content and purity was analyzed by cytospin and flow-cytometric immunofluorescence. In sepsis patients, the interface consisted of 11-52% mononuclear cells only, due to high contamination with granulocytes (48-89%). This was in contrast to a high proportion of mononuclear cells (88-100%) in healthy controls. The bottom fraction showed a cell purity of >or=92% polymorphonuclear granulocytes in sepsis patients as well as in healthy controls.
Ficoll-separated leukocytes of sepsis patients are not suitable for studying mononuclear cells but can be used for studying granulocytes with high purity. The mononuclear cell fraction is highly contaminated with granulocytes. Additional separation techniques are necessary to obtain a pure cell fraction.
Intensive Care Medicine 05/2008; 34(5):912-6. · 5.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic variants in immunomodulating genes have been suggested to contribute to the risk of cardiovascular disease. Glucocorticoids are important regulators of inflammatory processes and the immune system. Our aim was to determine the contribution of genetic glucocorticoid receptor variants, with different cortisol sensitivities, to the risk of cardiovascular disease.
The study was conducted in a large (n=7983) population-based, prospective cohort of the Rotterdam Study. The mean duration of follow-up was 8.9 years. Measures of cardiovascular disease were incident myocardial infarction, coronary heart disease, high-sensitivity C-reactive protein level, interleukin 6 level, and arteria carotis intima-media thickness.
Persons homozygous for haplotype 3, which is a common variant of the glucocorticoid receptor gene, had a more than 2-fold increased risk of myocardial infarction (hazard ratio, 2.1; 95% confidence interval, 1.13-4.07) and an almost 3-fold increased risk of coronary heart disease (hazard ratio, 2.6; 95% confidence interval, 1.40-4.81) compared with nonhomozygous persons. In addition, their C-reactive protein and interleukin 6 levels were higher, and carotis intima-media thickness was greater. No associations were found for the other haplotypes.
The glucocorticoid receptor gene haplotype 3 is a common genetic variant and is related to a more active proinflammatory system. This haplotype is associated with the risk of cardiovascular disease and its parameters. These results should be regarded as hypothesis generating until they have been replicated in other studies. Our findings suggest that genetically determined cortisol sensitivity is involved in the pathogenesis of cardiovascular disease and might identify a subgroup at risk.
Archives of Internal Medicine 02/2008; 168(1):33-9. · 11.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The glucocorticoid receptor (GR) is widely expressed in various tissues throughout the human body. At least three different 3'-splice variants of the GR have been reported: GR-alpha, which is functionally active; GR-beta, which is a dominant negative inhibitor of GR-alpha function; and GR-P, which is thought to activate the function of GR-alpha. At least seven different variants for exon 1 exist, 1A-1F and 1H, each with its own promoter. In this study, we explored if tissue-specific splicing of the 3'-end variants of the GR is influenced by alternative promoter usage. cDNAs of different tissues and cell lines were used to investigate which part of transcripts carrying each of the three major variants for exons 1, 1A, 1B, or 1C, encodes for the splice variants GR-alpha, GR-beta, and GR-P. Our data demonstrate that the expression of GR-alpha is preferentially regulated by promoter 1C and that for the expression of GR-P promoter 1B is predominantly used. This indicates that regulation of GR splice variants could partly occur through selective use of the multiple promoters, and that this is another way to sensitize cells and tissues to the different activities of the GR isoforms.
Journal of Molecular Endocrinology 03/2007; 38(1-2):91-8. · 3.58 Impact Factor