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    Hypospadias is a congenital malformation with both environmental factors and genetic predisposition involved in the pathogenesis. The role of maternal periconceptional folic acid supplement use in the development of hypospadias is... more
    Hypospadias is a congenital malformation with both environmental factors and genetic predisposition involved in the pathogenesis. The role of maternal periconceptional folic acid supplement use in the development of hypospadias is unclear. As folate levels may also be influenced by the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, we hypothesize that a gene-environment interaction between this polymorphism and folic acid use is involved in the etiology of hypospadias. We conducted a case-control study among 855 hypospadias cases and 713 population-based controls from the AGORA data- and biobank. Folic acid supplement use was derived from maternal questionnaires and infant and maternal DNA was used to determine the MTHFR C677T polymorphism using Taqman assays. We performed separate analyses for different hypospadias phenotypes (anterior/middle/posterior). Hypospadias was neither associated with folic acid use or the MTHFR C677T polymorphism, nor with their interaction. However, we did find an association with middle hypospadias when no supplements were used (odds ratio = 1.6; 95% confidence interval, 1.1-2.4), especially in infants carrying the CT/TT genotype (odds ratio = 2.5; 95% confidence interval, 1.4-4.7). In addition, more infants with these genotypes seemed to have posterior hypospadias, regardless of folic acid use. Our study does not suggest a major role for folic acid supplements or the MTHFR C677T polymorphism in the etiology of hypospadias in general, but not using folic acid and/or carrying the MTHFR C677T polymorphism may be associated with middle and posterior hypospadias. Therefore, we stress the importance of studying gene-environment interactions preferably in stratified analyses for different hypospadias phenotypes. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc.
    From the *Department of Occupational Medicine, Åarhus University Hospital, Aarhus, Denmark; the †Department of Epidemiology & Public Health, Imperial College, London, UK; the ‡Department of Epidemiology and... more
    From the *Department of Occupational Medicine, Åarhus University Hospital, Aarhus, Denmark; the †Department of Epidemiology & Public Health, Imperial College, London, UK; the ‡Department of Epidemiology and Biostatistics, Finnish Institute of Occupational ...
    is missing (Short communication).
    Male injecting drug users drove the onset of the HIV epidemic in Indonesia but over time more women have been diagnosed. We examined the relative proportion of female patients in an HIV cohort and characterized their probable transmission... more
    Male injecting drug users drove the onset of the HIV epidemic in Indonesia but over time more women have been diagnosed. We examined the relative proportion of female patients in an HIV cohort and characterized their probable transmission route and reproductive profile. Prospective cohort study in a referral hospital in West Java. Interviews with standardized questionnaires, physical and laboratory examinations were done for 2622 individuals enrolled in HIV care between 2007 and 2012. The proportion of women in this cohort was compared with national estimates. The general characteristics of HIV-infected women and men as well as the sexual and reproductive health of HIV-infected women were described. The proportion of female patients enrolled in HIV care increased from 22.2 % in 2007 to 38.3 % in 2012, in line with national estimates. Women were younger than men, fewer reported a history of IDU (16.1 vs. 73.8 %, p < 0.001) and more were tested for HIV because of a positive partner (25.5 vs. 4.0 %, p < 0.001). The majority of women were in their reproductive age, had children, and were not using contraceptives at the time of enrolment. HIV-infected women in Indonesia have specific characteristics that differ them from women in the general population. Further research to elucidate the characteristics of women exposed to HIV, their access to testing and care and sexual and reproductive needs can help reduce transmission to women and children in the context of concentrated HIV epidemic in Indonesia.
    The aim of this retrospective study was to assess the fetal biparietal diameter (BPD) and head circumference (HC) in the second trimester of pregnancy in fetuses with open spinal dysraphism. BPD and HC were measured at 16-26 weeks in 74... more
    The aim of this retrospective study was to assess the fetal biparietal diameter (BPD) and head circumference (HC) in the second trimester of pregnancy in fetuses with open spinal dysraphism. BPD and HC were measured at 16-26 weeks in 74 fetuses with open spinal dysraphism and compared with reference values. BPD was smaller in fetuses with open spinal dysraphism. Of all cases with open spinal dysraphism, 62.2% had a BPD <3rd percentile and 79.7% had a BPD <10th percentile. Of all patients, 54.1% had an HC <3rd percentile and 74.3% had an HC <10th percentile. Almost all fetuses with open neural tube defects have a smaller BPD and HC at 16-26 weeks compared with reference values, which implicates that this is part of the phenotype of children with open spinal dysraphism instead of an independent prognostic marker for a poor cognitive outcome. © 2014 S. Karger AG, Basel.
    The Pilcomayo River is polluted by tailings and effluents from upstream mining activities, which contain high levels of metals. The Weenhayek live along this river and are likely to have elevated exposure. To assess whether the Weenhayek... more
    The Pilcomayo River is polluted by tailings and effluents from upstream mining activities, which contain high levels of metals. The Weenhayek live along this river and are likely to have elevated exposure. To assess whether the Weenhayek have increased risk of reproductive and developmental disorders related to elevated metal exposure in comparison with a reference population. We assessed reproductive and developmental outcomes, i.e. fertility, fetal loss, congenital anomalies, and walking onset by means of structured interviews. We sampled hair, water and fish to assess the relative exposure of the Weenhayek. Samples were analyzed for Pb and Cd with ICP-MS techniques. The Weenhayek communities studied had a higher prevalence of small families (OR 2.7, 95% CI 1.3-6.0) and delayed walking onset (OR 2.7, 95% CI 1.4-5.1) than the reference population. Median Pb levels in Weenhayek hair were 2-5 times higher than in the reference population, while Cd levels were not elevated. In water and fish, both Pb and Cd levels were increased in the Weenhayek area. We found indications for increased risks of small families and delayed walking onset among the Weenhayek living along the Pilcomayo River. Lactants form a high risk group for lead exposure.
    Searching for a tool to quantify motor impairment in spina bifida, transcranial and lumbar magnetic stimulation were applied in affected newborn infants. Lumbar magnetic stimulation resulted in motor evoked potentials in both the... more
    Searching for a tool to quantify motor impairment in spina bifida, transcranial and lumbar magnetic stimulation were applied in affected newborn infants. Lumbar magnetic stimulation resulted in motor evoked potentials in both the quadriceps muscle and the tibialis anterior muscle in most (11/13) subjects. However, transcranial magnetic stimulation did not lead to any response at all. A strong left-to-right correlation existed for amplitude and for latency. Lumbar magnetic stimulation proved to be applicable in newborn infants with spina bifida. Although current concepts regarding spina bifida suppose lower motor neuron dysfunction, the results of this study suggest that lower motor neuron integrity is at least partly preserved after birth. Transcranial magnetic stimulation does not lead to responses in healthy newborn infants because of insufficient synaptogenesis, myelinogenesis, and axon thickness. Therefore, conclusions on upper motor neuron function in spina bifida cannot be drawn. To what extent the method used here can achieve the aim of quantifying motor impairment is a matter of further study.
    Spina bifida is a complex neuroembryological disorder resulting from incomplete closure of the posterior neural tube. Morbidity in the different fields of motor and cognitive neurodevelopment is variable in nature and severity, and often... more
    Spina bifida is a complex neuroembryological disorder resulting from incomplete closure of the posterior neural tube. Morbidity in the different fields of motor and cognitive neurodevelopment is variable in nature and severity, and often hard to predict. The current study investigates the relationship between cognitive functioning, fine motor performance and motor quality in children with spina bifida myelomeningocele (SBM) and SB-only, taking into consideration the cerebral malformations. Forty-one children were included (22 girls and 19 boys aged between 6 and 14 years, mean age 10;0 years) in the study. A comprehensive assessment was conducted of cognitive functioning and motor profile, including fine motor and visual-motor functioning, and motor quality. The performance outcomes were analyzed for the total group of children and separately for the nonretarded children (FSIQ> or =70, N=30) to eliminate the influence of global intellectual impairment. Although the children with spina bifida showed increased incidence of cognitive and fine motor impairment, and impaired motor quality, after exclusion of the overall retarded children no associations were found between cognitive functioning and motor profile. In the comparison of SBM to SB-only specific differences were found for performance IQ, visual-motor functioning and motor quality, but not fine motor functioning. Our findings underscore the role of cerebral malformation in spina bifida and its consequences for neuropsychological functioning. The complicated developmental interactions found strengthen the need for an individualized management of children with SB.
    MEPs and CMAPs as prognostic tools for spina bifida. The aim of this prospective study was to determine the prognostic value of neurophysiological investigations compared to clinical neurological examination in infants with spina bifida.... more
    MEPs and CMAPs as prognostic tools for spina bifida. The aim of this prospective study was to determine the prognostic value of neurophysiological investigations compared to clinical neurological examination in infants with spina bifida. Thirty-six neonates born with spina bifida between 2002 and 2007 were evaluated and followed for 2 years. Lumbar motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were obtained at the median age of 2 days old before surgical closure of the spinal anomaly. MEPs were recorded from the quadriceps femoris, tibialis anterior, and gastrocnemius muscles and CMAPs from the latter two muscles. Areas under the curve and latencies of the MEPs and CMAPs were measured. Clinical neurological outcome at the age of 2 years was described using Muscle Function Classes (MFCs) and ambulation status. The areas under the curve of MEPs and CMAPs in the legs were associated with lower neonatal levels of motor and sensory impairment. Better muscle function class of the lower limbs at 2 years of age was associated with larger MEP and CMAP areas of the gastrocnemius and tibialis anterior muscles at neonatal age. MEPs and CMAPs of the gastrocnemius and tibialis anterior muscles are of prognostic value for clinical neurological outcome in neonates born with spina bifida.
    The aim of this study was to systematically review and meta-analyse observational studies on prenatal maternal psychological stress and the subsequent development of asthma and wheezing in early childhood.All available published... more
    The aim of this study was to systematically review and meta-analyse observational studies on prenatal maternal psychological stress and the subsequent development of asthma and wheezing in early childhood.All available published literature from 1960 until November 2013 was systematically searched through electronic databases (PubMed, Embase, PsycInfo and Web of Science). All observational studies assessing associations between any form of prenatal maternal psychological stress and respiratory morbidity in the child were included. Data extraction, quality assessment and meta-analyses were performed.The overall meta-analysis included 10 studies and showed that the prevalence of wheezing, asthma and other respiratory symptoms is higher in children of mothers who were exposed to or experienced some form of psychological stress during pregnancy than in mothers who did not (pooled OR 1.56 (95% CI 1.36-1.80)). Comparable results were observed in subgroup analyses of stress exposure, perceived stress, asthma and wheezing.This study demonstrates that prenatal maternal psychological stress is associated with respiratory morbidity, including asthma and wheezing in the child. Future studies examining the early origins of asthma and wheezing need to account for the impact of prenatal maternal stress.
    Hypospadias is a frequent birth defect with three phenotypic subtypes. With data from the National Birth Defects Prevention Study, a large, multi-state, population-based, case-control study, we compared risk factors for second and third... more
    Hypospadias is a frequent birth defect with three phenotypic subtypes. With data from the National Birth Defects Prevention Study, a large, multi-state, population-based, case-control study, we compared risk factors for second and third degree hypospadias. A wide variety of data on maternal and pregnancy-related risk factors for isolated second and third degree hypospadias was collected by means of computer-assisted telephone interviews to identify potential etiological differences between the two phenotypes. Logistic regression was used to calculate odds ratios including a random effect by study center. In total, 1547 second degree cases, 389 third degree cases, and 5183 male controls were included in our study. Third degree cases were more likely to have a non-Hispanic black or Asian/Pacific Islander mother, be delivered preterm, have a low birth weight, be small for gestational age, and be conceived with fertility treatments than second degree cases and controls. Associations wit...
    Studies on associations between periconceptional cannabis exposure and birth defects have mainly relied on self-reported exposure. Therefore, the results may be biased due to under-reporting of the exposure. The aim of this study was to... more
    Studies on associations between periconceptional cannabis exposure and birth defects have mainly relied on self-reported exposure. Therefore, the results may be biased due to under-reporting of the exposure. The aim of this study was to quantify the potential effects of this form of exposure misclassification. Using multivariable logistic regression, we re-analysed associations between periconceptional cannabis use and 20 specific birth defects using data from the National Birth Defects Prevention Study from 1997-2005 for 13 859 case infants and 6556 control infants. For seven birth defects, we implemented four Bayesian models based on various assumptions concerning the sensitivity of self-reported cannabis use to estimate odds ratios (ORs), adjusted for confounding and under-reporting of the exposure. We used information on sensitivity of self-reported cannabis use from the literature for prior assumptions. The results unadjusted for under-reporting of the exposure showed an association between cannabis use and anencephaly (posterior OR 1.9 [95% credible interval (CRI) 1.1, 3.2]) which persisted after adjustment for potential exposure misclassification. Initially, no statistically significant associations were observed between cannabis use and the other birth defect categories studied. Although adjustment for under-reporting did not notably change these effect estimates, cannabis use was associated with esophageal atresia (posterior OR 1.7 [95% CRI 1.0, 2.9]), diaphragmatic hernia (posterior OR 1.8 [95% CRI 1.1, 3.0]), and gastroschisis (posterior OR 1.7 [95% CRI 1.2, 2.3]) after correction for exposure misclassification. Under-reporting of the exposure may have obscured some cannabis-birth defect associations in previous studies. However, the resulting bias is likely to be limited.
    Birth defects may originate through multiple mechanisms and may be caused by a variety of possible exposures, including medications in early pregnancy. In this review, we describe six principal teratogenic mechanisms suspected to be... more
    Birth defects may originate through multiple mechanisms and may be caused by a variety of possible exposures, including medications in early pregnancy. In this review, we describe six principal teratogenic mechanisms suspected to be associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption, and specific receptor- or enzyme-mediated teratogenesis. Knowledge about these mechanisms, for some of which evidence is mainly derived from animal models, may not only be relevant for etiologic and post-marketing research, but may also have implications for prescribing behavior for women of reproductive age. Since combinations of seemingly unrelated medications may have effects through similar teratogenic mechanisms, the risk of birth defects may be strongly increased in multi-therapy.
    Illicit drug use is associated with risky sexual behaviors in adolescents and young adults. However, few studies have examined these associations among drug users of all reproductive ages, using a control group of nonusers. Associations... more
    Illicit drug use is associated with risky sexual behaviors in adolescents and young adults. However, few studies have examined these associations among drug users of all reproductive ages, using a control group of nonusers. Associations between marijuana and cocaine use, and outcomes related to sexual behaviors and reproductive health, were assessed using data from the 2002 National Survey of Family Growth. Overall, 4,928 men and 7,643 women aged 15-44 were interviewed. Chi-square tests, t tests and multivariable logistic regression analyses were used; in supplementary analyses, men and women were stratified by age-group (25 or younger, and older than 25), to capture the understudied older adults who use drugs. Twenty-seven percent of men and 16% of women reported use of marijuana or cocaine in the last year. Drug users were younger than nonusers at first vaginal sex (mean, 15.2-16.1 vs. 17.3-17.5 years) and were more likely to have engaged in risky sexual behaviors in the last year, including having had sex with a nonmonogamous partner (odds ratios, 3.3-5.2 for men and 2.9-6.5 for women), while high on alcohol or drugs (10.1-18.0 and 8.1-24.2), or in exchange for money or drugs (2.7-2.8 and 2.3-9.2). They also were more likely to have undergone STD testing or treatment. Drug use was associated with risky sexual behaviors in both age-groups. Programs aimed at reducing sexual risks among drug users should address the behaviors of men and women of all reproductive ages.
    Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we... more
    Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously ...
    From the *Department of Occupational Medicine, Åarhus University Hospital, Aarhus, Denmark; the †Department of Epidemiology & Public Health, Imperial College, London, UK; the ‡Department of Epidemiology and... more
    From the *Department of Occupational Medicine, Åarhus University Hospital, Aarhus, Denmark; the †Department of Epidemiology & Public Health, Imperial College, London, UK; the ‡Department of Epidemiology and Biostatistics, Finnish Institute of Occupational ...
    In 2004, the Survey on Drug Use and Health showed that 5% of American women reported use of an illicit drug during pregnancy. The results of studies determining the association between periconceptional illicit drug use and birth defects... more
    In 2004, the Survey on Drug Use and Health showed that 5% of American women reported use of an illicit drug during pregnancy. The results of studies determining the association between periconceptional illicit drug use and birth defects have been inconsistent. We analyzed data from the National Birth Defects Prevention Study, a case-control study of major birth defects, and assessed all birth defects categories in which there were at least 250 interviewed case mothers. We included 10,241 infants with major congenital malformations (case infants) and 4,967 infants without major congenital malformations (control infants) born between 1997 and 2003 for whom there was a completed maternal interview with detailed information on prenatal illicit drug use and potential confounders. We used multivariable logistic regression to estimate the associations between cannabis, cocaine, and stimulant use in the month before pregnancy or during the first trimester (periconceptional period) and the occurrence of selected birth defects. In the periconceptional period, 5% of the 15,208 mothers reported any use of illicit drugs. We did not find associations between illicit drug use and most of the 20 eligible categories of congenital malformations. Periconceptional cannabis use seemed to be associated with an increased risk of anencephaly (adjusted odds ratio = 1.7; 95% confidence interval = 0.9-3.4), whereas cocaine use in the periconceptional period was associated with the risk of cleft palate (2.5; 1.1-5.4). There were very few suggestions of positive associations between periconceptional illicit drug use and the 20 birth defects categories.
    In case-control studies that assess associations between medication use and birth defects, detailed information on type of medication and timing of use is essential to prevent misclassification. However, data on the accuracy of recall of... more
    In case-control studies that assess associations between medication use and birth defects, detailed information on type of medication and timing of use is essential to prevent misclassification. However, data on the accuracy of recall of medication use during pregnancy are scarce. The aim of this study was to validate a self-administered questionnaire to assess prescription medication use in the 3 months before and during pregnancy. This validation study was embedded in Eurocat Northern Netherlands, a population-based birth defects registry that covers 10% of all births in The Netherlands. The questionnaire was validated among 560 mothers of infants with major birth defects registered from 1 January 2009 through 30 June 2010 by comparing it with a reference standard consisting of pharmacy data which were checked for compliance by maternal interviews. Sensitivity and specificity were calculated to quantify validity for any prescription medication use, groups of medications and individual medications. In addition, we determined whether maternal characteristics influenced disagreement between the questionnaire and the reference standard using logistic regression analyses. The sensitivity for any prescription medication use was 0.57, ranging between 0.07 (dermatological corticosteroids) and 0.83 (antihypertensives) for medication groups, and between 0.00 (naproxen) and 0.73 (salbutamol) for individual medications. Overall, specificity was high (0.93-1.00). Smoking during pregnancy and completing the questionnaire>2 years after delivery were associated with increased disagreement between the questionnaire for prescription medication use and the reference standard. The validity of the self-administered questionnaire for prescription medication use during pregnancy was moderate to poor for most medications and disagreement differed by some maternal characteristics. As many epidemiological studies use similar questionnaires to assess medication use these studies may need additional data sources such as pharmacy records or prescription databases for medication use next to self-reported methods. Also, previous knowledge on the effect of questionnaire design should be taken into account.
    OBJECTIVES: Female greenhouse workers, who constitute a major occupational group exposed to pesticides at childbearing age, were studied to measure the effects of pesticide exposure on time to pregnancy. METHODS: Data were collected... more
    OBJECTIVES: Female greenhouse workers, who constitute a major occupational group exposed to pesticides at childbearing age, were studied to measure the effects of pesticide exposure on time to pregnancy. METHODS: Data were collected through postal questionnaires with detailed questions on time to pregnancy, lifestyle factors (eg, smoking habits, coffee and alcohol consumption), and worktasks (eg, application of pesticides, re-entry activities,
    The hypothesis that intrauterine exposure to hairdressers' chemicals adversely affects neurodevelopment of the offspring was investigated. Neurodevelopmental characteristics were analysed using a historical cohort study of... more
    The hypothesis that intrauterine exposure to hairdressers' chemicals adversely affects neurodevelopment of the offspring was investigated. Neurodevelopmental characteristics were analysed using a historical cohort study of reproductive disorders among hairdressers in The Netherlands. Because exposure in hair salons to agents toxic to reproductive processes might have changed over time, two specific study periods were examined: from 1986 to 1988 and from 1991 to 1993. Nine thousand hairdressers and 9000 clothing sales clerks (referent group) who were in the reproductive age in the defined study periods were selected by the trade association for service jobs. Frequency matching assured comparability with regard to age. All women were invited by mail to complete a short self-administered questionnaire on their reproductive history, including questions on the ages of their child at the times of the first words, first sentences, and first steps, and the occurrence of seizures during fever. The results showed that in 1986 to 1988 more children of hairdressers started speaking their first words after 15 months and their first sentences after 24 months. For 1991 to 1993 no increased risks of these outcomes were found. Seizures during fever had occurred more often among children of hairdressers in 1986 to 1988, and in 1991 to 1993, especially when women had been working until maternity leave. Although the quality of the data in this explorative study requires careful interpretation, the consistent results seem to indicate adverse effects on neurodevelopment among offspring of hairdressers in the earlier years (1986 to 1988). In the later years the effect seemed to be disappearing. However, these findings should be confirmed in more detailed studies.

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