Intrauterine exposure to mild analgesics during pregnancy and the occurrence of cryptorchidism and hypospadia in the offspring: The Generation R Study

This article is available open access through the publisher’s website. Copyright @ 2012 The Authors.BACKGROUND - Recently, over-the-counter mild analgesic use during pregnancy has been suggested to influence the risk of reproductive disorders in the offspring. We examined the influence of maternal exposure to mild analgesics during pregnancy on the occurrence of cryptorchidism and hypospadia in their offspring. METHODS - Associations between maternal exposure to mild analgesics during pregnancy and cryptorchidism or hypospadia in the offspring were studied in 3184 women participating in a large population-based prospective birth cohort study from early pregnancy onwards in the Netherlands (2002–2006), the Generation R Study. Cryptorchidism and hypospadia were identified during routine screening assessments performed in child health care centres by trained physicians. The use of mild analgesics was assessed in three prenatal questionnaires in pregnancy, resulting in four periods of use, namely, periconception period, first 14 weeks of gestation, 14–22 weeks of gestation and 20–32 weeks of gestation. Logistic regression analyses were used to study the associations between maternal exposure to mild analgesics and cryptorchidism and hypospadia. RESULTS - The cumulative prevalence over 30 months of follow up was 2.1% for cryptorchidism and 0.7% for hypospadia. Use of mild analgesics in the second period of pregnancy (14–22 weeks) increased the risk of congenital cryptorchidism [adjusted odds ratio (OR) 2.12; 95% confidence interval (CI) 1.17–3.83], primarily due to the use of acetaminophen (paracetamol) (adjusted OR 1.89; 95% CI 1.01–3.51). Among mothers of cryptorchid sons, 33.8% reported (23 of 68) the use of mild analgesics during pregnancy, compared with 31.8% (7 of 22) of mothers with a boy with hypospadia and 29.9% (926 of 3094) of mothers with healthy boys. CONCLUSIONS - Our results suggest that intrauterine exposure to mild analgesics, primarily paracetamol, during the period in pregnancy when male sexual differentiation takes place, increases the risk of cryptorchidism.Erasmus University Rotterdam, School of Law and Faculty of Social Sciences, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR), Rotterdam

Hierarchical Regression for Multiple Comparisons in a Case-Control Study of Occupational Risks for Lung Cancer

BACKGROUND Occupational studies often involve multiple comparisons and therefore suffer from false positive findings. Semi-Bayes adjustment methods have sometimes been used to address this issue. Hierarchical regression is a more general approach, including Semi-Bayes adjustment as a special case, that aims at improving the validity of standard maximum-likelihood estimates in the presence of multiple comparisons by incorporating similarities between the exposures of interest in a second-stage model. METHODOLOGY/PRINCIPAL FINDINGS We re-analysed data from an occupational case-control study of lung cancer, applying hierarchical regression. In the second-stage model, we included the exposure to three known lung carcinogens (asbestos, chromium and silica) for each occupation, under the assumption that occupations entailing similar carcinogenic exposures are associated with similar risks of lung cancer. Hierarchical regression estimates had smaller confidence intervals than maximum-likelihood estimates. The shrinkage toward the null was stronger for extreme, less stable estimates (e.g., "specialised farmers": maximum-likelihood OR: 3.44, 95%CI 0.90-13.17; hierarchical regression OR: 1.53, 95%CI 0.63-3.68). Unlike Semi-Bayes adjustment toward the global mean, hierarchical regression did not shrink all the ORs towards the null (e.g., "Metal smelting, converting and refining furnacemen": maximum-likelihood OR: 1.07, Semi-Bayes OR: 1.06, hierarchical regression OR: 1.26). CONCLUSIONS/SIGNIFICANCE Hierarchical regression could be a valuable tool in occupational studies in which disease risk is estimated for a large amount of occupations when we have information available on the key carcinogenic exposures involved in each occupation. With the constant progress in exposure assessment methods in occupational settings and the availability of Job Exposure Matrices, it should become easier to apply this approach

Nationwide outbreak of STEC O157 infection in the Netherlands, December 2008-January 2009: continuous risk of consuming raw beef products.

The Netherlands experienced a nationwide outbreak of Shiga toxin-producing Escherichia coli (STEC) O157 with onset of symptoms from the end of December 2008 until the end of January 2009. A total of 20 laboratory-confirmed cases were linked to the outbreak strain, serotype O157: H-, stx1, stx2, eae and e-hly positive. The investigation into the source of this outbreak is still ongoing, but evidence so far suggests that infection occurred as a result of consuming contaminated raw meat (steak tartare)

Flexible modelling of vaccine effect in self-controlled case series models

The self-controlled case-series method (SCCS), commonly used to investigate the safety of vaccines, requires information on cases only and automatically controls all age-independent multiplicative confounders, while allowing for an age dependent baseline incidence. Currently the SCCS method represents the time-varying exposures using step functions with pre-determined cut-points. A less prescriptive approach may be beneficial when the shape of the relative risk function associated with exposure is not known a priori, especially when exposure effects can be long-lasting. We therefore propose to model exposure effects using flexible smooth functions. Specifically, we used a linear combination of cubic M-splines which, in addition to giving plausible shapes, avoids the integral in the log-likelihood function of the SCCS model. The methods, though developed specifically for vaccines, are applicable more widely. Simulations showed that the new approach generally performs better than the step function method. We applied the new method to two data sets, on febrile convulsion and exposure to MMR vaccine, and on fractures and thiazolidinedione use

Stressful life events and cancer risk

In a prospective cohort study in Denmark of 8736 randomly selected people, no evidence was found among 1011 subjects who developed cancer that self-reported stressful major life events had increased their risk for cancer

Circulating C-reactive protein and breast cancer risk – systematic literature review and meta-analysis of prospective cohort studies

We conducted a systematic literature review to explore the association between circulating C-reactive protein (CRP), a low-grade inflammation biomarker, and breast cancer risk. Relevant prospective studies in women were identified in PubMed and Web of Science until February 2015. Random-effects dose-response metaanalysis was conducted, overall and in post-menopausal women. Twelve out of 15 studies identified were included in the meta-analysis on any breast cancers (3,522 cases, 69,610 women) and nine on postmenopausal breast cancer (2,516 cases, 36,847 women). For each doubling of CRP concentration, a 7% (95% CI: 2%–12%) and 6% (95% CI: 1%–11%) increased risk was observed (I2=47% and 32%; P heterogeneity=0.04 and 0.17), respectively. The association was linear over most of the range of CRP concentrations. Positive associations remained in the studies that examined the exclusion of early years of follow-up. Associations were attenuated in studies adjusted for lifestyle factors, which partly explained the significant heterogeneity between studies in the overall analysis. On average, the associations in studies adjusted or not adjusted for body mass index were similar. Low-grade inflammation may have a role in breast cancer development. Additional prospective studies are needed to better understand confounding and effect modification from lifestyle factors

Quantifying uncertainty in health impact assessment: a case-study example on indoor housing ventilation.

Quantitative health impact assessment (HIA) is increasingly being used to assess the health impacts attributable to an environmental policy or intervention. As a consequence, there is a need to assess uncertainties in the assessments because of the uncertainty in the HIA models. In this paper, a framework is developed to quantify the uncertainty in the health impacts of environmental interventions and is applied to evaluate the impacts of poor housing ventilation. The paper describes the development of the framework through three steps: (i) selecting the relevant exposure metric and quantifying the evidence of potential health effects of the exposure; (ii) estimating the size of the population affected by the exposure and selecting the associated outcome measure; (iii) quantifying the health impact and its uncertainty. The framework introduces a novel application for the propagation of uncertainty in HIA, based on fuzzy set theory. Fuzzy sets are used to propagate parametric uncertainty in a non-probabilistic space and are applied to calculate the uncertainty in the morbidity burdens associated with three indoor ventilation exposure scenarios: poor, fair and adequate. The case-study example demonstrates how the framework can be used in practice, to quantify the uncertainty in health impact assessment where there is insufficient information to carry out a probabilistic uncertainty analysis

Selection of confounding variables should not be based on observed associations with exposure

In observational studies, selection of confounding variables for adjustment is often based on observed baseline incomparability. The aim of this study was to evaluate this selection strategy. We used clinical data on the effects of inhaled long-acting beta-agonist (LABA) use on the risk of mortality among patients with obstructive pulmonary disease to illustrate the impact of selection of confounding variables for adjustment based on baseline comparisons. Among 2,394 asthma and COPD patients included in the analyses, the LABA ever-users were considerably older than never-users, but cardiovascular co-morbidity was equally prevalent (19.9% vs. 19.9%). Adjustment for cardiovascular co-morbidity status did not affect the crude risk ratio (RR) for mortality: crude RR 1.19 (95% CI 0.93–1.51) versus RR 1.19 (95% CI 0.94–1.50) after adjustment for cardiovascular co-morbidity. However, after adjustment for age (RR 0.95, 95% CI 0.76–1.19), additional adjustment for cardiovascular co-morbidity status did affect the association between LABA use and mortality (RR 1.01, 95% CI 0.80–1.26). Confounding variables should not be discarded based on balanced distributions among exposure groups, because residual confounding due to the omission of confounding variables from the adjustment model can be relevant

Exploring the potential of antimicrobial hand hygiene products in reducing the infectious burden in low-income countries: An integrative review.

BACKGROUND: The purpose of this review was to understand whether adding antimicrobial agents to hand hygiene products could increase the health benefits of handwashing with plain soap (HWWS) in low-income settings. METHODS: A review of experimental studies comparing the effects of HWWS with antimicrobial soap and waterless hand sanitizer on health and hand contamination in naturalistic conditions was conducted. In addition, an analysis was completed of the evidence from laboratory studies examining the factors that may affect the impact of antimicrobial soap, taking into account the conditions in low-income settings. RESULTS: The review found no evidence for a superior effect of antimicrobial products compared with HWWS on disease incidence and limited evidence for an effect on hand contamination under naturalistic conditions. An analysis of the effectiveness of antimicrobial soap in laboratory settings suggested that it was only more effective than HWWS when handwashing frequency, duration, and product concentrations were above levels that could be expected in low-income settings. CONCLUSIONS: The limited available evidence suggests that under naturalistic conditions, antimicrobial products are no more effective than HWWS in removing pathogens from hands. Without significant improvement in efficacy, antimicrobial products are unlikely to produce greater health gains than HWWS in low-income settings