Abstract:

The present study aimed to conduct a systematic review and meta-analysis to evaluate the evidence on the association of maternal smoking during pregnancy with offspring body composition in childhood, adolescence and adulthood. MEDLINE, Web of Science and LILACS databases were searched. Reference lists were also screened. We included original studies, conducted in humans, that assessed the association of maternal smoking during pregnancy with offspring body mass index (BMI) and overweight in childhood, adolescence and adulthood, published through May 1st, 2018. A meta-analysis was used to estimate pooled effect sizes. The systematic review included 64 studies, of which 37 evaluated the association of maternal smoking during pregnancy with overweight, 13 with BMI, and 14 evaluated both outcomes. Of these 64 studies, 95 measures of effect were extracted and included in the meta-analysis. We verified that the quality of evidence across studies regarding maternal smoking in pregnancy and overweight and BMI of offspring to be moderate and low, respectively. Most studies (44 studies) were classified as moderate risk bias. Heterogeneity among studies included was high and, in the random-effects pooled analysis, maternal smoking during pregnancy increased the odds of offspring overweight (OR: 1.43, 95%CI: 1.35; 1.52) and mean difference of BMI (β: 0.31, 95%CI: 0.23; 0.39). In conclusion, offspring of mothers who smoked during pregnancy have higher odds of overweight and mean difference of BMI, and these associations persisted into adulthood.

Keywords:
Smoking; Pregnancy; Overweight; Body Mass Index; Meta-Analysis

Resumo:

Este estudo teve como objetivo realizar uma revisão sistemática e metanálise para avaliar as evidências sobre a associação entre tabagismo materno durante a gravidez e composição corporal dos filhos na infância, adolescência e vida adulta. Foram realizadas buscas nas bases de dados MEDLINE, Web of Science e LILACS, além de listas de referências. Incluímos estudos originais em seres humanos que avaliaram a associação entre tabagismo materno durante a gravidez e índice de massa corporal (IMC) e excesso de peso dos filhos na infância, adolescência e vida adulta, publicados até 1º de maio de 2018. A metanálise foi usada para estimar os tamanhos dos efeitos agregados. A revisão sistemática incluiu 64 estudos, dos quais 37 avaliaram a associação entre tabagismo materno durante a gravidez e excesso de peso, 13 com IMC e 14 com ambos os desfechos. Desses 64 estudos, foram extraídas 95 medidas de efeito, incluídas na metanálise. Verificamos que a qualidade das evidências nos estudos sobre o tabagismo materno e excesso de peso e IMC dos filhos era moderada e baixa, respectivamente. A maioria dos estudos (44) foi classificada como risco de viés moderado. A heterogeneidade entre os estudos era alta, e na análise de efeitos aleatórios agrupada, o tabagismo materno durante a gravidez aumentou a probabilidade de excesso de peso nos filhos (OR: 1,43; IC95%: 1,35; 1,52) e a diferença média do IMC (β: 0,31; IC95%: 0,23; 0,39). Conclui-se que filhos de mulheres que fumaram durante a gravidez têm maior probabilidade para excesso de peso e maior diferença média de IMC, e que essas associações persistem na vida adulta.

Palavras-chave:
Fumar; Gravidez; Sobrepeso; Índice de Massa Corporal; Metanálise

Resumen:

El objetivo del presente estudio fue llevar a cabo una revisión sistemática y metaanálisis para evaluar la evidencia de asociación del tabaquismo materno durante el embarazo con el índice de masa corporal de los hijos durante la infancia, adolescencia y etapa adulta. Se buscó información en las siguientes bases de datos: MEDLINE, Web of Science y LILACS. También se analizaron listas de referencia. Se incluyeron estudios originales, realizados con humanos, que evaluaron la asociación del tabaquismo materno durante el embarazo con el índice de masa corporal (IMC) en los hijos, así como el sobrepeso en la infancia, adolescencia y etapa adulta, publicado el 1 de mayo de 2018. Se realizó un metaanálisis para estimar el tamaño de los efectos combinados. La revisión sistemática incluyó 64 estudios, donde 37 evaluaron la asociación del tabaquismo materno durante el embarazo con el sobrepeso, 13 con el IMC, y 14 evaluaron ambos resultados. De estos 64 estudios, se obtuvieron 95 medidas de efecto que se incluyeron en el metaanálisis. Verificamos que la calidad de las evidencias en los diferentes estudios, respecto tabaquismo materno durante el embarazo y el sobrepeso, así como el IMC en los hijos, era moderada y baja, respectivamente. La mayor parte de los estudios (44 estudios) estaba clasificada como de riesgo moderado de sesgo. La heterogeneidad entre los estudios incluidos fue alta y, en los análisis agrupados de efectos aleatorios, el tabaquismo materno durante el embarazo incrementó la probabilidad de descendencia con sobrepeso (OR: 1,43; IC95%: 1,35; 1,52) y la diferencia media del IMC (β: 0,31; IC95%: 0,23; 0,39). En conclusión, los hijos de las madres que fumaron durante el embarazo tienen una mayor probabilidad de sobrepeso, así como una diferencia media del IMC, y estas asociaciones persisten en la etapa adulta.

Palabras-clave:
Fumar; Embarazo; Sobrepeso; Índice de Masa Corporal; Metaanálisis

Introduction

The epidemic of overweight and obesity is a public health problem, worldwide ¹1. Swinburn BA, Sacks G, Hall KD, McPherson K, Finegood DT, Moodie ML, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet 2011; 378:804-14.. Among the early life factors associated with overweight, it has been suggested that maternal smoking during pregnancy may increase offspring body mass index (BMI) and the risk of overweight ²2. Behl M, Rao D, Aagaard K, Davidson TL, Levin ED, Slotkin TA, et al. Evaluation of the association between maternal smoking, childhood obesity, and metabolic disorders: a national toxicology program workshop review. Environ Health Perspect 2013; 121:170-9.. However, it has been emphasized that some demographic, socioeconomics and lifestyle factors may contribute to the observed association between maternal smoking and offspring overweight. Mothers who smoke during pregnancy tend to weigh more, to have lower socioeconomic status and achieved schooling, which are also associated with a higher risk of offspring overweight ²2. Behl M, Rao D, Aagaard K, Davidson TL, Levin ED, Slotkin TA, et al. Evaluation of the association between maternal smoking, childhood obesity, and metabolic disorders: a national toxicology program workshop review. Environ Health Perspect 2013; 121:170-9.. In addition, offspring of smokers tend to be less physically active and have poor diet quality, which in turn could be mediators in the association of maternal smoking during pregnancy with offspring overweight ³3. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. Int J Obes (Lond) 2008; 32:201-10..

Moreover, it has also been reported that maternal smoking during pregnancy is positively associated with BMI in childhood ⁴4. Beyerlein A, Rückinger S, Toschke AM, Schaffrath Rosario A, von Kries R. Is low birth weight in the causal pathway of the association between maternal smoking in pregnancy and higher BMI in the offspring? Eur J Epidemiol 2011; 26:413-20.^,55. Florath I, Kohler M, Weck MN, Brandt S, Rothenbacher D, Schöttker B, et al. Association of pre- and post-natal parental smoking with offspring body mass index: an 8-year follow-up of a birth cohort. Pediatr Obes 2014; 9:121-34.^,66. Riedel C, Fenske N, Müller MJ, Plachta-Danielzik S, Keil T, Grabenhenrich L, et al. Differences in BMI z-scores between offspring of smoking and nonsmoking mothers: a longitudinal study of German children from birth through 14 years of age. Environ Health Perspect 2014; 122:761-7.^,77. Grzeskowiak LE, Hodyl NA, Stark MJ, Morrison JL, Clifton VL. Association of early and late maternal smoking during pregnancy with offspring body mass index at 4 to 5 years of age. J Dev Orig Health Dis 2015; 6:485-92., and some studies have reported that the impact of maternal smoking on offspring body composition would last until adulthood ⁸8. Power C, Atherton K, Thomas C. Maternal smoking in pregnancy, adult adiposity and other risk factors for cardiovascular disease. Atherosclerosis 2010; 211:643-8.^,99. Mamun AA, O'Callaghan MJ, Williams GM, Najman JM. Maternal smoking during pregnancy predicts adult offspring cardiovascular risk factors: evidence from a community-based large birth cohort study. PLoS One 2012; 7:e41106..

Two previously published systematic reviews and meta-analyses ³3. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. Int J Obes (Lond) 2008; 32:201-10.^,1010. Rayfield S, Plugge E. Systematic review and meta-analysis of the association between maternal smoking in pregnancy and childhood overweight and obesity. J Epidemiol Community Health 2017; 71:162-73. have reported that maternal smoking is associated with offspring overweight and obesity in childhood. In the more recent paper, it was evaluated data published until January 1, 2015 ³3. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. Int J Obes (Lond) 2008; 32:201-10., and in the meta analyses conducted for Oken et al. ³3. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. Int J Obes (Lond) 2008; 32:201-10. and Rayfield & Plugge ¹⁰10. Rayfield S, Plugge E. Systematic review and meta-analysis of the association between maternal smoking in pregnancy and childhood overweight and obesity. J Epidemiol Community Health 2017; 71:162-73. was included 14 and 39 studies, respectively. Nevertheless, these reviews have not evaluated whether the consequences of exposure to maternal smoking persists into adolescence and adulthood, as well as its association with mean BMI.

Therefore, in order to update the previously published meta-analysis and evaluate consequences of maternal smoking in pregnancy on body composition in adolescence and adulthood, we carried out the present meta-analysis.

Methods

Protocol and registration

This systematic review and meta-analysis were reported in accordance with PRISMA guidelines ¹¹11. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6:e1000097.. The protocol for systematic review and meta-analysis was registered in PROSPERO (registration number: CRD42018080334).

Data source and search strategy

MEDLINE, Web of Science and LILACS databases were searched for studies that evaluated the association of maternal tobacco smoking during pregnancy with offspring BMI and overweight. Databases were search from inception to May 1, 2018. There was no language restriction. In the literature search, each of the terms for exposure were combined with each of the outcomes terms described as follows.

MEDLINE: (cigarette smoke pregnancy OR cigarette smoking pregnancy OR intrauterine tobacco smoke exposure OR maternal smoking during pregnancy OR maternal smoking pregnancy OR nicotine pregnancy OR nicotine pregnant OR prenatal smoke OR prenatal smoking OR prenatal smoke exposure OR prenatal smoking exposure OR prenatal tobacco OR prenatal tobacco exposure OR prenatal tobacco smoke OR smoke pregnancy OR smoke pregnant OR smoking pregnancy OR smoking pregnant OR smoke pregnancy effect OR smoking pregnant effects OR smoking pregnancy offspring OR tobacco pregnancy OR tobacco pregnant OR tobacco smoke pregnancy OR tobacco smoking pregnancy) AND (adiposity OR adiposity risk OR body adiposity OR body mass index OR body mass index obesity OR bmi OR bmi obesity OR obese overweight OR obesity OR obesity body mass index OR obesity bmi OR obesity overweight OR obesity risk OR overweight OR overweight obesity OR overweight obese) [All Fields];

Web of Science: TS=((((((((((((((((((((((((((cigarette smoke pregnancy) OR cigarette smoking pregnancy) OR intrauterine tobacco smoke exposure) OR maternal smoking during pregnancy) OR maternal smoking pregnancy) OR nicotine pregnancy) OR nicotine pregnant) OR prenatal smoke) OR prenatal smoking) OR prenatal smoke exposure) OR prenatal smoking exposure) OR prenatal tobacco) OR prenatal tobacco exposure) OR prenatal tobacco smoke) OR smoke pregnancy) OR smoke pregnant) OR smoking pregnancy) OR smoking pregnant) OR smoke pregnancy effect) OR smoking pregnant effects) OR smoking pregnancy offspring) OR tobacco pregnancy) OR tobacco pregnant) OR tobacco smoke pregnancy) OR tobacco smoking pregnancy)) AND TS=(((((((((((((((((adiposity) OR adiposity risk) OR body adiposity) OR body mass index) OR body mass index obesity) OR bmi) OR bmi obesity) OR obese overweight) OR obesity) OR obesity body mass index) OR obesity bmi) OR obesity overweight) OR obesity risk) OR overweight) OR overweight obesity) OR overweight obese)) Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years;

LILACS: ( ( ( ( ( ( CIGARRETTE-SMOKING ) or “NICOTINE” ) or “SMOKE” ) or “SMOKE-EXPOSURE”) or “SMOKE/TOBACCO” ) or “SMOKING” ) or “SMOKING/NICOTINE” and ( ( ( “PREGNANCY” ) or “PREGNANT” ) or “PREGNANT WOMEN” ) or “PRENATAL” and ( ( ( ( ( ( ( ( “ADIPOSITY” ) or “BODY MASS INDEX” ) or “OBESE” ) or “OBESE/OVERWEIGHT” ) or “OBESITY” ) or “OBESITY-OVERWEIGHT” ) or “OVERWEIGHT” ) or “OVERWEIGHT-OBESE” ) or “OVERWEIGHT-OBESITY” [Words].

Two independent literature searches, using the same search strategy, were carried out. The searches were compared, and any disagreement was solved by a third reviewer.

Eligibility criteria

We included original studies, conducted in humans, that assessed the association of maternal tobacco smoking during pregnancy with offspring BMI and overweight in childhood (from the age of two years), adolescence and adulthood.

Review articles, editorials, comments, studies conducted with animals, that evaluated the intrauterine exposure to smoking of other drugs such as marijuana, or that assessed the exposure to second-hand smoke on pregnancy, or that evaluated children under two years of age were excluded from the review. Furthermore, we excluded those studies that reported only crude estimates, as well as, those that did not report the confidence interval or the standard error of the association between maternal smoking and offspring anthropometry, or did not provided data that allowed the calculation of these parameters. For these studies that did not provide sufficient data for the inclusion in the review, we tried to contact the authors and requested the information needed for including them.

Selection of studies

Two reviewers, independently, carried out the selection of the studies. After excluding the duplicates, titles and abstracts they were perused to exclude those studies that were obviously irrelevant for the review. The full-texts of the remaining studies were retrieved and those studies that were eligible for this review were identified. In addition to the electronic search, reference lists of the selected articles were examined to identify manuscripts that had not been captured by the database search. Disagreements were solved by a third reviewer.

Data extraction

Using a standardized protocol, two reviewers independently extracted the data from the included studies, and the forms were compared. Of each study, besides to data on exposure and outcome, we extracted the following information: publication year, country of data collection, study design, type of population studied (only one gender or both genders), sample size, maternal smoking recall time, source of information on maternal smoking, losses to follow-up, age at outcome assessment, anthropometric measures (e.g. techniques and methods of measurement, type of equipment), definition of overweight, control for confounding (adjust for variables socioeconomics, demographic and maternal anthropometry), control for potential mediators (birth conditions, breastfeeding/complementary feeding and lifestyle variables).

For those studies reporting more than two categories of maternal smoking during pregnancy (e.g., non-smoker/light smoker/heavy smoker), the effect measure reporting the comparison of the most extreme categories was included in the meta-analysis. For those studies that evaluated overweight and obesity separately, we extracted the effect measure for obesity. In the case of studies reporting effect measures at various ages, the outcome at the later age was considered. When the study results were stratified by gender and ethnicity, the effect measures of each of these strata was considered in the meta-analysis. For those studies that presented estimates adjusted for different settings of confounding variables, we considered the measure of effect adjusted for the greatest number of variables and that did not adjusted for potential mediators.

Assessment of quality of the evidence across studies

The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology was used to assess the quality of the body of retrieved evidence ¹²12. Ryan R, Hill S. How to GRADE the quality of the evidence. http://cccrg.cochrane.org/author-resources (accessed on 04/Jan/2019).
http://cccrg.cochrane.org/author-resourc... .

Assessment of risk of bias

Likelihood of risk of bias of individual studies was evaluated through Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) tool, developed by Morgan and colleagues ¹³13. The ROBINS-E tool (Risk Of Bias In Non-randomized Studies - of Exposures). https://www.bristol.ac.uk/population-health-sciences/centres/cresyda/barr/riskofbias/robins-e/ (accessed on 13/May/2019).
https://www.bristol.ac.uk/population-hea... ^,1414. Morgan RL, Thayer KA, Santesso N, Holloway AC, Blain R, Eftim SE, et al. A risk of bias instrument for non-randomized studies of exposures: a users' guide to its application in the context of GRADE. Environ Int 2019; 122:168-84..

Statistical analysis

We used Stata 14.0 (https://www.stata.com/) for the analyses, and analysed separately those studies that reported the mean difference in BMI and those that reported the odds ratio (OR) for overweight/obesity. Because the studies were carried out in different settings, using different designs and evaluated the subjects at different ages, a common effect size could not be assumed and the estimates were pooled using the random effects models ¹⁵15. Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods 2010; 1:97-111.. Meta-regression was used to assess the contribution of co-variables (sample size, study design, age at outcome assessment, adjustment for confounders) to the heterogeneity among the studies, and we estimated the percentage of the heterogeneity that was explained by the co-variables. If the inclusion of a co-variable increased the heterogeneity, the estimate on the change in the measure of heterogeneity was truncated to zero. Funnel plot and Egger test were used to investigate the possibility of publication bias ¹⁶16. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315:629-40..

Departures from original review protocol

In the original review protocol, risk of bias would be evaluated by adapted Newcastle-Ottawa Quality Assessment Scale. However, the use of scores to assess the quality of studies in meta-analysis has been criticized because most of the scores evaluate possible sources of bias as well as aspects linked quality of reporting, that are not directly linked to susceptibility to bias ¹⁷17. Jüni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA 1999; 282:1054-60.^,1818. Brouwers MC, Johnston ME, Charette ML, Hanna SE, Jadad AR, Browman GP. Evaluating the role of quality assessment of primary studies in systematic reviews of cancer practice guidelines. BMC Med Res Methodol 2005; 5:8.. Thus, we assessed the risk of bias using an instrument that is not based on scores, the ROBINS-E.

Results

In the literature search, 6,818 records were identified and, after duplicates were excluded, 4,364 titles and abstracts were perused. Of these, 98 texts were selected for full-text reading and 63 manuscripts were included in our review. Additionally, we included one of four papers identified in the search of reference lists and studies citing the manuscripts identified in the electronic search. Therefore, 64 studies were included in the meta-analysis, 37 evaluated the association of maternal smoking during pregnancy with overweight/obesity ¹⁹19. Toschke A, Koletzko B, Slikker Jr. W, Hermann M, von Kries R. Childhood obesity is associated with maternal smoking in pregnancy. Eur J Pediatr 2002; 161:445-8.^,2020. von Kries R, Toschke AM, Koletzko B, Slikker Jr. W. Maternal smoking during pregnancy and childhood obesity. Am J Epidemiol 2002; 156:954-61.^,2121. Bergmann KE, Bergmann RL, von Kries R, Böhm O, Richter R, Dudenhausen JW, et al. 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Matijasevich A, Brion MJ, Menezes AM, Barros AJ, Santos IS, Barros FC. Maternal smoking during pregnancy and offspring growth in childhood: 1993 and 2004 Pelotas cohort studies. Arch Dis Child 2011; 96:519-25.^,6060. Ehrenthal DB, Maiden K, Rao A, West DW, Gidding SS, Bartoshesky L, et al. Independent relation of maternal prenatal factors to early childhood obesity in the offspring. Obstet Gynecol 2013; 121:115-21.^,6161. Dior UP, Lawrence GM, Sitlani C, Enquobahrie D, Manor O, Siscovick DS, et al. Parental smoking during pregnancy and offspring cardio-metabolic risk factors at ages 17 and 32. Atherosclerosis 2014; 235:430-7.^,6262. Fairley L, Santorelli G, Lawlor DA, Bryant M, Bhopal R, Petherick ES, et al. The relationship between early life modifiable risk factors for childhood obesity, ethnicity and body mass index at age 3 years: findings from the Born in Bradford birth cohort study. BMC Obesity 2015; 2:9.^,6363. Thurber KA, Dobbins T, Kirk M, Dance P, Banwell C. Early life predictors of increased body mass index among Indigenous Australian children. PLoS One 2015; 10:e0130039.^,6464. Li L, Peters H, Gama A, Carvalhal MI, Nogueira HG, Rosado-Marques V, et al. Maternal smoking in pregnancy association with childhood adiposity and blood pressure. Pediatr Obes 2016; 11:202-9., and 14 evaluated both outcomes ⁸8. Power C, Atherton K, Thomas C. Maternal smoking in pregnancy, adult adiposity and other risk factors for cardiovascular disease. Atherosclerosis 2010; 211:643-8.^,99. Mamun AA, O'Callaghan MJ, Williams GM, Najman JM. Maternal smoking during pregnancy predicts adult offspring cardiovascular risk factors: evidence from a community-based large birth cohort study. PLoS One 2012; 7:e41106.^,6565. Oken E, Huh SY, Taveras EM, Rich-Edwards JW, Gillman MW. Associations of maternal prenatal smoking with child adiposity and blood pressure. Obes Res 2005; 13:2021-8.^,6666. Chen A, Pennell ML, Klebanoff MA, Rogan WJ, Longnecker MP. Maternal smoking during pregnancy in relation to child overweight: follow-up to age 8 years. Int J Epidemiol 2006; 35:121-30.^,6767. Koupil I, Toivanen P. Social and early-life determinants of overweight and obesity in 18-year-old Swedish men. Int J Obes (Lond) 2008; 32:73-81.^,6868. Fasting MH, Oien T, Storro O, Nilsen TI, Johnsen R, Vik T. Maternal smoking cessation in early pregnancy and offspring weight status at four years of age. A prospective birth cohort study. Early Hum Dev 2009; 85:19-24.^,6969. Braun JM, Daniels JL, Poole C, Olshan AF, Hornung R, Bernert JT, et al. Prenatal environmental tobacco smoke exposure and early childhood body mass index. Paediatr Perinat Epidemiol 2010; 24:524-34.^,7070. Iliadou AN, Koupil I, Villamor E, Altman D, Hultman C, Långström N, et al. Familial factors confound the association between maternal smoking during pregnancy and young adult offspring overweight. Int J Epidemiol 2010; 39:1193-202.^,7171. Pei Z, Flexeder C, Fuertes E, Thiering E, Koletzko B, Cramer C, et al. Early life risk factors of being overweight at 10 years of age: results of the German birth cohorts GINIplus and LISAplus. Eur J Clin Nutr 2013; 67:855-62.^,7272. Yang SM, Decker A, Kramer MS. Exposure to parental smoking and child growth and development: a cohort study. BMC Pediatr 2013; 13:104.^,7373. Durmus B, Heppe DHM, Taal HR, Manniesing R, Raat H, Hofman A, et al. Parental smoking during pregnancy and total and abdominal fat distribution in school-age children: the Generation R Study. Int J Obes (Lond) 2014; 38:966-72.^,7474. Suzuki K, Sato M, Zheng W, Shinohara R, Yokomichi H, Yamagata Z. Effect of maternal smoking cessation before and during early pregnancy on fetal and childhood growth. J Epidemiol 2014; 24:60-6.^,7575. Timmermans SH, Mommers M, Gubbels JS, Kremers SP, Stafleu A, Stehouwer CD, et al. Maternal smoking during pregnancy and childhood overweight and fat distribution: the KOALA Birth Cohort Study. Pediatr Obes 2014; 9:e14-25.^,7676. Robinson O, Martínez D, Aurrekoetxea JJ, Estarlich M, Somoano AF, Íñiguez C, et al. The association between passive and active tobacco smoke exposure and child weight status among Spanish children. Obesity (Silver Spring) 2016; 24:1767-77.. Because some studies reported more than one effect measure, 95 effect measures were extracted and included in the meta-analysis. Figure 1 shows the study selection flow chart.

Table 1 presents the main characteristics of the included studies. Thirteen studies had been published in the last five years, 52 were carried out in high income countries, 43 were cohort studies, and 57 evaluated the outcomes at childhood and adolescence. Regarding the assessment of maternal smoking, 24 studies gathered the information on tobacco smoking during pregnancy, and three studies used biochemical markers to verify intrauterine exposure to tobacco. In addition, considering the relevance of further discussing the likelihood of residual confounding, Supplementary Table 1 (http://cadernos.ensp.fiocruz.br/site/public_site/arquivo/suppl-e00176118_7666.pdf) provide information on the variables included by each study in the multivariable model.

We verified that the quality of evidence across studies regarding maternal smoking in pregnancy and overweight and BMI of offspring to be low. Details of assessment of quality are presented in Supplementary Table 2 (http://cadernos.ensp.fiocruz.br/site/public_site/arquivo/suppl-e00176118_7666.pdf).

With respect assessment of risk of bias, in classification for overall bias, no study presented a risk of serious or critical bias. Most studies (44 studies) were classified as moderate risk bias. A detailed assessment of risk bias is presented in Supplementary Table 3 (http://cadernos.ensp.fiocruz.br/site/public_site/arquivo/suppl-e00176118_7666.pdf).

Figure 2 shows that most of the studies that evaluated the association of maternal smoking with overweight/obesity, reported higher odds among offsprings of smoking mothers. In the pooled analysis, maternal smoking during pregnancy increased the odds of offspring overweight/obesity [random-effects pooled OR: 1.43 (95%CI: 1.35; 1.52)] and heterogeneity was high (I²: 73.9%). For BMI, the heterogeneity was also high (I²: 88.9%) and the pooled mean difference in BMI, using random-effects model, was 0.31kg/m² (95%CI: 0.23; 0.39) in the comparison between offspring of smoking and non-smoking mothers (Figure 3).

Table 2 shows the results stratified according to study characteristics. The odds ratio for overweight/obesity was not modified by age at the evaluation, whereas for BMI, in spite of the small number of studies that evaluated adolescents and adults, we observed that the difference increased, and age at assessment explained 51.8% of the heterogeneity among the studies. For overweight/obesity, study design explained 12.8% of the heterogeneity and the pooled OR was higher among cross-sectional and case-control studies. Independent of the outcome, a larger simple size was associated with a small magnitude of the association, but even among those studies that evaluated > 1,500 subjects an association with overweight [pooled OR: 1.37 (95%CI: 1.29; 1.43)] and BMI [pooled mean difference: 0.28 (95%CI: 0.18; 0.38)] was observed. Studies that used serum/urinary cotinine to verify the exposure to maternal smoking in pregnancy showed higher pooled OR for overweight and the source of information on maternal smoking explained 11.2% of the heterogeneity. For BMI, studies that used serum cotinine to assess maternal smoking or relied on the information from medical records observed a higher mean difference. Concerning control for confounding, those studies that adjusted for demographic and socioeconomic variables reported a lower pooled OR of overweight, whereas for BMI the pooled mean difference was higher among studies that controlled for socioeconomic status. On the other hand, studies that adjusted for demographic and socioeconomic variables reported a pooled OR that was slightly lower than those that did not adjusted for both confounders, whereas those studies that adjusted for both variables and at least one of the potential mediators reported the lowest pooled OR of overweight, and this methodological aspect explained 33.6% of heterogeneity.

Multivariable meta-regression including the study level variables that had non-zero proportions of heterogeneity explained, showed that these variables explained 57.5% and 75.7% of heterogeneity for the overweight and BMI outcomes, respectively.

The funnel plots suggest a small study effect (Supplementary Figures 1 and 2: http://cadernos.ensp.fiocruz.br/site/public_site/arquivo/suppl-e00176118_7666.pdf), but the Egger tests were not statistically significant (overweight: p = 0.284; BMI: p = 0.596).

Discussion

In the present systematic review and meta-analysis, we observed that maternal smoking in pregnancy was associated with a higher odds of offspring overweight/obesity. BMI was also higher among those subjects whose mothers smoked during pregnancy. Previous meta-analyses have also shown that maternal smoking in pregnancy increases the risk of offspring overweight. Oken et al. ³3. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. Int J Obes (Lond) 2008; 32:201-10. observed that children whose mothers smoked during pregnancy presented 50% higher risk of overweight (pooled adjusted OR: 1.50; 95%CI: 1.36; 1.65). Rayfield & Plugge ¹⁰10. Rayfield S, Plugge E. Systematic review and meta-analysis of the association between maternal smoking in pregnancy and childhood overweight and obesity. J Epidemiol Community Health 2017; 71:162-73. reported a pooled adjusted OR of 1.37 (95%CI: 1.28; 1.46) and 1.55 (95%CI: 1.40; 1.73) for childhood overweight and childhood obesity, respectively, among offspring of smoking mothers.

Some plausible mechanisms have been proposed to explain these associations. Studies with humans and animals have appointed that, when crossing the placenta, nicotine acts as a suppressant of appetite and body weight and the postnatal cessation of exposure to nicotine would result in hyperphagia and weight gain in the offspring ⁷⁷77. Li MD, Parker SL, Kane JK. Regulation of feeding-associated peptides and receptors by nicotine. Mol Neurobiol 2000; 22:143-65.^,7878. Jo YH, Talmage DA, Role LW. Nicotinic receptor-mediated effects on appetite and food intake. J Neurobiol 2002; 53:618-32.. Exposure to nicotine in pregnancy may also increase body adiposity through modifications in endocrine control of body weight homeostasis ⁷⁹79. Bruin JE, Gerstein HC, Holloway AC. Long-term consequences of fetal and neonatal nicotine exposure: a critical review. Toxicol Sci 2010; 116:364-74.. In addition, maternal smoking during pregnancy is causally related with fetal growth restriction and low birth weight ⁸⁰80. Surgeon General Report. The health consequences of smoking - 50 years of progress: a report of the surgeon general. https://www.hhs.gov/surgeongeneral/reports-and-publications/tobacco/index.html (accessed on 09/Jun/2019).
https://www.hhs.gov/surgeongeneral/repor... . In animals, it has been observed that exposure to nicotine in utero reduce the responsiveness to adrenergic stimuli and promote rapid weight gain ⁸¹81. Levin ED. Fetal nicotinic overload, blunted sympathetic responsivity, and obesity. Birth Defects Res A Clin Mol Teratol 2005; 73:481-4.. Analogously, prenatal exposure to nicotine in humans may decrease responsiveness to adrenergic stimuli via epinephrine and norepinephrine, which modulate the mobilization of lipids from adipose tissue ⁸²82. Schiffelers SLH, Saris WHM, Boomsma F, van Baak MA. ß1-and ß 2-adrenoceptor-mediated thermogenesis and lipid utilization in obese and lean men. J Clin Endocrinol Metab 2001; 86:2191-9..

Moreover, offspring of smoking mothers tend to have less healthy lifestyle habits, such as poorer diet, physical inactivity ³3. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. Int J Obes (Lond) 2008; 32:201-10., and smoking ⁸³83. Gilman SE, Rende R, Boergers J, Abrams DB, Buka SL, Clark MA, et al. Parental smoking and adolescent smoking initiation: an intergenerational perspective on tobacco control. Pediatrics 2009; 123:e274-81.. It has been reported that cigarette smoking is associated with increased abdominal fat accumulation ⁸⁴84. Barrett-Connor E, Khaw KT. Cigarette smoking and increased central adiposity. Ann Intern Med 1989; 111:783-7.^,8585. Canoy D, Wareham N, Luben R, Welch A, Bingham S, Day N, et al. Cigarette smoking and fat distribution in 21,828 British men and women: a population-based study. Obes Res 2005; 13:1466-75.. Nicotine could lead to fat accumulation through increased level of stress hormones like cortisol, which are related to fat depots ⁸⁶86. Cryer PE, Haymond MW, Santiago JV, Shah SD. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. N Engl J Med 1976; 295:573-7.. Therefore, offspring lifestyle could be a mediator in the association between maternal smoking and offspring overweight.

Because we excluded those studies that reported crude associations, we reduced the likelihood that confounding biased the pooled estimates. But the possibility of unmeasured confounding cannot be completely ruled out because important confounders may not have been included in the regression models. Furthermore, if a confounder was poorly measured or defined in a form that was not perfectly correct, residual confounding will occur. Although the association between maternal smoking and offspring overweight/BMI is fairly consistent across studies, some authors have indicated that unmeasured confounding, as familial factors, for example, may contribute to this association. Iliadou et al. ⁷⁰70. Iliadou AN, Koupil I, Villamor E, Altman D, Hultman C, Långström N, et al. Familial factors confound the association between maternal smoking during pregnancy and young adult offspring overweight. Int J Epidemiol 2010; 39:1193-202. evaluated 124,203 singleton males born between 1983 and 1988 in Sweden to investigate whether familial factors confound the association between maternal smoking during pregnancy and overweight in the offspring at about 18 years of age, and reported an association between maternal smoking during the first trimester of pregnancy and overweight. However, the magnitude of the association was lower within-family analyses, suggesting a partial confounding by familial factors.

Heterogeneity among studies included in this meta-analysis was high, and part of this heterogeneity derived from differences among the studies regarding sample size and other methodological characteristics.

Regarding sample size, the odds ratio and the mean difference were lower among those studies with a large sample size, but even among these studies, the associations were still statistically significant. Suggesting, therefore, that publication bias may be overestimating the magnitude of the associations but not causing it. In the analysis for risk of overweight, the pooled OR using the random effect model is 1.43 and when conducting a sensitivity analysis using the Trim and Fill method, the pooled estimate slightly changed 1.39 (95%CI: 1.33; 1.45) (data no shown). Suggesting that the publication bias had a small impact on the pooled estimate, similar to that indicated by the analysis stratifying by sample size.

Concerning the variables used to adjust for confounding, we observed that the pooled OR was lower among those studies that adjusted the estimates for demographic, socioeconomic variables, and potential mediators. Considering that, among the 44 studies that adjusted for both socioeconomic and demographic variables, 35 also adjusted for mediators (Supplementary Table 1: http://cadernos.ensp.fiocruz.br/site/public_site/arquivo/suppl-e00176118_7666.pdf), this attenuation, in part, is due to the simultaneous adjustment for socioeconomic and demographic variables and mediators.

Regarding the age, the mean BMI difference was higher in the studies with adults, whereas for overweight the association was not modified by age. This finding may be related to the fact that as the age increases the mean BMI also increases, thus, differences of the same relative magnitude lead to larger absolute values.

An intriguing finding was that those studies that adjusted for demographic and socioeconomic variables showed a lower pooled OR of overweight, whereas for BMI the pooled mean difference was higher among studies that adjusted for socioeconomic variables. We were not able to present a coherent and plausible explanation for this.

For those variables that did not explain the heterogeneity among the studies, in its turn, it is also possible that residual confounding may have had an important role in the non significant results.

One limitation of this study is that the dose-response and of cessation effect of maternal smoking on gestation on overweight/BMI of offspring could not be assessed, since most studies did not present estimates of effect measures stratified by smoking intensity and duration. Thus, new studies and/or meta-analysis evaluating the dose-response effect and cessation of maternal smoking during gestation in overweight/BMI of the offspring would be interesting to investigate in more detail the impact of exposure to tobacco on utero in adiposity later in life.

In conclusion, besides the high heterogeneity among studies, the present systematic review and meta-analysis suggests, as in previous meta-analysis, that offspring of mothers who smoked during pregnancy showed higher odds of overweight and BMI, and these associations persisted into adulthood. Taking into account that rates of prevalence of prenatal maternal smoking among the studies included in present meta-analysis are considerable (reaching up to 51.4% - data not shown), we reinforce the relevance of reducing maternal smoking during pregnancy. Smoking and obesity are among major risk factors for noncommunicable diseases and, their combined effects at young ages may also contribute to increase early morbidity and mortality ⁸⁷87. World Health Organization. Global status report on noncommunicable diseases 2014. Attaining the nine global noncommunicable diseases targets; a shared responsability. Geneva: World Health Organization; 2014.. Thus, by stimulating pregnant women to stop smoking (and/or by decreasing smoking prevalence rates in the population as a whole), we would also reduce the burden of childhood obesity at the population level.

Acknowledgments

We acknowledge the contributions of those authors who provided assistance with further information or necessary data for this systematic review and meta-analysis. This study was financed in part by the Brazilian Graduate Studies Coordinating Board (Capes; finance code 001).

References

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