Maternal smoking in pregnancy and blood pressure during childhood and adolescence: a meta-analysis

Vol.:(0123456789) 1 3 European Journal of Pediatrics https://doi.org/10.1007/s00431-023-04836-1 RESEARCH Maternal smoking inpregnancy andblood pressure duringchildhood andadolescence: ameta‑analysis NereaMourino1· LeonorVarela‑Lema1· JasjitS.Ahluwalia2· JuliaRey‑Brandariz1· CristinaCandal‑Pedreira1· AlbertoRuano‑Ravina1,3· AndreaVila‑Farinas1· AndrésTorres1· MónicaPérez‑Rios1,3 Received: 6 October 2022 / Revised: 12 January 2023 / Accepted: 20 January 2023 © The Author(s) 2023 Abstract Arterial hypertension during childhood or adolescence is rising, and smoking during pregnancy may constitute a modifiable risk factor. This study aims to evaluate the effect of maternal smoking during pregnancy on diastolic (DBP) and systolic blood pressure (SBP) in childhood and adolescence. A bibliographic search was conducted in PubMed, Embase, and CENTRAL databases in March 2022. Meta-analysis was performed with the difference in mean-adjusted SBP/DBP of children and adolescents aged 3–17years, according to maternal smoking/non-smoking in pregnancy. A random effects model was applied; a leave-one-out analysis and meta-analysis by subgroups were performed. A modified Newcastle–Ottawa scale was used to assess the quality of the studies. Evidence levels were rated using the GRADE system. Fifteen studies were included in the meta-analysis; all of them evaluated the mean-adjusted SBP difference in children or adolescents (N = 73,448), and 6 also that of DBP (N = 31,459). Results showed that maternal smoking during pregnancy significantly increased SBP (β = 0.31mmHg 95% CI 0.14–0.49). A greater increase in mean-adjusted SBP was observed in those studies that completed the recruitment before 1990, were conducted in non-European countries, used standard mercury or manual sphygmomanometry, adjusted for birth weight, and were in the lowest quality subgroup. No significant association was found for DBP. The GRADE level of evidence was low for SBP and very low for DBP. Conclusion: Smoking in pregnancy might increase SBP in childhood and adolescence. Due to the low level of evidence, solid inferences cannot be drawn about the clinical relevance of these findings. What is Known: • AHT is the leading cause of premature death among adults worldwide. • Deleterious effects derived from SHS exposure on children's health have been documented since early 1970.To date, there are contradictory results about the effects of prenatal SHS exposure on children’s BP. What is New: • Smoking in pregnancy may increase SBP during childhood and adolescence. • Maternal smoking during pregnancy could have greater influence on their offspring's SBP than on DBP. Keywords Tobacco· Pregnancy· Blood pressure· Meta-analysis· Cohort studies· Children· Adolescents Abbreviations AHT Arterial hypertension BMI Body mass index BP Blood pressure CIs Confidence intervals DBP Diastolic blood pressure ETS Environmental tobacco smoke Impact This study evaluated the effect of maternal tobacco use during pregnancy on diastolic and systolic blood pressure in childhood and adolescence. Smoking during pregnancy might increase SBP during childhood and adolescence. Due to the low level of evidence, solid inferences cannot be drawn about the clinical relevance of these findings. Communicated by Gregorio Milani. * Leonor Varela-Lema leonor[email protected] 1 Department ofPreventive Medicine andPublic Health, University ofSantiago de Compostela, SantiagodeCompostela, Spain 2 School ofPublic Health andAlpert School ofMedicine, Brown University, Providence, RI, USA 3 Consortium forBiomedical Research inEpidemiology andPublic health (CIBERESP), Madrid, Spain European Journal of Pediatrics 1 3 GRADE Grading of recommendations, assessment, development, and evaluation PRISMA Preferred reporting items for systematic reviews and meta-analysis SBP Systolic blood pressure Introduction High blood pressure (BP) or arterial hypertension (AHT) in children, defined as systolic blood pressure (SBP) or diastolic blood pressure (DBP) equal to or higher than the 95th percentile, by sex, age, and height, up to age 16, or ≥ 130/85mmHg for age 16 or older [1], is an increasingly frequent condition during childhood or adolescence [2]. It often tends to be asymptomatic, and is underdiagnosed by health professionals [3, 4]. The global prevalence of AHT in the general pediatric population (children aged 6 to 19years) is estimated at around 4.0%, with 3.0% for systolic hypertension and 1.9% for diastolic hypertension [2]. Even so, the US National Health and Nutrition Examination Survey shows that 13.3% of American children have high BP [5]. Like many chronic diseases, the etiology of AHT is complex and is thought to develop as a consequence of an interaction between genetic predisposition and the environment, mediated in part by epigenetic factors. It has been shown that tobacco use during pregnancy can cause changes in the placenta, generating fetal alterations which are associated with health problems, both pre- and postnatal [6]. Tobacco increases the risk of ectopic pregnancy, rupture of membranes, fetal mortality, intrauterine growth restriction, premature birth, low birth weight, and sudden infant death syndrome [7, 8]. Similarly, it can affect the growth of pulmonary parenchyma and airways, increasing the risk of asthma and respiratory infections, as well as giving rise to other cerebral and cardiovascular alterations [9, 10]. Globally, 1.7% of women are estimated to smoke during pregnancy; however, prevalence stands at 8.1% in the European region or at 5.9% in the Region of the Americas [11]. Since Barker published a study on the influence of adverse intrauterine conditions on postnatal development of cardiovascular diseases [12], a great deal of research has been done on how exposure to maternal smoking in the fetal period might affect the development of AHT during childhood, taking into account the atherogenic effect of this teratogen [13]. AHT is the leading cause of premature death among adults worldwide [14], and current physiopathologic and epidemiologic evidence suggests that childhood AHT increases the risk of essential AHT, as well as cardiovascular events later in life [15]. The precise role played by smoking during pregnancy in development of AHT in childhood and adolescence has not yet been established, and controversy remains with mixed findings from studies [16, 17]. Two previous reviews with meta-analysis were identified, but most of the studies included were cross-sectional, and the cohort studies included had a short follow-up time [16, 18]. Furthermore, one of the reviews drew no distinction between maternal smoking during pregnancy and children’s exposure to environmental tobacco smoke (ETS) [16]. The aim of this study was to analyze current evidence by conducting a systematic review with meta-analysis of prospective cohort studies and to evaluate the association between maternal smoking in pregnancy and their offspring’s DBP and/or SBP during childhood or adolescence. Material andmethods We carried out a systematic review with meta-analysis, following the standard PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines [19]. The systematic review protocol was registered in the PROSPERO database and updated in December 2022 (registration no. CRD42021247824). During the review process, we identified the need to modify the eligibility criteria relating to study design and participants’ target age range to improve the quality of the evidence. This justifies the updating of the initial protocol recorded in PROSPERO. Reassuringly, following the guidelines of the Cochrane Handbook, sensitivity analyses were further performed to identify if these particular decisions influenced our findings. Search strategy In March 2022, we conducted a bibliographic search of the MEDLINE (PubMed), EMBASE, and CENTRAL databases, applying a pre-designed search strategy (Supplementary Table1) drawn up by 3 expert reviewers in the matter. The search terms included both MeSH and free terms: “tobacco smoke pollution,” “smoking,” “tobacco smoking,” “cigarette smoking,” “pregnancy,” “hypertension,” “blood pressure,” “passive smoking,” “secondhand smoke,” “environmental tobacco smoke,” “smok*,” “maternal smoking,” “paternal smoking,” “arterial pressure,” “hypertension,” “systolic pressure,” “diastolic pressure,” and “mean blood pressure.” A manual review of the bibliographic references from included studies was performed to ensure the inclusion of all possible studies. No restrictions were applied in terms of country, study period, study design, or language. Eligibility criteria The review covered studies that evaluated the association between maternal smoking in pregnancy and the BP of their European Journal of Pediatrics 1 3 offspring aged 3 through 17years. We included all studies published in peer-reviewed journals that met the following PECOS question: “Among children or adolescents, what is the effect of maternal smoking during pregnancy on their mean-adjusted DBP and/or SBP, compared to those whose mothers did not smoke?”. The PECOS framework focuses on population, exposure, comparator, outcome and study design: Population: Pregnant mothers and their offspring aged 3 through 17years; exposure: Tobacco use during pregnancy; comparator: Non-tobacco use during pregnancy; outcome: Difference in children’s or adolescents’ mean-adjusted DBP and/or SBP (in mmHg); Study design: Prospective cohort studies that provided the necessary data to calculate mean-adjusted differences and their 95% confidence intervals (95% CIs). The studies with the following characteristics were excluded: studies that did not provide sufficient data to calculate mean-adjusted BP differences and their 95% CIs; studies including women who consumed exclusively e-cigarettes or other tobacco products; studies that reported combined results (women’s use of other tobacco products in addition to cigarettes); studies that evaluated exposure to ETS during pregnancy, not exclusively due to maternal smoking; studies that estimated mean DBP and/or SBP without adjustment for possible covariates; studies that included population under 3years old or over 17years old; studies that included exclusively female or male population since we intended to examine maternal smoking effects jointly in both sexes; and studies that included smoking children and/ or adolescents. Furthermore, we excluded studies published in a language other than Spanish, English, or Portuguese, and communications to congresses, letters to the editor, opinion articles, narrative reviews, case–control studies, cross-sectional studies, case series, simulation studies, and studies which had been withdrawn. Although cross-sectional studies were identified, they were not included in the main meta-analysis to avoid misleading results. Selection ofpapers andextraction ofdata After eliminating duplicated papers, 3 researchers screened the titles and abstract of all the papers yielded by the search. Each researcher evaluated eligibility separately on the basis of the title and abstract. In the case of papers considered potentially relevant, the full text was read to ensure that they fulfilled the inclusion/exclusion criteria. Differences of opinion about the inclusion or exclusion of any given paper were settled by consensus of the 3 reviewers. Where different papers based on the same study were identified, we included those that had the largest sample size and with the most up-to-date data. Where the outcome variable was adjusted for different confounding variables, we selected the model with the best fit. In the case of studies that exclusively provided meanadjusted DBP and/or SBP of children and/or adolescents according to maternal smoking, we used the EPIDAT program to calculate the coefficient of the difference between means along with the 95% CI. To extract the relevant information from each paper, a data extraction sheet was designed in Microsoft Excel. The data were manually extracted by 2 of the authors, and both sets of extractions were then reviewed by a third. Differences of opinion were discussed and settled by consensus. From each paper, data were extracted on [1] study design; [2] author and year of publication of the study; [3] period of recruitment of pregnant women; [4] country of study; [5] data source; [6] age of children in whom BP was evaluated; [7] sample size; [8] definition of maternal tobacco use in pregnancy; [9] number of BP measures; [10] BP measurement method, i.e., oscillometry or digital sphygmomanometry and standard mercury or manual sphygmomanometry; [11] difference in mean-adjusted SBP/DBP (in mmHg) according to maternal smoking in pregnancy, along with the 95% CI; and [12] adjustment for confounding variables. Assessment ofquality andlevel ofevidence The AMSTAR 2 tool was used to score the systematic review [20]. The quality of the studies included was evaluated using an adaptation of the Newcastle–Ottawa scale [21]. Two researchers screened each study separately by reference to the representativeness of the sample, sample size, ascertainment of the exposure to maternal smoking, number of BP measurements obtained, adjustment for covariates, and statistical test. Supplementary Table2 shows detailed information on the criteria and the number of points assigned to the studies according to each item. Studies were scored from 0 to 10 by each researcher, with the final score being reached by agreement. In the event of any difference of opinion, a third researcher was consulted. Studies that obtained a score of < 5 points were rated as poor quality, those with a score of 5–6 points as moderate quality, and those with a score of ≥ 7 points as high quality. While no studies were excluded on the basis of the evaluation of risk of bias, a sensitivity analysis was nonetheless performed with the higher quality studies. Evidence levels were rated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The GRADE system allows for classification of evidence into four grades of evidence (high quality, moderate, low, and very low) attending to the risk of bias, inconsistency, uncertainty, inaccuracy, publication bias, and other considerations [22]. European Journal of Pediatrics 1 3 Data analysis To perform the meta-analysis, we calculated the difference in mean-adjusted SBP/DBP of children or adolescents, according to whether their mothers had or had not been smokers during pregnancy. A random effects model was applied, and differentiated analyses were performed for DBP and/or SBP, using the study’s covariate-adjusted results. Inter-study heterogeneity was evaluated using the p-value of the Cochrane Q test and the I2 statistic. A p-value < 0.1 indicates the presence of heterogeneity, with such heterogeneity being considered substantial if I2 > 50% [23–25]. Presence of publication bias was analyzed using a funnel plot, Egger’s regression test for funnel plot asymmetry, and Begg’s test [26, 27]. In cases where the p-value is < 0.1, risk of publication bias was deemed to exist. We performed both a leave-one-out analysis to ascertain the influence of each of the studies, sensitivity analysis including cross-sectional studies and one prospective cohort study with 18-year-old males, and the following meta-analy- ses by subgroups: (1) study quality (low vs. medium/high); (2) studies that adjusted for children’s birth weight (yes vs. no); (3) recruitment period (1958–1989; 1990–2000; 2001–2007); (4) continent (European or non-European); (5) BP measurement method (digital sphygmomanometry or oscillometry vs. standard mercury or manual sphygmomanometry); and (6) age group (3–6.5years vs. 7–15years). All analyses were performed using the STATA statistical analysis software program v17. Results Search results The search yielded a total of 12,035 papers; 21 studies fulfilled the inclusion criteria and 15 were included in the metaanalysis (Fig.1). Supplementary Table3 shows the characteristics of those potentially relevant studies excluded from the systematic review after reading the full text (n = 34), including cross-sectional studies [28–31] and a prospective cohort study with 18-year-old males [32]. Fig. 1 Flowchart of studies selected for systematic review and meta-analysis in accordance with the PRISMA 2020 guidelines European Journal of Pediatrics 1 3 Table 1 Main characteristics of cohort studies Author, year (reference) Recruitment period Country Source Agec (years) N Definition of maternal smoking (pregnancy) BP measures (method)aAdjusted (SBP/ DBP) Law etal. 1991 [33] 1984–1985 UK Hospital 4–4.5 405 Daily cigarette use 3 × SBP (1) Yes Morley etal.d1995 [42] Not shown UK Hospital 7.5–8 618 Daily cigarette use 3 × SBP + DBP (1) + (2)b Yes/yes Williams and Poulton 1999 [43] 1972–1973 New Zealand Hospital 9 795 Use during pregnancy (yes/no) 3 × SBP + DBP (2) Yes/no Bergel etal.d2000 [46] 1987–1990 Argentina Clinical profile 5–9 518 Use during pregnancy (yes/no) 3 × SBP + DBP (2) Yes/no Blake etal.*2000 [49] 1989–1992 Australia Hospital 6 702 Use during pregnancy (yes/never) 2 × SBP + DBP (1) No/no Lawlor etal. 2004 [44] 1981–1984 Australia Hospital 5 3299 Use during pregnancy (yes/never) 3 × SBP (1) Yes Oken etal. 2005 [47] 1999–2002 USA Clinical profile 3 689 Use during beginning of pregnancy 5 × SBP (1) Yes Brion etal. 2007 [61] 1991–1992 UK Population 7 6509 Use in any trimester (yes/no) 2 × SBP + DBP (1) Yes/yes Laura etal.*2010 [64] 1993 Brazil Population 11 4452 Use during pregnancy (yes/no) 2 × SBP + DBP (1) No/no Wen etal. 2011 [36] 1959–1965 USA Hospital 7 30,461 Use during pregnancy (never, moderate, intense) 1 × SBP (2) Yes Ayer etal. 2011 [48] 1997–1999 Australia Hospital 8 405 Use during pregnancy (yes/no) 3 × SBP + DBP (1) Yes/no Belfort etal.22012 [45] 1984–1985 USA Hospital 6.5 694 Use during pregnancy (yes/no) 3 × SBP (1) + (2)bYes Leary etal. 2013 [62] 1991–1997 UK Population 15 4723 Use during pregnancy (yes/no) 2 × SBP (1) Yes Taal etal. 2013 [34] 2002–2006 The Netherlands Population 6 5447 Continued smoking during pregnancy 4 × SBP + DBP (1) Yes/yes Van den Berg etal. 2013 [41] 2003–2004 The Netherlands Hospital 5–6 3024 Use during pregnancy (yes/no) 2 or 3 × SBP + DBP (1) Yes/yes Yang etal. 2013 [63] 1996–1997 Bielorrusia Hospital 6.5 12,196 Use during pregnancy (yes/no) 2 × SBP + DBP (1) Yes/yes Rauschert etal.*2019 [73] 1989–1999 Australia Hospital 17 740 Use during the 18th and 34th week of gestation (yes/no) fnSBP + DBP (not shown) No/no European Journal of Pediatrics 1 3 Characteristics ofthestudies included All of the 15 studies included in the meta-analysis evaluated the difference in the mean-adjusted SBP of children and/or adolescents, aged 3 to 15years, according to maternal use/ non-use of tobacco (N = 73,448), and 6 also evaluated the difference in the mean-adjusted DBP (N = 31,459) (Table1). Most studies recruited pregnant women before or during the 1990s (n = 12), were conducted in non-European continental areas (n = 12), and used oscillometry to measure BP (n = 12). With the exception of one study, all of them obtained at least 2 BP readings. Six studies were excluded from the meta-analysis because they did not adjust BP for covariates, and because the data came from the same study (Generation R) as another paper with a larger sample size (Table1). Maternal smoking during pregnancy was measured using self-reported questionnaires. One study evaluated use with determination of cotinine in maternal serum during pregnancy and in cord blood (Table1). Adjustment variables, related both to the mother, offspring, father/partner, and BP measurement, differed among the studies, yet most adjusted for sex, age, height, weight, and socioeconomic status and/or educational level (Table2). Regarding the sources of funding for the 15 studies included in the meta-analysis, most study authors indicated that studies received funding (n = 13), particularly, from universities, Medical Research Council and National Institutes of Health; of note, the authors from one study did not disclose information on financial support [33]. Study quality The systematic review was rated as high quality using the AMSTAR 2 tool, considering that it provides an accurate and comprehensive summary of the results of available studies addressing the question of interest. In terms of the quality scores, 5 studies were rated as being high quality, 5 as moderate, and 5 as low quality when using a modified Newcastle–Ottawa scale (Supplementary Table4). Most of the studies displayed classification bias. Results ofthemeta‑analysis Maternal smoking in pregnancy significantly increased SBP during childhood or adolescence (β = 0.31mmHg; 95% CI: 0.14–0.49) (Fig.2). The Cochrane Q test indicated that there might be inter-study heterogeneity (p-value < 0.1) but that Nnumber of observations, UKUnited Kingdom, USAUnited States of America, SBPsystolic blood pressure,DBPdiastolic blood pressure * Studies excluded from the meta-analysis a (1) oscillometry or digital sphygmomanometry; (2) standard mercury or manual sphygmomanometry b Used both methods to measure BP; however, the authors specified that most of the readings were taken with oscillometry c It refers to the minimum and maximum ages (in years) of those children or adolescents included in the study d Data sourced from clinical trials e Sample size of 2 cohorts, GEYCKO and ABCD, respectively f Not specified Table 1 (continued) Author, year (reference) Recruitment period Country Source Agec (years) N Definition of maternal smoking (pregnancy) BP measures (method)aAdjusted (SBP/ DBP) Xie etal. 2020 [60] GECKO/ ABCD: 2003–2007 The Netherlands Population 5–6 1613/2052eUse during pregnancy (yes/no) 3 × SBP + DBP (1) Yes/yes De Smidt etal.*2021 [74] 2006–2017 South Africa Hospital 5 500 Use during pregnancy (yes/no) 3 × SBP + DBP (1) No/no Kok Grouleff etal.*2021 [75] 2019–2020 Greenland Hospital 3.5–5.5 76 Use during pregnancy (yes/no) nfSBP + DBP (not shown) No/no Cajachagua- Torres etal.*2021 [76] 2002–2006 The Netherlands Population 10 4792 Continued smoking during pregnancy 3 × SBP + DBP (1) No/no European Journal of Pediatrics 1 3 Table 2 Adjustment variables of studies included in the meta-analysis SBPsystolic blood pressure, BMIbody mass index, ETSenvironmental tobacco smoke, AHTarterial hypertension Authors Child/adolescent Mother Father/partner BP measurement Law etal.[33] Weight at age 4years SBP Morley etal.[42] Birth weight and current age and weight Socioeconomic level, single or multiple pregnancy Measurement method Williams etal.[43] Sex, birth weight, current weight, height, and BMI Height, single or multiple pregnancy, marital status, and socioeconomic level by educational level Socioeconomic level by educational level Bergel etal.[46] Sex, age, current height, and BMI Calcium supplementationduring pregnancy Lawlor etal.[44] Sex, birth weight, current age, weight, and height Age, BMI prior to pregnancy, order of birth of boy/girl, educational level, and income during pregnancy Oken etal.[47] Sex, birth weight, current age, height, and BMI Socioeconomic level by educational level and income, SBP in 3rd trimester, race/ ethnicity, and parity BP measurement conditions (order of readings, cuff size, arm position, and child’s activity) Brion etal.[61] Sex, current age, and BMI Age at the birth, parity, height, BMI, breastfeeding, and socioeconomic level by social class and educational level Age, height, BMI, socioeconomic level by social class, and educational level at child’s birth Wen etal.[36] Sex and gestational age Age at pregnancy, race/ethnicity, marital status, socioeconomic level, and parity Ayer etal. [48] Current exposure to ETS at home Belfort etal.[45] Sex, current age, and height Age, educational level, race/ethnicity, and annual income in household Measurement method, and child’s behavior during measurement Leary etal.[62] Sex, birth weight, age, current height, and BMI Age, height, BMI prior to pregnancy, history of AHT, parity, socioeconomic level by educational level, and social class (job occupation) Age, height, and BMI prior to child’s birth Room temperature, time of day, and child not talking during measurement and cuff size Rob Taal etal.[34] Sex, gestational age, birth weight, current age, and BMI Age, parity, educational level, race/ethnicity, BMI prior to pregnancy, BP, and breastfeeding Van der Berg etal. [41] Sex, age, height, and race/ethnicity Adequacy of income, and socioeconomic level by educational level Yang etal.[63] Sex and age Age, height, BMI, educational level, occupation, marital status at child’s birth, order of birth (no. of older siblings in household), alcohol consumption during pregnancy Age, height, BMI, educational level, occupation, marital status at child’s birth, and tobacco use Xie etal.[60] Sex, gestational age, birth weight, current age, height, and BMI, and early increase in BMI Educational level, BMI prior to pregnancy, AHT, and breastfeeding European Journal of Pediatrics 1 3 such heterogeneity was not substantial (I2 = 0.00%). The leave-one-out analysis showed that none of the studies significantly modified the results (Supplementary Fig.1). The funnel plot (Supplementary Fig.2) and Egger’s test suggested that there might be publication bias (p-value < 0.1). No significant associations were found for DBP (β = −0.16mmHg; 95% CI: −0.75–0.43) and inter-study heterogeneity was high (I2 = 73.10% and p-value of the Q test < 0.1) (Fig.3). None of the studies contributed substantially to reducing this heterogeneity (Supplementary Fig.3). Supplementary Fig.4 shows the funnel plot. Findings from the meta-analysis including cross-sectional studies show similar results and great heterogeneity for both SBP and DBP (β = 0.37mmHg; 95% CI: 0.03–0.70 [I2: 79.33%] and β = −0.13mmHg; 95% CI: −0.62–0.35 [I2: 59.76%], respectively] (Supplementary Figs.5 and 6). Inter-study heterogeneity disappeared in the sensitivity analyses restricting to prospective cohort studies measuring SBP (Fig.2). After including the prospective cohort study with 18-year-old males in the meta-analysis, similar results were found for both SBP and DBP (β = 0.26mmHg; 95% CI: 0.13–0.38 [I2: 0.00%] and β = −0.04mmHg; 95% CI: −0.54–0.47 [I2: 82.77%], respectively) (Supplementary Figs.7 and 8). Regarding the meta-analyses conducted by subgroups, a greater increase in mean-adjusted SBP was observed in the Fig. 2 Forest plot of studies which measured difference in mean-adjusted systolic blood pressure(in mmHg) between children and adolescents exposed or not exposed to maternal smoking in pregnancy Fig. 3 Forest plot of studies which measured difference in mean-adjusted diastolic blood pressure European Journal of Pediatrics 1 3 subgroup of studies that completed the recruitment before 1990, were conducted in non-European continental areas, used standard mercury or manual sphygmomanometry, adjusted for birth weight, and were in the lowest quality subgroup. However, inter-study heterogeneity was substantial for some subgroups (Table3). Subgroup analyses were not deemed for studies measuring DBP due to the small number (n = 6) and marked inter-study heterogeneity. The GRADE level of evidence was low for SBP and very low for DBP (Supplementary Table5). Discussion These results show that smoking in pregnancy increases children’s and adolescent’s SBP, though the difference in adjusted-means is small (< 1mmHg). With respect to DBP, no effect is in evidence, though the studies are very heterogeneous. Part of this heterogeneity could be due to some factors, including different adjustments for covariates and classification of maternal smoking, participants’ characteristics, or BP measurement method. Importantly, the fact that maternal smoking during pregnancy was associated with SBP but not DBP could be due to effects on the arterial stiffness or pulse pressure, which mainly influences SBP, rather than effects on peripheral vascular resistance, which predominantly affects DBP [34]. Fetal growth retardation and arterial resistance adaptations resulting from exposure to maternal smoking could lead to altered elastin synthesis, which becomes more pronounced with age; gradual loss of elastin and replacement by collagen may result in reduced distensibility of the aorta and large arteries, leading to higher SBP [35]. The estimates are consistent with those of a previous one conducted in 2008 [17], which observed a higher increase in BP; however, it drew no distinction between SBP and DBP (0.62mmHg 95% CI: 0.19–1.05) [17]. The results also coincide with those of another meta-analysis [16], which observed that passive exposure to tobacco (parental smoking or exposure to ETS from other smokers) significantly increased SBP (β = 0.26mmHg 95% CI 0.12–0.39) but not DBP (β = 0.07mmHg 95% CI −0.15–0.29). As with our analysis, the number of studies which evaluated DBP was limited to evaluate the possible causes of heterogeneity. Table 3 Results of metaanalysis by subgroups a Quality of the study was rated by applying a modified Newcastle–Ottawa scale. Studies that obtained a score of < 5 points were rated as low quality, those with a score of 5–6 points as moderate quality, and those with a score of 7 points or more as high quality b Two studies (Belfort etal. and Morley et al.) measured BP with both oscillometry and manual sphygmomanometry NAdjusted SBP β95% CI I2 (%) Overall 15 0.31 0.14–0.49 0.00 Subgroups Quality of the studya  Low 5 0.94 −0.09–1.97 59.99  Moderate-high 10 0.26 0.08–0.45 0.00 Adjustment for birth weight  Model adjusted for birth weight 7 0.69 0.06–1.32 64.25  Model without adjustment for birth weight 8 0.25 0.04–0.45 0.00 Recruitment period  1959–1989 6 0.87 0.28–1.47 57.21  1990–2000 5 0.10 −0.31–0.50 0.00  2001–2007 4 0.14 −0.28–0.57 0.00 Continent  European 8 0.09 −0.22–0.40 0.00  Non-European 7 0.67 0.25–1.09 36.94 Method for blood pressure measurementb  Oscillometry or digital sphygmomanometry 12 0.32 −0.04–0.68 30.04  Standard mercury or manual sphygmomanometry 5 0.81 0.15–1.47 43.01 Age group  3–6.5years 8 0.30 −0.07–0.67 9.96  7–15years 7 0.62 −0.01–1.24 0.00