Rapporteur report: cellular, animal and epidemiological studies of the effects of static magnetic fields relevant to human health

Three talks were presented in the session on “Cellular, Animal and Epidemiological Studies of the Effects of Static Magnetic Fields Relevant to Human Health”. The first talk presented the in vitro effects of static magnetic fields on cell cultures. The second talk presented the in vivo evidence obtained from animal studies. The final, third talk, presented the evidence obtained from epidemiological studies.

The overall conclusion of the three presentations and the following general discussion was that the scientific evidence available to date is weak and contains large gaps in knowledge either due to the poor quality of published studies or because of the lack of published research on certain health-related topics.

It was emphasized that the rapid development of new technological applications of static magnetic fields (e.g. magnetic levitation trains or magnetic resonance imaging—MRI) results in the human population at large, in certain occupations, and in a selected population of clinical patients being exposed to ever increasing static magnetic field strengths. It is of concern that the knowledge presently available concerning the health effects of these strong static magnetic fields is lagging a long way behind technological development.

In conclusion, it was suggested that there is an urgent need to perform new studies in all research areas (in vitro, in vivo and epidemiology) in order to fill the present gaps in knowledge and provide assurance that this technology will not cause any unwanted and unexpected health side effects.     

Epidemiological studies on adverse effects of prenatal ultrasound--which are the challenges?

A large number of foetuses are scanned on a routine basis and although it is generally assumed that prenatal ultrasound is safe; very few studies have in fact focused on possible adverse effects in humans. The epidemiological tools when studying possible adverse effects of prenatal ultrasound are randomised controlled trials and observational studies such as cohort and case–control studies. There are advantages and disadvantages with all study designs. In this review, some of the challenges that have to be met are discussed based on experiences from a randomised controlled trial, cohort studies and an ongoing case–control study.     

Are pre- or postnatal diagnostic X-rays a risk factor for childhood cancer? A systematic review

The risk of cancer after diagnostic X-rays received as fetus or during early childhood has been investigated in many studies. The results of recent epidemiological studies are summarized in a present systematic review. The strategies for literature search, inclusion criteria, and items for study quality assessment were defined in the study protocol. All epidemiological case control and cohort studies published in English between 1990 and 2006 that reported at least the size of the study population and risk estimates were included. Results were summarized separately for pre- and postnatal exposure and for each cancer site. Nineteen case control studies and six cohort studies matched the inclusion criteria. No association of leukemia with prenatal exposures was observed in nine case control studies. Heterogeneous results were found for postnatal exposures and leukemia in four studies. No significant effect of pre- and postnatal X-ray exposure was observed for other cancer sites (non-Hodgkin lymphomas, solid tumors and brain tumors). Most studies have limitations in study design, study size, or exposure measurement, and involve very low exposures. These results thus do not contradict previous evidence accumulated since 1956 indicating risk increases associated with prenatal X-ray exposure. Computed tomography is not covered in the studies and needs to be investigated in the future.     

Epidemiological prenatal ultrasound studies

Epidemiological studies have indicated no association between diagnostic ultrasound exposure during pregnancy and childhood malignancies. Diagnostic ultrasound imaging does not seem to influence birth weight, whereas frequent Doppler ultrasound was associated with reduced birth weight in one study. Most experts do not believe that ultrasound exposure during pregnancy is associated with reduced birth weight. There are no confirmed statistically significant associations between ultrasound and dyslexia and neurological development during childhood. However, two randomised controlled trials and two cohort studies have been unable to rule out a possible association between ultrasound and left-handedness among males.     

Exposure to extremely low-frequency magnetic fields and the risk of childhood cancer: update of the epidemiological evidence

There is an ongoing scientific controversy whether the observed association between exposure to residential extremely low-frequency magnetic fields (ELF-MF) and the risk of childhood leukaemia observed in epidemiological studies is causal or due to methodological shortcomings of those studies. Recent pooled analysis confirm results from previous studies, namely an approximately two-fold risk increase at ELF-MF exposures ≥0.4 μT, and demonstrate consistency of studies across countries, with different design, different methods of exposure assessment, and different systems of power transmission and distribution. On the other hand, recent pooled analyses for childhood brain tumour show little evidence for an association with ELF-MF, also at exposures ≥0.4 μT. Overall, the assessment that ELF-MF are a possible carcinogen and may cause childhood leukaemia remains valid. Ongoing research activities, mainly experimental and few new epidemiological studies, hopefully provide additional insight to bring clarity to a research area that has remained inconclusive.     

Utilizing Longitudinal Measures of Fetal Growth to Create a Standard Method to Assess the Impacts of Maternal Disease and Environmental Exposure

Impaired or suboptimal fetal growth is associated with an increased risk of perinatal morbidity and mortality. By utilizing readily available clinical data on the relative size of the fetus at multiple points in pregnancy, including delivery, future epidemiological research can improve our understanding of the impacts of maternal, fetal, and environmental factors on fetal growth at different windows during pregnancy. This study presents mean and standard deviation ultrasound measurements from a clinically representative US population that can be utilized for creating Z-scores to this end. Between 2006 and 2012, 18, 904 non-anomalous pregnancies that received prenatal care, first and second trimester ultrasound evaluations, and ultimately delivered singleton newborns at Brigham and Women’s hospital in Boston were used to create the standard population. To illustrate the utility of this standard, we created Z-scores for ultrasound and delivery measurements for a cohort study population and examined associations with factors known to be associated with fetal growth. In addition to cross-sectional regression models, we created linear mixed models and generalized additive mixed models to illustrate how these scores can be utilized longitudinally and for the identification of windows of susceptibility. After adjustment for a priori confounders, maternal BMI was positively associated with increased fetal size beginning in the second trimester in cross-sectional models. Female infants and maternal smoking were associated with consistently reduced fetal size in the longitudinal models. Maternal age had a non-significant association with increased size in the first trimester that was attenuated as gestation progressed. As the growth measurements examined here are widely available in contemporary obstetrical practice, these data may be abstracted from medical records by investigators and standardized with the population means presented here. This will enable easy extension of clinical data to epidemiologic studies investigating novel maternal, fetal, and environmental factors that may impact fetal growth.     

BMD-associated variation at the Osterix locus is correlated with childhood obesity in females

Recent genome wide association studies (GWAS) have revealed a number of genetic variants robustly associated with bone mineral density (BMD) and/or osteoporosis. Evidence from epidemiological and clinical studies has shown an association between BMD and BMI, presumably as a consequence of bone loading. We investigated the 23 previously published BMD GWAS-derived loci in the context of childhood obesity by leveraging our existing genome-wide genotyped European American cohort of 1106 obese children (BMI ≥ 95th percentile) and 5997 controls (BMI < 95th percentile). Evidence of association was only observed at one locus, namely Osterix (SP7), with the G allele of rs2016266 being significantly over-represented among childhood obesity cases (P = 2.85 × 10(-3)). When restricting these analyses to each gender, we observed strong association between rs2016266 and childhood obesity in females (477 cases and 2867 controls; P = 3.56 × 10(-4)), which survived adjustment for all tests applied. However, no evidence of association was observed among males. Interestingly, Osterix is the only GWAS locus uncovered to date that has also been previously implicated in the determination of BMD in childhood. In conclusion, these findings indicate that a well established variant at the Osterix locus associated with increased BMD is also associated with childhood obesity primarily in females.     

Prenatal exposure to diurnal temperature variation and early childhood pneumonia

BackgroundChildhood pneumonia is one of the leading single causes of mortality and morbidity in children worldwide, but its etiology still remains unclear.ObjectiveWe investigate the association between childhood pneumonia and exposure to diurnal temperature variation (DTV) in different timing windows.MethodsWe conducted a prospective cohort study of 2,598 children aged 3–6 years in Changsha, China. The lifetime prevalence of pneumonia was assessed by a questionnaire administered by the parents. Individual exposure to DTV during both prenatal and postnatal periods was estimated. Logic regression models was used to examine the association between childhood pneumonia and DTV exposure in terms of odds ratios (OR) and 95% confidence interval (CI).ResultsLifetime prevalence of childhood pneumonia in preschool children in Changsha was high up to 38.6%. We found that childhood pneumonia was significantly associated with prenatal DTV exposure, with adjusted OR (95%CI) =1.19 (1.02–1.38), particularly during the second trimester. However, childhood pneumonia not associated with postnatal DTV exposure. Sensitivity analysis indicated that boys are more susceptible to the pneumonia risk of diurnal temperature variation than girls. We further observed that the prevalence of childhood pneumonia was decreased in recent years as DTV shrinked.ConclusionsEarly childhood pneumonia was associated with prenatal exposure to the diurnal temperature variation (DTV) during pregnancy, particularly in the second trimester, which suggests fetal origin of childhood pneumonia.     

Descriptive epidemiology of small-bowel atresia in metropolitan Atlanta.

The epidemiological characteristics are presented of 46 children with small-bowel atresia, ascertained over a 6-year period by an active, population-based birth defect surveillance program in Atlanta, Georgia. The malformation occurred at a rate of 2.7/10,000 livebirths. The previously reported association of duodenal atresia and Down syndrome was confirmed was confirmed. No instances of familial association were noted, nor was any excessive prenatal exposure to drugs found. Thirty-two instances of isolated small-bowel atresia were analyzed in detail. The frequency of the isolated defect for blacks was twice that for whites because of a higher rate for black females. The isolated defect was commonest in the winter months. The relation between isolated small-bowel atresia, birth weight, and mortality was discussed. This small series cannot readily be subdivided into distinct epidemiological groups on the basis of the location of the atretic lesions along the length of the small bowel.     

Socioeconomic status and adiposity in childhood: a systematic review of cross-sectional studies 1990-2005

Background: Sobal and Stunkard's review (1989) of 34 studies from developed countries published after 1941, found inconsistent relationships between socioeconomic status (SES) and childhood adiposity. Inverse associations (36%), no associations (38%), and positive associations (26%) were found in similar proportions. In view of the trends in pediatric obesity, the relationship between SES and adiposity may have changed. Objective: To describe the cross‐sectional association between SES and adiposity in school‐age children from western developed countries in epidemiological studies since 1989. Methods and Procedures: PubMed database was searched to identify potentially relevant publications. Epidemiological studies from western developed countries presenting cross‐sectional data on the bivariate association between an SES indicator and objectively measured adiposity in childhood (5–18 years), carried out after 1989 were included. SES indicators included parental education, parental occupation, family income, composite SES, and neighborhood SES. Results: Forty‐five studies satisfied the review criteria. SES was inversely associated with adiposity in 19 studies (42%), there was no association in 12 studies (27%), and in 14 studies (31%) there was a mixture of no associations and inverse associations across subgroups. No positive SES‐adiposity associations were seen in unadjusted analyses. With parental education as the SES indicator, inverse associations with adiposity were found in 15 of 20 studies (75%). Discussion: Research carried out within the past 15 years finds that associations between SES and adiposity in children are predominately inverse, and positive associations have all but disappeared. Research is needed to understand the mechanisms through which parental social class influences childhood adiposity.     

Genes, ageing and longevity in humans: problems, advantages and perspectives

Many epidemiological data indicate the presence of a strong familial component of longevity that is largely determined by genetics, and a number of possible associations between longevity and allelic variants of genes have been described. A breakthrough strategy to get insight into the genetics of longevity is the study of centenarians, the best example of successful ageing. We review the main results regarding nuclear genes as well as the mitochondrial genome, focusing on the investigations performed on Italian centenarians, compared to those from other countries. These studies produced interesting results on many putative “longevity genes”. Nevertheless, many discrepancies are reported, likely due to the population-specific interactions between gene pools and environment. New approaches, including large-scale studies using high-throughput techniques, are urgently needed to overcome the limits of traditional association studies performed on a limited number of polymorphisms in order to make substantial progress to disentangle the genetics of a trait as complex as human longevity.     

Childhood leukemia--risk factors and the need for an interdisciplinary research agenda

The International Agency for Research on Cancer (IARC) has classified high as well as low-frequency fields as “possibly carcinogenic to humans” (Group 2B). For high frequency fields the recent assessment is based mainly on weak positive associations described in some epidemiological studies between glioma and acoustic neuroma and the use of mobile and other wireless phones. Also for lowfrequency fields the evidence is based on epidemiological findings revealing a statistic association between childhood leukemia (CL) and low-level magnetic fields. The basic findings are already 10 years old. They have since been supported by further epidemiological studies. However, the knowledge on the main/crucial question of causality has not improved. This fact and in addition the small, but statistically significant increased incidence of CL in the surrounding of German nuclear power plants have motivated the German Office for Radiation Protection (BfS) to work toward a better understanding of the main causes of CL. A long-term strategic research agenda has been developed which builds on an interdisciplinary, international network and aims at clarifying the aetiology of childhood acute lymphoblastic leukemia.     

Contribution of ultrasonographic examination to the prenatal detection of trisomy 21: experience from 19 European registers

The objective of this study was to evaluate the contribution of ultrasound scanning to the prenatal detection of trisomy 21 in a large unselected European population. Data from 19 congenital malformation registers in 11 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to three ultrasound investigations per patient. Routine serum screening was offered in four of the 11 countries and routine screening on the basis of maternal age amniocentesis in all. The results show that overall 53% of cases of trisomy 21 were detected prenatally with a range from 3% in Lithuania to 88% in Paris. Ninety-eight percent of women whose babies were diagnosed before 24 weeks gestation chose to terminate the pregnancy. Centres/countries that offer serum screening do not have a significantly higher detection rate of trisomy 21 when compared to those that offer maternal age amniocentesis and anomaly scanning only. Fifty percent of trisomy 21 cases were born to women aged 35 years or more. In conclusions, second trimester ultrasound plays an important role in the prenatal diagnosis of trisomy 21. Of those cases prenatally diagnosed, 64% of cases in women <35 years and 36% of those in women >or=35 years were detected because of an ultrasound finding. Ultrasound soft markers accounted for 84% of the scan diagnoses. There is evidence of increasing maternal age across Europe with 50% of cases of trisomy 21 born to women aged 35 years or more.     

Association between Prenatal and Postnatal Psychological Distress and Toddler Cognitive Development: A Systematic Review

PurposeMaternal psychological distress is one of the most common perinatal complications, affecting up to 25% of pregnant and postpartum women. Research exploring the association between prenatal and postnatal distress and toddler cognitive development has not been systematically compiled. The objective of this systematic review was to determine the association between prenatal and postnatal psychological distress and toddler cognitive development.MethodsArticles were included if: a) they were observational studies published in English; b) the exposure was prenatal or postnatal psychological distress; c) cognitive development was assessed from 13 to 36 months; d) the sample was recruited in developed countries; and e) exposed and unexposed women were included. A university-based librarian conducted a search of electronic databases (Embase, CINAHL, Eric, PsycInfo, Medline) (January, 1990-March, 2014). We searched gray literature, reference lists, and relevant journals. Two reviewers independently evaluated titles/abstracts for inclusion, and quality using the Scottish Intercollegiate Guideline Network appraisal tool for observational studies. One reviewer extracted data using a standardized form.ResultsThirteen of 2448 studies were included. There is evidence of an association between prenatal and postnatal distress and cognitive development. While variable effect sizes were reported for postnatal associations, most studies reported medium effect sizes for the association between prenatal psychological distress and cognitive development. Too few studies were available to determine the influence of the timing of prenatal exposure on cognitive outcomes.ConclusionFindings support the need for early identification and treatment of perinatal mental health problems as a potential strategy for optimizing toddler cognitive development.     

Sirenomelia associated with a "vanishing twin"

A case is presented of twin gestation in which one gestational sac was completely resorbed and the remaining twin was subsequently found to be sirenomelic. First-trimester prenatal ultrasound examination demonstrated a second gestational sac that disappeared 2 weeks later. The sonographic features that led to the diagnosis of sirenomelia in the remaining fetus included severe renal dysgenesis, persistently apposed lower extremities, and absence of fibulae. Postmortem examination, including angiographic studies of the fetus, revealed caudal dysgenesis and a single umbilical artery that arose from the abdominal aorta. Sirenomelia occurs more frequently in twin gestations than in singletons. This case suggests that the association between twinning and sirenomelia may be greater than is currently recognized. Two hypotheses are given to explain this association.     

Intrauterine exposure to diagnostic X rays and risk of childhood leukemia subtypes.

The relationship between childhood leukemia and prenatal exposure to low-dose ionizing radiation remains debatable. This population-based case-control study investigated the association between prenatal exposure to diagnostic X-ray examinations (for different types of examinations and at different stages of pregnancy) and the risk of childhood lymphatic and myeloid leukemia. All children born and diagnosed with leukemia between 1973-1989 in Sweden (578 lymphatic and 74 myeloid) were selected as cases, and each was matched (by sex and year of birth) to a healthy control child (excluding Down's syndrome). Exposure data were abstracted blindly from all available medical records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by conditional logistic regression. It was found that prenatal X-ray examinations resulting in direct fetal exposure were not associated with a significant overall increased risk for childhood leukemia (OR = 1.11, 95% CI 0.83-1.47), for lymphatic leukemia (OR = 1.04, 95% CI 0.77-1.40), or for myeloid leukemia (OR = 1.49, 95% CI 0.48-4.72). There was little evidence of a dose response or variation in risk by trimester of exposure or age at diagnosis. Thus X-ray examinations performed during pregnancy in the 1970s and 1980s in Sweden did not affect the risk of childhood leukemia discernibly.     

The use of digit ratios as markers for perinatal androgen action

Since the ratio of the second-to-fourth finger length was first proposed as a marker for prenatal androgen action in 1998, over 100 studies have been published that have either further tested the association between the digit ratio and prenatal androgens, or employed digit ratios as a marker to investigate the association between prenatal androgens and a variety of outcomes, including behavior, fertility, and disease risks. Despite the clear demand for an adult marker of prenatal androgen action and increased use of digit ratios as such a marker, its validity remains controversial. This review (1) evaluates current evidence for the relationship between digit ratios and prenatal androgens (using experimentation with animal models, amniotic testosterone, and congenital adrenal hyperplasia case-control studies), (2) describes opportunities for future validation tests, and (3) compares the potential advantages and disadvantages of digit ratio measures with more established methods for studying the effects of prenatal androgens.     

Significant association between GSTT1 null genotype and risk of asthma during childhood in Caucasians

Asthma is a complex multifactorial disorder and its management requires a better understanding of its various pathogenesis and mechanisms. Previous studies assessing the association between glutathione S-transferase T1 (GSTT1) null genotype and asthma risk during childhood reported conflicting results. To get a more precise estimation of the association between GSTT1 null genotype and risk of asthma during childhood, we performed a meta-analysis of 16 studies with a total of 18,558 subjects. Subgroup analyses were performed by ethnicity. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 %CI) was used to assess the association. Overall, there was a significant association between GSTT1 null genotype and increased risk of children asthma (OR = 1.25, 95 % CI, 1.02–1.54; P = 0.032). Subgroup analyses showed GSTT1 null genotype was associated with increased risk of children asthma in Caucasians (OR = 1.46, 95 % CI, 1.04–2.03; P = 0.027), but not in Asians (OR = 1.03, 95 % CI, 0.55–1.94; P = 0.928) and Africans (OR = 1.33, 95 % CI, 0.92–1.91; P = 0.127). There was no evidence of publication bias in the subgroup analysis of Caucasians. In conclusion, there is a significant association between GSTT1 null genotype and risk of asthma during childhood in Caucasians. More well-designed epidemiological studies are needed to further assess this association in Asians and Africans.     

Childhood leukemia and residential magnetic fields: Are pooled analyses more valid than the original studies?

The association seen in epidemiological studies between childhood leukemia and magnetic field strength in the child's home has been very important in influencing reviews of international groups and standard setting organizations. This association is usually based on the results of two published pooled analyses, which use definitions of exposure that differ from those of some the original studies. However, the results and conclusions of the pooled analyses differ from those of the three largest recent studies, which have the most sophisticated methodology and together account for the majority of the exposed cases at high exposure levels in the pooled analyses. These recent studies, using the exposure methods and the cut-off levels set a priori, each concluded that there was little evidence of any association. The pooled analyses, using different exposure measures and different cut-offs, conclude that an association exists at high exposure levels. It is not clear if the results of the pooled analysis are more valid than those of the recent major studies, although this has been often assumed in influential reviews.     

Use of ultrasound to monitor prenatal growth and development in the common marmoset (Callithrix jacchus)

The increasing use of non-human primates to study fetal development and neonatal management has necessitated the availability of fetuses of known gestational history. In this study, prenatal development and growth were investigated in the common marmoset (Callithrix jacchus) using ultrasound. The objectives of this study were: (1) to determine the accuracy of ultrasound for monitoring prenatal growth and development in common marmosets, (2) to determine if litter size influences prenatal growth trajectories, and (3) to assess growth discordancy among litter mates. Fifty pregnancies were monitored longitudinally using real-time abdominal sonography. During each examination the number of fetuses was recorded, and crown-rump length (CRL) and biparietal diameter (BPD) were measured. The results indicate that ultrasound is a reliable method for observation of gross morphological changes during prenatal development in this species. Measures of CRL and BPD taken early in gestation using ultrasound were in agreement with those from gross specimens. Triplets were significantly (P < 0.05) smaller than twins for both BPD and CRL. No significant relationship was found between litter size and within litter variation in CRL or BPD. This study is the first longitudinal investigation of prenatal growth and development in C. jacchus. The observations from this study will be of use for determining approximate gestational age of fetuses, as well as providing guidelines for routine monitoring of pregnancy in this species. © 1995 Wiley-Liss, Inc.