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Q. If people have known for a long time that smoking harms the unborn child, why continue researching the effects of nicotine or tobacco on the foetus?
A. I think there are several reasons why basic science studies can contribute to our knowledge of the human condition where it pertains to smoking and pregnancy. First of all, when you deal with the statistics that say conclusively that smoking has an adverse effect on the growth of the baby and causes increased mortality during the delivery, increased incidence of brain damage, learning disabilities, sudden infant death syndrome and attention deficit disorder, what you have to keep in mind is that those statistical relationships don't tell us why these things happen.
We know for example that women who smoke during pregnancy and smokers in general tend to be risk takers, more so than the rest of us. They tend to drink more. Women who smoke during pregnancy tend to make fewer pre-natal visits, which is a risk factor for the baby. Smokers tend to have poorer nutrition, and to abuse other substances as well. We've got to figure out what can we ascribe to smoking and what can we ascribe to "epi-phenomena", the other things that are associated with smoking and which can cause this kind of damage to the baby.
Where basic science helps is, I can take a rat and expose it during pregnancy to components of tobacco smoke and particularly, nicotine. We can do that in a setting in which we can mimic certain aspects of smoking; such as the fact that smoke contains carbon monoxide and hydrogen cyanide, and causes episodic hypoxia, or a deprivation of oxygen to the baby by shutting off the blood supply through the uterus. We can mimic that in the animal and we can do that in the absence of additional variables such as pre-natal care. We can fix the number of "pre-natal visits" our rats make to their "physicians". Taking the metaphor further, we can also deny them access to their favourite beer and make sure they don't take risks. In rats, by removing these variables, it's possible to study purely the effects of nicotine or nicotine with hypoxia which simulates what happens with smoking.
This is an important distinction to make. From the epidemiology in humans, I could not tell you whether it was advisable to take a woman who cannot quit smoking during pregnancy and put her on the nicotine skin patch, because the nicotine patch actually delivers more nicotine to the foetus than smoking does. But it doesn't contain carbon monoxide or hydrogen cyanide, nor does it cause episodic hypoxia by shutting down the blood supply to the baby the way smoking does. If we can separate those variables, which we can only do with animal studies, then we can start to make rational decisions about what to recommend to women instead of just telling them they've got to absolutely quit smoking, which obviously remains the best thing to do. If a woman is sufficiently motivated to stop smoking, fine. It's the women who can't stop smoking - between 20 and 35 per cent of women of child-bearing age - that we're dealing with.
Q. We hear so much about how smoking causes weight loss or causes the foetus to have a low birth weight. As far as I can recollect, that's about all we hear to do with smoking, but I presume it's important to focus your attention on nicotine as opposed to smoking and the other things to see what else nicotine by itself is capable of doing?
A. I think the focus on birth weight relates to the fact that low birth weight itself is one of the biggest risk factors for a difficult delivery. An infant who is growth-retarded does not have the energy reserves to survive the stress of being born. That's one of the reasons why there's so much peri-natal risk with growth retardation.
Animal studies enable us to answer the question of whether smoking, or nicotine as a component of smoking can cause brain injury over and above that which occurs when there's growth retardation. In other words, suppose you have a woman who smoked during pregnancy and her baby turns out to be of normal weight. Do we need to be concerned about that baby or is weight the whole story? It turns out that weight is not the whole story. In fact, it's a very misleading indicator, more so with nicotine than with virtually any other kind of damaging event during gestation. We focused on nicotine because we wanted to make distinctions between nicotine, the real drug in tobacco, and the other components of smoking which would cause episodic hypoxia and all the other agents. We had two objectives. One was to try to get a handle on the specific mechanism by which tobacco injures the foetus. The second was to determine if fetal growth retardation was an adequate predictor of that injury.
Really this required changing the entire way in which people study not only nicotine but drugs in pregnancy. Typically, up until about 10 years ago, the drug was just injected into the animal. If you look at the literature on this, it says an average smoker might take in x number of milligrams of nicotine. So this amount was packed into a syringe and injected into the animal. Certainly they'd get a lot of effects because the animal would be receiving the equivalent of a packet of cigarettes all at once. But obviously, those were trivial findings.
What we did instead was to take advantage of new technology. We took a mini pump and stuck that under the skin of the animal so it would receive a continuous low level infusion. This enabled us to deliver the total dose of nicotine that was appropriate to match human smoking, but to do so continuously over a day - it was a bit like the animal equivalent of the nicotine skin patch. What we found first of all was that nicotine itself was what's called a neuro-teratogen; it damages the developing brain. With smoking, hypoxia, carbon monixide and hydrogen cyanide do have effects. But nicotine all by itself has an injurious effect on the developing brain. Perhaps equally importantly, we found that the amount of nicotine that causes that damage was below the threshhold for causing growth retardation so that if you took a baby who was not growth retarded, whose mother smoked, that was not a guarantee that the brain wasn't affected.
Q. I understand that that kind of damage is quite quantifiable.It's not just a matter of saying the brain is damaged.
A. Yes. Typically when people start to look at how drugs damage the developing brain, they do a kind of "black box" study. The animal is exposed to the drug, and then when the animal grows up, its behaviour is tested. Although we don't have an animal equivalent of the IQ test, there are ways of determining whether animals can discriminate things properly and make certain judgements.The question then is what's inside the black box? How did all this come about? Obviously once we know that nicotine is the injurious substance, we can start to find these things out. This is actually an example of how what starts out as a very basic science study translates to vital information about human health.
There's really two types of damage. The first kind of damage is that in certain parts of the brain, many of the neurones are missing. Since neurones are what make you think and act, you don't want to be missing those. In our animal models of low level smoking, we found that the parts of the cerebral cortex that control higher intellectual functions, among other things, were missing 20 per cent of their nerve cells. And this is without growth retardation. The cells would be missing yet the brain weight would be normal, because the space would be filled in with glia, the support cells that simply provide the energetics and support for the nerve cells. That was one kind of damage.
The second kind of damage was functional damage. There was nothing wrong visually with the certain structures of the brain but the nerve cells weren't working properly. They were either wrongly wired up, or they were quiescent where they should have been active, they weren't firing as they should. When we investigated how this had happened, we had to back track and try to understand what the basic processes are that control the number of cells in the brain and whether a nerve will turn on or off at a certain stage.
The substances that communicate between the nerves, the neurotransmitters, not only provide the kind of communication that we think of as controlling our thinking and the way our brains work, they also provide their target cells with information about how to develop.
A cholinergic neuron makes the neurotransmitter acetylcholine. Some of its target cells contain a specific receptor protein called a nicotinic cholinergic receptor. As you can tell from its name, it responds to nicotine as well as to acetylcholine. The way the developing brain ordinarily works is, when this neuron makes contact with the target cell, acetylcholine flows across the cells from the neuron to its target cell. By depolarising that target cell, it tells that cell to stop dividing. The time has come instead to specialise. It's called differentiation. This is particularly important in the nervous system because once nerve cells make the decision to stop dividing they can never divide again. That's why when you get brain damage as an adult you can't really replace that function. You can work out ways around it, but the function of those cells will be lost forever because they can't be replaced.
Q. Is that a really critical event in development of the nervous system?
A. Absolutely. It's one of the crucial ways cells recognise what it is they're supposed to do in order for the brain to properly assemble itself. Imagine you've got that same synapse, the cholinergic/nicotinic target, but it hasn't grown in yet and it's not communicating. Suppose mum is smoking and the nicotine touches these receptors. This cell thinks "Ah ha! I have become innervated. I will stop dividing forever and I will specialise and make my axon go out, and find my target." But it does this at the wrong time. It does it before you've got the right number of cells. Plus it's now sending out its offshoot, its axon, to find its target cell. But the target cell may not even have migrated into the right place yet. So the axon gets lost and winds up innervating the wrong cells. It's like you have a radio with the wires going to the wrong places, and naturally, that causes functional disruption. This actually explains why we see fewer cells, why we see synaptic disorganisation, why we see cells there that don't work properly.
All this tells me two things about the human condition. It allows me to use nicotine as a probe to understand how the brain assembles itself. It also specifically confirms how nicotine works and that it is one of the most injurious substances in tobacco smoke.
How that translates to the human condition is as follows. We know that the action of nicotine is exerted on specific receptors. There's a certain point in development where these receptors emerge. Essentially up until that point, nicotine will not have this nasty effect on brain development. In the human nervous system, these receptors tend to emerge during the second trimester. So in fact, there is a period during which you can get a pregnant woman to quit smoking before irreversible brain damage occurs. If you ask an obstetrician what's the most dangerous period for exposure of the foetus to substances that cause birth defects, he or she will tell you, it's the first trimester, and that afterwards you don't have to worry. In fact, nicotine targets its effects through receptors that don't emerge until the second trimester, it's the second and third trimesters, and possibly even the post- natal period, that are the vulnerable periods. Second-hand smoke can actually also do this because your brain continues to assemble itself after birth. So from these basic science findings, we really have two things to translate directly to the human condition. One is the issue of how long a 'safe' period we have to convince the expectant mother to stop smoking, namely the first three months.
The second issue is one of a nicotine patch versus smoking. Here the answer isn't too clear. People ask me to come down definitively on one side or the other. And I really can't, because we know that there are other things in cigarette smoke besides nicotine that are injurious. On the other hand, for an average smoker, the patch will deliver a lot more nicotine to the foetus than smoking will, not only because it's got more nicotine in it than most smokers absorb on a per day basis, but also because the continuous infusion of nicotine winds up allowing the foetus to reach an equilibrium with the mother. So the foetus is getting the same plasma levels of nicotine as the mother is. The placenta acts as sort of a safety shield between the foetus and the mother in that it slows down the absorption of substances. For example, in obstetric practice, one of the big changes was to switch from long acting analgesics during delivery to short acting analgesics, because if you administer the latter, the mother doesn't feel pain and there isn't enough transfer to the foetus to suppress respiration after birth. The same thing is true of the nicotine you smoke versus nicotine you get in patch form. The foetus is to some extent screened from the big spike of nicotine in smoking because it's delivered over a very short period of time. With a patch, if you take that same amount of nicotine and spread it out over a long period of time, you wind up exposing the foetus to more.
We pick that up in animal models. It wasn't something that people had thought about too much before this. They thought about total doses of nicotine. In our animal models, we could take the same doses of nicotine by injection as by infusion. There were twice as many foetal deaths with infusion as with injections which mimic the spike and fall of nicotine. So it's not really an easy question to answer, whether you should patch a moderate smoker who's pregnant instead of let her keep smoking. It's really a value judgement on the part of her physician. How much does she smoke? How deeply does she inhale? If you have a woman who's smoking two packs a day, the patch would be a better option, because she's probably already getting a lot of nicotine as well as carbon monixide and hydrogen cyanide. I think it would be problematic to recommend putting a woman who's smoking just five cigarettes a day on the patches.
Q. It's damned if you do, damned if you don't, isn't it? Is the only real advice then for pregnant women to quit smoking?
A. I think that's always been the best option. Of course, if that advice worked, we wouldn't have to do the research would we? We wouldn't need to be concerned about it as a public health issue. The sad fact is that most women who smoke continue to smoke during pregnancy, or if they quit during pregnancy they start up again after pregnancy when they're nursing, and so expose the baby after birth. We know that the brain continues to develop and programme itself over the first few years of life.
Q. I'm struck by what an incredibly powerful and toxic substance nicotine is compared to say cocaine, yet so much fuss is made about cocaine smoking. How do you rationalise this?
A. It's interesting that you should bring that up because of course in the US, estimates of maternal cocaine use run from 10 to 15 per cent of all live births. It alarms a lot of people. The truth of the matter is that most women who smoke cocaine smoke cigarettes. In other words, if they just smoked cocaine, you wouldn't see anywhere near the same number of peri-natal deaths during and after delivery, or cases of Sudden Infant Death Syndrome. Nor would you see the same persistent behavioural problems. What we've done in essence is to make a societal judgement about cocaine with the result that the drug attracts a lot of adverse publicity. Even in the last presidential debate, one of the candidates brought cocaine up as an issue. Suddenly the headlines were screaming "Crack Baby Syndrome". You never see "Cigarette Baby Syndrome", yet it's a much bigger issue for public health.
It's no accident that there's an increase in Attention Deficit and Hyperactivity Disorder (ADHD) in school children. After World War Two, the number of women smokers skyrocketed. Depressingly, the rate of smoking is increasing among teenage girls. I think that foetal exposure to substances including tobacco is on the rise and may actually account for the very real increase in ADHD.
Q. What role does smoking during pregnancy play in Sudden Infant Death Sydnrome (SIDS)?
A. One of the main recommendations that was made to reduce the incidence of SIDS was to stop placing babies on their stomachs, because the triggering episode in SIDS is a period of asphyxia, caused either by obstruction of the airways or by sleep apnoea, a period during sleep when the baby stops breathing. To some extent, all babies have periods of depressed breathing, some more than others. However, that alone doesn't account for SIDS.
When you look at the role tobacco plays, tobacco use probably accounts for over half the incidence of SIDS. A very carefully controlled study done in Sweden attributed 70 per cent of Sudden Infant Death to tobacco smoking. That makes it the number one killer of infants under one year of age.
We actually looked at this in our animal models. Obviously we can't get our rats to sleep on a soft mattress or voluntarily have long episodes of sleep apnoea. But we can reduce the amount of oxygen they breath. We can lower their blood oxygen to the same levels experienced by a baby during sleep apnoea or during airway obstruction. What we found was that after the nicotine-exposed rats were given this hypoxic exposure, one third died, whereas the control animals, the animals that didn't receive nicotine, all survived, just as they should have.
We found two types of damage. One was brain damage in the respiratory centres that helps control whether you respond to low oxygen by increasing your breathing (as you should) or by decreasing your breathing (as you shouldn't). The second thing we found was a defect in the adrenal glands which, like the brain, has nicotinic receptor target cells. What happened was they'd been pushed along the course of development so that they'd lost one of their special properties. They no longer released adrenalin during the period of asphyxia, when oxygen levels fell. You rely on that release of adrenalin to keep you alive when your oxygen supply is restricted. These animals didn't have the response. It was exactly the same kind of underlying mechanism that we found in the brain. Nicotine accelerated the cell's development, so that there were fewer cells too far developed for their stage or age.
So nicotine turns out to be more important than cocaine, not only in terms of brain damage, but in terms of things like Sudden Infant Death.
Q. Nicotine is a poisonous substance. There's no doubt about it. Yet people are talking about its medicinal potential to treat mental disorders. I mean it sounds like we're really dealing with fire here.
A. Nicotine itself is sufficiently toxic that if you took the nicotine in a cigar and injected it you would die. In fact, in designing nicotine patches, one of the major issues that had to be addressed was what happens if you damage the patch. You wouldn't want the entire amount of nicotine in the patch to be absorbed instantly, because that would also be lethal. To give you an example of how toxic nicotine is, we have liquid nicotine free base in the laboratory which we have to keep stored in a sealed container with absorbent around it and a hood to trap the vapour because it volatilises. So no vapour is inhaled when you handle the bottle, you have to wear two sets of gloves. That's because if you spill it on your skin, you could absorb a lethal amount. So it is a fairly toxic substance. But you know, Paracelsus pointed out that all drugs are poisons. We simply use them as drugs because of the way they poison some things before they poison us completely. Nicotine isn't particularly spectacular in that regard. However, most people don't realise that when they're walking around with a packet of cigarettes, they're in fact carrying lethal doses of nicotine.
