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Introduction
Tourette syndrome (TS) and chronic tic disorders (CTD) are 2 neurodevelopmental disorders, which are usually diagnosed during childhood [1]. The prevalence of TS and CTD has been estimated to range from 2.6 to 38 and 3 to 50 per 1,000 children, respectively [2]. The prevalence of these disorders among boys is higher than that in girls [3]. These conditions affect the health status, familial and social relationships, education, employment, and daily life of patients [2].
Based on the results of genetic and familial studies, both TS and CTD are heritable conditions [4–6]; however, environmental factors are also important in the etiology of both TS and CTD [7]. Environmental factors such as smoking during pregnancy, pregnancy complications, low birth weight [8,9], and infection [10] have been shown to be associated with these disorders.
To date, several studies have assessed the effect of maternal smoking during pregnancy (MSDP) on the risk of TS and CTD among offspring [8,11,12]; however, there is controversy among the results of these studies. Therefore, this systematic review and meta-analysis aimed to estimate the association between MSDP and the risk of TS and CTD among offspring.
Methods
The present systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [13].
1. Search strategy
The literature evaluating the association between MSDP and TD/CTD disorders was systematically searched in the 3 electronic databases — PubMed, Scopus, and Web of Sciences, up to July 2019 without any limitations on type of document, time, or publication status. The following keywords were used in combination or alone: “Tourette syndrome”, “tic disorders”, “tics”, “Tourette”, “chronic tic”, “smoking”, “parental smoking”, “maternal smoking”, “pregnancy” and “child”. The search strategy used for each database is presented in detail in Appendix 1.
2. Study selection
The initial search was imported into Endnote software (version X6; Thomson Reuters, Toronto, Canada). After removing duplications, all potential documents were independently scanned by 2 authors (EA and KM) and in cases of disagreement, the 2 authors discussed the article and came to a consensus.
3. Eligibility criteria
The eligible articles were retrieved by evaluating the titles and abstracts of the identified studies, though the full text was screened if necessary. All observational studies, including cohort, case control, and cross-sectional studies, that evaluated the association between MSDP and TD/CTD were included which met the following criteria: 1) reported crude or adjusted relative risk and 95% confidence intervals (CIs) for the association between MSDP and TS/CTD, or 2) provided the original data about the association for estimating relative risk. Animal or in vitro studies, reviews, case studies, correspondences, editorials, book reviews, and conference or meeting abstracts were excluded.
4. Data extraction
The following items were extracted from each study: the name of the first author, year of publication, study design, country, type of study, outcome, classification system for diagnosis of the outcome, age, gender, MSDP levels, number of cases and controls (exposed to MSDP and non-exposed), source of control and matching variables for case control studies, crude and adjusted hazard ratio (HR), relative risk (RR) or odds ratio (OR) with 95% CIs, and adjusted confounders. We selected one specific adjusted RR from each study for the adjusted RRs to be independent and mutually exclusive in the meta-analysis.
5. Assessment the risk of bias
The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. This scale consists of the following main domains: selection, comparability, exposure, and outcome [14]. A study was classified as high quality (low risk of bias) when it received 6 or more stars.
6. Statistical analysis
Statistical analyses were performed using Stata SE version 11 (StataCorp, College Station, TX, USA). The outcome of interest was expected to be rare among both groups, i.e., exposed to MSDP and unexposed, whereby RR was approximated by HRs and ORs [15]. Heterogeneity among studies was evaluated using the I2 estimate; heterogeneity was considered as low, moderate, and high when I2 values were <25%, 25–50%, and >50%, respectively. An I2 value higher than 50% was considered a substantial and large heterogeneity [16]. In case of high heterogeneity among studies, summary relative measures from each study were combined using random-effects models, which incorporate heterogeneity in the weighted average of relative measure. However, both fixed-effect and random-effects analyses were considered to reveal the presence of small-study effects. Fixed-effect and random-effects analyses were performed using the inverse variance method. The potential publication bias was assessed using funnel plots, Begg’s test, and Egger’s test. P<0.05 was considered significant.
Results
1. Study inclusion and characteristics of included studies
The PRISMA flow diagram of the study selection is shown in Fig. 1. Initial searches yielded 641 citations, and after removing duplications and screening the titles and abstracts, 9 articles met the eligibility criteria [11,12,17–23]. Two studies [17,20] were not included in the final analysis because one of them [17] reported a mean difference in the number of patients with tic disorder according to prenatal smoking exposure (yes vs. no), and another study [20] reported a linear regression coefficient for the association between prenatal maternal smoking and increased symptom severity in TS. Finally, 7 observational studies [11,12,18,21–24] provided relative risks and were considered for quantitative meta-analysis.
The characteristics of these 7 studies are presented in Table 1. Of the included studies, 3 were cohort studies [11,18,21] consisting of 3,106,024 children, including 8,258 with TS or CTD. The 4 remaining were case control designs [12,22–24], with 205 exposed to MSDP among 1,073 TS/CTD cases. The sample of included studies varied largely in size, from 153 [24] to 3,026,861 [18]. The identified TS/CTD cases in the studies were predominantly among male patients with age under 15 years. The list of adjusted covariates in each study is given in Table 1.
2. Risk of bias assessment
Overall, all included studies were of good quality and had a low degree of bias (NOS stars ≥6). Based on the NOS, the maximum number of stars achieved among the cohort studies was 9, given to the one by Mathews et al. [21]. Among case control studies, those by Leivonen et al. [12] and Pringsheim et al. [23] received the highest number of stars, 8 each (Table 2).
3. Results of meta-analysis
In individual studies, adjusted HRs or ORs were reported for the association between MSDP and TS or CTD in several scenarios. For example, in 2 studies by Brander et al. [18] and Browne et al. [11], the association between MSDP and TS/CTD has been examined alone or with other comorbid psychiatric conditions. In the study by Brander et al. [18], 2 adjusted HRs were reported for the association between TS and CTD and 2 categories of MSDP, 1–9 cigarettes per day and ≥10 cigarettes per day; however, we pooled these 2 HRs. Finally, 7 adjusted HRs and ORs from 7 observational studies were included in the meta-analysis. The overall adjusted RR (95% CI) of MSDP on TS and CTD based on the fixed-effects model was 1.35 (95% CI, 1.17–1.56); I2=45.8%; P-value= 0.08 (Fig. 2). Corresponding figures based on the random-effects model were 1.44 (1.14–1.82) (forest plot not shown).
In terms of study design, the pooled RR (95% CI) from cohort studies was 1.30 (1.11–1.52); I2=35%; P-value=0.21; and the corresponding figure from case control studies was 1.65 (1.16–2.35); I2=54.2%; P-value=0.09. Stratification by the type of effect showed pooled associations when the HR and OR used for assessing the association were 1.32 (1.12–1.56); I2=65.2%; P-value=0.09, and 1.43 [1.10–1.85]; I2=49.8%, P-value=0.09, respectively. Furthermore, the resulting effect measures were stratified according to the outcome of interest. When excluding the OR from Pringsheim et al.’s study [23] (whose outcome was TS with attention-deficit/hyperactivity disorder [ADHD]), the pooled RR was 1.32 (1.14–1.52); I2=38.4%; P-value=0.15. After removing the ORs from the studies by Leivonen et al. [12] and Motlagh et al. [22] (were outcome was only TS) as well as the OR from the study by Pringsheim et al. [23], the pooled RR was 1.33 (1.14–1.55); I2=53.3%; P-value=0.09.
4. Publication bias
The funnel plot showed that the included studies were distributed relatively symmetrically on both sides of the vertical line, which reflected the absence of potential publication bias. Moreover, the P-value for the 2 tests (Begg’s and Egger’s tests) was >0.05, indicating no publication bias (Fig. 3).
Discussion
In this systematic review that led to the meta-analysis, a total of 641 potential articles were included. Finally, 7 adjusted RRs from 7 observational studies were pooled in the meta-analysis. The results showed that MSDP may be associated with a 35% increase in the risk of TS and CTD among offspring.
Although the biological mechanisms underlying the link between MSDP and TS/CTD are still not well understood, the findings from animal studies suggest that in utero nicotine exposure may influence fetal brain development and have short- and long-term effects on function [25–31]. Specifically, nicotine exposure during early fetal development adversely affects the function of neurotransmitters in the brain and synaptic development, causing neuronal loss and cell death [25]. In addition, MSDP can lead to an increased risk of adverse outcomes such as preterm birth and low birth weight, which are known to be potential risk factors for TD/CTD [8,21].
An important consideration in this meta-analysis is that the majority of the included RRs are estimated from cohort studies (weight=84%). Cohort studies are the “gold standard” among the observational epidemiological study designs, and meta-analyses of such studies can be considered as being at the top of the hierarchy of studies generating scientific evidence. In cohort studies, temporality between exposure and outcome can be well defined. In the cohort studies included [11,18,21] in this meta-analysis, information about MSDP was gathered mainly during pregnancy; however, in 2 of the case control studies included [22,23] this information was collected at the time of case diagnosis, which may increase the risk of recall bias and subsequent biased estimates of effect for the association between MSDP and TS/CTD. Another factor to be considered is that the included cohort studies varied in confounder adjustment. For example, in the studies by Browne et al. [11] and Mathews et al. [21], the confounding factor of alcohol consumption during pregnancy was considered in the multivariable analysis; however, in the study by Brander et al. [18] this confounder was not included in the analysis. This differing approach to confounder adjustment among the cohort studies can influence the pooled estimation. Another issue with the included cohort studies is that they [11,18,21] tried to adjust for many potential confounders in the MSDP-TS/CTD pathway.
We found the association between MSDP and TS/CTD to be similar to that in other meta-analyses that evaluated the association of MSDP with other neurodevelopmental disorders. For example, in 2 meta-analyses [32,33], an association between MSDP and ADHD has been identified, and in another meta-analysis [34], an association between MSDP and autism spectrum disorder in offspring has been documented.
It is important to consider the association between MSDP and TS/CTD in the presence of potential confounders. The risk of TS/CTD may be different for the offspring of mothers who smoked only in part of pregnancy compared to those whose mothers smoked during the whole pregnancy. For example, among the included studies, the one by Mathews et al. [20] showed that the effects of smoking in the last 2 months of pregnancy for TS and TS/CTD were 0.99 and 1.25 respectively, and these were different when compared to those reported by other included studies that assumed smoking in the whole pregnancy. A dose-response meta-analysis of cigarette dose and the risk of TS/CTD is needed when smoking is measured as a continuous variable. Previous literature offers a link between MSDP and TS and CTD disorders but is confounded by the presence of comorbidities [12,22].
Another source that could explain the heterogeneity among studies is the role of the interaction between MSDP and other risk factors. For example, in one review, maternal smoking and low birth weight were only 2 important determinants of TS [8] and in one study by Santangelo et al. [35] coffee, cigarettes, and alcohol exposure were combined as one single factor that was a risk factor TS. In another study by Bos-Veneman et al. [17], the association between MSDP and TS/ADHD is stronger in children with a family history of mental disorders than in those without a family history of mental disorders.
The present meta-analysis has several strengths and limitations. This study is the first meta-analysis that aimed to investigate the association between MSDP and TS/CTD among offspring, including mainly cohort studies and case control studies, with a relatively large sample sizes and low risk of bias. However, the number of studies included in the meta-analysis was 7 (3 cohort and 4 case-control studies); therefore, the effect of publication bias and small study effects on the results should be considered when interpreting the results.
Another limitation of this systematic review was the variety in the reported outcomes in the included studies. However, in addition to estimating a pooled measure of association, we reported a specific study measure of association for each outcome, for example TS/CTD spectrum, only TS, only CTD, TS/CTD, and TS with ADHD.
Moreover, this study may be accompanied by a degree of selection bias because of potentially missed studies indexed in databases such as Embase and the Cochrane Library, limiting full-text review to English language articles, or no systematic attempt to obtain gray literature.
Conclusion
The results of this systematic review and meta-analysis indicated that the MSDP may be associated with the risk of TS and CTD in offspring; therefore, the planning and implementation of educational and prevention programs for mothers to stop smoking, especially during pregnancy, seems to be necessary.
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