Maternal smoking based on pre-birth health examination and risk of neurodevelopmental disorders in offspring: insights from a Korean mother–child cohort

Abstract

Background

Neurodevelopmental disorders affect a substantial proportion of children and often persist into adulthood, with lifelong consequences. We investigated the association between maternal smoking and neurodevelopmental disorders in offspring.

Methods

We performed a nationwide population-based mother–child cohort study of infants born between 2009 and 2018. Maternal smoking status was obtained from the closest NHIS general health examination conducted within 2 years prior to delivery and categorized as never, former, or current smokers. Offspring were followed up until 2021 for diagnoses of intellectual disability, autism spectrum disorder (ASD) (ascertained through governmental disability registration), and attention-deficit/hyperactivity disorder (ADHD) (ascertained through insurance records).

Results

Among the 861,876 offspring (51.4% boys; median follow-up 8.3 years), 790,728 (91.7%) were born to never-smoking mothers, 36,046 (4.2%) to former smokers, and 35,102 (4.1%) to current smokers. Offspring of women with any history of smoking had a higher cumulative incidence of all neurodevelopmental disorders than those of never smokers (all log-rank P < 0.001). After multivariate adjustment, maternal smoking was associated with a significantly increased risk of each outcome. Compared with offspring of never smokers, offspring of former smokers had hazard ratios (HRs) of 1.21 (95% confidence interval [CI] 1.04–1.41) for intellectual disability, 1.29 (95% CI 1.10–1.51) for ASD, and 1.18 (95% CI 1.12–1.26) for ADHD. Compared with offspring of never smokers, offspring of current smokers had higher risks (HR 1.44, 95% CI 1.25–1.66 for intellectual disability; HR 1.52, 95% CI 1.31–1.76 for ASD; HR 1.35, 95% CI 1.27–1.42 for ADHD). HR varied across pack-year tertiles among both former and current smokers; elevated risk estimates were observed even in the lowest tertile, particularly among current smokers across outcomes and among former smokers for intellectual disability and ADHD, without a strictly monotonic gradient.

Conclusions

Maternal smoking status as assessed from pre-birth health examinations was associated with increased risks of intellectual disability, ASD, and ADHD in their offspring. These findings support public health efforts to reduce smoking in women of reproductive age.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12916-026-04782-3.

Background

Neurodevelopmental disorders, including intellectual disability, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD), affect a substantial proportion of children and often persist into adulthood with lifelong consequences. These conditions impose a profound burden on affected individuals, families, and healthcare systems [1, 2]. Although neurodevelopmental disorders are typically diagnosed in early childhood or later, their origins can be traced back to prenatal brain development. Genetic predisposition and environmental exposure during gestation play critical roles in shaping neurodevelopmental trajectories [3]; therefore, identifying and addressing modifiable prenatal risk factors has become a key focus of current preventive efforts [4].

Among various prenatal exposures, maternal smoking has been suggested as a modifiable risk factor for adverse neurodevelopmental outcomes in offspring [5, 6]. Maternal smoking contributes to a range of adverse perinatal outcomes, including preterm birth, low birth weight, and sudden infant death syndrome [7, 8]. Nicotine and other neurotoxic components of tobacco smoke can cross the placental barrier and may disrupt the developing fetal brain via mechanisms such as oxidative stress, chronic fetal hypoxia, altered neurotransmitter signaling, and epigenetic reprogramming [9, 10]. Despite global decline in smoking rates among women of reproductive age in recent decades [11], a substantial proportion of women of reproductive age smoke before pregnancy and continue to smoke during pregnancy [7, 8, 11]. Strengthening the evidence base, improving risk communication, and implementing targeted smoking cessation strategies in this population are key public health priorities [8].

Previous studies examining the association between maternal smoking and neurodevelopmental disorders in offspring have produced inconsistent findings, possibly owing to various methodological limitations [5, 6]. In particular, the association appears to be more robust for ADHD [12, 13], whereas the evidence for intellectual disability or ASD has been weaker or less consistent [14–16]. These studies were based on relatively small samples, limiting statistical power, and several relied on retrospective self-reported smoking status, introducing recall bias. Confounding factors, particularly maternal medical, psychiatric, and socioeconomic factors associated with smoking behaviors and child neurodevelopment, are often insufficiently controlled. In addition, some studies have assessed child outcomes using parent-reported symptoms without clinical validation, potentially compromising diagnostic accuracy. Moreover, few investigations have rigorously quantified the intensity or duration of maternal smoking exposure, hindering the evaluation of dose–response relationships.

To address these research gaps, we aimed to clarify the association between maternal smoking and the risk of neurodevelopmental disorders in offspring, specifically intellectual disability, ASD, and ADHD, using the Korean Mother–Child Cohort, a large nationwide cohort comprising over 860,000 mother–child pairs. Maternal smoking status was prospectively collected from the National Health Insurance Service (NHIS) health examination records within 2 years prior to delivery, and offspring neurodevelopmental outcomes were ascertained through national registries and insurance records. We performed dose–response analyses based on cumulative smoking exposure, adjusted for a wide range of maternal and pregnancy-related factors, and conducted stratified analyses to explore potential effect modifications based on the child’s sex.

Methods

Ethical statement

This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. E-2503–152–1625). The study was conducted in accordance with the principles of the Declaration of Helsinki (2013 amendment). The requirement for informed consent was waived because the analysis used routine de-identified administrative data.

Data source and study population

This nationwide, population-based cohort study used data from the Korean NHIS database. The NHIS is the single public health insurer that covers the entire Korean population and provides biannual general health check-ups for eligible adults. The NHIS database contains individual demographic information, medical diagnoses, and health check-up results. The diagnoses were coded according to the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Details of this database have been previously reported [17]. We additionally obtained mortality data from Statistics Korea, as described previously [18]. Figure 1 presents a flowchart of the study design and participant selection. We identified 3,527,248 live births (offspring) in Korea between 2009 and 2018. We excluded offspring with missing birth dates or those whose mothers gave birth more than once in the same calendar year (n = 11,770). We also excluded offspring born to women who had not undergone a general health check-up < 2 years before birth (n = 2,642,981) and those with any missing covariate data (n = 10,621). After these exclusions, a total of 861,876 mother–offspring pairs were included in the final study cohort. The children were followed up from birth until the first occurrence of a neurodevelopmental outcome of interest or until December 31, 2021, whichever occurred first.

Fig. 1.

Flow chart of the study population. A schematic flow diagram illustrating the selection of the study participants. Comparison of characteristics between included and excluded populations is provided in Additional file: Table S11

Definitions of exposure, outcomes, and covariates

The primary exposure was maternal smoking status, ascertained from the NHIS general health examination conducted within 2 years prior to delivery (i.e., the closest examination before childbirth). If more than one examination was available within the 2-year window, we used the examination closest to delivery. Smoking status was self-reported at the time of the examination using standardized questionnaires [17, 19, 20]. Based on questionnaire responses, mothers were classified as never smokers, former smokers (reported a history of smoking but not current smoking at the examination), or current smokers (reported current smoking at the examination). Cumulative smoking exposure up to the examination was additionally quantified in pack-years (packs per day × years of smoking) as reported at the examination. Because the timing of the health examination could occur either before conception or during pregnancy and smoking behavior may change after the examination, we could not ascertain smoking status specifically during pregnancy nor the duration of abstinence among former smokers. For exposure-stratified analyses, former and current smokers were each further categorized into tertiles of pack-years. Detailed definitions of all covariates are provided in Additional file 1: Table S1.

The study outcomes were defined as the first recorded diagnosis of intellectual disability, ASD, or ADHD in the offspring during the follow-up period. All diagnoses were made by board-certified psychiatrists in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Intellectual disability and ASD cases were confirmed through official registration under the Act on Welfare of Persons with Developmental Disabilities in Korea, which involves a rigorous multistage review by clinicians and national health insurance officials to establish eligibility for governmental support. These disability registrations are linked to the NHIS database annually. ADHD was defined as at least one outpatient visit or hospitalization with a relevant ICD-10-CM diagnostic code (F90.0–F90.9); individuals with prior diagnoses of intellectual disability or ASD were excluded to minimize diagnostic overlap with ADHD. We also performed a sensitivity analysis defining ADHD as requiring at least two separate diagnoses. The index date was each child’s date of birth, and the follow-up duration was calculated from the index date until the first occurrence of an outcome for those who developed a disorder, or until December 31, 2021 for those who did not, whichever came first.

Several covariates were extracted for adjustment. Child sex, birth order (e.g., firstborn), and mode of delivery (Cesarean section or vaginal) were obtained from birth records. Household income from the NHIS was considered low for participants in the lowest 20% income bracket or were medical aid beneficiaries. Individuals residing in administrative districts with populations exceeding 1 million were classified as living in metropolitan areas. Maternal body mass index (BMI), blood pressure, and laboratory results, including fasting blood glucose, cholesterol, and serum creatinine levels, were obtained from the NHIS general health examination (within 2 years prior to delivery) used for exposure assessment. BMI and estimated glomerular filtration rate were treated as continuous variables in the analysis. Maternal comorbidities such as diabetes mellitus, hypertension, dyslipidemia, and depressive disorders were defined using diagnostic codes, treatment history, and health check-up data. Information on maternal alcohol intake and physical activity was collected via health examination questionnaires, as previously described. Detailed definitions of the covariates are provided in Additional file 1: Table S1 [20]. Obstetric information on low birth weight and preterm birth was obtained from ICD-10-CM codes recorded at birth: P07.0 and P07.1 for low birth weight, and P07.2 and P07.3 for preterm birth.

Statistical analyses

Categorical variables are presented as numbers and percentages and were compared across maternal smoking groups using the chi-squared test or Fisher’s exact test, as appropriate. Continuous variables are expressed as means ± standard deviations or medians with interquartile ranges (IQRs) and were compared using one-way analysis of variance for the three-group comparison. The incidence of each outcome was calculated as the number of events per 1000 person-years of follow-up. Time-to-event outcomes were depicted using Kaplan–Meier curves, and the log-rank test was used to compare the cumulative incidence across groups. We used multivariate Cox proportional hazards regression to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for offspring neurodevelopmental disorder outcomes associated with maternal smoking status. In addition, sensitivity analyses were conducted using Fine–Gray subdistribution hazard models, treating intellectual disability, ASD, and ADHD as competing risks. For exposure–stratified analyses among smokers, we examined HRs according to tertiles of cumulative smoking exposure (pack-years) within former smokers and within current smokers, using never smokers as the reference group. We also performed subgroup analyses based on offspring sex to assess potential effect modifications. To assess effect modification by offspring sex, we included an interaction term between maternal smoking status and offspring sex in the Cox proportional hazards models, and P for interaction was derived from the Wald test. Statistical significance was set at P < 0.05. All the analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Baseline characteristics

The study included 861,876 offspring, of whom 443,004 (51.4%) were male, 355,943 (41.3%) were delivered via Cesarean section, and 601,881 (69.8%) were firstborn. Baseline characteristics of the study population are summarized in Additional file 1: Table S2.

Offspring were categorized into three groups based on maternal smoking status: never-smoking (n = 790,728; 91.7%), former smokers (n = 36,046; 4.2%), and current smokers (n = 35,102; 4.1%). Table 1 shows the maternal and offspring characteristics according to these groups. There was no significant difference in the sex distribution of offspring across the groups (P = 0.448). However, several differences were observed between women with a history of smoking and those who never smoked. On average, women in the former smoker and current smoker groups had slightly higher BMIs and were slightly older than the never-smoking (P < 0.001 for overall comparisons). They also had a higher prevalence of comorbid conditions such as diabetes mellitus, hypertension, dyslipidemia, and depression (all P < 0.001). Socioeconomic and lifestyle factors revealed notable differences: mothers who smoked were more likely to be in the low-income bracket and had a higher prevalence of alcohol consumption (all P < 0.001). The three groups were similar in terms of parity and multiple-birth rates.

Table 1.

Baseline maternal and offspring characteristics by maternal smoking status

	Offspring of never smokers (n = 790,728)	Offspring of former smokers (n = 36,046)	Offspring of current smokers (n = 35,102)	P-value
Maternal characteristics
	32.1 ± 3.8	32.3 ± 4.4	31.3 ± 4.8	< 0.001
BMI, kg/m2	21.2 ± 3.0	22.0 ± 3.5	21.9 ± 3.8	< 0.001
Neurodevelopmental disorders, %
Intellectual disability	214 (0.03)	10 (0.03)	4 (0.01)	0.208
ASD	0 (0.0)	0 (0.0)	0 (0.0)	N/A
ADHD	51 (0.01)	4 (0.01)	3 (0.01)	0.526
Past medical history, %
Diabetes mellitus	5697 (0.7)	362 (1.0)	485 (1.4)	< 0.001
Hypertension	13,138 (1.7)	808 (2.2)	971 (2.8)	< 0.001
Dyslipidemia	31,014 (3.9)	1704 (4.7)	1348 (3.8)	< 0.001
Depressive disorder	10,607 (1.3)	764 (2.1)	954 (2.7)	< 0.001
Physical examination
Systolic BP, mmHg	110.3 ± 10.9	110.9 ± 11.5	111.9 ± 11.7	< 0.001
Diastolic BP, mmHg	69.3 ± 8.2	69.7 ± 8.6	70.6 ± 8.7	< 0.001
Laboratory data
Fasting blood glucose, mg/dL	88.3 ± 11.6	89.1 ± 12.9	89.5 ± 15.1	< 0.001
Total cholesterol, mg/dL	179.1 ± 31.0	181.4 ± 31.9	177.6 ± 30.8	< 0.001
LDL cholesterol, mg/dL	99.9 ± 29.1	99.4 ± 29.5	95.7 ± 29.9	< 0.001
HDL cholesterol, mg/dL	63.6 ± 19.4	64.1 ± 16.9	63.2 ± 17.4	< 0.001
GFR, ml/min/1.73m2	107.5 ± 18.3	107.6 ± 17.7	107.0 ± 17.7	< 0.001
Lifestyle factors
Living in metropolitan areas, %	376,296 (47.6)	17,191 (47.7)	15,866 (45.2)	< 0.001
Low income, %	102,541 (13.0)	6172 (17.1)	7444 (21.2)	< 0.001
Alcohol consumption				< 0.001
Non-drinker	435,060 (55.0)	11,538 (32.0)	9178 (26.2)
Mild drinker	344,165 (43.5)	21,542 (59.8)	20,952 (59.7)
Heavy drinker	11,503 (1.5)	2966 (8.2)	4972 (14.2)
Regular physical activity	81,689 (10.3)	4199 (11.7)	3712 (10.6)	< 0.001
Obstetric history, %
First childbirth	549,094 (69.4)	24,897 (69.1)	27,890 (79.5)	< 0.001
Twin or higher-order multiple gestation	28,868 (3.7)	1330 (3.7)	979 (2.8)	< 0.001
Cesarean section	320,572 (40.5)	17,388 (48.2)	17,983 (51.2)	< 0.001
Male sex of the neonate	406,478 (51.4)	18,424 (51.1)	18,102 (51.6)	0.448
Offspring characteristics
Low birth weight (< 2.5 kg), %	23,423 (3.0)	1099 (3.1)	1030 (2.9)	0.601
Preterm birth (gestational age < 37 weeks), %	27,624 (3.5)	1361 (3.8)	1272 (3.6)	0.009
Year of birth, %				< 0.001
2009	60 (0.0)	2 (0.0)	2 (0.0)
2010	32,896 (4.2)	1319 (3.7)	1290 (3.7)
2011	83,047 (10.5)	3285 (9.1)	3399 (9.7)
2012	109,185 (13.8)	4540 (12.6)	4801 (13.7)
2013	99,289 (12.6)	4352 (12.1)	4456 (12.7)
2014	101,305 (12.8)	4585 (12.7)	4577 (13.0)
2015	103,048 (13.0)	4738 (13.1)	4639 (13.2)
2016	96,964 (12.3)	4648 (12.9)	4172 (11.9)
2017	86,164 (10.9)	4374 (12.1)	3950 (11.3)
2018	78,770 (10.0)	4203 (11.7)	3816 (10.9)

ADHD attention-deficit/hyperactivity disorder, ASD autism spectrum disorder, BMI body mass index, BP blood pressure, GFR glomerular filtration rates, HDL high-density lipoprotein, LDL low-density lipoprotein, N/A not applicable

Incidence of neurodevelopmental disorders

During a median follow-up of 8.3 years (IQR 5.8–10.8 years), we identified 3547 cases of intellectual disability, 3148 cases of ASD, and 24,147 cases of ADHD in the offspring. Figure 2 illustrates the Kaplan–Meier curves for each outcome according to maternal smoking status. The cumulative incidence of all three neurodevelopmental disorders was significantly higher among children of former smokers and current smokers than among those of never smokers (log-rank P < 0.001 for all comparisons). Offspring of current smokers exhibited the highest cumulative incidence of neurodevelopmental disorders, followed by those of former smokers, whereas offspring of never smokers exhibited the lowest incidence of neurodevelopmental disorders. Notably, the incidence of neurodevelopmental disorders, especially ADHD, increased sharply at approximately 6 years, which corresponds to the age of school entry in Korea. Additional file 1: Figure S1 provides additional cumulative incidence curves comparing the offspring of never smokers with all smokers (combining former smokers and current smokers), indicating a divergence in risk that emerges in early childhood and becomes more pronounced by 6–7 years.

Fig. 2.

Kaplan–Meier curves for the cumulative incidence of neurodevelopmental disorders according to maternal smoking status. Cumulative incidence of intellectual disability, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) in offspring stratified based on maternal smoking status (never-smokers, former smokers, and current smokers). Numbers below the x-axis indicate the number of participants at risk in each group at 2-year intervals throughout the follow-up period

Maternal smoking and offspring neurodevelopmental risk

After adjusting for covariates (Table 2), maternal smoking history was significantly associated with an elevated risk of neurodevelopmental disorders in offspring. Compared to children of never smokers, those of former smokers had a higher risk of intellectual disability (adjusted HR 1.21, 95% CI 1.04–1.41), ASD (HR 1.29, 95% CI 1.10–1.51), and ADHD (HR 1.18, 95% CI 1.12–1.26). The risks were significantly greater for children of current smokers: the adjusted HR was 1.44 (95% CI 1.25–1.66) for intellectual disability, 1.52 (95% CI 1.31–1.76) for ASD, and 1.35 (95% CI 1.27–1.42) for ADHD, compared to the never smokers. These adjusted risk estimates are presented in Fig. 3, which shows the HRs for each outcome in the offspring of former smokers and current smokers compared to the offspring of never smokers. Additional analyses with adjustment for birth year and stratification by birth period are presented in Additional file 1: Table S3 and Additional file 1: Table S4, respectively. Analyses stratified by timing of diagnosis (≤ 6 years vs > 6 years) are presented in Additional file 1: Table S5. Multivariate analysis also demonstrated that offspring with any maternal smoking history (former smokers or current smokers) had a significantly increased risk of neurodevelopmental disorders compared to offspring of never smokers (Additional file 1: Table S6). When ADHD was defined using a more stringent criterion requiring at least two separate diagnoses, similar results were observed (Additional file 1: Table S7). In sensitivity analyses using competing risk models, the associations between maternal smoking and risks of offspring neurodevelopmental disorders remained consistent (Additional file 1: Table S8).

Table 2.

Incidence and adjusted hazard ratios of offspring neurodevelopmental disorders by maternal smoking status

	No. of offspring	No. of events	IR per 1000 PY	Model 1 HR (95% CI)	Model 2 HR (95% CI)	Model 3 HR (95% CI)
Intellectual disability
From never smokers	790,728	3155	0.513	1 (reference)	1 (reference)	1 (reference)
From former smokers	36,046	177	0.650	1.28 (1.10–1.49)	1.27 (1.09–1.48)	1.21 (1.04–1.41)
From current smokers	35,102	215	0.797	1.56 (1.36–1.79)	1.60 (1.39–1.84)	1.44 (1.25–1.66)
ASD
From never smokers	790,728	2784	0.453	1 (reference)	1 (reference)	1 (reference)
From former smokers	36,046	166	0.609	1.35 (1.15–1.58)	1.34 (1.15–1.57)	1.29 (1.10–1.51)
From current smokers	35,102	198	0.734	1.62 (1.41–1.87)	1.66 (1.44–1.92)	1.52 (1.31–1.76)
ADHD
From never smokers	790,728	21,627	3.332	1 (reference)	1 (reference)	1 (reference)
From former smokers	36,046	1153	4.008	1.25 (1.18–1.32)	1.25 (1.18–1.33)	1.18 (1.12–1.26)
From current smokers	35,102	1367	4.822	1.47 (1.40–1.56)	1.48 (1.40–1.57)	1.35 (1.27–1.42)

ADHD attention-deficit/hyperactivity disorder, ASD autism spectrum disorder, CI confidence interval, HR hazard ratio, IR incidence rate, PY person-years

Model 1 is unadjusted; Model 2 adjusts for maternal age and child sex; Model 3 adjusts for maternal age, body mass index, maternal history of neurodevelopmental disorder, diabetes mellitus, hypertension, dyslipidemia, depressive disorders, residential area, income level, alcohol intake, physical activity, first childbirth, twin or higher-order multiple gestation, Cesarean section, and child sex

Fig. 3.

Association between maternal smoking status and offspring neurodevelopmental risk. Forest plots displaying the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for intellectual disability, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) in the offspring of former smokers and current smokers

In analyses stratified by cumulative smoking exposure, elevated risks of neurodevelopmental disorders were even observed among the offspring of women with a relatively light smoking history, indicating complex, differential risk patterns across smoking history tertiles (Table 3). Compared with offspring of never smokers, those of current smokers in the lowest exposure tertile (< 1.75 pack-years) had significantly increased risks of intellectual disability (HR 1.35, 95% CI 1.05–1.73); ASD (HR 1.55, 95% CI 1.21–1.99); and ADHD (HR 1.33, 95% CI 1.21–1.46). Offspring of current smokers in the highest exposure tertile (≥ 4.00 pack-years) showed greater risk increases (HR 1.72, 95% CI 1.39–2.13 for intellectual disability; HR 1.57, 95% CI 1.24–1.99 for ASD; and HR 1.54, 95% CI 1.41–1.69 for ADHD versus never smokers) than those of the other groups. Among the offspring of former smokers, hazard ratios also varied across pack-year tertiles, although the pattern was less consistent and not strictly monotonic (Additional file 1: Table S9).

Table 3.

Risks of offspring neurodevelopmental disorders by cumulative smoking exposure among current smoker mothers

	No. of offspring	No. of events	IR per 1000 PY	Model 1 HR (95% CI)	Model 2 HR (95% CI)	Model 3 HR (95% CI)
Intellectual disability
From never smokers	790,728	3155	0.513	1 (reference)	1 (reference)	1 (reference)
From current smokers, 1 st tertile	11,463	64	0.712	1.38 (1.08–1.77)	1.46 (1.14–1.87)	1.35 (1.05–1.73)
From current smokers, 2nd tertile	11,674	59	0.767	1.28 (0.99–1.66)	1.33 (1.03–1.73)	1.21 (0.93–1.57)
From current smokers, 3rd tertile	11,965	92	1.024	2.02 (1.65–2.49)	1.99 (1.61–2.44)	1.72 (1.39–2.13)
ASD
From never smokers	790,728	2784	0.453	1 (reference)	1 (reference)	1 (reference)
From current smokers, 1 st tertile	11,463	64	0.712	1.57 (1.23–2.01)	1.65 (1.29–2.12)	1.55 (1.21–1.99)
From current smokers, 2nd tertile	11,674	61	0.678	1.50 (1.16–1.93)	1.56 (1.21–2.01)	1.43 (1.11–1.85)
From current smokers, 3rd tertile	11,965	73	0.812	1.80 (1.43–2.27)	1.77 (1.40–2.23)	1.57 (1.24–1.99)
ADHD
From never smokers	790,728	21,627	3.332	1 (reference)	1 (reference)	1 (reference)
From current smokers, 1 st tertile	11,463	451	4.775	1.42 (1.30–1.56)	1.43 (1.30–1.57)	1.33 (1.21–1.46)
From current smokers, 2nd tertile	11,674	398	4.206	1.28 (1.16–1.41)	1.29 (1.17–1.42)	1.18 (1.07–1.30)
From current smokers, 3rd tertile	11,965	518	5.486	1.73 (1.59–1.89)	1.74 (1.59–1.89)	1.54 (1.41–1.69)

ADHD attention-deficit/hyperactivity disorder, ASD autism spectrum disorder, CI confidence interval, HR hazard ratio, IR incidence rate, PY person-years

Tertiles of cumulative smoking exposure for current smokers: 1 st tertile < 1.75 pack-years; 2nd tertile 1.75– < 4.00 pack-years; 3rd tertile ≥ 4.00 pack-years

Model 1 is unadjusted; Model 2 adjusts for maternal age and child sex; Model 3 adjusts for maternal age, body mass index, maternal history of neurodevelopmental disorder, diabetes mellitus, hypertension, dyslipidemia, depressive disorders, residential area, income level, alcohol intake, physical activity, birth order, twin or higher-order multiple gestation, Cesarean section delivery, and child sex

Subgroup analyses

Next, we assessed whether the offspring’s sex modified the association between maternal smoking and neurodevelopmental outcomes (Additional file 1: Table S10). A significant interaction between maternal smoking and offspring sex was observed for ASD risk (P for interaction < 0.001). Specifically, female offspring appeared more susceptible to the effects of maternal smoking on ASD: female offspring of former smokers had an adjusted HR of 2.00 (95% CI 1.48–2.70) for ASD, and those of current smokers had a similar HR of 2.04 (95% CI 1.51–2.75), compared to female offspring of never-smokers. In contrast, among male offspring, the relative risks of ASD associated with maternal smoking were modest (HR 1.13, 95% CI 0.94–1.36 for sons of former smokers; HR 1.40, 95% CI 1.18–1.66 for sons of current smokers). No significant interactions based on sex were observed for intellectual disability or ADHD (P for interaction = 0.128 and 0.398, respectively).

Discussion

In this large nationwide cohort study, we examined the association between maternal smoking status ascertained from pre-birth health examinations and the risk of neurodevelopmental disorders in offspring. The main findings were as follows: First, compared with offspring of never smokers, offspring of both former and current smokers had higher risks of intellectual disability, ASD, and ADHD. Second, elevated risk estimates were observed even among women with relatively low cumulative smoking exposure, and hazard ratios varied across pack-year tertiles among both former and current smokers without a strictly monotonic gradient; the separation across tertiles was generally more evident among current smokers, and patterns were less consistent among former smokers (particularly for ASD). Third, the association between maternal smoking and ASD was more pronounced in female offspring than in male offspring.

Our results reinforce and extend the evidence that prenatal tobacco exposure may adversely affect neurodevelopmental outcomes in offspring. Identifying modifiable prenatal risk factors is essential given the profound and lifelong impact of neurodevelopmental disorders such as intellectual disability, ASD, and ADHD on children and their families [1, 21–23]. Previous studies examining maternal smoking during pregnancy and neurodevelopmental disorders in children have reported inconsistent results [24–28]. Although a link between maternal smoking and ADHD in offspring has been consistently observed across several studies [12, 13], evidence for an association with intellectual disability or ASD has been less consistent [14–16]. To address these limitations, we used a large, well-characterized cohort with objectively verified diagnoses and comprehensive covariates. In our analysis, despite the relatively low absolute incidence of intellectual disability and ASD, we were able to identify significant associations between maternal smoking and all three neurodevelopmental disorders in the offspring after controlling for numerous confounders; moreover, we characterized the variation in risk across smoking exposure levels.

Our study design offers several strengths compared to that of existing literature. We utilized a nationwide cohort of over 860,000 mother–child pairs, providing robust statistical power to detect even modest increases in the risk of relatively rare outcomes such as intellectual disability and ASD. Critically, our study employed rigorous outcome definitions: cases of intellectual disability and ASD were confirmed through a government registration system that required specialist diagnosis and verification, and ADHD was identified via clinical diagnostic codes rather than through unvalidated parent reports. This approach ensures high diagnostic validity and minimizes outcome misclassifications. Moreover, we adjusted for a wide range of maternal factors, including chronic physical conditions, depression, metabolic health indicators, and lifestyle behaviors, which could confound the relationship between smoking and developmental disorders in offspring. Smoking status was obtained from a routine NHIS health examination within 2 years prior to delivery and was recorded independently of offspring outcomes, which helps reduce recall bias. However, because the examination could occur either before conception or during pregnancy and smoking behavior may change after the examination, we could not directly ascertain smoking status specifically during pregnancy or the duration of abstinence among former smokers. We classified mothers as never, former, or current smoker and additionally considered cumulative exposure to explore exposure-stratified patterns. Offspring of both former and current smokers had higher risks than those of never smokers, with higher risks among offspring of current smokers. Elevated risks were observed even in the lowest pack-year tertile, suggesting that earlier cessation and avoidance of smoking among women of reproductive age may be important.

Although the present study was not designed to interrogate biological mechanisms, our findings are biologically plausible in light of prior research. Tobacco smoke exposure during gestation has been hypothesized to disrupt fetal brain development through multiple pathways. For ADHD, some proposed mechanisms include fetal hypoxia due to carbon monoxide in smoke, alterations in the development of the dopaminergic neurotransmitter system, and changes in telomere dynamics and brain inflammation in utero [5, 12]. In the case of ASD, toxic compounds in cigarette smoke can cross the placenta and may trigger oxidative stress and inflammatory cascades in the fetal brain, potentially leading to abnormal neurodevelopment [10]. Similarly, intellectual impairment may result from overlapping mechanisms, such as chronic hypoxia and direct neurotoxicity of nicotine and other chemicals, which can affect overall brain growth and connectivity [16]. In our study, maternal smoking history proximate to birth was associated with higher risks of ADHD, ASD, and intellectual disability, supporting the possibility that tobacco exposure may influence broad neurodevelopmental processes rather than disorder-specific pathways. In exposure-stratified analyses, elevated risk estimates were observed even in the lowest within-group pack-year tertile, most clearly among current smokers across outcomes and also among former smokers for intellectual disability and ADHD, whereas patterns across tertiles were less consistent for ASD among former smokers. Taken together, these observations are compatible with hypotheses implicating oxidative stress and chronic fetal hypoxia, which may occur even at relatively low levels of tobacco smoke exposure (e.g., nicotine and carbon monoxide). Because we could not directly test mechanistic pathways in this study, these interpretations should be considered cautiously.

One intriguing observation in our study was the sex-specific differences in the risk of ASD. We found that female offspring of women who smoked had approximately twice the risk of ASD compared to those of nonsmokers, whereas the risk increase among male offspring of smokers was modest. This result is notable because ASD is typically more common in males than females in the general population [28]. Our finding of disproportionately elevated ASD risks among female offspring is consistent with previous studies suggesting that female fetuses may be less buffered against or more vulnerable to certain environmental insults, such as tobacco exposure [29, 30]. However, this explanation remains inconclusive, and future research is needed to clarify the interplay between prenatal exposure, sex hormones, and neurodevelopmental outcomes.

We also noted a marked increase in the cumulative incidence of ADHD and, to a lesser extent, ASD at around 6 years of age in our cohort. This increase coincides with the typical age at school entry, when children’s difficulties with attention, hyperactivity, or social communication may become more apparent in structured classroom settings. This observation aligns with previous findings indicating that the structured demands and behavioral expectations associated with school entry around the age of 6 years may unmask underlying neurodevelopmental difficulties, potentially reflecting developmental immaturity [31, 32]. In this study, maternal smoking status was associated with higher risks of ASD and other neurodevelopmental disorders. Therefore, conducting more thorough evaluations in children of mothers with smoking history may facilitate earlier diagnosis, prior to school entry, potentially allowing for timely interventions and greater support.

From a public health perspective, our study highlights the prevention of maternal smoking as a potentially impactful strategy for reducing the burden of neurodevelopmental disorders. Conditions such as intellectual disability and ASD often lead to lifelong challenges and require extensive support across multiple domains. While ADHD may be more responsive to treatment and less impairing in some cases, it is nevertheless associated with substantial academic, behavioral, and social difficulties that also necessitate meaningful intervention and support. Given that effective treatments or cures for ASD and intellectual disability remain limited, primary prevention is crucial. Reducing tobacco exposure among women of reproductive age, including around the time of pregnancy, may represent an important strategy to help reduce the population-level burden of these disorders. Our findings support targeted smoking cessation programs for women of reproductive age. The observed associations are biologically plausible, given the aforementioned evidence suggesting that prenatal tobacco exposure may induce fetal hypoxia, oxidative stress, inflammatory responses, and alterations in neurotransmitter systems that are critical for brain development. In addition, our results add to the existing body of literature reporting associations between maternal smoking and offspring neurodevelopmental disorders, particularly ADHD, while extending the evidence to intellectual disability and ASD in a large nationwide cohort. Taken together, these findings suggest that maternal smoking may represent a potentially modifiable risk factor for adverse neurodevelopmental outcomes.

This study had several limitations. First, it is important to acknowledge that causality cannot be established owing to the observational nature of our study. While randomized controlled trials would provide the most definitive evidence, randomizing pregnant women to smoke would be unethical. Therefore, a well-designed observational study with a large sample size and long-term follow-up remains the best alternative. Second, our assessment of maternal smoking was based on a questionnaire administered during a health check-up < 2 years before birth. We did not have data on changes in smoking behaviors before or during pregnancy. It is possible that some women who were classified as current smokers quit smoking after the health examination, or conversely, that some former smokers relapsed after the health examination. Further, the impact of smoking before and during pregnancy may differ in its effects on offspring. Third, we did not obtain data on paternal or household smoking exposure. Paternal smoking can also influence the neurodevelopment of offspring through secondhand smoke, shared genetic vulnerabilities, and the home environment. Given the plausible association between secondhand smoke exposure and neurodevelopmental disorders in children [10, 33], this limitation raises the possibility of exposure misclassification that should be carefully considered. Another limitation is that, although we were able to identify offspring born from multiple gestations, we could not determine whether these births were twins, triplets, or higher-order multiple births, nor could we ascertain which siblings belonged to the same multiple gestation. Although our cohort was large and drawn from the entire country, these findings should be interpreted with caution due to potential selection bias. A substantial proportion of the initially eligible population was excluded, primarily because information from general health examinations prior to pregnancy was unavailable. To address this concern, we provide a comparison of baseline characteristics between the included and excluded populations in Additional file 1: Table S11. Accordingly, the findings may not be fully generalizable to settings with different demographics, healthcare systems, or smoking cultures.

Conclusions

In this nationwide cohort, maternal smoking status ascertained from NHIS health examinations within 2 years prior to delivery was associated with increased risks of intellectual disability, ASD, and ADHD in offspring. Elevated risks were observed among both former and current smokers. In exposure-stratified analyses, risk estimates varied across pack-year tertiles in both groups without a strictly monotonic gradient; elevated risk estimates were already observed at relatively low cumulative exposure, particularly among current smokers across outcomes. Although causal inference is limited by the observational design and potential exposure misclassification due to changes in smoking behavior over time, these findings support efforts to reduce smoking among women of reproductive age and to promote cessation as early as possible, including around the time of pregnancy.

Abbreviations

ADHD

Attention-deficit/hyperactivity disorder

ASD

Autism spectrum disorder

BMI

Body mass index

CI

Confidence interval

DSM-5

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

HR

Hazard ratio

ICD-10-CM

International Classification of Diseases, Tenth Revision, Clinical Modification

IQR

Interquartile range

NHIS

National Health Insurance Service

Authors’ contributions

CSP and MJ contributed to conceptualization, formal analysis, funding acquisition, investigation, project administration, resources, supervision, validation, visualization, and writing-original draft. BK contributed to conceptualization, data curation, formal analysis, investigation, methodology, software, and visualization. SK, TMR, HL, HKK, YJK, and JWK contributed to data curation, investigation, supervision, and writing – review & editing. KH contributed to conceptualization, data curation, formal analysis, investigation, methodology, resources, software, visualization, and writing – review & editing. JBP contributed to conceptualization, formal analysis, funding acquisition, investigation, project administration, resources, supervision, validation, visualization, and writing – review & editing. All authors read and approved the final manuscript.

Funding

This study was supported by grants from the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (grant Nos. RS-2024–00449868 and RS-2024–00438808), and by the Boston–Korea Innovative Research Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (grant No. RS-2024–00403047), Republic of Korea.

Data availability

The data used in this study are available from the NHIS National Health Information Database for researchers who meet the criteria for access to confidential data, subject to NHIS approval. The data are not publicly available due to privacy and legal restrictions.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. E-2503-152-1625). The study was conducted in accordance with the principles of the Declaration of Helsinki (2013 amendment). The requirement for informed consent was waived because the analysis used routine de-identified administrative data.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.