Hershey Medical Center Technical Workshop Report: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings

Researching chemicals in human milk can be conducted without discouraging breastfeeding

Continued monitoring of environmental chemicals is important for understanding human exposure and potentially related health risk(s). Cinar et al. [1] contribute to our knowledge on infant exposures to environmental chemicals in breast milk. However, the messages implicit both in the title and in the paper itself are unnecessarily alarming and are likely to be interpreted by mothers and health professionals as indicating that breast feeding is generally unsafe in certain regions of Turkey. For example, the conclusion that “Rural area also may not be safe for breastfeed babies” is based on an evaluation of 90 women, without regard to differences in their potential exposure patterns; lifestyle, smoking status, occupation, body mass index, or residential history. It is unclear whether these women are in any way representative of rural areas in Turkey, or rural areas in general. Further, the authors do not provide reference values with which to compare the levels of metals that they report, and the values that they report for several metals are 10-1000 times higher than the levels reported in other studies (although it is unclear whether they have reported the levels with correct units; the authors note that the mothers’ levels were lower than recommended levels of 10 microg/L (Hg) and 30 microg/L (Pb) while describing the mothers’ reported levels as being in the low parts per million range [Table 4]). Only under exceptional circumstances including clinical treatment with certain pharmaceuticals or in cases of accidental poisonings have the occurrence of chemicals in breast milk resulted in a recommendation to avoid breastfeeding. Otherwise, studies have shown that breastfeeding can counter subtle adverse effects associated with in utero maternal exposure to hazardous substances [2]. Numerous studies demonstrate the superiority of breastfeeding in lowering risk of adverse health outcomes when compared to formula-fed infants. Thus, the World Health Organization recommends six months of exclusive breastfeeding. Cinar et al. [1] recognized that human milk provides all of the vitamins and essential minerals and trace elements (micronutrients) that are required for the normal development of infants as well as many brain-protective substances. They do not describe the exposures associated with formula-feeding in the regions under study and so the reader has no basis for understanding whether infant exposures to metals would be higher or lower based on the choice of formula over breastfeeding. Further, there is no evidence that formula feeding would attenuate any effects that may occur from fetal exposures [3]. Scientists conducting biomonitoring research using human milk have an obligation to understand the sensitivity of this issue and the impact their information and/or message may have on health professionals and breastfeeding mothers. Indeed, Geraghty et al. [4] highlighted the potential harm from poor reporting methods in breast milk monitoring of environmental chemicals; American women responded that they would immediately wean if told that phthalates were in their milk. It is incumbent on us to strive to contextualize human milk biomonitoring data, constructing a message that puts into perspective both risks of environmental hazards and benefits of breastfeeding. Formula-feeding should never be implied (implicitly or explicitly) as a means to attenuate maternal-infant exposure to environmental chemicals, especially without data to support such a message (5). The otherwise interesting paper of Cinar et al. [1] gives the false impression that milk of Turkish mothers is unsafe and that if the infant is not breastfed, chemical exposures will not occur

Contemporary assessment and pharmacotherapy of Tourette syndrome

To develop a guide to clinical assessment and pharmacotherapy for children and adults with Tourette syndrome (TS), we reviewed published literature over the past 25 years to identify original articles and reviews on the assessment and pharmacological treatment of Tourette syndrome, attention—deficit/hyperactivity disorder (ADHD) and obsessive—compulsive disorder (OCD). The literature search also included a survey of reviews published in book chapters. The assessment section was compiled from several reviews. Pharmacological treatments were classified into those with strong empirical support (as evidenced by two positive placebo-controlled studies for tics, OCD, or ADHD in TS samples); modest empirical support (one positive placebo-controlled study), or minimal support (open-label data only). We conclude that accurate diagnosis, including identification of comorbid conditions, is an essential step toward appropriate treatment for patients with TS. In many patients with TS, symptom management requires pharmacotherapy for tics or coexisting conditions. The evidence supporting efficacy and safety for medications used in patients with TS varies. But this evidence offers the best guide to clinical practice