Abstract
Maternal Body Mass Index in Early Pregnancy and Risk of Epilepsy in Offspring
Razaz N, Tedroff K, Villamor E, Cnattingius S. JAMA Neurol. 2017;74:668–676. doi:10.1001/jamaneurol.2016.6130. Published online April 3, 2017.
IMPORTANCE: There is growing concern about the long-term neurologic effects of prenatal exposure to maternal overweight and obesity. The causes of epilepsy are poorly understood and, in more than 60% of the patients, no definitive cause can be determined. OBJECTIVES: To investigate the association between early pregnancy body mass index (BMI) and the risk of childhood epilepsy and examine associations between obesity-related pregnancy and neonatal complications and risks of childhood epilepsy. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study of 1:441 623 live single births at 22 or more completed gestational weeks in Sweden from January 1, 1997, to December 31, 2011, was conducted. The diagnosis of epilepsy as well as obesity-related pregnancy and neonatal complications were based on information from the Sweden Medical Birth Register and National Patient Register. Multivariate Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95%CIs after adjusting for maternal age, country of origin, educational level, cohabitation with partner, height, smoking, maternal epilepsy, and year of delivery. Data analysis was conducted from June 1 to December 15, 2016. MAIN OUTCOMES AND MEASURES: Risk of childhood epilepsy. RESULTS: Of the 1 421 551 children born between January 1, 1997, and December 31, 2011, with covariate information available, 7592 (0.5%) were diagnosed with epilepsy through December 31, 2012. Of these 3530 (46.5%) were female. The overall incidence of epilepsy in children aged 28 days to 16 years was 6.79 per 10 000 child-years. Compared with offspring of normal-weight mothers (BMI 18.5 to <25.0), adjusted HRs of epilepsy by maternal BMI categories were as follows: overweight (BMI 25.0 to <30.0), 1.11 (95%CI, 1.04–1.17); obesity grade I (BMI 30.0 to <35.0), 1.20 (95%CI, 1.10–1.31); obesity grade II (BMI 35.0 to <40.0), 1.30 (95%CI, 1.12–1.50); and obesity grade III (BMI ≥40.0), 1.82 (95%CI, 1.46–2.26). The rates of epilepsy were considerably increased for children with malformations of the nervous system (adjusted HR, 46.4; 95%CI, 42.2–51.0), hypoxic ischemic encephalopathy (adjusted HR, 23.6; 95%CI, 20.6–27.1), and neonatal convulsions (adjusted HR, 33.5; 95%CI, 30.1–37.4). The rates of epilepsy were doubled among children with neonatal hypoglycemia (adjusted HR, 2.10; 95%CI, 1.90–2.33) and respiratory distress syndrome (adjusted HR, 2.43; 2.21–2.66), and neonatal jaundice was associated with more than a 50% increased risk of epilepsy (adjusted HR, 1.47; 95%CI, 1.33–1.63). The elevated risk of epilepsy in children of overweight or obese mothers was not explained by obesity-related pregnancy or neonatal complications. CONCLUSIONS AND RELEVANCE: The rates of childhood epilepsy increased with maternal overweight or obesity in a dose-response manner. Given that overweight and obesity are modifiable, prevention of obesity may be an important public health strategy to reduce the incidence of childhood epilepsy.
Commentary
The paper under commentary assessed the rates of childhood onset epilepsy in children born to mothers delivering between January 1997 and December 2011 in a Swedish population-based cohort of nearly 1.5 million live single births after 22 gestational weeks. In a “dose-related” manner in association with body mass index (BMI), the rate of childhood onset epilepsy up to age 16 years was significantly increased in the offspring of overweight and obese mothers compared to mothers with normal weight: by 10% in the overweight population, by 20% in the obese population, by 30% in the more obese population, and by 80% in the severely obese population. While increased rates of childhood-onset epilepsy incidence were found in children born with malformations of the nervous system, hypoxic ischemic encephalopathy, neonatal convulsions, neonatal hypoglycemia, neonatal respiratory distress syndrome, or neonatal jaundice, the risk factor of maternal obesity remained an independent factor.
What is the biologic plausibility of this association? Razaz and colleagues discussed maternal inflammatory factors and increased levels of leptin crossing the placenta as possible causative contributors to the onset of epilepsy. Putting mechanisms aside and focusing just on the epidemiology for now, given the alarming global increase in obesity, this report portends an incidence of epilepsy that could approach pandemic levels.
Obesity is truly epidemic throughout the world. In the United States, obesity (BMI of 30 kg/m2 or higher) in women has risen from 25 to 110 million persons from 1975 until the present. Severe obesity (BMI of 35 kg/m2 or higher) has increased from 12 to 48 million over this period. Other regions with as dramatic a rise in obesity are the Middle East and Near East. In northern Europe, the site of the study herein, obesity rates increased over this period but not nearly as greatly as in the United States (1). The rates of obesity affliction rival that of the “black plague” but borne by fast-food distribution trucks rather than rodents. Obesity is more insidiously lethal but leads to early death just the same. Undoubtedly, the rise and market domination of industrially constructed, calorically dense, and insula-addicting processed foods is the main contributor to this epidemic.
Both epilepsy and obesity incidence are common diseases by epidemiological criteria (2), with obesity clearly more frequently present. Therefore, if the authors’ findings are valid, the longitudinal incidence of epilepsy should be increasing in parallel with obesity. But is it?
Longitudinal changes in epilepsy incidence have not been a focus of research; most studies are cross-sectional without comparing rates across time within a population. A recent systematic review and meta-analyses shows an overall global incidence of 6.38 per 1,000 persons with a 95% confidence interval of 5.57–7.30 (3). The incidence rate is higher in low- to middle-income countries.
In this same epidemiological report, there are two papers each from three distinct geographic areas performed at different time points. These are presented in the Figure, with dates, sites, incidence, and direction of change in epilepsy incidence shown over time. The change in incidence rates over time within each country is not significant, but the direction of change is consistent: Rates are increasing. This may be a contributing effect of obesity, but a true biologic plausibility for cause and effect is far from evident. The reported incidence of epilepsy overall is highest in the mature age group (4, 5). The meta-analysis does not reveal this, however, and shows a 33% higher rate of epilepsy onset before age 18 years compared to those older than 18; therefore, it supports the possibility of maternal obesity as a risk factor.
Direction of change in epilepsy incidence for different geographic areas over the time shown.
The authors conclude that being overweight and developing obesity is modifiable and, as such, prevention of obesity could be an important public health approach toward reducing the risk of childhood onset epilepsy. This data is certainly very provocative and merits validation; the impact is incalculable in terms of health care dollars and just plain pain and suffering. Fast foods and processed foods may have more complex and dire consequences than we think.