Cigarette smoking in pregnancy

1. Cigarette smoking in pregnancy
주산기 분과 김윤영

2. Introduction

3. 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

5. 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

7. 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

9. 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

10. Pathophysiology

11. 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).

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 pathophysiology
• 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)

14. Placental mitochondria 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)

15. Placenta 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

16. Placenta pathophysiology

17. Chromosomal instability 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

18. Neurotransmitters pathophysiology
• 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.

20. 흡연이 산모와 태아에 미치는 영향

21. 산모에 대한 영향 Effect
• 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

22. maternal age <15y 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

23. 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

24. 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

25. 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.

26. 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.

27. 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

28. 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 .

29. 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.

30. CHD Effect
• 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

31. Intellectual performance (IP) 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

33. 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 .

34. Brain 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

35. ADHD Effect
• 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

36. Sudden infant death syndrome (SIDS) 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

38. • 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

39. 감사합니다.