Nicotine Intake in Pregnant Smokers and a General Population of Smokers.

OBJECTIVE: The purpose of this study was to assess whether pregnant smokers have the same nicotine intake from cigarettes as a general population of smokers and whether the known lower daily cigarette consumption among pregnant smokers is associated with higher nicotine intake among pregnant smokers. METHOD: The study was a cross-sectional comparison of pregnant smokers and a general population of smokers in smoking cessation clinics. Participants were treatment-seeking pregnant (n = 476), nonpregnant female (n = 116), and male (n = 195) smokers who participated in two independent smoking cessation trials. Nicotine intake was measured as saliva cotinine/ cigarette/kg body weight ratio. RESULTS: The mean saliva cotinine (µg/L)/ cigarette/kg body weight (0.21, SD = 0.15) of pregnant smokers was similar to that of nonpregnant female smokers (0.24, SD = 0.14) and higher than that of male smokers (0.18, SD = 0.12, p = .002) despite a substantially lower number of cigarettes per day (pregnant smokers: 12, SD = 6; nonpregnant female smokers: 26.6, SD = 11.7; male smokers: 23.5, SD = 9.5, p < .001). Among pregnant smokers, saliva cotinine, as expected, increased in parallel with the number of cigarettes per day, but nicotine intake (cotinine/cigarette/kg body weight) was inversely associated with daily cigarette consumption (p < .001). No association between cigarettes per day and nicotine intake was observed in male and nonpregnant female smokers (p = .43). CONCLUSIONS: This secondary analysis showed that pregnant smokers' nicotine intake was similar to that of a general population of smokers despite a lower cigarette consumption rate. Among pregnant smokers, lower daily cigarette consumption was associated with higher nicotine intake from cigarettes, suggesting compensatory smoking.

Cigarette Smoking During Pregnancy: Do Complete Abstinence and Low Level Cigarette Smoking Have Similar Impact on Birth Weight?

OBJECTIVES: Despite awareness of negative health outcomes associated with smoking, pregnant smokers might reduce their tobacco consumption thinking that a low smoking rate reduces smoking-related negative birth outcomes. We aimed to assess in a clinical sample whether there is a smoking rate that would not impact on birth weight (BW). METHODS: Pregnant smokers ≥18 years, gestational age of 9-20 weeks of amenorrhea, motivated to quit smoking, smoking ≥5 cigarettes/day (cpd) and their newborns (381 singleton, live births) were included in this secondary analysis of a French smoking cessation trial. RESULTS: The mean BW when the mother quit smoking was 3417 g (95 % CI: 3098-3738 g); when smoking >0<5 cpd, 3081g (3003-3159 g); when smoking 5-9 cpd, 3043 g (2930-3157 g); and when smoking ≥10 cpd, 2831 g (2596-3157 g) (p = .006). The corresponding effect sizes ranged from medium to large (Cohen's d for BW: 0.54, 0.57 and 0.85) compared to BW when the mother quit. In the multivariable analysis, adjusted for all significant confounders, when the mother smoked on average >0<5 cpd, the loss in BW was 228 g; when smoking 5-9 cpd, 251 g; and when smoking ≥10 cpd, 262 g (all p ≤ .02) compared to newborns' BW of mothers who stopped smoking since quit date. CONCLUSIONS: Even low cigarette consumption during pregnancy is associated with BW loss. All efforts should be made to help pregnant smokers quit completely during their pregnancy. IMPLICATIONS: As an alternative to quitting smoking, pregnant smokers reduce their smoking rate thinking that this diminishes smoking-related negative health outcomes. No study has established whether low smoking rate (more than 0 but less than 5 cpd) during pregnancy impacts BW compared to abstinence from smoking. Among treatment-seeking pregnant smokers BW of newborns of mothers who smoked even less than 5 cpd was significantly lower than of those whose mothers quit; effect sizes of different consumption levels on BW ranged from moderate (>0<5 cpd) to large (≥10 cpd). Even low smoking rate is associated with reduced BW compared to complete maternal smoking abstinence.

Fetal exposure to tobacco: nicotine and cotinine concentration in amniotic fluid and maternal saliva.

OBJECTIVE: Fetal exposure to tobacco constituents is a risk factor for negative birth outcomes. We aimed to determine the relationships between nicotine and cotinine concentrations in amniotic fluid and maternal saliva. METHODS: As part of a therapeutic trial, 42 pregnant smokers agreed to sample amniotic fluid (8 samples from amniocentesis, 34 at birth). Their smoking characteristics were collected along with the newborns' birth outcomes. RESULTS: The median concentrations [IQR] in amniotic fluid and saliva were 11 [7-31] and 38 [7-174] µg/L for nicotine and 72 [22-123] µg/L and 55 [17-109] µg/L for cotinine, respectively. Multivariate models showed that saliva cotinine concentration predicted amniotic fluid nicotine and cotinine concentrations (R2 = 0.398, p < 0.0001 and R2 = 0.708, p < 0.0001 respectively). Amniotic fluid nicotine or cotinine concentration was not associated with birth weight. In multivariate analysis, the time elapsed since the last cigarette was the only variable associated with increased birth weight (R2 = 0.237, p = 0.002). CONCLUSIONS: Maternal saliva sampling for the determination of cotinine concentration is of interest to monitor fetal exposure to nicotine of any origin. Nevertheless, the time elapsed since the last cigarette was a better predictor of birth weight than the biomarkers' concentrations in amniotic fluid or maternal saliva.

Relationships between nicotine and cotinine concentrations in maternal milk and saliva.

AIM: Breastfeeding may be impaired due to nicotine excreted into the milk of smoking mothers. We investigated the relationships between nicotine and cotinine concentrations in maternal milk and saliva among breastfeeding smokers. METHODS: The 41 mothers reported their cigarette consumption between waking up and milk and saliva sampling. The median sampling time took place four days after delivery. Nicotine and cotinine concentrations were determined by liquid chromatography and UV detection, after a single-step saliva or three-step milk liquid-to-liquid extraction. RESULTS: The median (interquartile range) concentrations in milk and saliva were 7 (6-22) and 27 (4-207) µg/L for nicotine and 24 (5-111) and 22 (4-120) µg/L for cotinine, respectively. Milk cotinine was positively associated with saliva cotinine (p < 0.0001) and cigarette consumption (p = 0.039) and inversely associated with the time since the last cigarette (p = 0.0004, model R(2) = 0.90). Milk nicotine was associated with saliva nicotine concentration (p = 0.0017) and cigarette consumption (p = 0.0023, model R(2) = 0.63). CONCLUSION: Saliva nicotine concentration was not a very good estimate of milk nicotine concentration in breastfeeding mothers. Saliva cotinine concentration may be used instead of milk cotinine concentration to estimate tobacco or nicotine exposure among breastfed neonates or infants.

Nicotine patches in pregnant smokers: randomised, placebo controlled, multicentre trial of efficacy.

OBJECTIVE: To determine the efficacy of 16 hour nicotine patches among pregnant smokers, with the dose individually adjusted according to saliva cotinine levels (potential range 10-30 mg/day). DESIGN: Randomised, double blind, placebo controlled, parallel group, multicentre trial (Study of Nicotine Patch in Pregnancy, SNIPP) between October 2007 and January 2013. SETTING: 23 maternity wards in France. PARTICIPANTS: 476 pregnant smokers aged more than 18 years and between 12 and 20 weeks' gestation, who smoked at least five cigarettes a day. After exclusions, 402 women were randomised: 203 to nicotine patches and 199 to placebo patches. Data were available on 192 live births in each group. INTERVENTIONS: Nicotine and identical placebo patches were administered from quit day up to the time of delivery. Doses were adjusted to saliva cotinine levels when smoking to yield a substitution rate of 100%. Participants were assessed monthly and received behavioural smoking cessation support. MAIN OUTCOME MEASURES: The primary outcomes were complete abstinence (self report confirmed by carbon monoxide level in expired air ≤ 8 ppm) from quit date to delivery, and birth weight. The secondary outcomes were point prevalence of abstinence, time to lapse (a few puffs) or relapse, and delivery and birth characteristics. All data were analysed on an intention to treat basis. RESULTS: Complete abstinence was achieved by 5.5% (n=11) of women in the nicotine patch group and 5.1% (n=10) in the placebo patch group (odds ratio 1.08, 95% confidence interval 0.45 to 2.60). The median time to the first cigarette smoked after target quit day was 15 days in both groups (interquartile range 13-18 in the nicotine patch group, 13-20 in the placebo patch group). The point prevalence abstinence ranged from 8% to 12.5% in the nicotine patch group and 8% to 9.5% in the placebo patch group without statistically significant differences. The nicotine substitution rate did not differ from 100%, and the self reported median compliance rate was 85% (interquartile range 56-99%) in the nicotine patch group and 83% (56-95%) in the placebo patch group, assessed at 1016 visits. The mean birth weight was 3065 g (SE 44 g) in the nicotine patch group and 3015 g (SE 44 g) in the placebo patch group (P=0.41). Diastolic blood pressure was significantly higher in the nicotine patch group than in the placebo patch group. The frequency of serious adverse events was similar between the groups, although more non-serious adverse reactions, mainly of skin, occurred in the nicotine patch group. CONCLUSION: The nicotine patch did not increase either smoking cessation rates or birth weights despite adjustment of nicotine dose to match levels attained when smoking, and higher than usual doses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00507975.

Folate and homocysteine in the cerebrospinal fluid of patients with Alzheimer's disease or dementia: a case control study.

BACKGROUND: Amyloid deposition in the brain is an early event in Alzheimer's disease (AD), but a dysfunction of the blood-brain barrier or a disturbance in the metabolism of folate and homocysteine (Hcy) may affect the development of dementia. We investigated if the concentrations of folate and Hcy would be modified in cerebrospinal fluid (CSF) of clinically diagnosed AD patients. METHODS: We included 70 AD patients, 33 patients with another type of dementia (nAD) and 30 age-matched control subjects. Plasma Hcy was assayed as well as Hcy, folate, Aß1-42 and T-tau in CSF. We used ANOVAs for comparison between groups, and then pairwise comparisons by Wilcoxon tests with Bonferroni-corrected p values. Correlations were tested with the Spearman's rank test. RESULTS: Levels of Aß1-42, T-tau and folates in CSF were significantly different between groups, but not Hcy. In addition, the average folate in CSF was lower in AD patients compared with controls (18.7 ± 2.4 vs. 20.3 ± 1.7 nmol/l, Bonferroni-corrected p value < 0.02). There was no correlation between Aß1-42 or T-tau and folate or Hcy in CSF, regardless of the group. In the AD group, there was a significant inverse correlation between Hcy and folate in CSF (ρ = -0.63, p < 0.0001), whereas in the nAD group, a significant correlation was found for Hcy between plasma and CSF (ρ = 0.59, p < 0.0005). CONCLUSION: The concentration of folate in CSF was found to be decreased in AD patients. These findings support the hypothesis of a possible role of folate in the onset or worsening of AD.

Adjustment of nicotine replacement therapies according to saliva cotinine concentration: the ADONIS* trial-a randomized study in smokers with medical comorbidities.

AIMS: To assess the efficacy of nicotine replacement therapies (NRT) when the daily dose was adapted according to saliva cotinine concentrations. DESIGN: Randomized, multi-centre, single-blind, controlled trial. SETTING: Twenty-one smoking cessation clinics in France. PARTICIPANTS: A total of 310 smokers with medical comorbidities, motivated to quit, smoking ≥ 10 cigarettes/day, for whom smoking cessation was mandatory. NRT was administered for 3 months. The standard care group received nicotine patches with monthly dose decreases; buccal absorption NRT could be co-administered at the discretion of the investigator. In the dose adaptation group, the aim was a 100 ± 5% nicotine substitution with respect to smoking state based on the determination of saliva cotinine concentrations. NRT daily doses were prescribed according to the previous week's saliva cotinine concentrations in the dose adaptation group; saliva cotinine concentrations were not provided in the standard care group. MEASUREMENTS: Prolonged abstinence rate (weeks 9-12, main outcome measure), point-prevalence and continuous abstinence rate, saliva cotinine concentration, NRT daily dose, craving for cigarettes. FINDINGS: The median daily prescribed NRT dose was 30 and 31 mg/day in the first study week and 17.25 and 35.5 mg/day during weeks 9-12 in the standard care group and dose adaptation group, respectively. Saliva cotinine remained stable in the dose adaptation group and decreased in the standard care group (P < 0.01) by weeks 9-12. The cotinine substitution rate was significantly lower in the standard care group than in the dose adaptation group. Despite differences in NRT doses and cotinine substitution rates, prolonged (standard care group: 26.4%, dose adaptation group: 30.3%), continuous (standard care group: 8%, dose adaptation group: 12%) and point-prevalence abstinence rates were similar. CONCLUSIONS: In smokers with medical comorbidities and highly motivated to quit, adaptation of the nicotine replacement therapy daily dose according to saliva cotinine does not appear to be substantially superior to standard nicotine replacement therapy use.

Elevated gamma-glutamyltransferase activity and perturbed thiol profile are associated with features of metabolic syndrome.

BACKGROUND: Prospective cohort studies have revealed that plasma gamma-glutamyltransferase (GGT) activity exhibits a positive association with coronary artery disease. GGT which is equally elevated in metabolic syndrome (MS), is the major regulator of circulating concentrations of thiol compounds derived from glutathione (GSH) cleavage, ie, cysteine and cysteinyl glycine. We compared the circulating thiol profile in a cohort of patients displaying atherogenic dyslipidemia with and without MS. METHODS AND RESULTS: This cross-sectional study involved 1131 dyslipidemic patients in primary prevention of whom 26% presented with MS. GGT activity and plasma cysteinyl-glycine and cysteine concentrations were higher in MS patients; by contrast, levels of GSH were significantly lower (P<10 to 4 for all comparisons versus patients without MS). We compared patient groups on the basis of the number of MS criteria which were concomitantly present. A progressive decrease in glutathione levels in contrast to a progressive increase in both cysteinyl-glycine and cysteine levels, and GGT activity, was observed as a function of the number of MS components in the overall population (P for trend <10(-6)). CONCLUSIONS: Dyslipidemic patients exhibiting MS are characterized by elevated GGT activity which is associated with perturbed metabolism of thiol compounds.

Fenofibrate increases homocystinemia through a PPARalpha-mediated mechanism.

Plasma homocysteine levels increase in humans treated with fibrates but the molecular mechanisms are unknown. The goal of the present study was to determine the mechanism of this increase using animal models. Firstly, an increase in homocysteine was observed in mice treated with fenofibrate irrespective of the genetic background C57BL/6 or SV129. Secondly, as the effect of fenofibrate on gene expression is mediated through activation of the peroxisome proliferator-activated receptor alpha (PPARalpha), a transcription factor belonging to the nuclear receptor family, it was determined whether the effect of fenofibrate on homocysteine levels were modulated through PPARalpha activation. Using PPARalpha-deficient mice, it was shown that the homocysteine increase after fenofibrate treatment was completely abolished in these animals. It can be concluded that fibrates increase homocystinemia through a PPARalpha-mediated mechanism and that mice constitute an animal model for analyzing the molecular mechanisms behind the homocysteine increase after fibrate therapy in dyslipidemic patients.