Impact of Nicotine Replacement and Electronic Nicotine Delivery Systems on Fetal Brain Development
2.1. Literature Search Strategy
2.2. Study Selection
3.1. Pharmacokinetics and Dynamics of Nicotine, NRT, and ENDS
3.2. Current Guidelines for NRT and ENDS Use during Pregnancy
3.3. Nicotine Replacement Therapy (NRT)
3.4. Electronic Nicotine Delivery Systems (ENDS)
Conflicts of Interest
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|Author (Year)||Aim of Study||Type of Study||Methods||Outcomes||Key Results|
|Thomas et al. ||To examine the behavioral effects of nicotine exposure in the rat during the third trimester equivalent of the human brain growth spurt.||Animal study||Sprague-Dawley rat pups were exposed to nicotine (6.0 mg/kg/day) from postnatal days (PD) 4–9 via an artificial rearing procedure. Two control groups were employed, an artificially reared control group and a normally reared control group. Activity level was measured on PD 18–19.||Women who use tobacco products during late gestation may place their fetuses at risk for hyperactivity later in life, particularly during early adolescence.||-Nicotine-exposed subjects were significantly overactive compared with both control groups, which did not differ significantly from one another.|
-This behavioral alteration was observed in the absence of nicotine-induced body weight deficits.
|Mahar et al. ||To explore the consequences of chronic developmental nicotine exposure on cerebral neuroplasticity in the offspring.|
Authors focused on two forms of neural plasticity in the dentate gyrus (DG) of the hippocampus that are highly sensitive to the environment: granule cell neurogenesis and long-term potentiation (LTP).
|Randomized trial in animal models|
Nicotine = 7
Sterile saline = 9
|Pregnant rats were implanted with osmotic mini-pumps delivering either nicotine or saline solutions.|
Offspring were chronically exposed to nicotine in utero and then through breastmilk. Plasma nicotine and metabolite levels were measured in dams and offspring.
Corticosterone levels, DG neurogenesis, and glutamatergic electrophysiological activity were measured in pups.
|Synaptic plasticity of offspring is disrupted in utero and in breastfed dams passively exposed to nicotine in an NRT-like model.|
It does reveal changes affecting connectivity in the growing brain.
|-Juvenile (P15) and adolescent (P41) offspring exposed to nicotine throughout prenatal and postnatal development displayed no significant alteration in DG neurogenesis compared with control offspring.|
-Chronic NRT-like exposure during prenatal and postnatal
development does not alter basal stress hormone levels in pups.
-NRT-like nicotine exposure
significantly increased LTP in the DG of juvenile offspring as measured in vitro from hippocampal slices, suggesting that the mechanisms underlying nicotine-induced LTP enhancement previously described in adult rats are already functional in pups.
|Roy et al. ||To evaluate cellular morphology and regional architecture in the juvenile and adolescent hippocampus and the somatosensory cortex in rats exposed to nicotine prenatally.||Animal study||Pregnant rats were given nicotine throughout gestation via minipump infusion of 2 mg/kg/day|
On postnatal days 21 and 30, brains were perfusion fixed, coronal slices were taken and the morphology of the dorsal hippocampus and somatosensory cortex was characterized.
|These data demonstrate that prenatal nicotine|
exposure compromises neuronal maturation, leading to long-lasting alterations in the structure of key brain regions involved in cognition, learning, and memory.
|-In the hippocampal CA3 region and dentate gyrus, a decrease in cell size was found with corresponding decrements in cell layer thickness, and increments in cell packing density.|
-Smaller, transient changes were seen in CA1. In layer five of the somatosensory cortex, although there was no significant decrement in the average cell size, there was a reduction in the proportion of medium-sized pyramidal neurons, and an increase in the proportion
of smaller, nonpyramidal cells. All regions showed elevated numbers of glia.
|Slotkin et al. ||To assess nicotine effects on fetal brain development.||Animal study||Nicotine was administered to rats throughout gestation or in adulthood (postnatal days PN90-107), using regimens that reproduce plasma levels in smokers, assessing effects on serotonin (5HT) receptors, the 5HT transporter, and responses mediated through adenylyl cyclase (AC).||Animal studies show that nicotine itself leads to deficits in the number of neurons, neuronal and synaptic damage, and cognitive dysfunction.|
The replacement of
tobacco with NRT during pregnancy could not be safe due to experimental evidence concerning nicotine’s injurious and
enduring effects on neuronal systems.
|-Prenatal nicotine exposure elicited persistent suppression of 5HT1A receptors and upregulation of 5HT2 receptors, effects that were selective for males and that first emerged in young adulthood.|
-AC activity was reduced and there was uncoupling of receptor-mediated responses.
-With nicotine exposure restricted to adulthood, there were few changes in 5HT synaptic proteins during treatment or in the first 2 weeks post-treatment, distinctly different from the robust alterations seen earlier with similar nicotine regimens given in adolescence.
|Slotkin et al. ||To assess the effects of tobacco exposure on brain cells and lipid peroxidation in Rhesus monkeys.||Animal study||Rhesus monkeys were exposed to environmental tobacco smoke (ETS) during gestation and through 13 months postnatally, or postnatally only (6–13 months). At the conclusion of exposure, cerebrocortical regions and the midbrain for cell damage markers and lipid peroxidation were examined.||Perinatal or postnatal ETS exposure in primates elicits changes in brain cell development.||-For perinatal ETS, two patterns were seen in the various regions:|
(1) cell loss (reduced DNA concentration) and increases in cell size (increased protein/DNA ratio), (2) replacement of larger neuronal cells with smaller and more numerous glia (increased DNA concentration, decreased protein/ DNA ratio).
-Perinatal ETS exposure reduced the level of lipid peroxidation as assessed by the concentration of thiobarbituric acid reactive species, whereas postnatal ETS did not.
|Morales-Suarez-Varela et al. ||To examine whether maternal smoking and use of nicotine substitutes during the first 12 weeks of pregnancy increased the prevalence of congenital malformations.||Danish National Birth Cohort, prospective data.|
20,603 were exposed to tobacco smoking during the first 12 weeks of pregnancy.
|Birth outcomes were collected by linkage to the Central Population Register, the National Patients Register, and the National Birth Register.|
Congenital malformations from the Hospital Medical Birth Registry.
|No increase in congenital malformations related to prenatal tobacco smoking.|
An increased risk of malformations in non-smokers using nicotine substitutes.
|-Children exposed to prenatal tobacco smoking had no increase in congenital malformations prevalence in both crude and adjusted analyses.|
-Children born to nonsmokers, but who used NRT, had a slightly increased relative congenital malformations prevalence ratio; relative prevalence rate ratio was 1.61 (95% confidence interval 1.01–2.58), which represents a 60% increased risk.
-When the analysis was restricted to musculoskeletal malformations, the relative prevalence rate ratio was 2.63 (95% confidence interval 1.53–4.52).
|Strandberg-Larsen et al. ||To assess if the use of NRT during pregnancy increases the risk of stillbirth.||Danish National Birth Cohort, prospective data|
87,032 singleton pregnancies.
|Outcome of pregnancy was identified by register linkage, with <1% loss to follow-up.|
Cox regression analyses to estimate the hazard ratio (HR) and 95% CI of stillbirth according to the use of NRT, type of NRT use, and a combination of NRT use and smoking.
|The use of NRT during|
pregnancy does not increase the risk of stillbirth.
|-A total of 495 pregnancies (5.7 in 1000 births) ended in stillbirth, eight of which were among NRT users.|
-After adjustment for confounders, women who used NRT during pregnancy had an HR of 0.57 (95% CI 0.28–1.16) for stillbirth compared with those who did not use NRT
-Smoking during pregnancy was associated with an increased risk of stillbirth (HR 1.46, 95% CI 1.17–1.82).
-Women who both smoked and
used NRT had a HR of 0.83 (95% CI 0.34–2.00) compared with nonsmoking women who did not use NRT
|Cooper et al. ||To compare:|
(1) At delivery, the clinical effectiveness and cost- effectiveness for achieving biochemically-validated smoking cessation of NRT patches with placebo patches in pregnancy.
(2) In infants at 2 years of age, the effects on behavior, development, and disability.
placebo-controlled, parallel group
1050 pregnant smokers
521 NRT/529 placebo.
|Participants were randomly assigned (1:1) to receive 8 week courses of NRT patches (15 mg/16 h) or matched placebo. Follow-up at 4 weeks after randomization, delivery, and until infants were 2 years old.|
Participants: self-reported, prolonged abstinence from smoking between a quit date and childbirth, validated at delivery by carbon monoxide (CO) measurement and/or salivary cotinine (COT).
Infants, at 2 years: absence of disability or problems with behavior and development.
Economic: cost per quitter.
|NRT patches had no enduring significant effect on smoking in pregnancy; however, 2 year olds born to women who used NRT were more likely to have survived without any developmental impairment.||-Numbers of adverse pregnancy and birth outcomes were similar in both trial groups, except for a greater number of caesarean deliveries in the NRT group.|
-At 1 month after randomization, the validated cessation rate was higher in the NRT group (21.3% vs. 11.7%, OR, (95% CI), 2.05 (1.46 to 2.88)).
-At delivery, no difference between groups’ smoking cessation rates: 9.4% in the NRT and 7.6% in the placebo group (OR (95% CI), 1.26 (0.82 to 1.96)).
-Infants: at 2 years, analyses were
based on data from 888 out of 1010 (87.9%) singleton infants (including four postnatal infant deaths) 445/503 (88.5%) NRT, 443/507 (87.4%) placebo, and used multiple imputation. In the NRT group, 72.6% (323/445) had no impairment compared with 65.5% (290/443) in placebo (OR 1.40, 95% CI 1.05 to 1.86).
|Author (Year)||Aim of Study||Type of Study||Methods||Outcomes||Key Results|
|Bahl et al. ||Compare sensitivity of human embryonic stem cells (hESC) and mouse neural stem cells (mNSC) to (adult) human pulmonary fibroblasts (hFP) after ENDS refill liquid exposure.||In vitro||Cell exposure to 35 refill liquids (n = 35) using MTT assay for cell metabolic activity assessment.||Embryonic stem cells (hESC, mNSC) are more sensitive than adult lung fibroblasts (hFP). Cytotoxic effects may cause embryonic loss or developmental defects during pregnancy.||15 refill samples showed moderate cytotoxity (IC 50: 0.1%–1%) to hESC and mNSC. 10 refill samples had little or no effect on hPF (IC50 > 1%).|
|Zahedi et al. ||Assessment of ENDS nicotine-containing refill fluids and their aerosols on neural stem cell (NSC) mitochondria.||In vitro||24 h cell incubation and exposure to refill fluids and aerosols compared with untreated controls.||ENDS refill fluids and aerosols provoke stress-induced mitochondrial hyperfusion (SIMH) in NSC. SIMH was accompanied by alterations in mitochondrial morphology and dynamics. ENDS are not as harmless as often claimed. Even short-term exposure can stress cells and lead to morbidity or disease.||SIMH increased at 0.3% nicotine concentration, and cell swelling increased at 0.5% and 1% nicotine concentration.|
|Lauterstein et al. ||Transcriptome RNA-sequencing of frontal brain cortex (FBC) in mice exposed to ENDS aerosols (±nicotine) compared with air-exposed controls.||Animal study (pregnant C57BL/6 mice)||Pre- and postnatal exposure via whole body inhalation. Analyses of gene expression in FBC.||ENDS exposure alters brain development, causing chronic neuropathology. Decrease in memory, cognition, and neurotransmission. Increase in hyperactive behavior, emotional behavior, and death.|
ENDS non-nicotine: significant gene expression changes in FBC. Components other than nicotine may affect neurodevelopment. ENDS are associated to adverse neurobiological and neurobehavioral outcome similar to early life conventional cigarettes.
|Gene expression changes (GEC)|
-ENDS non-nicotine: 2630
-ENDS nicotine: 1393
-ENDS non-nicotine: 2615
-ENDS nicotine: 152
|Smith et al. ||ENDS nicotine exposure during rapid brain growth period is associated with behavioral changes in adult mice.||Animal study (pregnant C57BL/6 mice)||Pre- and postnatal exposure to 2.4% nicotine in 1,2-PDO versus 0% nicotine/1,2-PDO. Assessment of cotinine levels and behavioral testing at 14 weeks of age. (Gestational day 15–19 and postnatal day 2–16 are equivalent to third trimester brain growth in humans.)||ENDS nicotine increases cotinine levels, activity, and number of head dipping and rearing, and increased cognitive flexibility. ENDS may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.||Cotinine levels: 2.4%/PG: 23.7 ± 4.2 ng/mL. 0%/PG: 2.8 ± 0.3 ng/mL.|
|Nguyen et al. ||Maternal ENDS aerosol exposure on murine offspring and assessment of impact on behavior and global DNA methylation in brain tissue.||Balb/C female mice||3 groups (n = 24). ENDS + nicotine (n = 8), ENDS nicotine-free (n = 8), and air (n = 8). Exposure 6 weeks before pregnancy, during pregnancy, and lactation.|
Behavioral assessment at 12 weeks of age.
Epigenetic testing of brain tissues at day 1 and 20 days, and 13 weeks after birth.
|Maternal ENDS + nicotine aerosol causes short-term memory deficits, reduced anxiety, and hyperactivity in offspring. Cognitive and epigenetic changes were observed in the offspring. The use of ENDS during pregnancy may have hitherto undetected neurological consequences on newborns.||Epigenetic testing: ENDS+nicotine-free aerosol showed statistically significant higher global DNA methylation compared with the air group at day 1 and 20. At week 13, no significant global DNA methylation change was observed in hippocampus.|
Significant alterations of 13 key genes were detected.
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Sailer, S.; Sebastiani, G.; Andreu-Férnández, V.; García-Algar, O. Impact of Nicotine Replacement and Electronic Nicotine Delivery Systems on Fetal Brain Development. Int. J. Environ. Res. Public Health 2019, 16, 5113. https://doi.org/10.3390/ijerph16245113
Sailer S, Sebastiani G, Andreu-Férnández V, García-Algar O. Impact of Nicotine Replacement and Electronic Nicotine Delivery Systems on Fetal Brain Development. International Journal of Environmental Research and Public Health. 2019; 16(24):5113. https://doi.org/10.3390/ijerph16245113Chicago/Turabian Style
Sailer, Sebastian, Giorgia Sebastiani, Vicente Andreu-Férnández, and Oscar García-Algar. 2019. "Impact of Nicotine Replacement and Electronic Nicotine Delivery Systems on Fetal Brain Development" International Journal of Environmental Research and Public Health 16, no. 24: 5113. https://doi.org/10.3390/ijerph16245113