Maternal cigarette smoking during pregnancy can negatively impact the fetus and increase risks of birth defects like congenital heart disease (CHD). Studies have found interactions between genetic factors in the fetus and maternal smoking that influence CHD risk. For example, fetuses with certain genotypes in genes related to nicotine metabolism and detoxification had a higher risk of CHD if their mother smoked during pregnancy compared to fetuses without those genotypes. Overall, maternal smoking poses risks to the developing fetus, and some children may be especially susceptible to effects of the toxins in tobacco smoke due to their genetic makeup.

1. Cigarette smoking in pregnancy
강서미즈메디병원 산부인과
임옥룡
2010년 4월13일

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

3. 서 론

4. 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

6. 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)

8. 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

10. 병리과정

11. 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

12. 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

13. 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

14. 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)

15. 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)

17. • 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

18. 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

19. 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

21. • 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)

22. 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.

24. 산모에 대한 영향

25. 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

27. 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)

28. 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)

29. 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

30. 태아에 대한 영향

31. 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

32. 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

33. 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

36. • 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

37. • 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)

39. 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)

40. 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

42. 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

44. 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)

46. 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

47. 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

48. 금 연

49. 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

51. 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

52. 결 론

53. 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)

54. THANKS!!!