마더세이프라운드 임옥룡 cs2_0406

Cigarette smoking in pregnancy 강서미즈메디병원 산부인과 임옥룡 2010년 4월13일

Contents 1. 서론 4. 태아에 대한 영향 2. 병리과정 5. 금연 3. 산모에 대한 영향 6. 결론

서 론

서론I • 4000 chemicals identified in tobacco smoke • Smoking ; a practice in which a substance, most commonly tobacco, is burned and the smoke tasted or inhaled(cigarettes, hand-rolled from loose tobacco and rolling paper, pipes, cigars, hookahs, bongs) • The Center for Disease Control and Prevention(CDC) ; 34% West Virginia(reproductive age) 22.4% smoking rates of reproductive age women in US(2006) • Active smoking ; overall rate of smoking during pregnancy 11.8%(12-31%) • Heavy smoking ; 11-20 cigarettes/day • Very heavy smoking ; >20 cigarettes/day • Passive smoking ; inhalation of smoke, called secondhand smoke or environmental tobacco smoke(ETS), from tobacco products used by others. exposure to smoking on average at least once per week and at least 1 cigarette each time, from other people at home or in public places, from 1 month before to 2 months after pregnancy • Maternal smoking • Paternal smoking • Thirdhand smoking ; recently coined to identify the residual tobacco smoke contamination

서론II • In adults, nicotine directly affects CNS by stimulating sympathetic nervous system to release epinephrine from the adrenal cortex(accomplished through its agonist action on the nicotinic acetylcholine receptor(nAChR)), resulting in an increase in both BP and heart rate(HR) • Small, frequent doses of nicotine produce alertness and arousal, whereas sustained exposure has a sedative action, reduces anxiety, and induces euphoria • At commonly used doses, nicotine enhances intellectual performance, decreases depression and anxiety, and activates the dopamine reward system(nicotine addiction)

서론III • First report of cancer caused by tobacco was made in 1761 when Hill reported a correlation between snuff and oral cancer • The Ninth Report on Carcinogens(RoC) as known human carcinogens • Tobacco use in pregnancy ; considered a human developmental toxicant and potential teratogen. • Gestational smoking associated with placental pathologies, preterm birth, low birth weight and structural malformations in the offspring. It has also been related to neurobehavioral abnormalities, abnormal somatic growth and increased blood pressure in childhood • Cigarette smoking in pregnancy associated with infant morbidity and mortality(dose dependent) • Use in pregnancy is quite prevalent especially in the younger, less educated and economically disadvantaged women, a population that often receives limited antenatal care and therefore insufficient prenatal detection of congenital anomalies

병리과정

병리과정 • Cigarette smoke contains scores of toxin(cyanide, sulphides, cadmium, carcinogenic hydrocarbons, nicotine) induce direct cellular damage • In particular, Nicotine, cotinine, aldehydres and carbon monoxide studied more extensively due to placental permeability to these substances ; increased concentrations(15%) in the fetal circulation compared to those measured in the maternal compartment. • Negative biological impact of maternal cigarette smoking on placental function, nutrient and oxygen transfer, protein metabolism, enzymatic activity, fetal development, pointed out that the exact cellular mechanism remains unknown to date • Nicotine considered neuroteratogenic negative biological impact of maternal cigarette smoking and related to neurodevelopmental and behavioral placental function abnormalities in childhood nutrient and oxygen transfer (constricts uterine arteries-fetal hypoxia). protein metabolism enzymatic activity Fetal development

Cord blood concentration on chronic maternal smoking lower higher thyroxine Leptin carbonyl group an lipid HDL cholesterol peroxides osteocalcin bone isoenzyme of alkaline phosphatase ascorbic acid IGF-1 IGFBP-3 beta-carotene

protein metabolism 병리과정 • Nicotine ; depress active amino-acid uptake by human placental villi and trophoblast invasion (a key sodium-dependent transporter of neural amnio acids such as alanine, glutamine, an glycine. In particular, Ach suggested to be an important placental signalling molecule that, through stimulation of nAChR, controls uptake of nutrients, blood flow and fluid volume in placental vessels, and vascularization during placental development. • Carbon monoxide increases fetal carboxyhemoglobin formation(impairing fetal oxygenation - fetal hypoxia) which if severe enough may exert a teratogenic or embryotoxic effect • Cadmium ; decrease expression and activity of 11 beta-hydroxysteroid dehydrogenase type 2 (linked to FGR ; endocrine disruptor) tobacco constituents exert direct effect on villous cytotrophoblast proliferation and differentiation placentation formation of placental membrane feto-placental growth and development

enzymatic activity 병리과정 • Tobacco usage alter mitochondrial respiratory function in cardiomyocytes and lung tissue. • Reduction(30%) in the enzymatic activity of complex III(mitochondrial membrane-bound cytochrome bc1 proton pump complex) ; demonstrated in placental mitochondria from smokers compared with nonsmokers. • Enzymatic activity of complex III and mitochondrial DNA(mtDNA) content are inversely related to the daily consumption of cigarettes indicating that maternal smoking associated with placental mitochondrial dysfunction(contribute to restricted fetal growth by limiting energy availability in cells)

placenta 병리과정 • Placental morphological damage related to heavy chronic maternal smoking identified as early as the first trimester of pregnancy ; established that the mean placental weight in smokers is decreased, depending on the number of cigarettes smoked by the mother per day throughout pregnancy. • Placentas of smokers and of those who stopped smoking after conception exhibit a reduced capillary volume, surface area and length compared with the placentas of nonsmokers and of those who stopped before pregnancy • Total surface area of syncytial knots is reduced in smokers(smoking reduces the incidence of trophoblast apoptosis)

• Smoking in pregnancy associated with dysregulation of trophoblastic expression of molecules that govern cellular responses to oxygen tension. Hypoxia and nicotine exposure(pVHL and HIF2a) and angiogenic factors(VEGFs). Moreover, passive exposure to tobacco smoke has almost the same detrimental effects as active smoking on placental development

metallothionein 병리과정 • Metal-binding protein, metallothionein(MT ; a particular protein with low molecular weight and high sulfhydryl content, which attaches metallic ions) ; involved in the protection of human trophoblastic cells from heavy metal-induced, oxidative stress-induced, apoptosis, higher levels of MT found in placentas of smokers • MT are in excess to bind all cadmium ions present in placentas exposed to maternal smoking. By contrast, most placental zinc remains unbound to MTs • MT-2 isoform(induced by smoking ) could be involved in placental cadmium and zinc retention ; reduce the transference of zinc to the fetus, contributing to the detrimental effects on fetal growth and development

chromosomal instability 병리과정 • Maternal smoking before and during pregnancy associated with increased chromosomal instability in amniocytes(DNA adducts, gene mutations, chromosomal aberrations, and micronuclei examined) • Exposures during fetal development may influence cancer risks(diethylstilbesterol ; powerful transplacental carcinogen, vaginal clear cell carcinoma, testicular cancer. Gestational exposure to alcohol ; childhood leukemia) • Chromosome aberrations in peripheral lymphocytes of healthy individuals are significantly associated with increased cancer risks. Translocation frequencies shown to be elevated in smokers compared to non-smokers • Cancer influenced by interactions(gene-gene and gene-environmental interactions) among frequency and timing of exposures and genetic susceptibility. Genetic polymorphisms that increase the risk for cancer among smokers identified • Both GSTM1 and OGG1 genes highly polymorphic in population and have important roles in metabolizing and repairing of the compounds in cigarette smoke and repairing of DNA damage induced by cigarette smoke

• Benzopyrene ; metabolically activated to the diol-epoxide derivative ; benzopyrene-trans-7,8- dihydrodiol-9, 10-epoxide, a carcinogen(BPDE-I) ; covalently fixed on DNA and gives BPDE-I-DNA adducts ; linked to the accumulation of BPDE-I-DNA adducts in placenta and umbilical cord blood(smaller). • Both active maternal smoking and secondary maternal exposure increase in fetal HPRT mutations • Smoking 10 or more cigarettes per day for at least 10 y and during pregnancy is associated with increased chromosomal instability in amniocytes. Band 11q23, known to be involved in leukemogenesis, seems especially sensitive to genotoxic compounds contained in tobacco. • These recent data suggest that maternal smoking contains geneotoxicants capable of inducing chromosomal instability(increase in the risk of childhood malignancies)

neurotransmitters 병리과정 • Nicotine accentuates neurotransmitter function in adults but desensitizes these functions in prenatally exposed infants and children. This desensitization causes an abnormal response throughout the lifespan. • Furthermore, nicotine use by adolescents and adults can alleviate some of the symptoms caused by these neurotransmitter problems while they increase the risk for nicotine addiction.

산모에 대한 영향

산모에 대한 영향 • Maternal smoking impairs placental development and anatomy • Affect placental nutrient function by reducing maternal uterine blood flow(hypoxia) • Further it can cause placenta previa, placental abruption, PPROM

transcriptome 산모에 대한 영향 • Tobacco smoke-induced alterations in transcriptome have been studied in human lung cells, peripheral blood cells(tobacco smoke causes significant changes in gene expression levels in the exposed tissues, indicating negative effects on the regulation of biological processes)

gene expression 산모에 대한 영향 • Huuskonen et al. studied alterations in gene expression for xenobiotic- and steroid-metabolizing genes in a small set of term placentas of smoking women and identified induction of CYP1 family members and the glutathione-S-transferase gene(GSTA1)

maternal age <15y 산모에 대한 영향 • Two groups of younger(<15 y) and older(15-19 y) adolescent mothers were compared to mature mothers(20-24 y) • Risk for intrapartum stillbirth among smoking adolescents <15 y of age was twice risk for older adolescent and mature mothers. • Risk of intrapartum stillbirth among smokers decreased as maternal age increased

태아에 대한 영향

태아에 대한 영향 • Miscarriage, fetal growth restriction, stillbirth, preterm birth, SIDS • In the fetal brain, nicotine activate nicotinic receptors, which play an important role during development of the brain. Increase Childhood and adolescent morbidity from cognitive difficulties, ADHD, conduct disorders, behavioral problems, depression • Smoking enhances the secretion of amylase(pancreas biological parameters) by the exocrine pancreas and higher fetal plasma amylase activity in mothers who smoked compared with nonsmokers, indicates that nicotine or its metabolites affect fetal pancreas as early as 12 weeks gestation) • Childhood cancer(induce chromosomal instability) • Recent studies also investigated the interactions between genetic variants and maternal smoking in the pathogenesis of birth defects including oral cleft and congenital heart disease

SIDS 태아에 대한 영향 • Human infants exposed prenatally to nicotine have lower epinephrine and norepinephrine levels in cord blood at birth when compared to the blood levels of these cathecholamines in unexposed infants • Concerns about imbalance in autonomic tone are well documented in the SIDS literature, because this imbalance may decrease the infant’s ability to response to cardiovascular and respiratory challenges, resulting in death. • Infants of mothers who smoke have a two- to four-fold increased vulnerability compared to unexposed infants

LBW 태아에 대한 영향 • Exposure to smoking during pregnancy associated with slow pre- and postnatal-growth and nearly doubles a woman’s risk of having a low birth weight baby(<2500g) • In Crete, Greece, 2007-2008(1400 mother-child pairs), comparing smokers to nonsmokers, the adjusted odds ratio(OR) 2.8 for low birth weight and 2.6 for fetal growth restriction. 119g reduction in birth weight, an 0.53cm reduction in length, and a 0.35cm reduction in HC. Smoking cessation early during pregnancy modified significantly these pregnancy outcomes indicating the necessity for primary smoking prevention

• Neonates born to women who reported smoking from the first trimester had a 0.6-1.9% reduction in most neonatal anthropometric measurements, resulting in an overall reduction of birth weight of 110-130g(4%) compared to neonates born to mother who never smoked and were not exposed to passive smoking during pregnancy. • Neonate’ birthweight is lower by more than 180g in comparison with the group of nonexposed(In mothers heavily exposed to passive smoking) • Exposure of fetus to passive and/or light active smoking ; reduction of not only weight and fat mass and but also most anthropometric parameters. • Tar content of cigarette is more closely related to the reduction in fetal growth than to the number of cigarette smoked. • Maternal exposure to tobacco smoke in early pregnancy(serum cotinine concentrations at 20-24 weeks of gestation) ; adversely affects fetal head development(BPD) as assessed by US

• Interaction between maternal metabolic genotypes associated with cigarette smoking and infant birthweight(maternal cigarette smoking during pregnancy associated with reduced birth weight or increased risk of low birth weight. • Fetuses with GSTT1(del) had a mean birth weight reduction among smokers of 262g whereas in fetuses without GSTT1(del) the effect of tobacco exposure was nonsignificant(mean reduction 87g)

oral cleft 태아에 대한 영향 • Odds ratio(OR) for CL/P associated with maternal passive smoking was Adjusted ORs 2.0 • Adjusted ORs for exposure levels of 1-6 times per week and more than 6 times per week(at least 1 cigarette each time) were 1.6 and 2.8 • Examined the association between maternal passive smoking and the risk of CL/P in a Chinese population with high prevalence of orofacial clefts(about 3/1000)

oral cleft 태아에 대한 영향 • A hospital based case-control study conducted to identify interactions between the 538(T---C) polymorphic site of bone morphogenetic protein 4 gene(BMP4T538C) and exposures in pregnancy with nonsyndromic cleft lip, with or without cleft palate(nsCL/P) • BMP4T538C could be used as a genetic susceptibility marker for nsCL/P; maternal passive smoking exposure is a risk factor for nsCL/P; maternal multivitamin supplements are a protective factor • Fetuses with NAT1 1088 and 1095 polymorphisms have a higher risk of orofacial clefts if their mother smokes • Fetuses that are homozygous null for GSTM1(glutathione S-transferase) and whose mothers smoked >20 cigarettes per day, present with a 7- fold increased risk of orofacial clefts • Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers associated with a 6-fold increased risk for cleft lip

CHD 태아에 대한 영향 • In neonates with CHD 64 of 157 mothers(40.8%) reported smoking in pregnancy, whereas in the control group 41 of 208 mothers(19.7%) were smokers. Periconceptional tobacco smoking was associated with increased risk of CHD in the offspring(OR 2.75) • The incidence of neonatal heart disease in women who were non-smokers or smoked 1-10 and >= 11 cigarettes per day increased with the level of fetal tobacco exposure(35.8% versus 55.3% versus 64.3%), suggesting a dose effect

IP 태아에 대한 영향 • In a population-based Swedish cohort study on 205777 singleton males born to Nordic mothers between 1983 and 1988 • Association between maternal smoking during pregnancy and the risk of poor intellectual performance in young adult male offspring(risk of poor intellectual performance was increased in sons of smoking mothers compared with sons of non-smokers. An increased risk of poor intellectual performance for both sons if the mother was only smoking in the first pregnancy, but in neither son if the mother was only smoking in the second pregnancy)

brain 태아에 대한 영향 • Effect of a neurotoxin such a nicotine depends on both dose and timing of exposure. • Nicotine exposure changes the intensity and timing of brain cell development and the programming of neurodevelopmental events on a cellular level. • Found evidence of associations between prenatal exposure to smoking and subsequent deficits in childhood, including cognitive development, school achievement(learning) and behavioral adjustment. • Later, in development, exposure to nicotine changes higher sensory, memory, and motor functions through its effects on hippocampal, cerebellar, and sensory cortex development • Nicotine addiction ; also increased in people who were exposed to nicotine in utero

ADHD 태아에 대한 영향 • Systemic analysis of 24 studies of children who were prenatally exposed to substances of abuse found an increased risk for ADHD-related disorders among children whose mothers smoked during pregnancy. • Children with a specific polymorphism(genetic variation) in the dopamine transporter and exposure to maternal smoking have a significantly higher incidence to hyperactivity impulsivity than children without this combination of environmental and genetic risk

금 연

금 연I • In an attempt to increase efficacy, prenatal treatment has incorporated the use of smoking cessation medications such as bupropion or nicotine replacement therapies(NRTs)(in a sample of 296 women 29% reporteded by using cessation medication during pregnancy, whereas 46% reported being offered a nonphamacological cessation aid, booklets, or referral to a smoking cessation program). These practice patterns appear to be consistent with clinical guidelines that recommended considring medication for heavier smokers and for smokers who fail nonpharmacological methods. When medications were discussed, nicotine replacement was talked about more than twice as often as bupropion. Of the women offered a pharmacologic treatment, 10% actually used medication during their pregnancy • Bupropion, varenicline are commonly used medications for smoking cessation in genetal population. No human data to support use of varenicline during pregnancy, however, bupropion(malformation rate 2.3%, 2.2%) appears to have no more side effects in fetus than selective serotonine uptake inhibitor(SSRI) medications used for depression. Use of bupropion should be recommended only if potential for benefit outweighs the potential unknown risk • NRTS in pregnancy was terminated early because of an increase in adverse events in the treatment group(adverse events not associated with NRT use, but they were potentially serious ; preterm birth, low birth weight, preeclampsia, placental abruption, placental previa, neonatal ICU admission, fetal demise, infant death). Continuous nicotine exposure more hazardous than intermittent smoking, although no direct data to prove or disprove this assumption

금 연II • Bupropion appears to be the least toxic of the cessation drugs, is as effective as NRT, and does not expose fetus to nicotine. When NRT used during pregnancy and lactation, intermittent dosing is most likely better than continuous use. NRT should be avoided in the first trimester and used with caution for the remaining duration of pregnancy. Removal of nicotine patch at night will decrease nicotine exposure to fetus. Gum, lozenges, or nasal spray also decrease amount of nicotine exposure to fetus(however, decreased compliance because of poor taste and oropharyngeal irritation) • Cognitive behavioral therapy(CBT ; first choice), support groups, self-help aids, hypnosis(one of more popular nonpharmacological aids, although its effectiveness not well established) • The greatest success in smoking cessation obtained with a combination of both CBT and pharmacologic treatment • Lactation ; nicotine excreted in breast milk, in a dose dependent manner, with breast milk levels 2.9 times higher than maternal plasma. Nicotine lower prolactin level, which decrease milk supply and may account for the lower incidence of breastfeeding among women who smoke. Therefore, psychosocial factors are likely to contribute to the lower rates of breastfeeding found in women who smoke

결 론

결 론 • Folate 5mg(+ Multivitamin) • Quit smoking • Main impact of antenatal smoking exposure 1)Miscarriage 2)Ectopic pregnancy 3)Placenta previa 4)Placenta abruption 5)PPROM 6)LBW 7)FGR 8)Oral clefts 9)CHD 10)IP 11)ADHD • Chromosomal instability(BPDE-1-DNA adducts) ; childhood cancer • Genotype(mother-fetus ; GSTT1) • Genetic polymorphism(BMP4T538C)

THANKS!!!

마더세이프라운드 임옥룡 cs2_0406

by mothersafe on Jul 10, 2010

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마더세이프라운드 임옥룡 cs2_0406 — Presentation Transcript