Use of Swedish smokeless tobacco during pregnancy: A systematic review of pregnancy and early life health risk.

BACKGROUND AND AIMS: Smokeless tobacco is a heterogeneous product group with diverse composition and prevalence globally. Tobacco use during pregnancy is concerning due to the risk of adverse pregnancy outcomes and effects on child health. Nicotine may mediate several of these effects. This systematic review measured health outcomes from Swedish smokeless tobacco (snus) use during pregnancy. METHOD: Literature search was conducted by an information specialist in May 2022. We included human studies of snus use during pregnancy compared with no tobacco use, assessed risk of bias, conducted a meta-analysis and assessed confidence in effect-estimates using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). RESULTS: We included 18 cohort studies (42 to 1 006 398 participants). Snus use during pregnancy probably (moderate confidence in risk estimates) increase the risk of neonatal apnea, adjusted odds ratio 95% confidence interval [aOR (95% CI)] 1.96 (1.30 to 2.96). Snus use during pregnancy possibly (low confidence in risk estimates) increase the risk of stillbirths aOR 1.43 (1.02 to 1.99), extremely premature births aOR 1.69 (1.17 to 2.45), moderately premature birth aOR 1.26 (1.15 to 1.38), SGA aOR 1.26 (1.09 to 1.46), reduced birth weight mean difference of 72.47 g (110.58 g to 34.35 g reduction) and oral cleft malformations aOR 1.48 (1.00 to 2.21). It is uncertain (low confidence in risk estimates, CI crossing 1) whether snus use during pregnancy affects risk of preeclampsia aOR 1.11 (0.97 to 1.28), antenatal bleeding aOR 1.15 (0.92 to 1.44) and very premature birth aOR 1.26 (0.95 to 1.66). Risk of early neonatal mortality and altered heart rate variability is uncertain, very low confidence. Snus using mothers had increased prevalence of caesarean sections, low confidence. CONCLUSIONS: This systematic review reveals that use of smokeless tobacco (snus) during pregnancy may adversely impact the developing child.

Infant lung function and maternal physical activity in the first half of pregnancy.

Background and aim: Physical activity (PA) in pregnancy is important for maternal and possibly offspring health. To study the early origins of lung function we aimed to determine whether PA in the first half of pregnancy is associated with lung function in healthy 3-month-old infants. Methods: From the general population-based Preventing Atopic Dermatitis and Allergies in Children birth cohort recruiting infants antenatally in Norway and Sweden, all 812 infants (48.8% girls) with available tidal flow-volume measures in the awake state at 3 months of age and mid-pregnancy data on PA were included. PA was self-reported by the mothers and, based on intensity, we categorised them as active or inactive during pregnancy. Furthermore, we defined active mothers as fairly or highly active. The main outcome was a ratio of time to peak tidal expiratory flow to expiratory time (t PTEF/t E) <0.25. Associations were analysed by logistic regression, adjusting for maternal age, education, parity, pre-pregnancy body mass index, in utero nicotine exposure and parental atopy. Results: The mean±sd t PTEF/t E was 0.391±0.08 and did not differ significantly according to maternal PA level in pregnancy. The 290 infants of inactive mothers had higher odds of having t PTEF/t E <0.25 compared to infants of all active mothers (OR 2.07, 95% CI 1.13-3.82; p=0.019) and compared to infants (n=224) of fairly active (OR 2.83, 95% CI 1.26-7.24; p=0.018) but not highly active mothers (n=298). Conclusion: Based on self-reported maternal PA in the first half of pregnancy, 3-month-old infants of inactive compared to active mothers had higher odds of a low t PTEF/t E.

Infant tidal flow-volume parameters and arousal state.

Background: Infant lung function can be assessed with tidal flow-volume (TFV) loops. While TFV loops can be measured in both awake and sleeping infants, the influence of arousal state in early infancy is not established. The aim of the present study was to determine whether TFV loop parameters in healthy infants differed while awake compared to the sleeping state at 3 months of age. Methods: From the population-based Scandinavian Preventing Atopic Dermatitis and ALLergies in children (PreventADALL) birth cohort, 91 infants had reproducible TFV loops measured with Exhalyzer® D in both the awake and sleeping state at 3 months of age. The TFV loops were manually selected according to a standardised procedure. The ratio of time to peak tidal expiratory flow (t PTEF) to expiratory time (t E) and the corresponding volume ratio (V PTEF/V E), as well as tidal volume (V T) and respiratory rate were compared using nonparametric tests. Results: The mean (95% CI) t PTEF/t E was significantly higher while awake compared to the sleeping state: 0.39 (0.37-0.41) versus 0.28 (0.27-0.29); with the corresponding V PTEF/V E of 0.38 (0.36-0.40) versus 0.29 (0.28-0.30). The V T was similar, while the respiratory rate was higher while awake compared to the sleeping state: 53 (51-56) breaths·min-1 versus 38 (36-40) breaths·min-1. Conclusion: Higher t PTEF/t E, V PTEF/V E and respiratory rate, but similar V T while awake compared to the sleeping state suggests that separate normative TFV loop values according to arousal state may be required in early infancy.

Infant lung function: criteria for selecting tidal flow-volume loops.

Background: Tidal flow-volume (TFV) loops are commonly recorded in infants during sleep, due to the more regular breathing patterns compared to the awake state. Standardised deselection of loops outside pre-specified ranges are based on periods of regular breathing, while criteria and available software for visual evaluation of TFV loops are lacking. We aimed to determine the reliability of standardised criteria for manual selection of infant TFV loops. Methods: Using a pre-defined set of criteria, three independent raters manually evaluated TFV loops among 57 randomly selected awake healthy 3-month-old infants with available TFV measurements in the Scandinavian Preventing Atopic Dermatitis and ALLergies in children (PreventADALL) study. The TFV loops were sampled using the Eco Medics Exhalyzer D. Criteria for selecting TFV loops included reproducible shape and volume with only one peak in tidal expiratory flow (PTEF), excluding loops with no clear or uneven flow towards PTEF. By intraclass coefficient (ICC), the reliability of agreement between raters was determined for the time to PTEF (t PTEF) to expiratory time (t E) and other TFV loop parameters. Results: Five infants had unsuccessful tests. Among the remaining 52 infants, the raters selected a median of 25, 26 and 15 loops per test. The ICCs (95% CI) were 0.97 (0.92-0.98) for t PTEF/t E, 0.99 (0.99-1.00) for respiratory rate, 0.98 (0.97-0.99) for tidal volume per kg and 0.98 (0.97-0.99) for expiratory volume, reflecting excellent agreement in all categories. Conclusion: Manual TFV loop selection using standardised criteria provides a reliable alternative for lung function measures in awake infants with interrupted breathing cycles in a real-life setting.

The effect of nicotine-containing products and fetal sex on placenta-associated circulating midpregnancy biomarkers.

BACKGROUND: In utero exposure to nicotine, largely assessed by smoking, is a risk factor for impaired offspring health, while potential effects of non-combustible nicotine use such as snus (oral moist tobacco), are less well-known. Maternal serum concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) may be viewed as "placenta health markers", known to differ by fetal sex. Maternal smoking during pregnancy has been associated with lower levels of circulating sFlt-1, while the effect of snus on placenta-associated angiogenic factors is unknown. Our aim was to explore if snus and/or smoking exposure was associated with midpregnancy maternal levels of sFlt-1, PlGF and sFlt-1/PlGF ratio if these associations were modified by fetal sex. METHODS: Midpregnancy (16-22 gestational weeks) serum from 2603 Scandinavian women enrolled in the population-based multi-center PreventADALL (Preventing Atopic Dermatitis and ALLergies in children) study was analysed for sFlt-1 and PlGF concentrations by electrochemiluminescence, deriving the sFlt-1/PGF ratio. Nicotine use was assessed by electronic questionnaires at enrollment in 2278 of the women. Univariable and multivariable linear regression models on log transformed outcomes were used to assess the association between nicotine use and biomarker levels. Interaction terms were included to identify whether the associations were modified by fetal sex. RESULTS: Median sFlt-1, PlGF and sFlt-1/PlGF ratios among women with nicotine exposure information were similar to those of all included women and differed by fetal sex. Current snus use was significantly associated with reduced maternal circulating PlGF levels in adjusted analyses [ß - 0.12, (95% CI - 0.20; 0.00) compared to never use, p = 0.020]. A significant interaction between fetal sex and snus exposure was observed for PIGF (p = 0.031). Prior or periconceptional snus use was significantly associated with PIGF in male fetus pregnancies [ß - 0.05 (95% CI - 0.09 to (- 0.02)) and ß - 0.07 (95% CI - 0.12 to (- 0.02)) compared to never use, p = 0.002]. Smoking was not significantly associated with any circulating biomarkers levels. CONCLUSIONS: Midpregnancy maternal angiogenic profile differed by periconceptional snus use and fetal sex. Snus exposure, perceived as "safe" by users, before or during pregnancy seems to affect midpregnancy placental health in a sex dimorphic manner.

Fetal Thoracic Circumference and Lung Volume and Their Relation to Fetal Size and Pulmonary Artery Blood Flow.

OBJECTIVE: Research on early origins of lung disease suggests the need for studying the relationships of thoracic and lung size with fetal size and pulmonary circulation. The primary aim of this study is therefore to explore the associations between fetal thoracic circumference, lung volume, and fetal size. We also aim to assess if lung volume and thoracic circumference are associated with fetal pulmonary artery blood flow velocity measures. METHODS: Cross-sectional assessment of singleton pregnancies from the general population (n = 447) at 30 gestational weeks (GW) was performed using ultrasound measurement of fetal thoracic circumference, lung volume, head and abdominal circumference, and femur length. We obtained Doppler blood flow velocity measures from the proximal branches of the fetal pulmonary artery. Associations between variables were studied using Pearson's correlation and multiple linear regression analyses. RESULTS: Both thoracic circumference and lung volume correlated with fetal size measures, ranging from r = 0.64 between thoracic circumference and abdominal circumference, to r = 0.28 between lung volume and femur length. Adjustment for gestational age, maternal nicotine use, pre-pregnancy body mass index, and fetal sex marginally influenced the associations with abdominal circumference. The correlations of thoracic circumference and lung volume with pulmonary artery blood flow velocity measures were weak (r ≤ 0.17). CONCLUSION: We found moderate to low correlation between thoracic circumference, lung volume, and fetal size at 30 GW. The closest relationship was with the abdominal circumference. We found low correlations of thoracic circumference and lung volume with pulmonary artery blood flow velocity measures.

Skin Barrier Function and Infant Tidal Flow-Volume Loops-A Population-Based Observational Study.

Background: The relationship between the skin barrier- and lung function in infancy is largely unexplored. We aimed to explore if reduced skin barrier function by high transepidermal water loss (TEWL), or manifestations of eczema or Filaggrin (FLG) mutations, were associated with lower lung function in three-month-old infants. Methods: From the population-based PreventADALL cohort, 899 infants with lung function measurements and information on either TEWL, eczema at three months of age and/or FLG mutations were included. Lower lung function by tidal flow-volume loops was defined as a ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) <0.25 and a tPTEF <0.17 s (<25th percentile). A high TEWL >8.83 g/m2/h (>75th percentile) denoted reduced skin barrier function, and DNA was genotyped for FLG mutations (R501X, 2282del4 and R2447X). Results: Neither a high TEWL, nor eczema or FLG mutations, were associated with a lower tPTEF/tE. While a high TEWL was associated with a lower tPTEF; adjusted OR (95% CI) 1.61 (1.08, 2.42), the presence of eczema or FLG mutations were not. Conclusions: Overall, a high TEWL, eczema or FLG mutations were not associated with lower lung function in healthy three-month-old infants. However, an inverse association between high TEWL and tPTEF was observed, indicating a possible link between the skin barrier- and lung function in early infancy.

Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial.

BACKGROUND: Skin emollients applied during early infancy could prevent atopic dermatitis, and early complementary food introduction might reduce food allergy in high-risk infants. The study aimed to determine if either regular skin emollients applied from 2 weeks of age, or early complementary feeding introduced between 12 and 16 weeks of age, reduced development of atopic dermatitis by age 12 months in the general infant population. METHODS: This population-based 2×2 factorial, randomised clinical trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway; and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine ultrasound pregnancy screening at 18 weeks were cluster-randomised at birth from 2015 to 2017 to the following groups: (1) controls with no specific advice on skin care while advised to follow national guidelines on infant nutrition (no intervention group); (2) skin emollients (bath additives and facial cream; skin intervention group); (3) early complementary feeding of peanut, cow's milk, wheat, and egg (food intervention group); or (4) combined skin and food interventions (combined intervention group). Participants were randomly assigned (1:1:1:1) using computer- generated cluster randomisation based on 92 geographical living area blocks as well as eight 3-month time blocks. Carers were instructed to apply the interventions on at least 4 days per week. Atopic dermatitis by age 12 months was the primary outcome, based on clinical investigations at 3, 6 and 12 months by investigators masked to group allocation. Atopic dermatitis was assessed after completing the 12-month investigations and diagnosed if either of the UK Working Party and Hanifin and Rajka (12 months only) diagnostic criteria were fulfilled. The primary efficacy analyses was done by intention-to-treat analysis on all randomly assigned participants. Food allergy results will be reported once all investigations at age 3 years are completed in 2020. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). The study is registered at clinicaltrials.gov, NCT02449850. FINDINGS: 2697 women were recruited between Dec 9, 2014, and Oct 31, 2016, from whom 2397 newborn infants were enrolled from April 14, 2015, to April 11, 2017. Atopic dermatitis was observed in 48 (8%) of 596 infants in the no intervention group, 64 (11%) of 575 in the skin intervention group, 58 (9%) of 642 in the food intervention group, and 31 (5%) of 583 in the combined intervention group. Neither skin emollients nor early complementary feeding reduced development of atopic dermatitis, with a risk difference of 3·1% (95% CI -0·3 to 6·5) for skin intervention and 1·0% (-2·1 to 4·1) for food intervention, in favour of control. No safety concerns with the interventions were identified. Reported skin symptoms and signs (including itching, oedema, exanthema, dry skin, and urticaria) were no more frequent in the skin, food, and combined intervention groups than in the no intervention group. INTERPRETATION: Neither early skin emollients nor early complementary feeding reduced development of atopic dermatitis by age 12 months. Our study does not support the use of these interventions to prevent atopic dermatitis by 12 months of age in infants. FUNDING: The study was funded by several public and private funding bodies: The Regional Health Board South East, The Norwegian Research Council, 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 at the Karolinska Institute, Freemason Child House Foundation in Stockholm, Swedish Research Council for Health, Working Life and Welfare-FORTE, Oslo University Hospital, the University of Oslo, and Østfold Hospital Trust.

The severity of acute bronchiolitis in infants was associated with quality of life nine months later.

AIM: Acute bronchiolitis in infancy increases the risk of later asthma and reduced health-related quality of life (QoL). We aimed to see whether the severity of acute bronchiolitis in the first year of life was associated with QoL nine months later. METHODS: The parents of 209 of 404 of children hospitalised for acute bronchiolitis in eight paediatric departments in south-east Norway at a mean four months of age (range 0-12 months) completed the Infant/Toddler Quality of Life Questionnaire sent by mail nine months after the acute illness. Disease severity was measured by length of stay and the need for supportive treatment. Interactions with gender, inclusion age, prematurity, maternal ethnicity and maternal education were examined. RESULTS: Reduced QoL in four domains was associated with increased length of stay and need for ventilatory support. Physical abilities and general health were associated with both severity markers, whereas bodily pain and discomfort and change in health were associated with length of stay. Ventilatory support was more negatively associated with QoL than atopic eczema and also associated with reduced parental emotions and parental time. CONCLUSION: The severity of acute bronchiolitis in infants was associated with reduced QoL nine months later.