June 8, 1998 NOTE: Theodore Slotkin's paper "Fetal Nicotine or Cocaine Exposure: Which One is Worse?" is available at http://www.dukenews.duke.edu/nicotine/slotkin.htm
DURHAM, N.C. -- The medical community, government and media have neglected unequivocal scientific evidence that nicotine from maternal smoking causes possibly 100,000 fetal deaths each year as well as massive numbers of crib deaths, according to a Duke University Medical Center pharmacologist.
Also neglected are the severe neurological problems in "cigarette babies" of smoking pregnant women.
This neglect comes despite the fact that the widespread, chronic ingestion of nicotine by one-fourth of all pregnant women probably produces far more damage than the more limited and episodic use of cocaine.
Professor of Pharmacology Theodore Slotkin bases his conclusions on a detailed review of research findings, including his own, published in a paper titled "Fetal Nicotine or Cocaine Exposure: Which One is Worse?" in the June issue of the Journal of Pharmacology and Experimental Therapeutics.
Animal studies have revealed that nicotine, and hence smoking during pregnancy, inflicts serious damage on the fetus even at nicotine levels too low to cause the traditionally accepted sign of damage -- low birth weight, said Slotkin.
"Maternal smoking during pregnancy kills between tens of thousands and possibly over a hundred thousand babies each year in utero," he said in an interview. "It also results in tens of thousands of admissions to intensive care units after birth and kills or brain-damages more during the birth process. Smoking is also responsible for one-third to two-thirds of all cases of Sudden Infant Death Syndrome (SIDS).
"And none of these figures takes into account the enormous increase in learning disabilities, attention deficit and hyperactivity disorder and other behavioral problems that we know are part of the outcome of maternal smoking."
Children and adolescents who take up smoking also may suffer brain damage, said Slotkin, who is now exploring this phenomenon in animal studies.
"Most smokers begin smoking in adolescence," he said. "And it is quite possible that nicotine exposures in a still-developing adolescent brain also can cause irreversible changes in the development, structure and function of specific nerve pathways.
"Such effects might explain why nicotine is often more viciously addictive in adolescents than it is in adults, and why the adolescent smoker becomes the lifelong smoker."
Slotkin also asserted that the worldwide increase in smoking will eclipse AIDS in the death and societal disruption it causes.
He calls for a nationwide campaign to persuade pregnant women to quit smoking. That campaign should concentrate on counseling, although it can include careful use of nicotine patches, inhalers and gum during the first trimester of pregnancy. This strategy is contrary to popular belief that drugs are most harmful to the fetus during that early period, said Slotkin. His findings show that nicotine does most damage to the fetus during the second and third trimesters, meaning that pregnant women have a "window of opportunity" early in pregnancy to quit smoking.
Slotkin also calls for a large increase in medical research and education on nicotine's effects. In his paper, he notes that despite the documented damage from smoking, "both the press and the medical community continue to regard tobacco as separate from, and less serious than, illicit drugs of abuse."
He cited a survey of the most prominent medical pharmacology texts in use in the U.S., which "showed that over 80 percent of the pages devoted to substance abuse concerned illicit drugs, just over 10 percent concerned alcohol, and less than 5 percent concerned tobacco.
"In contrast, illicit drugs account for only a handful of deaths annually, alcohol 50,000 and tobacco 400,000," he wrote.
Scientific research on fetal and childhood development also neglects tobacco studies, wrote Slotkin, with cocaine the subject of three to four times the number of published research papers as nicotine.
Also, wrote Slotkin, many physicians perceive cocaine as causing birth defects and counsel pregnant cocaine users to have abortions, even though "cocaine is less likely to cause malformations than is cigarette smoking."
Recent laboratory studies with rats have been the key to pinpointing nicotine as one of the major damaging constituents of cigarette smoke to the fetus, said Slotkin.
"Until now, although we had statistical or epidemiological associations of the effects of women smoking during pregnancy on the outcomes of their children, those kinds of associations didn't automatically connote a causal relationship," he said.
"Many other factors accompany the smoking lifestyle, including lower socio-economic status, which leads to poor prenatal care, as well as other risky behaviors, including use of other drugs of abuse and alcohol.
"However, with our animal research, we can test individual components of tobacco, determining which actually elicit such effects as brain damage or sensitivity to hypoxia after birth, which can trigger SIDS."
Studies by Slotkin and his colleagues over the past decade have involved using implantable minipumps to infuse precisely metered doses of nicotine into the bloodstreams of pregnant rats, and then studying in detail the biochemical, anatomical and behavioral effects on the rats' offspring.
These studies have revealed details of the mechanisms by which nicotine damages the brains of the fetal rats. The experiments show that nicotine mimics a key brain neurotransmitter chemical, acetylcholine, which is normally released in a precise sequence of signals that tell the sensitive growing brain cells how to "wire" their connections. However, nicotine stimulates the same cell receptors as acetylcholine, at the wrong time and with inappropriate intensity, confusing the normal development process and causing the fetal brain to permanently miswire itself. Nicotine also kills brain cells outright by causing them to "age" prematurely and die, said Slotkin.
Nicotine causes similar damage outside the brain, overstimulating cells in the peripheral nervous system and adrenal glands that secrete adrenalin and noradrenalin. This stimulation causes them to lose a key survival mechanism prematurely in the newborn.
To protect itself from damage due to inadequate oxygen, the fetus and newborn depend on the adrenal hormone system to "alert" its body to react to periods of hypoxia -- for example during birth itself and after birth during mild apnea during sleep -- by increasing breathing and heart rate. The infant needs the adrenal system because its heart and respiratory system are not yet fully wired with nerve cells to allow them to respond reflexively to hypoxia. Thus, nicotine's damage to this critical survival system may predispose the newborn to crib death, or SIDS.
Despite such clear dangers, said Slotkin, "the sad truth is that most women who smoke don't quit during pregnancy." Although about half of smoking pregnant women report that they have quit, he said, blood or urine tests show that the proportion of women who actually stop smoking during pregnancy is small.
Use of the transdermal nicotine patch to quit smoking was once believed a desirable alternative, because such chemicals as carbon monoxide and hydrogen cyanide in cigarette smoke can cause major damage, said Slotkin. However, because nicotine has now been clearly implicated as a key cause of fetal brain damage, Slotkin advocates that the patch's use be carefully circumscribed.
"It's no longer a question of just blindly applying the patch to quit smoking," he said. "It's now a question of whether a pregnant woman smokes enough so that the transdermal patch will increase or decrease the amount of nicotine that she is taking in. Use of the patch is further complicated by the fact that it is available over the counter, with no physician or pharmacist instruction for the woman."
Thus, Slotkin advocates far more care in use of the transdermal patch to keep the nicotine dose as low as possible. Nicotine inhalers and gum might be a more desirable alternative because they maintain lower nicotine levels, he said. His research also has shown that nicotine does less damage if its bloodstream levels are allowed to drop periodically, allowing the fetal brain to "recover" from the chemical insult. Thus, for example, he recommends removing the patch at night. Slotkin said his research clearly indicates the advantage of such treatment during the first trimester.
"Nicotine works on a very specific set of proteins that, although they're present from early in pregnancy, aren't really there in very large numbers until the second trimester. This tells us that if we're going to intervene with the transdermal patch or other nicotine-based therapies, the first trimester is the time to do this.
"Unfortunately, most obstetricians now first counsel and cajole their patients to quit smoking, and then when that doesn't work -- as it usually doesn't -- they'll put the patch on in the second trimester, exactly the wrong time to begin nicotine replacement therapy."
Slotkin also emphasizes to obstetricans the inadequacy of the Surgeon General's warning that links evidence of smoking-related fetal damage primarily to low birth weight.
"We have fallen into the trap of thinking that if a baby is of normal weight, then no damage has been done. But in our animal studies -- in which we could simulate smoking levels from two packs a day down to half a pack -- we find that all the brain damage that occurs at growth-retarding levels of nicotine is still present at doses that don't affect growth. The brain is much more sensitive than the rest of the body," said Slotkin.
Nor should the medical community or the public blindly accept the popular myth that crack cocaine causes more severe damage.
"A major point is that virtually all crack users also smoke cigarettes," he said. "So, in developing the statistical associations of crack baby syndrome, researchers have generally not separated out the effects due to cigarette smoking.
"For example, many previously believed that crack cocaine caused SIDS, but when investigators began to look at the incidence of SIDS in the offspring of women who used crack cocaine, they found it to be no higher than in the offspring of women who smoke cigarettes. So cocaine itself might not actually be causing SIDS, but rather the associated cigarette smoking."
In addition to neglect by the medical community of nicotine's dangers, Slotkin also sees such problems in government regulatory efforts.
"To me, the denouement of our neglect of cigarette smoking as a source of damage to children came during the recent Congressional hearings on tobacco company policies and the potential for the FDA to regulate cigarettes as a nicotine delivery device. Not once in those hearings did the issue of maternal smoking and children's health get raised. And yet to me and to other people in the field, this is potentially the most damaging event to our society caused by tobacco abuse."
Slotkin hopes the media will give tobacco its proper attention as a substance hazardous to children, both unborn and born.
"I certainly don't want to downplay the risk of cocaine, but tremendous publicity has been given crack baby syndrome, with major articles in newspapers and cover stories in news magazines. None of that kind of attention has been paid to the damage caused by cigarette smoking, which involves a much larger population of children than those whose mothers are involved with crack cocaine.
"Given that this is not a case where someone is simply damaging their own bodies and is aware of it, but instead is damaging someone else's entire future, I fail to understand why there aren't articles, headlines, magazine covers, or presidential statements targeting cigarette smoking in pregnancy. It's something that we stand a reasonable chance of influencing with publicity, whereas cocaine abuse is not."
Slotkin also sees the explosion of cigarette smoking in developing countries as threatening to become a major global public health problem.
"As we increase our efforts to reduce smoking, there is increasing pressure on tobacco companies to make their profits elsewhere," said Slotkin. "And they're doing that very successfully. The World Health Organization estimates that sometime in the next decade, the annual number of deaths from tobacco around the world will pass the 10 million mark, which eclipses virtually any disease that we have a chance of controlling."
"Damage from increases in cigarette smoking certainly eclipses AIDS in developing countries, and it will mean a new generation of children exposed to cigarette smoke. The impact on those countries' social structures and economies is unfathomable.
"It's one thing to have a large number of babies needing intensive care in the First World where we have the facilities and can afford it. But in the Third World, these babies are just going to die. What's more, the impact on those countries' educational systems, which don't have the resilience that we have to handle children with behavioral problems and learning disabilities, will be enormous."
Slotkin's research awards include the 1992 Alton Ochsner Award for Research on Smoking and Health, considered the highest honor for research on tobacco-related diseases. Most recently, he was awarded the 1998 Otto Krayer Award of the American Society for Pharmacology and Experimental Therapeutics (ASPET), given to "a distinguished, mature investigator whose research has contributed significantly to a better understanding of the mechanisms of action of drugs or other chemicals."
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