Cigarette smoking in pregnancy

주산기 분과 김윤영

Introduction

introduction

• 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)

• 4000 chemicals identified in tobacco smoke

• 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

introduction

• 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 : alertness, arousal

• Sustained exposure : sedative action, reduces anxiety, induces euphoria

• At commonly used doses, nicotine enhances intellectual performance, decreases

depression and anxiety, and activates the dopamine reward system

: nicotine addiction

introduction

• Tobacco use in pregnancy

: human developmental toxicant and potential teratogen

• Gestational smoking associated

– Placental pathologies, preterm birth, low birth weight, structural

malformations

– Neurobehavioral abnormalities, abnormal somatic growth, increased blood

pressure in childhood

– 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

introduction

• Fetal concentration of carboxyhemoglobin : generally higher than

maternal levels (higher affinity of fetal hemoglobin to carbon monoxide)

• Nicotine

– Lipid soluble : large distribution volume(2~3L/kg)

– Readilly permeates cell membrane

– T1/2: 1~3hrs

– Cotinine: major metabolite of nicotine

T1/2: 10~14hrs

• Maternal systemic exposure to nicotine and accumulation of nicotine,

cotinine in fetal hair : significant correlation

Pathophysiology

pathophysiology

• Cigarette smoke contains scores of toxin (cyanide, sulphides, cadmium,

carcinogenic hydrocarbons, nicotine) induce direct cellular damage

• Nicotine, cotinine, aldehydres, 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).

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

• Nicotine

– Depress active amino-acid uptake by human placental villi, trophoblast invasion

• 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)

Protein metabolism pathophysiology

• 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)

Placental mitochondria pathophysiology

• 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

• Tobacco constituents exert direct effect on villous cytotrophoblast proliferation

and differentiation

– Placentation

– Formation of placental membrane

– Feto-placental growth and development

Placenta pathophysiology

Placenta pathophysiology

pathophysiology

• 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 instability

• 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.

Neurotransmitters pathophysiology

흡연이 산모와 태아에 미치는 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 Effect

Effect

• 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 <15y

Pregnancy Complications Effect

• Increased incidence of subfertility, ectopic pregnancy, spontaneous

abortion, placenta previa, placenta abruption, bleeding early or late in

pregnancy preterm delivery, fetal death, neonatal death (including

Sudden Infant Death Syndrome)

• Decreased levels of chorionic gonadotropin : mechanism for the

increased rates of miscarriage among smokers

• Decreased fecundability

• Dose-response relationship

• Reduced risk of preeclampsia

Effect

• 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

Pregnancy Complications Effect

• Abruptio placentae, placenta previa and amniotic infections were

positively associated with the number of cigarettes smoked and the

duration of smoking.

– The cadmium content of placentas from smokers was nearly three

times that of non-smokers.

• Disturbance of ovarian cycles, inflammatory gynecological diseases,

spontaneous abortion, toxicosis of pregnancy, premature delivery,

chronic hypoxia of fetuses and hypotrophy of newborns.

• Placentas from smoking women and found an increase in the

metabolism of polynuclear aromatic hydrocarbon (PAH) however DNA

adducts of PAH were not increased.

Low brth weight (LBW) Effect

• Smoking doubles the risk of low birth weight and increases the risk of fetal-growth restriction 2~3 fold.

• Intrauterine growth restriction

– 200 g lighter

– Clear dose-response relationship for this effect

– Heavy smoking results in more severe weight reduction

– "passive smoking”

– Disparity can be detected sonographically

between 10 and 20 weeks.

Low brth weight (LBW) Effect

• If smoking is stopped during the first half of gestation, birth weights are virtually normal.

• Higher Perinatal mortality– Reduced birth weight and/or gestational age. – Increased risk of preterm birth

• The effects of smoking on fetal growth– Various investigators to premature placental

maturation– Chronic reduction in placental blood flow – Increase in cadmium levels– Carbon monoxide→ fetal hypoxia

Craniosynostosis Effect

• Significant association between maternal smoking during the first trimester

• Premature closure of the sagittal suture showed an association with maternal

smoking

• For coronal suture defects, no association with maternal smoking could be

detected.

• Dose-response relationship,

• The US National Birth Defects Study concluded :"moderately increased" risk

(odds ratio 1.5) associated with smoking, although the results were not

statistically significant .

Infant cleft palate Effect

• Infant cleft palate

– Significant dose-related association

– TGF alpha or B3 polymorphisms, suggesting a genetic-environmental

interaction in the production of this abnormality.

– Without evaluation of TGF alpha : The magnitude of the risk estimate

ranged from 1.21 to 2.73 (ref 57 and citations contained therein). A

273% risk increase would change the rate of facial clefts from 1/500

to 1/183.

– The absence of the GSTT1 gene during development .

:encode 20 different glutathione S-transferase enzymes,-critical role in

detoxification of polycyclic aromatic hydrocarbons in cigarette smoke

during palate formation.

• 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

CHD Effect

• Association between maternal smoking during pregnancy and the

risk of poor intellectual performance in young adult male offspring

– In a population-based Swedish cohort study on 205777 singleton males

born to Nordic mothers between 1983 and 1988

• 3~4 month delay in reading achievement

• No intellectual impairment

• Reduced neurological and intellectual maturation in six-year-olds

• Increase in the incidence of "minimal brain dysfunction"

• Increase in behavioral abnormalities

:hyperactivity, shortened attention span

Intellectual performance (IP) Effect

• Long term growth and development - physical growth,

mental development, and behavior of offspring

– The identification of many long term effects is limited by

the large number postnatal environmental confounders

that are difficult to control.

• For example, a 2009 study reported finding a modest

increase in risk of psychotic symptoms in adolescent

children of women who smoked .

Intellectual performance (IP) Effect

Effect

• 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

Brain

• 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

ADHD Effect

• 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

Sudden infant death syndrome (SIDS) Effect

• Folate 5mg(+ Multivitamin)

• Quit smoking

• Main impact of antenatal smoking exposure

:Miscarriage, Ectopic pregnancy, Placenta previa, Placenta

abruption, PPROM, LBW, FGR, Oral clefts, CHD, IP, ADHD

감사합니다.