Roseanne McNamee

Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events.

CONTEXT Most societies believe that a mothers psychological state can influence her unborn baby. Severe adverse life events during pregnancy have been consistently associated with an elevated risk of low birth weight and prematurity. Such events during the first trimester have also been associated with risk of congenital malformations. OBJECTIVE To assess the effect in offspring of antenatal maternal exposure to an objective measure of stress on risk of adverse neurodevelopment, specifically schizophrenia. We hypothesized that the strongest relationship would be to maternal exposures during the first trimester. DESIGN Population-based study. SETTING Denmark. PARTICIPANTS In a cohort of 1.38 million Danish births from 1973 to 1995, mothers were considered exposed if 1 (or more) of their close relatives died or was diagnosed with cancer, acute myocardial infarction, or stroke syndrome up to 6 months before conception or during pregnancy. Offspring were followed up from their 10th birthday until their death, migration, onset of schizophrenia, or June 30, 2005; admissions were identified by linkage to the Central Psychiatric Register. Main Outcome Measure Schizophrenia. RESULTS The risk of schizophrenia and related disorders was raised in offspring whose mothers were exposed to death of a relative during the first trimester (adjusted relative risk, 1.67 [95% confidence interval, 1.02-2.73]). Death of a relative during other trimesters or up to 6 months before pregnancy were not linked with a higher risk of schizophrenia. CONCLUSIONS Our population-based study suggests that severe stress to a mother during the first trimester may alter the risk of schizophrenia in offspring. This finding is consistent with ecological evidence from whole populations exposed to severe stressors and suggests that environment may influence neurodevelopment at the feto-placental-maternal interface.

Advanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort.

Background Recent decades have witnessed an increase in mean maternal age at childbirth in most high-resourced countries. Advanced maternal age has been associated with several adverse maternal and perinatal outcomes. Although there are many studies on this topic, data from large contemporary population-based cohorts that controls for demographic variables known to influence perinatal outcomes is limited. Methods We performed a population-based cohort study using data on all singleton births in 2004–2008 from the North Western Perinatal Survey based at The University of Manchester, UK. We compared pregnancy outcomes in women aged 30–34, 35–39 and ≥40 years with women aged 20–29 years using log-linear binomial regression. Models were adjusted for parity, ethnicity, social deprivation score and body mass index. Results The final study cohort consisted of 215,344 births; 122,307 mothers (54.19%) were aged 20–29 years, 62,371(27.63%) were aged 30–34 years, 33,966(15.05%) were aged 35–39 years and 7,066(3.13%) were aged ≥40 years. Women aged 40+ at delivery were at increased risk of stillbirth (RR = 1.83, [95% CI 1.37–2.43]), pre-term (RR = 1.25, [95% CI: 1.14–1.36]) and very pre-term birth (RR = 1.29, [95% CI:1.08–1.55]), Macrosomia (RR = 1.31, [95% CI: 1.12–1.54]), extremely large for gestational age (RR = 1.40, [95% CI: 1.25–1.58]) and Caesarean delivery (RR = 1.83, [95% CI: 1.77–1.90]). Conclusions Advanced maternal age is associated with a range of adverse pregnancy outcomes. These risks are independent of parity and remain after adjusting for the ameliorating effects of higher socioeconomic status. The data from this large contemporary cohort will be of interest to healthcare providers and women and will facilitate evidence based counselling of older expectant mothers.

Confounding and confounders

Confounding should always be addressed in studies concerned with causality. When present, it results in a biased estimate of the effect of exposure on disease. The bias can be negative—resulting in underestimation of the exposure effect—or positive, and can even reverse the apparent direction of effect. It is a concern no matter what the design of the study or what statistic is used to measure the effect of exposure. The potential for confounding can be reduced by good study design, but in non-randomised studies this is unlikely to resolve the problem fully. Hence statistical adjustment methods, to reduce the bias caused by measured confounders, are also frequently considered. Such adjustment presupposes that one knows which factors are confounders. However, recent literature on methods for identifying confounders suggest that these are not always obvious. Indeed, in pursuit of guidelines, authors have had to reexamine the meanings of confounding and confounders with some ambiguity and conflict emerging. This literature is reviewed and a recent modification to the traditional definition of a confounder, which emphasises causal rather than statistical relationships, is described and illustrated. Some well known problems in occupational epidemiology, arising from health related selection, are considered in the light of recent ideas. Control of confounding through study design is not addressed, nor is the article concerned with details of statistical methods for adjustment. An overview of design and analysis in relation to confounding by age may be useful additional reading.1 It is assumed that the reader has at least a basic knowledge of epidemiological methods. Unless otherwise stated, definitions and comments apply to all causal study designs including case–control studies. ### Example Consider a study of the relationship between exposure to silica dust and lung cancer where the rate of lung cancer in exposed workers is twice that in unexposed subjects, giving …

Regression modelling and other methods to control confounding

Confounding is a major concern in causal studies because it results in biased estimation of exposure effects. In the extreme, this can mean that a causal effect is suggested where none exists, or that a true effect is hidden. Typically, confounding occurs when there are differences between the exposed and unexposed groups in respect of independent risk factors for the disease of interest, for example, age or smoking habit; these independent factors are called confounders. Confounding can be reduced by matching in the study design but this can be difficult and/or wasteful of resources. Another possible approach—assuming data on the confounder(s) have been gathered—is to apply a statistical “correction” method during analysis. Such methods produce “adjusted” or “corrected” estimates of the effect of exposure; in theory, these estimates are no longer biased by the erstwhile confounders. Given the importance of confounding in epidemiology, statistical methods said to remove it deserve scrutiny. Many such methods involve strong assumptions about data relationships and their validity may depend on whether these assumptions are justified. Historically, the most common statistical approach for dealing with confounding in epidemiology was based on stratification ; the standardised mortality ratio is a well known statistic using this method to remove confounding by age. Increasingly, this approach is being replaced by methods based on regression models . This article is a simple introduction to the latter methods with the emphasis on showing how they work, their assumptions, and how they compare with other methods. Before applying a statistical correction method, one has to decide which factors are confounders. This sometimes1–4 complex issue is not discussed in detail and for the most part the examples will assume that age is a confounder. However, the use of automated statistical procedures for choosing variables to include in a regression model …

The lagged effect of cold temperature and wind chill on cardiorespiratory mortality in Scotland

Aims: To investigate the lagged effects of cold temperature on cardiorespiratory mortality and to determine whether “wind chill” is a better predictor of these effects than “dry bulb” temperature. Methods: Generalised linear Poisson regression models were used to investigate the relation between mortality and “dry bulb” and “wind chill” temperatures in the three largest Scottish cities (Glasgow, Edinburgh, and Aberdeen) between January 1981 and December 2001. Effects of temperature on mortality (lags up to one month) were quantified. Analyses were conducted for the whole year and by season (cool and warm seasons). Main results: Temperature was a significant predictor of mortality with the strongest association observed between temperature and respiratory mortality. There was a non-linear association between mortality and temperature. Mortality increased as temperatures fell throughout the range, but the rate of increase was steeper at temperatures below 11°C. The association between temperature and mortality persisted at lag periods beyond two weeks but the effect size generally decreased with increasing lag. For temperatures below 11°C, a 1°C drop in the daytime mean temperature on any one day was associated with an increase in mortality of 2.9% (95% CI 2.5 to 3.4), 3.4% (95% CI 2.6 to 4.1), 4.8% (95% CI 3.5 to 6.2) and 1.7% (95% CI 1.0 to 2.4) over the following month for all cause, cardiovascular, respiratory, and “other” cause mortality respectively. The effect of temperature on mortality was not observed to be significantly modified by season. There was little indication that “wind chill” temperature was a better predictor of mortality than “dry bulb” temperature. Conclusions: Exposure to cold temperature is an important public health problem in Scotland, particularly for those dying from respiratory disease.

Reduced infant birthweight consequent upon maternal exposure to severe life events.

Objective: To investigate the association between maternal exposure to severe life events and fetal growth (birthweight and small for gestational age). Stress has been associated with adverse pregnancy outcome. Methods: Mothers of 1.38 million singleton live births in Denmark between January 1, 1979 and December 31, 2002 were linked to information on their spouses, parents, siblings, and older children. Exposure was defined as death or serious illness in a relative during pregnancy or in the 6 months before conception. Linear regression was used to examine the effect of exposure on birthweight. Log-linear binomial regression was used to assess the effect of exposure on small for gestational age. Results: Death of a relative during pregnancy or in the 6 months before conception reduced birthweight by 27 g (adjusted estimate −27 g, 95% Confidence Interval (CI) = −33, −22). There was a significant association between maternal exposure to death of a relative and risk of a baby weighing below the 10th percentile (adjusted relative risk (RR) = 1.17, 95% CI = 1.13, 1.22) and 5th percentile (adjusted RR = 1.22, 95% CI = 1.15, 1.29). Conclusions: Mothers exposed to severe life events before conception or during pregnancy have babies with significantly lower birthweight. If this association is causal, the potential mechanisms of stress-related effects on birthweight include changes in lifestyle due to the exposure and stress-related dysregulation of the hypothalamic-pituitary-adrenal axis during pregnancy. IUGR = intrauterine growth restriction; CVA = cerebrovascular accident; AMI = acute myocardial infarction; SGA = small for gestational age; VSGA = very small for gestational age; GHQ = general health questionnaire; SES = socioeconomic status.

Case-control study of stroke and the quality of hypertension control in north west England.

Abstract Objective: To examine the risk of stroke in relation to quality of hypertension control in routine general practice across an entire health district. Design: Population based matched case-control study. Setting: East Lancashire Health District with a participating population of 388 821 aged (80. Subjects: Cases were patients under 80 with their first stroke identified from a population based stroke register between 1 July 1994 and 30 June 1995. For each case two controls matched with the case for age and sex were selected from the same practice register. Hypertension was defined as systolic blood pressure !160 mm Hg or diastolic blood pressure !95 mm Hg, or both, on at least two occasions within any three month period or any history of treatment with antihypertensive drugs. Main outcome measures: Prevalence of hypertension and quality of control of hypertension (assessed by using the mean blood pressure recorded before stroke) and odds ratios of stroke (derived from conditional logistic regression). Results: Records of 267 cases and 534 controls were examined; 61% and 42% of these subjects respectively were hypertensive. Compared with non-hypertensive subjects hypertensive patients receiving treatment whose average pre-event systolic blood pressure was controlled to <140 mm Hg had an adjusted odds ratio for stroke of 1.3 (95% confidence interval 0.6 to 2.7). Those fairly well controlled (140-149 mm Hg), moderately controlled (150-159 mm Hg), or poorly controlled (!160 mm Hg) or untreated had progressively raised odds ratios of 1.6, 2.2, 3.2, and 3.5 respectively. Results for diastolic pressure were similar; both were independent of initial pressures before treatment. Around 21% of strokes were thus attributable to inadequate control with treatment, or 46 first events yearly per 100 000 population aged 40-79. Conclusions: Risk of stroke was clearly related to quality of control of blood pressure with treatment. In routine practice consistent control of blood pressure to below 150/90 mm Hg seems to be required for optimal stroke prevention. Key messages A case-control study based on the community stroke register and practice records showed a prevalence of hypertension of 61% for stroke patients and 42% in controls Quality of control of blood pressure was clearly related to the risk of stroke, independent of baseline blood pressure Detection and treatment rates of hypertension were high but control of blood pressure to below 150/90 mm Hg in treated hypertensive patients was only 33% in cases and 42% in controls When achieving optimal control of hypertension (to <150/90 mm Hg) in the most at risk and treatable age range (40-79 years) 86 hypertensive patients currently not well controlled need to be treated over five years to prevent one stroke

Rates of preterm birth following antenatal maternal exposure to severe life events: a population-based cohort study

BACKGROUND Preterm birth and other pregnancy complications have been linked to maternal stress during pregnancy. We investigated the association between maternal exposure to severe life events and risk of preterm birth. METHODS Mothers of all singleton live births (n = 1.35 million births) in Denmark between 1 January 1979 and 31 December 2002 were linked to data on their children, parents, siblings and partners. We defined exposure as death or serious illness in close relatives in the first or second trimesters or in the 6 months before conception. Log-linear binomial regression was used to estimate the effect of exposure on preterm birth, very preterm birth and extremely preterm birth. RESULTS There were 58 626 (4.34%) preterm births (<37 weeks), 11 732 (0.87%) very preterm births and 3288 (0.24%) extremely preterm births in the study cohort. Severe life events in close relatives in the 6 months before conception increased the risk of preterm birth by 16% (relative risk, RR = 1.16, [95% CI: 1.08-1.23]). Severe life events in older children in the 6 months before conception increased the risk of preterm birth by 23% (RR = 1.23, [95% CI: 1.02-1.49]) and the risk of very preterm birth by 59% (RR = 1.59, [95% CI: 1.08-2.35]). CONCLUSIONS Our population-based cohort study suggests that maternal exposure to severe life events, particularly in the 6 months before pregnancy, may increase the risk of preterm and very preterm birth.

Work-related asthma in France: recent trends for the period 2001–2009

Objective Knowledge on the time-course (trends) of work-related asthma (WRA) remains sparse. The aim of this study was to describe WRA trends in terms of industrial activities and the main causal agents in France over the period 2001–2009. Method Data were collected from the French national network of occupational health surveillance and prevention (Réseau National de Vigilance et de Prévention des Pathologies Professionnelles (RNV3P)). Several statistical models (non-parametric test, zero-inflated negative binomial, logistic regression and time-series models) were used and compared with assess trends. Results Over the study period, 2914 WRA cases were included in the network. A significant decrease was observed overall and for some agents such as isocyanates (p=0.007), aldehydes (p=0.01) and latex (p=0.01). Conversely, a significant increase was observed for cases related to exposure to quaternary ammonium compounds (p=0.003). The health and social sector demonstrated both a growing number of cases related to the use of quaternary ammonium compounds and a decrease of cases related to aldehyde and latex exposure. Conclusions WRA declined in France over the study period. The only significant increase concerned WRA related to exposure to quaternary ammonium compounds. Zero-inflated negative binomial and logistic regression models appear to describe adequately these data.

The impact of maternal celiac disease on birthweight and preterm birth: a Danish population-based cohort study

BACKGROUND Adverse pregnancy outcomes have been associated with maternal celiac disease (CD). In this study, we investigate the effect of treated and untreated maternal CD on infant birthweight and preterm birth. METHODS A population-based cohort study consisted of all singleton live births in Denmark between 1 January 1979 and 31 December 2004 was used. A total of 1,504,342 babies were born to 836,241 mothers during the study period. Of those, 1105 babies were born to women with diagnosed CD and 346 were born to women with undiagnosed CD. Women with diagnosed CD were considered as treated with a gluten free diet while women with undiagnosed CD were considered as untreated. The outcome measures were: birthweight, small for gestational age (SGA: birthweight <10th centile), very small for gestational age (VSGA: birthweight <5th centile) and preterm birth. We compared these measures in treated and untreated women with those of a reference group (no history of CD). RESULTS Women with untreated CD delivered smaller babies [difference = -98 g (95% CI: -130, -67)], with a higher risk of SGA infants [OR = 1.31 (95% CI: 1.06, 1.63)], VSGA infants [OR = 1.54 (95% CI: 1.17, 2.03)] and preterm birth [OR = 1.33 (95% CI: 1.02, 1.72)] compared with women without CD. Women with treated CD had no increased risk of reduced mean birthweight, risk of delivering SGA and VSGA infants or preterm birth compared with women without CD. CONCLUSION Untreated maternal CD increases the risk of reduced birthweight, the risk of delivering SGA and VSGA infants and preterm birth. Diagnosis and presumed treatment of maternal CD with a gluten-free diet appeared to result in a birthweight and preterm birth rate similar to those in women without CD.