Evaluation of the association between maternal smoking, childhood obesity, and metabolic disorders: a national toxicology program workshop review

Abstract

Background: An emerging literature suggests that environmental chemicals may play a role in the development of childhood obesity and metabolic disorders, especially when exposure occurs early in life.

Objective: Here we assess the association between these health outcomes and exposure to maternal smoking during pregnancy as part of a broader effort to develop a research agenda to better understand the role of environmental chemicals as potential risk factors for obesity and metabolic disorders.

Methods: PubMed was searched up to 8 March 2012 for epidemiological and experimental animal studies related to maternal smoking or nicotine exposure during pregnancy and childhood obesity or metabolic disorders at any age. A total of 101 studies-83 in humans and 18 in animals-were identified as the primary literature.

Discussion: Current epidemiological data support a positive association between maternal smoking and increased risk of obesity or overweight in offspring. The data strongly suggest a causal relation, although the possibility that the association is attributable to unmeasured residual confounding cannot be completely ruled out. This conclusion is supported by findings from laboratory animals exposed to nicotine during development. The existing literature on human exposures does not support an association between maternal smoking during pregnancy and type 1 diabetes in offspring. Too few human studies have assessed outcomes related to type 2 diabetes or metabolic syndrome to reach conclusions based on patterns of findings. There may be a number of mechanistic pathways important for the development of aberrant metabolic outcomes following perinatal exposure to cigarette smoke, which remain largely unexplored.

Conclusions: From a toxicological perspective, the linkages between maternal smoking during pregnancy and childhood overweight/obesity provide proof-of-concept of how early-life exposure to an environmental toxicant can be a risk factor for childhood obesity.

Figure 1

Human studies on maternal smoking during pregnancy and childhood overweight and obesity. The primary grouping of studies is based on study design [cross-sectional, prospective, or retrospective]. Within each study design, main findings are grouped by whether the outcome was overweight or obesity. Studies are then sorted alphabetically within these grouping categories. Abbreviations: AK Nat, Alaska Native; ALSPAC, Avon Longitudinal Study of Parents and Children; Amer Ind, American Indian; AMICS, Asthma Multicenter Infant Cohort Study; BBC, British Birth Cohort; CESAR, Central European Study on Air Pollution and Respiratory Health; cig, cigarettes; CLASS, Children’s Lifestyle and School Performance study; cont, continuous; CPP, Collaborative Perinatal Project; GDM, gestational diabetes mellitus; Gen R, Generation R Study; NCDS, National Child Development Study; NLSY, National Longitudinal Survey of Youth; PACT, Prevention of Allergy among Children of Trondheim study; PedNSS, Pediatric Nutrition Surveillance System; PrevOR, prevalence ratio; WIC, Women, Infants, and Children program. ^aRelative risk estimates for bracketed statistics, i.e., [crudePrevOR], calculated based on data presented in the paper using an open source epidemiology statistics programs, OpenEpi (http://www.openepi.com/menu/openEpiMenu.htm).

Figure 2

Human studies on exposure to smoking during pregnancy related to T1D. Studies are grouped by the nature of the smoke exposure (maternal, paternal, or secondhand smoke during childhood). Studies are then sorted by specific outcome measure (e.g., GAD Ab+), and presented alphabetically within a given outcome measure. Abbreviations: ABIS, All Babies in Southeast Sweden cohort; adjHR, adjusted hazard ratio; autoAb, auto antibodies; BBC, British Birth Cohort; BCS70, 1970 British Birth Cohort study; BPASU, British Paediatric Association Surveillance Unit; CC, case–control; cross-sect, cross-sectional; DAISY, Diabetes Autoimmunity Study in the Young; ESPED, German pediatric surveillance unit; GADA, glutamic acid decarboxylase antibodies; IA-2A, insulinoma antigen 2A; NCDS, National Child Development Study; pros, prospective; retro, retrospective; SHS, secondhand smoke. ^aRelative risk estimates [crudeRR] calculated based on data presented in the paper using an open source epidemiology statistics programs, OpenEpi (http://www.openepi.com/menu/openEpiMenu.htm).

Figure 3

Human studies on exposure to smoking during pregnancy and findings related to T2D or metabolic syndrome. The primary grouping is whether the outcome was related to T2D, glucose, or insulin or metabolic syndrome. Studies are then sorted by specific outcome measure (e.g., HOMA-IR) and presented alphabetically within a given outcome measure. Abbreviations: A1C, glycosylated haemoglobin A1c; adjMR, adjusted mean ratio; BBC, British Birth Cohort; cig, cigarettes; cross-sect, cross-sectional; GINIplus, German Infant Nutritional Intervention study; HOMA-IR, Homeostatic model assessment for insulin resistance; LISAplus, Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood study; MoBa, Norwegian Mother and Child Cohort Study; NCDS, National Child Development Study; NS, not significant; pros, prospective; trim, trimester.

Figure 4

Animal studies of prenatal or prenatal + lactational exposure to nicotine or cigarette smoking and adiposity-related end points. The primary grouping of studies is based on whether the end point was related to adiposity or body weight. Within each end point category, main findings are grouped by whether the exposure was to nicotine or cigarette smoke. Within each exposure category, main findings were sorted based on specific end point (A to Z). Abbreviations: AUC, area under the curve; BAT, brown adipose tissue; BW, body weight; eWAT, epididymal white adipose tissue; GD, gestational day; inhal, inhalation; inj, injection; MCS, mainstream cigarette smoke; PND, postnatal day; sc, subcutaneous; w, weeks. ^aValue was assumed or estimated based on data presented in publication. ^bIn Ng et al. (2009) animals were exposed via whole body inhalation to mainstream cigarette smoke (smoke inhaled by an active smoker) at a particle concentration of 15 mg/m³; in Chen et al. (2011) dams were exposed to exposed to cigarette smoke via a perspex chamber for 30 min 5 days/week (2 cigarettes/day, nicotine ≤ 1.2 mg, carbon monoxide ≤ 15 mg). ^cDose level summarized in graph. *Statistically significant effect at specified dose level as reported in publication. In some cases statistical significance of percent control response differs from author’s interpretation (e.g., author’s statistical analysis considered multiple comparisons, i.e., analysis of variance).

Figure 5

Animal studies of prenatal or prenatal + lactational exposure to nicotine and glucose homeostasis-related end points. The primary grouping of studies is based on whether the end point was based on glucose or insulin. Within the end point category, main findings were sorted based on specific end point (A to Z). Abbreviations: AUC, area under the curve; GD, gestational day; ipGTT, intraperitoneal glucose tolerance test; inj, injection; OGTT, oral glucose tolerance test; PND, postnatal day; sc, subcutaneous; w, weeks. ^aValue was assumed or estimated based on data presented in publication. *Statistically significant effect at specified dose level as reported in publication. **In some cases statistical significance of percent control response differs from author’s interpretation (e.g., author’s statistical analysis considered multiple comparisons, i.e., analysis of variance).

Figure 6

Animal studies of prenatal or prenatal + lactational exposure to nicotine and pancreatic end points. The primary grouping of studies is based on the type of pancreatic effect. Within the effect category, main findings were sorted based on whether treatment occurred only during prenatally (black) or prenatal + lactational (green). Abbreviations: GD, gestational day; PND, postnatal day; sc, subcutaneous; w, weeks. ^aValue was assumed or estimated based on data presented in publication. *Statistically significant effect at specified dose level as reported in publication.