Abstract
Background
Smoking in pregnancy has detrimental effects on infant respiratory health, while the effects of other nicotine-containing products on infant lung function are unclear. We aimed to explore if smokeless tobacco such as snus used in pregnancy increased the risk of lower lung function in infancy and if the associations differed by sex.
Methods
From the Scandinavian population-based Preventing Atopic Dermatitis and ALLergies in Children birth cohort, we included 1163 infants with available tidal flow-volume measurements at 3 months of age and maternal self-reported use of nicotine-containing products in pregnancy. The risk of a ratio of time to peak tidal expiratory flow to total expiratory time <25th percentile by any nicotine exposure, snus exclusively and cigarette smoking with or without other nicotine-containing products was explored by regression analyses adjusting for maternal age, education and asthma.
Results
Overall 120 out of 1163 (10.3%) infants were exposed to any nicotine in utero, 71 out of 120 by snus exclusively and 49 out of 120 by smoking, with six also exposed to snus. By pregnancy week 6, 85.8% of mothers reported stopping nicotine use. The risk of lower lung function was higher in children exposed in utero to nicotine-containing products with an odds ratio (OR) of 1.63 (95% confidence interval (CI) 1.02–2.59) with a similar tendency for snus exclusively (OR 1.55, 95% CI 0.88–2.71) and smoking (OR 1.79, 0.84–3.84). Effect estimates were similar after adjusting for covariates. No differences of the effect by sex were observed.
Conclusion
Our study suggests that in utero exposure to not only cigarettes, but also snus, may negatively affect infant lung function.
Shareable abstract
Smoking in pregnancy is known to affect infant respiratory health negatively, while effects of in utero exposure to smokeless tobacco are unknown. This study suggests that maternal use of snus in pregnancy may be harmful to the developing fetal lung. https://bit.ly/3v7lQdI
Introduction
Reduced lung function in early life is associated with an increased risk of subsequent wheeze and asthma in childhood [1–3] and tracks through childhood and adolescence into adulthood, with lower initial values conferring greater risk of asthma or COPD [4–6]. Observations of diminished lung function a few days after birth in neonates born to smoking mothers [7–9] point to origins of respiratory disease being established during pregnancy. Human lung development encompasses lung budding in the embryonic stage, airway branching from around gestational week (GW) 7–17 and saccular development from around 24 GWs with alveolarisation that continue through childhood [10]. Any of these stages may be affected by exposures [11, 12] with in utero smoking shown to increase the risk of impaired infant lung function and increase risk for wheeze and asthma later in life [13]. Emerging evidence indicates that the negative effects of in utero smoking exposure is largely mediated through nicotine [14], with fetal levels shown to be equal to, or even exceeding, those of the mother [15].
Maternal smoking during pregnancy has decreased over the last decades worldwide [16, 17], while alternative nicotine-containing products, including smokeless tobacco, are gaining popularity in several parts of the world [18, 19]. Snus, having long traditions for use in Norway and Sweden and exempted from EU legislation on sales ban, is currently more commonly used on a daily basis in young men and women compared to cigarettes [20]. Among women aged 25–49 years, 5% reported daily use of snus in 2015 and 11% in 2022 [21–23], and a Norwegian register study found decreasing smoking rates during pregnancy in the years 2012–2017, while snus use remained constant [24]. Snus is a moist ground tobacco product placed under the lip, either as a pinched portion or a premade portion in a sachet, containing nicotine and other chemicals which are absorbed mainly through the oral mucosa. Compared to cigarettes, snus gives a slower rise of plasma nicotine concentration that stays elevated for a longer time period after removal, resulting in increased levels of absorbed nicotine [25]. Sale of e-cigarettes containing nicotine is prohibited in Norway, but they were sold legally in Sweden from July 2017, i.e. after the inclusion of mothers in this study [26].
According to some large register studies, use of snus in pregnancy is associated with increased risk of adverse outcomes in the offspring including preterm delivery [27–29], small for gestational age (SGA) [30] and stillbirth [31]. Studies on human infant lung function after intrauterine exposure to nicotine-containing smokeless tobacco are lacking. Animal studies on the effect of antenatal nicotine exposure have shown deleterious effects on structural changes in lung development, postnatal lung function and respiratory health, with striking similarities to the known hazardous effects of maternal smoking [14, 17].
Lung function measurement with tidal flow–volume (TFV) loops is feasible in both healthy and sick infants and children, either awake or asleep. Reduced ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) in infancy is associated with later obstructive disease, wheeze and asthma [2, 32, 33]. Lower tPTEF/tE ranging from <0.254 [3, 34] in sleeping infants to <0.20 [33] and <0.30 [2] in awake infants has previously been demonstrated to be associated with later respiratory disease. The tPTEF/tE has been proven sensitive to detect impaired lung function at birth in infants of smoking mothers [7], as well as improved lung function in infants of smoking mothers receiving vitamin C supplementation during pregnancy compared to placebo [35].
Previous studies have demonstrated a possible sex-dependent response to early life exposures [36]. A reduced tPTEF/tE was observed in male but not female infants born to mothers with asthma [37], to mothers who smoked during pregnancy [9, 38], and in infants with subsequent lower respiratory tract infections with wheeze [34].
We hypothesise that exposure to snus in pregnancy increases the risk of lower lung function in infancy. The primary aim of the present study was therefore to explore if snus exposure in pregnancy is associated with lower lung function in early infancy. The secondary aim was to explore if the effect of snus exposure in pregnancy on infant lung function differed by fetal sex.
Study design and methods
Study design
This study is embedded in the prospective general population-based birth cohort Preventing Atopic Dermatitis and ALLergies in Children (PreventADALL) study [39]. Briefly, 2697 non-selected women were recruited mid-pregnancy in relation to national ultrasound examination at GW 18, between December 2014 and October 2016 in Oslo and Østfold (Norway) and Stockholm (Sweden). At birth, 2397 infants born at or after GW 35.0 without serious neonatal disease were included. In this sub-study, 1163 infants underwent lung function measurement at 3 months of age and information on antenatal exposure to nicotine-containing products was obtained (figure 1).
FIGURE 1.
Flow chart of the study cohort. Of 1163 infants with lung function measurements, 89 infants had measurements in both the awake and sleeping state. TFV: tidal flow volume.
Through electronic questionnaires completed by the participating mother, information on general demographics, maternal lifestyle and exposures was collected around GWs 18 and 34, and breastfeeding at around 3 months post-partum. Birth mode and concurrent anthropometric measurements were recorded from electronic hospital charts. Infant lung function was measured at the Oslo and Stockholm study sites from July 2015 to July 2017 as part of the scheduled 3-month follow-up visits.
Written informed consent was obtained from the women at primary enrolment in pregnancy and by both parents at newborn inclusion. The study was approved by the regional committees for medical and health research ethics in South-Eastern Norway (2014/518) and in Sweden (2014/2242–31/4). The study was registered at ClinicalTrials.gov (number NCT02449850).
Data collection
Detailed information on use of snus, cigarette smoking, electronic cigarettes, nicotine replacement therapies or other nicotine-containing products was obtained from electronic self-reported questionnaires: at enrolment around GW 18 for the period prior to pregnancy and at 2-week intervals during pregnancy, and at GW 34 for the period since completing the previous questionnaire. Questions regarding snus and cigarettes were mutually exclusive regarding time of use prior to and/or current use in pregnancy, including details quantifying products used and week of cessation when applicable, as described in detail elsewhere [40].
As tidal breathing parameters differ in awake versus sleeping tests [41], lung function was primarily measured in the awake state at 3 months of age with the infant in a supine position with head and neck in neutral position, using the Exhalyzer D (EcoMedics, Duernten, Switzerland) equipment [42]. Measurement of tidal breathing was attempted in all children at the 3-month follow-up at the study sites in Oslo and Stockholm. When not feasible in the awake state, due to an uneasy or crying child or failure to obtain stable tidal breathing, TFV loops were obtained in supine naturally sleeping infants, and for some when possible in both arousal states. Evaluation of TFV loops and post-processing analyses were performed according to standardised criteria as described elsewhere [42].
Outcomes, explanatory variables and confounders
The primary outcome was low lung function defined as tPTEF/tE below the 25th percentile in awake infants and the secondary outcome was low lung function in sleeping infants. Further lung function outcome was tidal volume per kilo (VT per kg) as a continuous variable. As there is no consensus on a cut-off limit differentiating between lower lung function by tidal breathing and association with respiratory disease, we used tPTEF/tE <0.25 in awake infants and <0.20 in sleeping infants for sensitivity analyses.
We generated two exposure variables to nicotine-containing products: First no nicotine in pregnancy (“never”) versus any use of nicotine (“any nicotine”), including cigarettes, snus and other nicotine-containing products. Second, nicotine exposure was categorised into “never”, snus use exclusively (“snus”), and smoking including those using snus in addition to cigarettes or other nicotine-containing products (“smoke/dual”) as we explored the effect of snus alone on infant lung function. Household smoking during pregnancy was not included due to minimally reported exposure (three mothers only, see online supplementary material for details).
We identified the following confounders to be included in the multivariable models, based on a directed acyclic graph (supplementary figure S1): maternal age, maternal asthma (yes, no) and maternal education (<4 years, ≥4 years). Only factors arising before pregnancy affecting both the exposure and the outcome were considered.
Statistical analysis
Categorical variables are presented as n (%) and continuous variables as mean±sd or range. We assessed associations between nicotine exposure in utero and low lung function with univariable and multivariable regression models, and report adjusted and unadjusted odds ratios (ORs) with 95% confidence intervals (CI) and p-values from logistic regression models for tPTEF/tE, and β-coefficients with 95% CI and p-values for VT per kg from linear regression models. Missing data on maternal education and maternal asthma were defined as separate categories in the multivariable models. For the sensitivity analyses, we performed exact logistic regression due to small samples in the exposed groups. All statistical analyses were conducted separately according to arousal state, and lung function tests for infants with measurements in both arousal states were included in the analysis of both awake and sleeping tests. To explore potential differential associations by fetal sex, an interaction between fetal sex and nicotine exposure was included in the multivariable logistic and linear regression models. The significance level was set to 5%. Analyses were performed using SPSS Statistics (version 29; IBM, Chicago, IL, USA) for the logistic regression, and Stata/SE (version 16.1; StataCorp LLC, College Station, TX, USA) for the linear regression and sensitivity analyses.
Results
Among the 1163 infants included in this study, 49% were girls, born at mean±sd GW 40.0±1.4 with mean±sd birthweight of 3.55±0.48 kg. At the time of TFV measurement their mean±sd age was 13.2±1.0 weeks and mean±sd weight 6.23±0.78 kg. The included infants (figure 1) were largely comparable to the excluded infants except for a higher proportion of girls, mothers of higher age and education level, lower birthweight and lower age at the 3-month follow-up visit (supplementary table S1). Background characteristics among infants of mothers who used nicotine-containing products in pregnancy were similar to non-exposed infants (table 1). Lung function measurements were available in 881 awake and 371 sleeping infants; 89 infants had measurements in both arousal states.
TABLE 1.
Background characteristics of 1163 mother–child pairs included in the present study from the PreventADALL cohort
| Characteristics | Infants exposed to nicotine in utero# | Infants not exposed to nicotine in utero¶ | ||
|---|---|---|---|---|
| n | Mean±sd or % | n | Mean±sd or % | |
| Mothers | ||||
| Age of mother years | 120 | 32.0±3.8 | 1043 | 33.0±4.0 |
| Maternal education ≥4 years | 54/120 | 45 | 631/956 | 66 |
| Married/cohabitant mother | 115/120 | 96 | 943/963 | 98 |
| Parity <1 (nullipara) | 82/120 | 68 | 619/1043 | 59 |
| Maternal asthma | 24/120 | 20 | 156/959 | 16 |
| Infants (birth) | ||||
| Female | 66/120 | 55 | 506/1043 | 49 |
| Gestational age at birth weeks | 119 | 40.2±1.4 | 1039 | 40.0±1.4 |
| Caesarian section | 20/120 | 17 | 170/1041 | 16 |
| Birthweight kg | 120 | 3.56±0.4 | 1037 | 3.55±0.5 |
| Infants (3 months) | ||||
| Age weeks | 119 | 13.3±1.1 | 1042 | 13.2±1.0 |
| Weight kg | 119 | 6.26±0.8 | 1040 | 6.23±0.8 |
| Length cm | 118 | 61.8±2.4 | 1030 | 61.8±2.4 |
| Breastfed exclusively at 3 months | 63/103 | 61 | 615/900 | 68 |
Data are presented as n, mean±sd or %. The group “Infants exposed to nicotine in utero” entails all infants of mothers reporting any use of nicotine-containing products in pregnancy, including snus, cigarettes, dual use of snus and cigarettes or other nicotine-containing products. #: n=120; ¶: n=1043.
Any use of nicotine-containing products during pregnancy was reported by 120 out of 1163 women (10.3%), of whom 71 (59.2%) reported use of snus exclusively. Among the 49 (40.8%) women categorised to “smoke/dual”, 42 mothers reported use of cigarettes only, six were dual users of cigarettes and snus, and one reported use of other nicotine-containing products. None of the participants reported use of e-cigarettes or nicotine replacement therapy. By GW 6, 103 out of 120 (85.8%) reported quitting use of any nicotine-containing products, whereas eight women (6.7%) continued use of nicotine-containing products after pregnancy week 30.
The mean±sd (range) tPTEF/tE was 0.39±0.08 (0.19–0.63) in awake infants and 0.27±0.07 (0.13–0.47) in sleeping infants. The 25th percentile cut-off value for tPTEF/tE was 0.33 and 0.23 in awake and sleeping infants, respectively.
The risk for having a tPTEF/tE below the 25th percentile among awake infants was significantly increased by in utero exposure to any type of nicotine-containing products during pregnancy (OR 1.63, 1.02–2.59, p=0.040; figure 2 and table 2 in the univariable analysis). After adjusting for maternal age, maternal education and maternal asthma, the estimate was similar but no longer statistically significant (OR 1.51 (0.94–2.43), p=0.086; figure 2 and table 2). When looking at exclusive snus use during pregnancy, effect estimates were similar and pointed towards an increased risk for reduced lung function (OR 1.44 (0.82–2.54) in the multivariable model, table 2). The risk was similar for children exposed to smoking (with or without snus) (OR 1.67, 0.77–3.60) in the multivariable model. Both estimates did not reach statistical significance. Effect estimates were smaller and not significant in sleeping infants (table 2). In the sensitivity analyses, the risk of tPTEF/tE <0.25, as observed in four out of 881 awake infants who were exposed to nicotine-containing products in utero, and <0.20, as observed in four out of 371 sleeping infants, was not statistically significant with OR 0.79 (0.20–2.25) and OR 0.81 (0.20–2.43), respectively.
FIGURE 2.
Forest plot showing the odds ratio with 95% confidence intervals for awake tPTEF/tE <25th percentile at 3 months of age and nicotine exposure in utero in the groups “any nicotine” (n=90), “snus” (n=60) and “smoke/dual” (n=30). The reference group is no nicotine exposure in pregnancy (n=791). *p-value=0.040. Multivariable analysis adjusting for maternal age, maternal education and maternal asthma. tPTEF/tE: ratio of time to peak tidal expiratory flow to expiratory time.
TABLE 2.
Association between in utero exposure to nicotine-containing products and infant tPTEF/tE below the 25th percentile at 3 months of age from logistic regression models, in awake (n=224) and sleeping (n=94) infants
| Awake tPTEF/tE <25th percentile | Sleeping tPTEF/tE <25th percentile | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Univariable OR (95% CI) |
p-value | n | Multivariable OR (95% CI) |
p-value | pinteraction | n | Univariable OR (95% CI) |
p-value | n | Multivariable OR (95% CI) |
p-value | pinteraction | |
| Nicotine exposure | 0.040 | 0.086 | 0.876 | 0.540 | 0.757 | 0.940 | ||||||||
| Never (ref.) | 791 | 1.0 | 791 | 1.0 | 330 | 1.0 | 330 | 1.0 | ||||||
| Any nicotine | 90 | 1.63 (1.02–2.59) | 90 | 1.51 (0.94–2.43) | 41 | 1.25 (0.61–2.57) | 41 | 1.12 (0.54–2.34) | ||||||
| Nicotine exposure | 0.114 | 0.217 | 0.987 | 0.824 | 0.951 | 0.918 | ||||||||
| Never (ref.) | 791 | 1.0 | 791 | 1.0 | 330 | 1.0 | 330 | 1.0 | ||||||
| Snus only | 60 | 1.55 (0.88–2.71) | 60 | 1.44 (0.82–2.54) | 21 | 1.21 (0.45–3.22) | 21 | 1.09 (0.41–2.94) | ||||||
| Smoke/dual | 30 | 1.79 (0.84–3.84) | 30 | 1.67 (0.77–3.60) | 20 | 1.30 (0.48–3.48) | 20 | 1.15 (0.42–3.17) | ||||||
The reference group “never” includes all females who did not report use of tobacco or nicotine in pregnancy. The “any nicotine” group includes all women who reported use of any nicotine-containing products at any time during pregnancy. The “snus” group includes women who reported use of snus exclusively during pregnancy. The “smoke/dual” group includes smokers and dual smokers and snus users during pregnancy, including one woman reporting use of other nicotine-containing products than cigarettes and snus.
Covariates used in the multivariable analysis: maternal age, maternal asthma, maternal education level. The interaction term included infant sex by nicotine exposure.
Sleeping infants exposed to any nicotine in utero had significantly higher mean values of VT per kg compared to non-exposed infants (β-coefficient 0.70 (0.06–1.34)) in the multivariable model. There were no significant differences observed among infants measured in the awake state or stratified to separate nicotine-containing products (table 3). The associations between in utero nicotine exposure and infant lung function did not differ by infant sex, all pinteraction ≥0.065 (tables 2 and 3).
TABLE 3.
Association between in utero exposure to nicotine-containing products and infant tidal volume (VT) per kilogram at 3 months of age from linear regression models, in awake and sleeping infants
| n | Univariable difference in means# (95% CI) | p-value | Marginal means# (95% CI) | Multivariable difference in means# (95% CI) | p-value | Marginal means# (95% CI) | pint | |
|---|---|---|---|---|---|---|---|---|
| Awake VT per kg | ||||||||
| Nicotine exposure | 0.132 | 0.079 | 0.067 | |||||
| Never | 784 | Ref. | 7.03 (6.88–7.18) | Ref. | 7.02 (6.87–7.17) | |||
| Any nicotine | 89 | 0.36 (−0.11–0.83) | 7.39 (6.94–7.83) | 0.43 (−0.05–0.90) | 7.45 (7.00–7.90) | |||
| Nicotine exposure | 0.267 | 0.170 | 0.065 | |||||
| Never | 785 | Ref. | 7.03 (6.88–7.18) | Ref. | 7.02 (6.87–7.17) | |||
| Snus | 59 | 0.46 (−0.11–1.03) | 7.49 (6.94–8.03) | 0.53 (−0.04–1.11) | 7.55 (7.00–8.11) | |||
| Smoke/dual | 30 | 0.17 (−0.61–0.95) | 7.19 (6.43–7.96) | 0.22 (−0.57–1.01) | 7.24 (6.47–8.01) | |||
| Sleeping VT per kg | ||||||||
| Nicotine exposure | 0.058 | 0.032 | 0.971 | |||||
| Never | 329 | Ref. | 7.78 (7.57–7.99) | Ref. | 7.77 (7.56–7.98) | |||
| Any nicotine | 41 | 0.61 (−0.22–1.24) | 8.39 (7.79–8.98) | 0.70 (0.06–1.34) | 8.47 (7.87–9.07) | |||
| Nicotine exposure | 0.156 | 0.093 | 0.999 | |||||
| Never | 329 | Ref. | 7.78 (7.57–7.99) | Ref. | 7.77 (7.56–7.98) | |||
| Snus | 21 | 0.70 (−0.15–1.56) | 8.48 (7.65–9.31) | 0.76 (−0.10–1.62) | 8.53 (7.69–9.36) | |||
| Smoke/dual | 20 | 0.51 (−0.37–1.38) | 8.29 (7.43–9.14) | 0.64 (−0.25–1.53) | 8.41 (7.55–9.27) |
The reference group “never” includes all females who did not report use of tobacco or nicotine in pregnancy. The “any nicotine” group includes all women who reported use of any nicotine-containing products at any time during pregnancy. The “snus” group includes women who reported use of snus exclusively during pregnancy. The “smoke/dual” group includes smokers and dual smokers and snus users during pregnancy, including one woman reporting use of other nicotine-containing products than cigarettes and snus. Covariates used in the multivariable analysis: maternal age, maternal asthma, maternal education level. The interaction term included infant sex by nicotine exposure. pint: pinteraction. #: given in millilitres per kilogram.
Discussion
Infants in this non-selected population-based birth cohort study born to the 10.3% of women who used snus, cigarettes or other nicotine-containing products during pregnancy had an increased risk of low lung function at 3 months of age compared to non-exposed infants.
In general, two-thirds of the total nicotine exposure was through exclusive snus use, and nicotine exposure ceased around GW 6 in 85.8%. Exclusive snus use, as well as smoke/dual use, tended to increase the risk of lower lung function in the 3-month old infants, although not reaching statistical significance. A small increase in difference in mean values for VT per kg was observed in sleeping infants exposed to any nicotine, while the other analyses on VT per kg as well as the sensitivity analyses for tPTEF/tE <0.25 in awake and <0.20 in sleeping infants did not reveal significant associations. No differential effect on the association between nicotine exposure and lung function was detected for male and female infants.
To our knowledge, this is the first prospective mother–child study exploring the effects of in utero snus exposure on human infant lung function. The increased risk of low lung function at 3 months of age by in utero exposure to nicotine dominated by snus use is partly novel and is supported by previous studies demonstrating reduced lung function in infants of smoking mothers [7–9]. We are not aware of previous human studies exploring the potential effects of in utero smokeless tobacco exposure on infant lung function; however one registry study found increased risk of asthma/wheeze in children of mothers using snus before and in early pregnancy [43], and the findings in this study are in line with the suggested aberrant effects on lung function and development being largely attributed to nicotine per se [14]. The risk of low lung function was only statistically significant among awake infants exposed to any nicotine. However, effect estimates in infants exposed to maternal snus exclusively were similar to that of any nicotine exposure, although somewhat lower than for the one third exposed to smoking including dual use with snus, neither reaching statistical significance, probably due to the small numbers involved.
In contrast to a previous birth cohort study from the 1990s where reduced lung function was associated with in utero maternal cigarette smoking reported by 27% of mothers [7], any nicotine exposure was reported by 10.3% of mothers in the present study, with two-thirds being exposed to snus only, in line with the shift from use of cigarettes to snus in recent years in the Scandinavian population [21, 22]. Previously, a dose-dependent increased risk of extreme prematurity (GW <28) has been associated with continued use of snus and cigarettes after GW 8–12 [27]. Further, women who ceased use of snus or cigarettes early in pregnancy had no increased risk of premature birth compared to non-users of tobacco, while mothers using snus or cigarettes throughout pregnancy had an increased risk of both very and moderately premature birth [28] as well as both preterm and term offspring being born SGA, but not if the use of snus ceased before pregnancy week 8–12. In contrast, for smoking the association with term SGA was evident even for early pregnancy use of cigarettes [30]. While Hoo et al. [9] examined premature infants where smoking in pregnancy was defined as smoking after pregnancy week 4 and found a significantly lower tPTEF/tE ratio in exposed infants, most women in our study stopped the use of nicotine-containing products before pregnancy week 6, and yet we found an increased risk for reduced tPTEF/tE in infants exposed to any nicotine-containing products in utero and similar effect estimates when stratifying for exclusive snus use. Overall, the in utero snus and smoking exposure in the PreventADALL study appears relatively limited and of shorter duration compared to previous studies demonstrating aberrant effect of smoking on offspring birth outcomes and lung function [7–9]. Collectively, therefore, it is likely that our study was underpowered to conclude on the risk of lower lung function by exclusive in utero snus exposure.
The ratio of tPTEF/tE reflects the degree to which expiratory flow and timing are modulated; however, the exact effect of nicotine on infant lung function is not fully known. As summarised by Spindel et al. [14], antenatal nicotine exposure in different animal models resulted in reduced lung function, increased hyperreactivity and morphological changes in the lung, consistent with alterations in infants of smoking mothers. Although the critical period for exposure to nicotine in pregnancy is unclear, studies in mice suggest a primary effect of nicotine on airway growth of conducting airways rather than the alveolarisation period, with an increased number of airways of small diameter with nicotine exposure [44]. Carlsen et al. [7] found declining ratios of tPTEF/tE with increasing exposure to cigarettes in pregnancy, although the study did not explore potential critical exposure periods for infant lung function impairment. Supporting the findings in the present study, where 85.8% of the women stopped snus use or smoking by pregnancy week 6, in a pooled analysis of eight birth cohorts in Europe, maternal smoking only in the first trimester, but not later in pregnancy or in the first year postnatally, was associated with an increased risk of wheeze and asthma at 4–6 years of age [13]. Collectively, one may therefore speculate that exposure to nicotine including smokeless tobacco may be particularly critical in early organogenesis. Our results suggest that exposure to nicotine-containing products early in pregnancy may impact lung budding starting in the fourth week of fetal life, preceding airway branching which completes during the second trimester, with potential life-long effects demonstrated by tracking of lung function through life [17].
We did not observe significant differences for tPTEF/tE in nicotine-exposed versus non-exposed sleeping infants. We are not aware of other studies exploring the effect of exposure to nicotine-containing products in utero comparing arousal states, as previous studies have been conducted in either awake or sleeping infants [7–9, 35]. The significant increase in mean difference in VT per kg in sleeping infants exposed to any nicotine in the multivariable model only is in contrast to a previous study where no difference in VT per kg was detected between infants exposed to smoking in utero or not [9]; however, statistical methods used differed. No significant findings in the sensitivity analyses may be due to small sample size in single strata.
The lack of differential association by sex of exposure to nicotine-containing products antenatally and lung function is in contrast to other studies where boys exposed to maternal smoking in utero were found to have lower lung function compared to girls [9, 38]. However, the non-significant findings could also be a result of low power in our dataset, and different statistical methods and lung function measurement techniques.
Strengths and limitations
A strength of this study is the prospective design of a large population of generally healthy infants with detailed questionnaires on use of nicotine-containing products reported during pregnancy to avoid recall bias. The lung function measurements were conducted by trained study personnel and standardised according to international guidelines and a standard operating procedure [42]. The maternal population is representative for the general female Scandinavian population with low smoking rates and higher prevalence of snus use.
Owing to the relatively infrequent nicotine use during pregnancy in this non-selected population of pregnant women, we did not quantify the amount of tobacco use. As none reported use of e-cigarettes and household smoking was rare, these were not included in further analyses. Largely healthy term infants were included in this study, and we cannot rule out a possible under-observation of adverse outcomes related to snus exposure in preterm infants [28]. We did not assess and could thus not control for exposure to nicotine through breastfeeding. Lung function measurements were only obtained in two out of three study sites due to organisational considerations, limiting our group of participants. We were unable to quantify a potential contribution of nicotine or other hazardous constitutes in snus such as tobacco-specific nitrosamines that may also adversely impact the fetus [17, 20], although snus lacks combustion products such as carbon monoxide.
Clinical implications
At present, it is not clear if the effects of snus use in pregnancy are similar to those of smoking or less detrimental on lung function and development, and our study could not confirm or reject this. This study adds to the hypothesis that nicotine-related alterations in lung development can occur in the first weeks of fetal life, even before the woman knows she is pregnant. Advances in recent years regarding reduced smoking rates in pregnancy could be lost if knowledge on the likely detrimental effects of nicotine from other nicotine-containing products are not adequately addressed.
Conclusion
Our study suggests that not only exposure to cigarette smoking but also other nicotine-containing products such as snus during pregnancy may negatively affect early life infant lung function. Our study supports the advice against any use of nicotine-containing products in pregnancy.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material 00958-2023.SUPPLEMENT2 (182.2KB, pdf)
Acknowledgements
We sincerely thank all families participating in the PreventADALL (Preventing Atopic Dermatitis and ALLergies in children) study as well as study personnel who have contributed to recruit participants, perform lung function measurements and other relevant examinations and in general managing the study: Live S. Nordhagen (VID Specialized University, Oslo, Norway), Carina Saunders (Division of Paediatric and Adolescent Medicine, Oslo University Hospital, and University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, Oslo, Norway), Kim A.M.S. Endre (Department of Dermatology and Venerology, Oslo University Hospital, Oslo, Norway), Oda C. Lødrup Carlsen (Department of Acute Psychiatry, Akershus University Hospital, Oslo, Norway), Runa H. Kaldestad (Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway), Sandra Götberg (Astrid Lindgren Children's Hospital, Karolinska University Hospital, and Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden), Caroline-Aleksi Olsson Mägi (Astrid Lindgren Children's Hospital, Karolinska University Hospital, and Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden), Sandra G. Tedner (Astrid Lindgren Children's Hospital, Karolinska University Hospital, and Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden) and Ellen Tegnerud (Astrid Lindgren Children's Hospital, Karolinska University Hospital, and Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden). In memoriam Kai-Håkon Carlsen.
Provenance: Submitted article, peer reviewed.
This article has an editorial commentary: https://doi.org/10.1183/23120541.00294-2024
The study was performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment).
This study is registered at www.clinicaltrials.gov with identifier number NCT02449850.
Ethics statement: The study was approved by the regional committees for medical and health research ethics in South-Eastern Norway (2014/518) and in Sweden (2014/2242-31/4).
Conflict of interest: K.E.S. Bains reports support for the present manuscript from The PreventADALL study was supported by sponsors to the institutions listed in the financial disclosures outlined in the manuscript. Salary for the PhD project of K.E.S. Bains was provided by Xtrastiftelsen and Klosterstiftelsen.
Conflict of interest: E.M. Rehbinder reports receiving personal fees from honoraria for lectures from Sanofi Genzyme, Leo Pharma, NAAF, PEF and Abbvie, outside the submitted work.
Conflict of interest: The remaining authors have nothing to disclose.
Support statement: The PreventADALL study has been funded by the following funding bodies: The Regional Health Board South East, The Norwegian Research Council, Oslo University Hospital, the University of Oslo, Health and Rehabilitation Norway, the Foundation for Healthcare and Allergy Research in Sweden – Vårdalstiftelsen, Swedish Asthma and Allergy Association's Research Foundation, Swedish Research Council – the Initiative for Clinical Therapy Research, The Swedish Heart–Lung Foundation, SFO-V Karolinska Institutet, Østfold Hospital Trust, the European Union (MeDALL project), by unrestricted grants from the Norwegian Association of Asthma and Allergy, the Kloster Foundation, Thermo-Fisher Uppsala, Sweden, by supplying allergen reagents, Norwegian society of Dermatology and Venerology, and Arne Ingel's legat. Funding information for this article has been deposited with the Crossref Funder Registry.
References
- 1.Yuksel B, Greenough A, Giffin F, et al. Tidal breathing parameters in the first week of life and subsequent cough and wheeze. Thorax 1996; 51: 815–818. doi: 10.1136/thx.51.8.815 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Haland G, Carlsen KC, Sandvik L, et al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med 2006; 355: 1682–1689. doi: 10.1056/NEJMoa052885 [DOI] [PubMed] [Google Scholar]
- 3.Young S, Arnott J, Le Souef PN, et al. Flow limitation during tidal expiration in symptom-free infants and the subsequent development of asthma. J Pediatr 1994; 124: 681–688. doi: 10.1016/S0022-3476(05)81355-1 [DOI] [PubMed] [Google Scholar]
- 4.Stern DA, Morgan WJ, Wright AL, et al. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet 2007; 370: 758–764. doi: 10.1016/S0140-6736(07)61379-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Guerra S, Lombardi E, Stern DA, et al. Fetal origins of asthma: a longitudinal study from birth to age 36 years. Am J Respir Crit Care Med 2020; 202: 1646–1655. doi: 10.1164/rccm.202001-0194OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bui DS, Lodge CJ, Burgess JA, et al. Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life. Lancet Respir Med 2018; 6: 535–544. doi: 10.1016/S2213-2600(18)30100-0 [DOI] [PubMed] [Google Scholar]
- 7.Carlsen KC L, Jaakkola JJ, Nafstad P, et al. In utero exposure to cigarette smoking influences lung function at birth. Eur Respir J 1997; 10: 1774–1779. doi: 10.1183/09031936.97.10081774 [DOI] [PubMed] [Google Scholar]
- 8.Stick SM, Burton PR, Gurrin L, et al. Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 1996; 348: 1060–1064. doi: 10.1016/S0140-6736(96)04446-7 [DOI] [PubMed] [Google Scholar]
- 9.Hoo AF, Henschen M, Dezateux C, et al. Respiratory function among preterm infants whose mothers smoked during pregnancy. Am J Respir Crit Care Med 1998; 158: 700–705. doi: 10.1164/ajrccm.158.3.9711057 [DOI] [PubMed] [Google Scholar]
- 10.Kurihara C, Kuniyoshi KM, Rehan VK. Preterm birth, developmental smoke/nicotine exposure, and life-long pulmonary sequelae. Children (Basel) 2023; 10: 608. doi: 10.3390/children10040608 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Stocks J, Hislop A, Sonnappa S. Early lung development: lifelong effect on respiratory health and disease. Lancet Respir Med 2013; 1: 728–742. doi: 10.1016/S2213-2600(13)70118-8 [DOI] [PubMed] [Google Scholar]
- 12.Martinez FD. Early-life origins of chronic obstructive pulmonary disease. N Engl J Med 2016; 375: 871–878. doi: 10.1056/NEJMra1603287 [DOI] [PubMed] [Google Scholar]
- 13.Neuman A, Hohmann C, Orsini N, et al. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med 2012; 186: 1037–1043. doi: 10.1164/rccm.201203-0501OC [DOI] [PubMed] [Google Scholar]
- 14.Spindel ER, McEvoy CT. The role of nicotine in the effects of maternal smoking during pregnancy on lung development and childhood respiratory disease. Implications for dangers of E-cigarettes. Am J Respir Crit Care Med 2016; 193: 486–494. doi: 10.1164/rccm.201510-2013PP [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Luck W, Nau H, Hansen R, et al. Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers. Dev Pharmacol Ther 1985; 8: 384–395. doi: 10.1159/000457063 [DOI] [PubMed] [Google Scholar]
- 16.Lange S, Probst C, Rehm J, et al. National, regional, and global prevalence of smoking during pregnancy in the general population: a systematic review and meta-analysis. Lancet Glob Health 2018; 6: e769–e776. doi: 10.1016/S2214-109X(18)30223-7 [DOI] [PubMed] [Google Scholar]
- 17.McEvoy CT, Spindel ER. Pulmonary effects of maternal smoking on the fetus and child: effects on lung development, respiratory morbidities, and life long lung health. Paediatr Respir Rev 2017; 21: 27–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.O'Connor R, Schneller LM, Felicione NJ, et al. Evolution of tobacco products: recent history and future directions. Tob Control 2022; 31: 175–182. doi: 10.1136/tobaccocontrol-2021-056544 [DOI] [PubMed] [Google Scholar]
- 19.Sieminska A, Jassem E. The many faces of tobacco use among women. Med Sci Monit 2014; 20: 153–162. doi: 10.12659/MSM.889796 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Folkehelseinstituttet . Helserisiko ved snusbruk. 2019.. www.fhi.no/globalassets/bilder/rapporter-og-trykksaker/2019/helserisiko-ved-snusbruk-rapport-2019-v2.pdf
- 21.F olkehelseinstituttet . Folkehelserapporten – Røyking og snusbruk i Noreg. 2022.. Date last accessed: 22 May 2023. Date last updated: 6 April 2022. www.fhi.no/nettpub/hin/levevaner/royking-og-snusbruk-i-noreg/
- 22.Folkhälsomyndigheten . Vuxnas bruk av tobaks- och nicotinprodukter. Date last accessed: 22 May 2023. Date last updated: 15 December 2022. www.folkhalsomyndigheten.se/livsvillkor-levnadsvanor/andts/utveckling-inom-andts-anvandning-och-ohalsa/anvandning/anvandning-av-tobaks-och-nikotinprodukter/vuxnas-bruk-av-tobaks--och-nikotinprodukter/
- 23.F olkehelseinstituttet . Utbredelse av snusbruk i Norge. Date last accessed: 4 February 2024. Date last updated: 12 April 2023. www.fhi.no/le/royking/tobakkinorge/bruk-av-tobakk/utbredelse-av-snusbruk-i-norge/?term=
- 24.Rygh E, Gallefoss F, Grotvedt L. Trends in maternal use of snus and smoking tobacco in pregnancy. A register study in southern Norway. BMC Pregnancy Childbirth 2019; 19: 500. doi: 10.1186/s12884-019-2624-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.SCENIHR . Health effects of smokeless tobacco products. Brussels, European Comission. 2008.. Date last accessed: 3 November 2023. https://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_013.pdf [Google Scholar]
- 26.Glo bal State of Tobacco Harm Reduction . Smoking, vaping, HTP, NRT and snus in Sweden. 2024. Date last updated: 10 October 2023. https://gsthr.org/countries/profile/swe/
- 27.Dahlin S, Gunnerbeck A, Wikstrom AK, et al. Maternal tobacco use and extremely premature birth: a population-based cohort study. BJOG 2016; 123: 1938–1946. doi: 10.1111/1471-0528.14213 [DOI] [PubMed] [Google Scholar]
- 28.Baba S, Wikstrom AK, Stephansson O, et al. Influence of smoking and snuff cessation on risk of preterm birth. Eur J Epidemiol 2012; 27: 297–304. doi: 10.1007/s10654-012-9676-8 [DOI] [PubMed] [Google Scholar]
- 29.Wikstrom AK, Cnattingius S, Galanti MR, et al. Effect of Swedish snuff (snus) on preterm birth. BJOG 2010; 117: 1005–1010. doi: 10.1111/j.1471-0528.2010.02575.x [DOI] [PubMed] [Google Scholar]
- 30.Baba S, Wikstrom AK, Stephansson O, et al. Changes in snuff and smoking habits in Swedish pregnant women and risk for small for gestational age births. BJOG 2013; 120: 456–462. doi: 10.1111/1471-0528.12067 [DOI] [PubMed] [Google Scholar]
- 31.Wikstrom AK, Cnattingius S, Stephansson O. Maternal use of Swedish snuff (snus) and risk of stillbirth. Epidemiology 2010; 21: 772–778. doi: 10.1097/EDE.0b013e3181f20d7e [DOI] [PubMed] [Google Scholar]
- 32.Hevroni A, Goldman A, Blank-Brachfeld M, et al. Use of tidal breathing curves for evaluating expiratory airway obstruction in infants. J Asthma 2018; 55: 1331–1337. doi: 10.1080/02770903.2017.1414234 [DOI] [PubMed] [Google Scholar]
- 33.Carlsen KC L, Carlsen KH, Nafstad P, et al. Perinatal risk factors for recurrent wheeze in early life. Pediatr Allergy Immunol 1999; 10: 89–95. doi: 10.1034/j.1399-3038.1999.00028.x [DOI] [PubMed] [Google Scholar]
- 34.Martinez FD, Morgan WJ, Wright AL, et al. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N Engl J Med 1988; 319: 1112–1117. doi: 10.1056/NEJM198810273191702 [DOI] [PubMed] [Google Scholar]
- 35.McEvoy CT, Schilling D, Clay N, et al. Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial. JAMA 2014; 311: 2074–2082. doi: 10.1001/jama.2014.5217 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Liptzin DR, Landau LI, Taussig LM. Sex and the lung: observations, hypotheses, and future directions. Pediatr Pulmonol 2015; 50: 1159–1169. doi: 10.1002/ppul.23178 [DOI] [PubMed] [Google Scholar]
- 37.de Gouveia Belinelo P, Collison AM, Murphy VE, et al. Maternal asthma is associated with reduced lung function in male infants in a combined analysis of the BLT and BILD cohorts. Thorax 2021; 76: 996–1001. doi: 10.1136/thoraxjnl-2020-215526 [DOI] [PubMed] [Google Scholar]
- 38.Li YF, Gilliland FD, Berhane K, et al. Effects of in utero and environmental tobacco smoke exposure on lung function in boys and girls with and without asthma. Am J Respir Crit Care Med 2000; 162: 2097–2104. doi: 10.1164/ajrccm.162.6.2004178 [DOI] [PubMed] [Google Scholar]
- 39.Carlsen KC L, Rehbinder EM, Skjerven HO, et al. Preventing Atopic Dermatitis and ALLergies in Children: the PreventADALL study. Allergy 2018; 73: 2063–2070. doi: 10.1111/all.13468 [DOI] [PubMed] [Google Scholar]
- 40.Kreyberg I, Bains KES, Carlsen KH, et al. Stopping when knowing: use of snus and nicotine during pregnancy in Scandinavia. ERJ Open Res 2019; 5: 00197-2018. doi: 10.1183/23120541.00197-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Bains KES, Fardig M, Gudmundsdottir HK, et al. Infant tidal flow-volume parameters and arousal state. ERJ Open Res 2022; 8: 00163–2022. doi: 10.1183/23120541.00163-2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Bains KES, Gudmundsdottir HK, Fardig M, et al. Infant lung function: criteria for selecting tidal flow-volume loops. ERJ Open Res 2022; 8: 00165–2022. doi: 10.1183/23120541.00165-2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Lundholm C, Gunnerbeck A, D'Onofrio BM, et al. Smoking and snuff use in pregnancy and the risk of asthma and wheeze in pre-schoolchildren: a population-based register study. Clin Exp Allergy 2020; 50: 597–608. doi: 10.1111/cea.13593 [DOI] [PubMed] [Google Scholar]
- 44.Wongtrakool C, Wang N, Hyde DM, et al. Prenatal nicotine exposure alters lung function and airway geometry through alpha7 nicotinic receptors. Am J Respir Cell Mol Biol 2012; 46: 695–702. doi: 10.1165/rcmb.2011-0028OC [DOI] [PMC free article] [PubMed] [Google Scholar]
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