Maternal smoking during pregnancy and newborn telomere length (TL): a systematic review and meta-analysis of observational studies

Abstract

Background

Telomeres indicate cellular aging. Shortened telomeres are linked to various diseases and mortality, influenced by factors like inflammation, genetics, and environmental exposures, including smoking. Assessing newborn telomere length (TL) and maternal smoking association remains unexplored. A systematic review aims to fill this gap, potentially advancing clinical understanding and guiding future research.

Methods

This systematic review involved searching six English electronic databases—PubMed, Scopus, PsycINFO, Web of Science, Embase, and CINAHL Complete—for records from their inception until February 2024. The review focused solely on observational studies. Included studies assessed the impact of maternal smoking during pregnancy on the TL of newborns. The quality of these studies was evaluated using the Newcastle–Ottawa quality assessment scale. A random-effect model was employed, and the statistical analysis was conducted with Stata software version 17.

Results

Eight of 485 initial studies were included for systematic and five for meta-analysis. Eight studies involving 2,797 participants investigated prenatal smoking’s impact on infant telomere length, predominantly using qPCR and umbilical cord blood cells for measurement of TL. Five studies with 1,822 participants assessed the effect of maternal smoking during pregnancy on newborn TL, revealing a significant negative correlation (-0.19 [-0.32, -0.09]). Despite high heterogeneity (I2: 85.57%), no publication bias was found. Sensitivity analysis, excluding one study, showed a stronger correlation (-0.27 [-0.36, -0.17]) and reduced heterogeneity (I2: 53.21%). Subgroup analysis by nationality indicated a slightly stronger correlation in North American studies (-0.21 [-0.30, -0.12]) compared to Asian studies (-0.17 [-0.52, 0.17]). No significant differences were observed (p = 0.85).

Conclusion

A meta-analysis found maternal smoking in pregnancy correlates negatively with neonatal telomere length, impacting aging. Urgent awareness and further research are needed for preventive measures.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12884-025-08273-w.

Introduction

The notion of ‘telomere’ was initially postulated by McClintock and Muller, esteemed researchers in their field [1, 2]. Telomeres, situated at the terminal positions of chromosomes, consist of repetitive DNA sequences comprising thousands of consecutive TTAGGG nucleotide sequences alongside a repertoire of associated proteins [3].

The presence of telomeres is imperative for the process of DNA replication. During each replication cycle, telomeres experience gradual shortening until they reach a specific threshold. Consequently, the length of telomeres serves as a biological indicator of cellular aging [4]. The telomere length (TL) attrition is influenced by multiple factors, including inflammation, oxidative stress, and repetitive cell replication, thereby establishing a connection between TL and chronological aging [5]. Notably, the shortening of TL not only acts as a biomarker but also appears to be a causal factor in a myriad of physical and mental disorders, as well as mortality [6]. Scholars have suggested that TL may serve as a general risk factor for chronic diseases, including cancer, diabetes, and cardiovascular diseases [7–9]. Moreover, telomere shortening has been linked to conditions such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis [10], as well as inflammation [11] and mental illnesses [12]. Furthermore, diminished TL in leukocytes has been associated with heightened mortality rates [13, 14]. Despite the apparent connection between TL and the previously mentioned age-related diseases, as well as the conceptual appeal of using telomere shortening to explain proliferative exhaustion and cell ageing, this mechanism is inadequate to account for the ageing process in non-proliferating, quiescent, or terminally differentiated cells [15].

It is assumed that TL at birth can significantly forecast TL in later stages of life [16]. Initial investigations have posited that TL is inherited maternally through an X-linked mechanism [17]. Furthermore, genetic factors have been observed to contribute to TL, with twin studies indicating that genetics explain nearly 70% of individual variations. These studies have also revealed a stronger correlation between mother and offspring in comparison to father and offspring, alongside a significant positive association with paternal age at the time of offspring birth [18]. TL is also influenced by an array of environmental factors [19]. Telomeres are remarkably susceptible to impairment caused by alkylation, ultraviolet irradiation, and oxidative stress [20].

Additionally, factors such as nutrition [21], air pollution [22], physical activity [23], and cigarette smoking [23] exert an impact on TL. Maternal smoking during pregnancy has been previously associated with shorter TL in offspring [24–26]. Cigarette smoke affects TL through some possible mechanisms. It harbors numerous oxidants and free radicals that can inflict damage upon DNA [27, 28]. Moreover, cigarette smoke can impede the body’s antioxidative defense system [29].

To date, the relationship between TL and maternal smoking has been scarcely systematically investigated. Nevertheless, in 2020, Wei et al. examined the association between prenatal smoking exposure and telomere lengths [30], and the present study encompasses a broader corpus of published literature while also evaluating the factors influencing this relationship. Our objective was to accurately quantify any associations systematically while also assessing and comparing these associations across a wide range of study-level characteristics. By doing so, we aspired to propel advancements in clinical practice and guide the design of future investigations. To the best of our knowledge, no published review has compiled research findings explicitly examining the relationship between maternal smoking and newborn TL.

Methods

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020 [31]. The registration number in PROSPERO is CRD42024521826.

Search strategy

From inception until February 10, 2024, a search was conducted in English electronic databases. The following keywords were used: “telomere” OR “telomere shortening” AND “infant” OR “newborn” OR “child” OR “mother” OR “maternal” AND “smoking.” Searches were carried out in the specified databases (PubMed, Scopus, Embase, PsycINFO, Web of Science, and CINAHL Complete). Detailed search strategies for each database are available (refer to Supplementary Material 1). Additionally, the references of the included studies (relevant studies for full text review) and relevant reviews were reviewed to identify potentially eligible articles.

Eligibility criteria

The studies included those that investigated the impact of maternal smoking during pregnancy on the telomere length (TL) of newborns at birth. For the final evaluation, studies were selected based on PECO (Population, Exposure, Comparison, Outcomes) criteria:

• Population: Newborns at the time of delivery.

• Exposure: Maternal smoking during pregnancy, excluding secondhand smokers.

• Comparison: Newborns whose mothers did not smoke tobacco during pregnancy. Validated tools such as questionnaires and medical records, or any other reliable methods, may be used to assess tobacco smoking.

• Outcomes: Telomere length of newborns at birth.

The following studies were excluded: [1] Studies examining smoking at times other than during pregnancy; [2] Studies measuring the TL of newborns at times other than at birth; [3] Duplicate studies or those with overlapping participants; [4] Reviews, editorials, conference papers, case series/reports, secondary analyses, qualitative designs, or animal experiments.

The following criteria were for qualitative analsysis. For the meta-analysis, we included only those studies that specifically examined this relationship. The analysis was conducted by calculating the correlation coefficients that reflect the association between maternal smoking during pregnancy and telomere length in newborns. This approach allowed us to synthesize findings from multiple studies, providing a clearer understanding of how maternal smoking may influence telomere length at birth.

Study selection

Two authors (MG and MS) independently screened the titles and abstracts of studies that were potentially eligible. Afterward, other authors individually assessed the full texts of those studies that met the criteria. To address any disagreements, the authors held several meetings to achieve a consensus. During the review process, a third author (RM) provided additional assistance whenever necessary.

Data extraction

The following information was independently extracted by two authors (MG and MS) from the included articles: the names of the authors and year of publication, the country of the study, the type of study, the sample size, the ethnicity of participants, the ratio of males to females, the smoking status of participants, the source of the newborn’s telomere, the tool used for TL assessment, and the main findings of the study (Table 1).

Table 1.

Overview of included studies

Author, year	Country	Study type	Sample size	Ethnicity	Male (%)	Type of smoking	Source of infantile telomere	Smoking assessment tool	Quantifiable method	Main results	Limitation and strength	NOS and Risk of bias
Imam et al. 2012 (38)	Canada	Cohort	223 SM:89	Caucasian, Hispanic, Black, Asian, other	56%	Cigarettes	UCB	NM	NM	Smoking in mother was associated with a reduction in TL. (Pearson: r=−0.197; P = 0.03). No controlled factor.	The study results might be limited as paternal data were omitted.	7/Low
Almanzar et al. 2013 (33)	Austria	Cross sectional	169 SM:59	Caucasian	57%	Cigarettes	UCB	standardized questionnaire	Number of cigarette	Smoking mothers had neonates with longer TL in comparison to nonsmoking mothers (P < 0.01). No controlled factor.	Strength: Strict inclusion criteria in this study might limit the effects of confounding factors. Limitation: Smoking status was determined by serum cotinine level, which reflects recent exposure to cigarettes rather than long -term use. So, women who had not smoked for a few days prior to birth might have been omitted as they had low levels of cotinine level.	8/Low
Salihu et al. 2015 (40)	USA	Cross-sectional	T:86 SM:23	Black, White, Hispanic, and other	NM	Cigarettes	UCB	questionnaire and a salivary cotinine test	Salivary cotinine test	Smoking during pregnancy was associated with shorter TL, with the lowest TL in SM neonates (P < 0.05). No controlled factor.	A small sample size limited the study results. The strength of this article is the simultaneous use of a questionnaire and serum cotinine level.	9/Low
Enlow et al. 2018 (36)	US	Cross-sectional	T: 151 SM:32	White, black, Hispanic	55%	cigarette	UCB	maternal self-report	NM	The negative association between maternal smoking in pregnancy and TL. (Pearson: r=−0.18; P = 0.025). No controlled factor.	Limitations: The unconventional site of samples for TL estimation (peripheral blood mononuclear cells) may be considered a limitation.	7/Low
Minamoto et al. 2020 (39)	Japan	Cross-sectional	T: 578 SM:35	Japanese	T:52% SM:	NM	UCB	Medical records	NM	Smoking had no effect on TL shortening. (Pearson: r = 0.0026; P = 0.957). No controlled factor.	The racial homogeneity of the participants is both a strength and a limitation of this article. Another limitation might be the Quality of DNAs	7/Low
Enlow et al. 2021 (34)	USA	cohort	T:146 SM:2	White, Black, Hispanic, Asian, Other	50.7%	Cigarettes	UCB	Questionnaires	NM	Negative Association between TL in infants and smoking in mothers. (Pearson: r=−0.25; P = 0.04). No controlled factor.	Leukocyte DNA used to measure TL, was derived from the buffy coat which is both a strength and limitation.	8/Low
Hahn et al. 2021 (37)	brazil	Case-control	T:222 SM:52 Control:99	Hispanic	T: 47.3% (55.8% Of the SMs children)	Tobacco	epithelial mucosal cells.	NM	NM	Healthy-term newborns TL was not affected by their mothers smoking during pregnancy (p > 0.05). T/S ratio of smoking mother was 1.192, and in control was 1.251. No controlled factor.	Limitation: Children with TL abnormalities might have been excluded due to strict criteria. The small sample size and use of Buccal DNA for TL estimation were the limitattions.	7/Low
Chen et al. 2022 (35)	Singapore	Cross-sectional	T:721 SM:39	Chinese, Malay, Indian	52.4% M: 378	NM	UCB	Questionnaire	Plasma cotinine concentration	Strong effects of maternal smoking during pregnancy on TL (β = − 0.35, P < 0.05). No controlled factor.	Strength: In addition to the self-reported questionnaire, plasma cotinine level was also measured to avoid recall bias or underreported smoking.	8/Low

^∗ Abbreviations: SHS Second hand smoker, NM not mentioned, T total, SM smoking mother, M male, TL telomerase length, UCB umbilical cord blood, NOS Newcastle–Ottawa Quality assessment scale

Quality assessment

Two authors (MG and MS) independently conducted quality assessments using the Newcastle–Ottawa Quality (NOS) Assessment Scale [32] to determine the risk of bias in the final studies. Any disagreements were resolved through discussion and consensus, involving a third investigator (HM) if necessary. Cohort studies were categorized as having a low risk of bias (≥ 7 scores), moderate risk (5–6 scores), or high risk of bias (≤ 4 scores), with a maximum overall quality score of 9 stars. Similarly, cross-sectional studies were classified based on their risk of bias as low (≥ 7 scores), moderate (5–6 scores), or high (≤ 4 scores).

Quantitative analysis

For the meta-analysis, we incorporated studies that evaluate the relationship between maternal smoking during pregnancy and telomere length in newborns. In our meta-analysis, the I2 metric was used to evaluate how heterogeneity affected combined outcomes. When the I² figure exceeded 50%, indicating substantial heterogeneity, random-effects models were applied to combine the data. To determine the final effect size, correlation coefficient and standard error (SE) statistics were utilized. The extracted regression coefficients were combined using a random effects model (restricted maximum-likelihood model). Publication bias was evaluated with the Begg and Egger tests as well as a funnel plot. Further investigation included a subgroup analysis based on nationality. A sensitivity analysis was conducted using a leave-one-out meta-analysis approach, where each study is excluded one at a time. This method evaluates how each individual study influences the overall effect size estimate from the remaining studies. All analyses were executed using Stata software (version 17, Stata Corporation, College Station, Texas, USA). P-values below 0.05 were deemed statistically significant.

Results

Selection of studies

Out of the original 485 studies, 222 were excluded because of duplication. The remaining 263 studies were evaluated, systematically reviewing eight studies [33–40] A meta-analysis was then conducted, incorporating five studies that provided the required quantitative data for analysis (refer to details in Fig. 1).

Fig. 1.

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram of search results

Study characteristics

The characteristic features of the included articles are reviewed in Table 1. The eight articles involved 2797 participants, with the least sample size of 68 to most 746 [33–40]. The studies included for quantitative analysis involved 333 participants with a history of smoking during pregnancy. Six studies were cross-sectional, one was case-control, and the rest were cohort. Participants were of diverse ethnicities.

While three of the studies measured serum cotinine levels to document smoking, the rest of the authors used standardized questionnaires to determine smoking status [33, 35, 40]. Most studies (7 of 8) used infantile umbilical cord blood (UCB) cells for relative TL measurement; only Hahn et al. used epithelial mucosal cells instead [37]. TL was measured with qPCR in all studies.

Imam et al., among the first cohort articles investigating different factors on TL reported a negative association between smoking and infantile TL. Their study was designed for HIV-positive mothers, a significant percentage of whom were also smokers [38].

Almanzar et al., on the other hand, reported longer TL in newborns of smoking mothers in comparison to non-smoking mothers [33]. Chen et al. stated a strong correlation between maternal smoking and newborn’s TL, gathering data precisely via both questionnaires and serum cotinine to avoid bias [35]. Bosquet Enlow et al. concluded a negative association of maternal smoking on infant’s TL in two different studies focusing on prenatal environmental factors and TL [34, 36]. Salihu HM et al. also reported shorter TL for infants of smoking mothers [40]. Two studies (Hahn et al. and Minamoto et al.) found no association between prenatal smoking exposure and infant’s TL [37, 39].

Risk of bias within studies

According to the NOS, all 8 studies [33–40] included in the analysis demonstrate a low risk of bias (≥ 7 stars), indicating good quality as depicted in Table 1.

Synthesis of results

Overall results

To evaluate the effect of maternal smoking during pregnancy on newborn’s TL, we included five studies involving 1822 participants in the analysis. The analysis revealed a significant negative correlation (r: −0.19 [−0.32, −0.09]) between maternal smoking during pregnancy and newborn’s TL, although there was considerable heterogeneity among the studies (I2: 85.57%) (Fig. 2). Publication bias was assessed using funnel plot and Egger and Begg tests, depicted in Fig. 3. The funnel plot showed no evidence of publication bias, a finding corroborated by Egger (p = 0.95) and Begg (p = 0.81) tests.

Fig. 2.

Forest plot of the overall result

Fig. 3.

Funnel plot of the overall result

A sensitivity analysis (Fig. 4) indicated that excluding the Minamoto et al. study had a notable impact on the overall results, resulting in a correlation coefficient of −0.27 [−0.36, −0.17]. The outcomes post-exclusion of this study are illustrated in Fig. 5. Moreover, after removing this study, the heterogeneity decreased (I2: 53.21%).

Fig. 4.

Sensitivity analysis of the included studies

Fig. 5.

Meta-analysis of all included studies after removing one study (Sensitivity analysis)

Furthermore, a subgroup meta-analysis based on nationality was performed. The analysis revealed no significant differences between studies conducted in North America (correlation coefficient: −0.21 [−0.30, −0.12]) and studies conducted in Asia (correlation coefficient: −0.17 [−0.52, 0.17]) (p = 0.85) (Fig. 6).

Fig. 6.

Subgroup meta-analysis of included studies based on nationality

Discussion

This systematic review and meta-analysis found a negative correlation between smoking during pregnancy and TL in offspring. Eight studies with 2,326 participants (including 331 smokers) were analyzed. The meta-analysis of five studies revealed a significant negative correlation between maternal smoking and newborn TL. Subgroup analysis showed no significant correlation in Asian studies but a significant negative correlation in North American studies with low heterogeneity.

Most studies found a significant negative association between maternal smoking in pregnancy and neonatal leukocyte telomere length (LTL). Almanzar’s cross-sectional study found a significant positive correlation between newborn LTL and maternal smoking in 58 heavily addicted mothers, using self-reported questionnaires and blood cotinine levels. This correlation remained consistent after a multiple linear regression analysis adjusting for other covariates such as maternal age at birth, gestational week, sex, birth weight and length, head circumference, and APGAR scores [33]. Enlow et al.‘s cross-sectional study found maternal smoking during pregnancy significantly shortens telomere length in male newborns (r = −0.28, p = 0.011), with insignificant effects in females (r = −0.05, p = 0.706). In this study, the correlation between TL and a wide range of covariates and confounding variables such as maternal age, ethnicity, pregnancy complications (eclampsia, pre-eclampsia, and gestational diabetes(GDM)), pre-pregnancy BMI, gestational age, newborn birthweight, maternal emotional support in childhood, mental health in pregnancy, stress exposures in childhood and pregnancy and maternal education were also determined [36]. Minamoto’s cross-sectional study found no association between maternal smoking and newborns’ TL. They also reported no statistically significant correlation between TL and maternal age, BMI, GDM, stress, alcohol consumption, preterm delivery, fetal growth restriction, newborn sex, and placental weight. But interestingly, they showed pregnancies achieved by Assisted Reproductive Technology (ART) may negatively be associated with neonatal TL [39]. A large longitudinal study (n = 222) found no significant differences in neonatal telomere length between smoking and non-smoking mothers after adjustment for maternal age and neonatal sex. They also showed no significant association between childbirth weight and neonatal TL [37]. Enlow et al. found that maternal lifetime smoking (> 50 cigarettes) before pregnancy was associated with shorter neonatal TL, while active smoking during pregnancy showed no significant effect. Among various confounding variables (neonatal sex, maternal prenatal BMI, parity, history of preterm labor, pre-eclampsia, chronic hypertension, pre-existing diabetes, GDM, etc.) a history of maternal pre-eclampsia was found to be inversely associated with neonatal TL as well [34]. In a study by Chen et al., in addition to maternal smoking, Other contributing factors that could explain neonatal TL such as neonatal sex, paternal age, maternal TL, plasma Insulin-like growth factor-binding protein 3 (IGFBP3), and plasma fasting glucose levels were measured, from which maternal TL, paternal age and female sex were positively correlated with neonatal TL and the rest were inversely correlated [35].

Telomere shortening, a hallmark of cellular aging, can be accelerated by oxidative stressors like reactive oxygen species (ROS), leading to impaired cell division and premature senescence [41]. However, on some occasions, telomere shortening doesn’t happen due to this physiological process; it occurs due to exposure to offensive agents in inflammation and oxidative stress. In fact, due to the structure of telomeres, which are rich in guanine bases(TTAGGG), they are highly susceptible to oxidative stressors such as reactive oxygen species (ROS) [41]. Exposure to ROS causes damage to the sequence of the molecule and leaves it unrepaired, resulting in the limited ability of cell division, biological repair, and early cellular senescence. Possessing these features made the TL a biomarker for biological aging and cumulative stress. As previously shown, TL is inversely associated with adverse health outcomes such as cardiovascular diseases, overweight, type-2 diabetes, and cancer diagnosis [41, 42].

Early life TL is influenced by various environmental and genetic factors. Environmental factors encompass maternal stress, nutrition, chemical exposures (alcohol, air pollution, smoking), sleep apnea, obesity, education, and income. Genetic factors like maternal TL, paternal age, and sexual/racial differences also play a role [43, 44]. Chemical exposure, specifically smoking, is important since it is considered a risk factor for shorter telomere, both in mothers and their respective children [35]. It causes shorter TL in neonates of both mothers who used to smoke before but not during pregnancy and mothers who continue to smoke during pregnancy [45]. Smoking’s impact on telomere length stems from its inflammatory and oxidative nature. Tobacco smoke contains numerous oxidative compounds, inducing ROS production, exposing cellular components, particularly the genome, to prolonged oxidative stress [41, 42]. Telomeres, being structurally weaker, are prone to oxidative damage, especially targeted by smoking-induced inflammation, which triggers leukocyte activation and increased mitosis. Consequently, LTL diminishes at accelerated rates [42].

Previous reviews align with the current study, indicating a negative link between prenatal tobacco exposure and neonatal TL. Another review on TL in newborns suggested maternal tobacco use, along with stress and alcohol dependency, as significant TL-shortening factors, estimating a 3.9% to 9.7% TL loss. Second-hand exposure showed no TL association [43]. Werlang et al. (2019) conducted a systematic review of fetal exposure effects on neonatal TL. They associated sleep apnea and psychological stress with TL shortening, but maternal smoking, hyperglycemia, and hypertension effects were inconclusive due to limited studies, potentially reducing review power to detect associations [46]. Another review study, which attempted to provide an overview of TL determinants in children and neonates, reported cigarette smoking in pregnancy among the critical risk factors that promote an inflammatory environment in utero with various oxidative agents for the fetus and causes an increased rate of telomere loss during pregnancy [44]. Another review study confirmed the association between smoking during pregnancy and neonatal TL. Smoking increased double-stranded DNA breakage in placenta cells on the fetal side and shortened fetal telomeres. TL reduction was most significant in active smokers, followed by passive smokers, with minimal changes in non-smokers’ neonates [45].

As discussed above, the statistical analyses and most of the studies included in this review have shown a negative association between maternal smoking in pregnancy and neonatal TL, except for three [33, 37, 39]. Inconsistent results regarding the impact of smoking on TL may stem from various factors. Smoking or smoke exposure alone might not solely account for shorter TL in mothers or neonates. A recent meta-analysis of 18 longitudinal studies suggests that smoking alone may not significantly reduce TL over a usual lifetime unless exposed for 167 years. Neonates of smoking mothers may inherit shortened telomeres regardless of maternal smoking during pregnancy [47]. Smoking during pregnancy exacerbates the reduction of fetal telomere length, aligning with previous studies linking maternal telomere length as a crucial factor positively influencing neonatal telomere length [35, 48]. The paternal age may also positively affect the TL of neonates, and it has been shown that older fathers provide longer telomeres [35]. Among the included studies with a significant negative association between maternal smoking and neonatal TL, the studies conducted by Chen and Imam both reported shorter TL in smoking mothers compared to non-smoking peers [35, 38]. However, Almanzar et al. reported no significant differences between smoking and non-smoking mothers regarding their TL. They did not report any data on the paternal age of the neonates [49]. So, it might be possible that neonates of smoking mothers also had higher paternal age and consequently inherited longer telomeres compared to the neonates of non-smoking mothers, which can explain the opposite results reported in their study. We believe this might similarly explain the insignificant results of two other studies [37, 39], although they didn’t report any comparison between smoking and non-smoking mothers’ lengths of telomeres. Focusing only on the Japanese population in the study by Minamoto limited the power of the study to investigate any association [39]. It has been demonstrated that intrauterine growth retardation is associated with the smoking habits of mothers, which causes shorter neonatal TL [50]. In his study, Hahn excluded neonates weighing less than 2.5 Kg., which might decrease the chance of observing any association between maternal smoking and neonatal TL [37]. The study identifies limitations including inadequate DNA extraction and analysis methods, possibly explaining insignificant results. Smoking’s impact on neonatal telomere length varies among different tissues. Telomere length was measured in buccal mucosal cells, possibly less influenced by intrauterine stressors. The study suggests higher telomerase activity in pregnancy may protect against telomere shortening, a theory not universally supported by other studies [34], neglecting sex differences might obscure the link between maternal smoking and neonatal telomere length. Neither study conducted sex stratification analysis for smoking risk factors [33, 37, 39].

Strengths, limitations, and suggestions

This study represents the first comprehensive review and meta-analysis examining the link between smoking during pregnancy and neonatal TL. The quality assessment indicated low bias risk in the included studies. In contrast to the present systematic review, the previous reviews have studied the effects of smoking exposure on TL in populations other than neonates or assessed the effects in a population with different age groups, which provides an ambiguous answer to the question of how neonates are affected. Also, no other review study has provided a meta-analysis to show an overall effect of smoking exposure on neonatal TL yet. However, limitations were noted. Primarily, most studies were observational with cross-sectional designs, limiting their ability to establish causality between maternal smoking and neonatal TL. Furthermore, the small sample size, particularly of smokers, weakened the study’s strength. High statistical heterogeneity (I2 = 85.57%) persisted in the meta-analysis, albeit reduced to a moderate level (I2 = 53.21%) after sensitivity analysis. It must also be noted that the included studies were heterogeneous clinically and methodologically. Various study designs(case-control, cross-sectional, cohort), differences in diagnostic tools(serum cotinine levels or self-report questionnaires for smoking habit diagnosis), and diverse sites of sampling for TL measurement(venous blood leukocytes, cord blood leukocytes, or mucosal epithelial cells) are some examples of the heterogeneity among included studies which may affect the precision of overall effect of the present review. Future research should address these shortcomings by employing larger sample sizes and robust study designs to better understand the association between smoking during pregnancy and neonatal TL.

Conclusion

This systematic review and meta-analysis demonstrated a significant negative correlation between maternal smoking during pregnancy and neonatal TL, a manifestation of biological aging. Regarding the pivotal role of TL in developing chronic diseases and mortality, appropriate actions must be taken to increase the knowledge of women in the fertility age. Considering the inconsistent results of the current evidence, we also recommend more future studies to be conducted and reveal the full mechanism of effects of smoking on neonatal telomere.

Authors’ contributions

RM and HM initiate the concept and conduct the initial investigation. SM, HM, MG, and AG conduct the evaluation and incorporate the findings, and RM is responsible for composing the initial draft. RM and ES undertake the analysis. Oversight throughout all stages is provided by HM, NM, and JA. All authors approve the final version for publication.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.