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SMOKING DURING PREGNANCY: EVEN
WORSE THAN YOU
THINK
STOCKHOLM—
New data bolsters already staggering
evidence linking in utero cigarette smoke exposure with long-term health impairments.
In addition to its established dangers to the fetus, maternal smoking during pregnancy
has now been shown to increase the risks for diabetes and obesity, criminal behavior,
and substance abuse in adults.[1,2]
DIABETES
AND OBESITY
Scott M. Montgomery, PhD,
and colleagues have shown that not all of smoking’s effects on a fetus manifest
themselves during childhood: New links with early adult-onset diabetes and obesity
stretch the latency for health effects several decades beyond the exposure period.[1]
After sifting through data from 11,359 Britons born in 1958, the researchers found that the children of mothers who smoked
after the fourth month of pregnancy were significantly more likely to develop type 2 diabetes by age 33 than were the children of nonsmokers. Even after the analysis was adjusted for confounding variables (such as
social factors, birth weight, body mass index, and whether the child smoked at age 16 years), the offspring of moderate and heavy smokers were found to be 4.13- and 4.55-fold more likely, respectively, than offspring of nonsmoking mothers to develop diabetes.
Among adult nondiabetic offspring, risk for obesity correlated significantly with degree of maternal smoking: The odds ratios (ORs) for offspring of light, medium, and heavy smokers were 1.34, 1.35, and 1.38, respectively.
The authors suspect that both diabetes and obesity may stem from “lifelong metabolic dysregulation, possibly due to fetal malnutrition or toxicity” caused by smoking during pregnancy. “There are a number of possibilities we’re investigating,” said Dr. Montgomery, a Principal Research Fellow at the Center for Clinical Epidemiology at Karolinska Hospital in Stockholm. “For one, fetal malnutrition due to maternal smoking may influence the expression or function of insulin receptors, thereby increasing the risk of subsequent insulin resistance, type 2
diabetes, and obesity,” he noted. This makes sense, he explained, because low birth weight (LBW; ie, below 2500 g), which has long been linked with maternal smoking, is associated with insulin resistance and type 2
diabetes.
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MOTHER'S
GENOTYPE SHAPES
TOBACCO'S
IMPACT ON FETUS
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| BOSTON—Maternal
smoking does not harm all fetuses equally, Xiaobin Wang, MD, MPH,
ScD, and colleagues have found: Specific maternal genotypes enhance the adverse
effects of cigarette smoking on infant birth outcomes.[1] Offspring of mothers
with particular polymorphisms in genes encoding enzymes involved in toxin metabolism
are more likely to have low birth weights (LBWs), preterm births, and intrauterine
growth restriction (IUGR) if they are exposed in utero to smoke; genotype determination
at these loci might identify mothers especially at risk for smoking-associated
poor birth outcomes.
“Metabolism is essential
to cigarette smoke detoxification,” Dr. Wang, Associate Professor of Pediatrics
at Boston University School of Medicine, told RESPIRATORY REVIEWS.
The human genes CYP1A1 and GSTT1 encode enzymes that metabolize
smoke toxins: CYP1A1 enhances polycyclic aromatic hydrocarbon (PAH) toxicity,
whereas GSTT1 promotes elimination of toxins from the body. “Both
enzymes are relevant to the metabolism of cigarette smoke,” said Dr. Wang;
she added, “CYP1A1 and GSTT1 are highly polymorphic in our
study population, permitting us to examine gene-smoke interactions” and how
they affect pregnancy outcomes.
In Dr. Wang’s study,
which included more than 700 women and their infants, maternal CYP1A1 and
GSTT1 genotypes in nonsmokers were not associated with adverse birth outcomes.
However, newborns whose smoking mothers were homozygous for the A allele of the
CYP1A1 gene were 1.3 times more prone to LBW than were the offspring of
nonsmokers (mean deficit, 252 g); those whose smoking mothers possessed at least
one variant a allele (Aa/aa genotype) had more than a threefold higher risk for
LBW (mean deficit, 520 g).
CYP1A1 variant genotypes
also significantly enhanced smoking’s deleterious effect on IUGR. Among the
offspring of smokers with CYP1A1 Aa/aa genotype, the odds ratio (OR) for
IUGR was 4.1; it was 1.9 among infants born to smokers with CYP1A1 AA genotype.
Infants born to smokers with
the GSTT1 gene were 1.7 times more likely to suffer LBW than were the offspring
of nonsmokers; their mean deficit was 285 g. However, infants born to smokers
lacking the gene had a significantly higher OR (3.5) for LBW, and they were, on
average, 642 g underweight. Absence of the GSTT1 gene in a smoking mother
also doubled the risk for premature birth. Newborns whose smoking mothers possessed
the CYP1A1 Aa/aa genotype and lacked GSTT1 suffered the largest
reduction in birth weight: 1,285 g, on average.
Although exactly how smoking
affects a fetus remains unclear, CYP1A1 variant genotypes are associated
with smoking-related DNA adduct formation. “Positive dose-response relationships
were shown between levels of the smoking-related adducts and ... smoke exposure
during pregnancy,” Dr. Wang noted. Additionally, “newborns with elevated
levels of PAH-DNA adducts had significantly decreased birth weight, birth length,
[and] head circumference” than did newborns with lower adduct levels. “On
the other hand,” she said, “the GSTT1 enzyme is important in
protecting against genotoxic damage, such as sister chromatid exchanges and the
formation of hemoglobin adducts due to ethylene oxide present in tobacco smoke.”
The latter could interfere with oxygen transfer to impair fetal growth.
—Mimi
Zucker, PhD
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Reference
1. Wang X, Zuckerman B, Pearson
C, et al. Maternal cigarette smoking, metabolic gene polymorphism, and infant
birth weight. JAMA. 2002;287:195-202.
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CRIMINAL
BEHAVIOR AND SUBSTANCE ABUSE
The behavioral effects of in utero tobacco exposure on adult offspring underscore even more dramatically the breadth and persistence of smoking’s impact on an unborn child. Previous research had shown that the sons of women who smoked during pregnancy are more than twice as likely as the sons of nonsmokers to have a criminal record by age 22; this relationship is independent of confounding factors, including socioeconomic status, maternal drug use during pregnancy, or paternal criminal history. However, it has been unknown whether a similar relationship might be found in the adult daughters of women who smoked during pregnancy.
“We wanted to examine
a potential gender difference in this area,” said Patricia Brennan, PhD,
Assistant Professor of Psychology at Emory University in Atlanta. And, based on
others’ findings, “we thought that substance abuse would be an important
secondary outcome to consider as well,” she told RESPIRATORY
REVIEWS.
Dr. Brennan and colleagues
examined arrest records and substance abuse admissions data for 4,169 males and
3,943 females born between 1959 and 1961 in Copenhagen.[2] “Both males and
females whose mothers smoked during [the third trimester of] pregnancy were more
likely to be hospitalized with substance abuse diagnoses” than were the children
of nonsmokers, and both sexes were also more likely to be arrested for a criminal
offense, said Dr. Brennan.
However, the associations between maternal smoking during pregnancy and criminal behavior and substance abuse were much stronger in males than in females. Furthermore, “In females, the substance abuse problems appeared to explain the increased risk for criminal offending,” Dr. Brennan noted.
“We do not know the mechanism by which maternal prenatal smoking is associated with negative behavioral outcomes
in offspring, but one possible mechanism is nicotine,” Dr. Brennan suggested. She cited evidence that prenatal exposure of male rats to nicotine could elevate adult testosterone levels. High testosterone levels in men are linked with alcohol abuse and, weakly, with aggression, suggesting that altered hormone levels could contribute to criminal behavior.
Additionally, in utero exposure
is associated with impulsivity and learning deficits in children. These factors,
if persisting, could contribute to adult crime and substance abuse.
—Mimi Zucker, PhD
References
1. Montgomery SM, Ekbom A. Smoking during pregnancy and diabetes mellitus in a
British longitudinal birth cohort. BMJ. 2002;324:26-27.
2. Brennan PA, Grekin ER, Mortensen EL, Mednick SA. Relationship of maternal smoking
during pregnancy with criminal arrest and hospitalization for substance abuse
in male and female adult offspring. Am J Psychiatry. 2002;159:48-54.
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