Cigarette smoking in pregnancy

강서미즈메디병원 산부인과

임 옥 룡2010년 4월13일

Contents

1. 서론

2. 병리과정

3. 산모에 대한 영향

4. 태아에 대한 영향

5. 금연

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

and related to neurodevelopmental and behavioral

abnormalities in childhood

(constricts uterine arteries-fetal hypoxia).

negative biological impact of maternal cigarette smoking

placental function

nutrient and oxygen transfer

protein metabolism

enzymatic activity

Fetal development

Cord blood concentration on chronic maternal smoking

lower higher

thyroxine Leptin

HDL cholesterolcarbonyl group an lipid

peroxides

osteocalcin

bone isoenzyme of alkaline

phosphatase

ascorbic acid

IGF-1

IGFBP-3

beta-carotene

protein metabolism

• 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

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)

enzymatic activity병리과정

• 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)

placenta병리과정

• 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

• 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

metallothionein병리과정

• 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

chromosomal instability병리과정

• 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)

• 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.

neurotransmitters병리과정

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

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)

transcriptome산모에 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)

gene expression산모에 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

maternal age <15y산모에 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

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

SIDS태아에 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

LBW태아에 대한 영향

• 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)

• 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 cleft태아에 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

oral cleft태아에 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

CHD태아에 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)

IP태아에 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

brain태아에 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

ADHD태아에 대한 영향

금 연

• 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 연I

• 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

금 연II

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)

결 론

THANKS!!!