There is conclusive evidence that cigarette smoking is associated with a dose-dependent decrease in birth weight. This decrease in birth weight is independent of other factors, and can be greatly reduced by cessation of smoking in early pregnancy. In addition, smoking increases the risk of spontaneous abortion, prematurity and perinatal mortality. These increased deaths are a result of the increased risks of abruptio placentae (a third trimester complication of pregnancy resulting from haemorrhage and accumulation of blood between the placenta and the wall of the uterus), placenta previa (anatomical positioning of the placenta over the cervical opening, which may lead to caesarian section), premature rupture of the membranes and intrauterine growth retardation seen in smokers.1
Smokers are exposed not only to nicotine, but to a vast array of chemicals that are known to be harmful, including carbon monoxide, aromatic hydrocarbons, tar, and cyanic and sulphuric compounds.
Nicotine replacement therapy has been shown to be effective in helping smokers to quit.2 The advantages of its use in pregnancy are simple. The foetus is exposed to lower concentrations of nicotine than when the mother was smoking (if an appropriate dosing regimen is used) and is not exposed to the other noxious chemicals found in the inhaled smoke. Secondly, the mother and child benefit from the long-term health advantages associated with cessation.
The disadvantages are that mothers who may have been able to give up alone may turn to the use of nicotine replacement therapy, and there may be a medicolegal difficulty in justifying the prescription of a substance known to be harmful to the foetus.
The antidepressants amfebutamone (bupropion) and nortriptyline have also been shown to increase smoking cessation rates in a small number of clinical trials. The use of clonidine in smoking cessation is limited by its side effects; anxiolytics and lobeline have not been shown to be effective.3
A recent report by the Tobacco Advisory Group of the Royal College of Physicians has highlighted the problems of smoking cessation in the United Kingdom. Most smokers do not smoke out of choice but because of an addiction to nicotine. The strength of the addiction is thought to be similar to or exceeding that seen with drugs of abuse such as heroin or cocaine.4
Cigarettes deliver rapid doses of nicotine to brain receptors, where the addiction is at least in part mediated by stimulation of dopamine release in the nucleus accumbens.4 Nicotine is highly addictive, with only about 2 per cent of smokers succeeding in quitting every year.4
The major psychological motivation to smoke appears to be the avoidance of negative mood states caused by smoking withdrawal. The nicotine in replacement therapies thus relieves the withdrawal symptoms associated with smoking.
Approximately 30 per cent of women who smoke in Britain continue to smoke during pregnancy.4
There are comprehensive data indicating that smoking during pregnancy is associated with adverse effects on foetal development; however, there is no consistent evidence to suggest that smoking results in an increased risk of foetal malformations. There is evidence to suggest that maternal smoking is associated with an increased risk of ectopic pregnancy, spontaneous abortion, and late foetal and neonatal deaths. The most consistent effect reported is intrauterine growth retardation.
The mechanisms causing growth retardation have not been established. Chronic reduction in placental perfusion, premature placental maturation, foetal hypoxia due to carbon monoxide in the smoke and increased concentrations of cadmium are thought to be contributory factors.
Babies born to women who smoke 10 to 20 cigarettes per day are approximately 200g lighter than those born to comparable women who do not smoke.5 Furthermore, there is a clear dose-response relationship for this effect, ie, the more the mother smokes the greater the reduction in birth weight. If smoking is stopped or significantly reduced prior to 20 weeks of gestation, the birth weights are likely to be within the normal range.6 Changing to low yield brands actually achieves little if any reduction in the intake of nicotine and tar because smokers tend to smoke the cigarette more deeply or intensively. Thus the health benefits from this are, if anything, small.4
The available data indicate that it is smoking per se rather than associated factors, such as poor maternal nutrition, that cause growth impairment. As there is no consistent decrease in the length of gestation associated with smoking, the reduced birth weights are due to retardation of growth.
Long-term follow up studies indicate that smoking during pregnancy may be associated with poor postnatal development in the children, eg, adverse effects on physical growth, mental development and behaviour have been reported. In 1983, Naeye and Tafari reported an increase in behavioural abnormalities (eg, hyperactivity, shortened attention span) in the offspring of smoking mothers; however, negligible differences were reported for reading, writing and language skills.7 Whether these effects are directly related to exposure to cigarette smoke or are the result of socioeconomic influences is uncertain.
Scwartzbaum published a study in 1992 suggesting that in utero exposure to cigarette smoke may be associated with an increased risk of childhood cancers in those infants.8 However, these associations have been contradicted by other studies.9,10
In 1998, Anderson and Cook published a report linking maternal smoking prenatally with an increased incidence of sudden infant death syndrome (SIDS).11 The incidence of SIDS was also seen to be increased with exposure to passive smoking after birth.
Pure nicotine, as found in nicotine replacement therapies, does have potential adverse effects on human health but does not appear to cause cancer or significant cardiovascular disease. It is likely to be less hazardous than smoking during pregnancy.4
Nicotine can freely cross the placenta.12 Clinical studies have reported that nicotine concentrations in the placenta, amniotic fluid and foetal serum were consistently higher than maternal serum values when measured at various stages throughout pregnancy.12
The majority of epidemiological studies do not suggest that exposure to nicotine or cigarette smoking during pregnancy is associated with an increased risk of congenital abnormalities. There is, however, good evidence that nicotine impairs foetal growth and can lead to an increased risk of spontaneous abortion and premature delivery. A likely cause of the foetal growth retardation is induction of foetal ischaemia and hypoxia as a result of the effect of nicotine on the placental circulation. Animal studies have shown that nicotine increases uterine vascular resistance and reduces uterine blood flow, possibly by an action on catecholamine release.13 Smoking acutely and chronically reduces placental blood flow in pregnant women, presumably through an effect of nicotine.
Nicotine can also inhibit the production of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation, in arteries.14
Pregnant women who smoke are often highly motivated to quit, especially during early pregnancy, but many continue to smoke. In 1999, a Health Education Authority survey found that only 10 per cent of women who were smoking immediately prior to pregnancy stopped, and 4 per cent cut down. During pregnancy an additional 20 per cent quit and 33 per cent cut down, but of the 30 per cent who had quit, 19 per cent had relapsed while pregnant.4
The recent Cochrane review on the effectiveness of interventions to help people stop smoking found that both individual counselling and group therapy increased the chances of quitting, although neither was more effective than the other.3 Such interventions are often sufficient to ease the withdrawal process and should be routinely offered to pregnant smokers and could reasonably form part of antenatal teaching for this group.
Nicotine replacement therapies have been shown to increase the chances of quitting about one and a half to two times.3 This increase is on top of that offered by other interventions, such as behavioural support. All trials of nicotine replacement have included at least brief advice, and should NRT be considered during pregnancy, this is the minimum that should be offered.
Amfebutamone (bupropion) and nortriptyline have also been shown to aid smoking cessation in a small number of clinical trials3 but no published information is available regarding their efficacy or safety during pregnancy.
In the first instance, pregnant women who smoke should be advised of the adverse outcomes associated with smoking during pregnancy and offered counselling and supportive behavioural therapies in order to help them to stop.
Other than the sublingual tablets (Nicorette Microtabs), nicotine replacement therapies are contraindicated for use during pregnancy; therefore, it is not possible routinely to recommend their use during pregnancy because of the lack of safety data.
However, should supportive measures fail, then nicotine replacement therapies could be reasonably considered in addition to continuing support, providing the foetal nicotine exposure can be kept at a level lower than there would have been had the mother continued to smoke.
Cigarette smokers systemically absorb about 1mg of nicotine and 10 to 15mg of carbon monoxide from each cigarette. Thus, a pack per day smoker on average consumes 20mg of nicotine and 200 to 300mg of carbon monoxide.15
A full account from the patient regarding her individual smoking habits is required to assess the most appropriate level of nicotine replacement. A nicotine dose below that which she would have consumed were she still smoking should be chosen, and the most suitable mode of delivery.
There are few published data regarding the use of nicotine replacement therapy in human pregnancy. In one study of smoking women, the application of a transdermal nicotine patch (21mg for 6h) did not result in any adverse foetal outcomes.16 In another pilot study, six out of seven smoking pregnant women who were using a transdermal nicotine patch over the course of one week had lower serum and salivary cotinine (nicotine metabolite) levels than their smoking counterparts.17 These patches released nicotine over a 16h period, allowing for an 8h exposure-free period that mimics the period of sleep. Thus foetal exposure to nicotine or cotinine overnight would not be greater than that seen in smokers.
Another study has shown that nicotine kinetics were similar in women whether they smoked or used transdermal nicotine patches.18
A case of spontaneous abortion during therapy with the Nicorette patch has been reported to the manufacturer.19
All forms of NRT have been shown to be effective, and there is no conclusive data to suggest that one form may be more effective than another.3 Mothers should be made aware that these therapies are not harmless to their infants, and thus should be used as for as short a time as possible in order to aid their withdrawal.
The lack of safety data regarding any of the modes of nicotine replacement therapy during pregnancy makes it difficult to recommend a regimen of choice and individual preferences should be discussed. However, the transdermal patches deliver a continual dose of nicotine to which the foetus would also be continually exposed, and for this reason their use should be discouraged where possible. The use of sublingual tablets, inhalators, spray and gum should all be at the lowest possible effective dose and as infrequently as the mother's cravings allow.
In view of the lack of safety information, and the medicolegal implications with prescribing a drug known to have harmful effects on the developing baby, it is essential that the clinician receives a full, written consent from the patient should nicotine treatment be considered appropriate. The patient should be fully informed of the risks and benefits of the treatment prior to the decision to prescribe. If the patient wishes to go ahead with nicotine replacement therapy then it should be documented that she has fully understood all the information given, and is willing to comply with the treatment regimen prescribed.
Nicotine chewing gum Nicotine enters the bloodstream via the buccal mucosa with a plateau blood nicotine level reached after around 30 minutes.
The gum offers the advantage that the foetus is not continually exposed to nicotine and the mother can adjust her requirements to fit her cravings. Only about 0.9mg from one piece of 2mg gum and 1.2mg from one piece of 4mg gum reaches the systemic circulation.4
Nicotine inhalator As with the gum, nicotine is absorbed buccally via the inhalator delivery system. About 20 puffs on the inhalator are equivalent to one puff of a cigarette, frequent puffing for about 20 minutes delivers 1mg nicotine.4 The inhalator thus offers another method of delivering low doses of nicotine at intervals to fit the mother's individual cravings, and avoids continuous foetal exposure.
Nicotine sublingual tablets The only preparation not entirely contraindicated in pregnancy, nicotine sublingual tablets are held under the tongue for 20 to 30 minutes as they dissolve and deliver a nicotine dose of 2mg via the buccal route. Systemic availability is approximately 50 per cent due to extensive first-pass metabolism.20 These tablets have the same advantages as the gum and inhalator, in that they allow maternal control of the cravings while avoiding long term foetal exposure.
Nicotine nasal spray The nasal spray mode of nicotine delivery provides the most rapid nicotine absorption. The plateau is reached in about 10 minutes. Each single spray delivers about 0.5mg nicotine via the nasal mucosa. The nasal spray appears to have a higher incidence of side effects than other NRT methods and may be best avoided for this reason.4
Nicotine transdermal patches Patches should be avoided unless all other treatments are unacceptable due to the continued nicotine delivery that they provide. The use of 16h patches, rather than the 24h varieties allows the foetus an 8h "break ", mimicking the overnight sleep of smoking mothers should this method be preferred.
Less nicotine is transferred to the infant during breastfeeding than occurs during pregnancy, the amount of exposure being similar to that of passive smoking.21
Amfebutamone (bupropion) and nortriptyline Although effective in a small number of clinical trials for smoking cessation, the use of amfebutamone and nortriptyline treatments during pregnancy cannot be recommended. Too little data exist regarding their use during pregnancy and the potential effects of these drugs on the developing foetus to be able to justify their use for smoking cessation in this group of patients. Nortriptyline has not been associated with an increased risk of malformations when used in the treatment of depressive illness in pregnancy;22 however, antidepressant medicines used chronically during pregnancy can, like all centrally acting drugs, lead to the development of neonatal withdrawal symptoms in the neonate.
Clonidine Clonidine has also been shown to have some benefits in aiding smoking cessation. However, the recent Cochrane review has highlighted the high incidence of side effects, including postural hypotension, associated with its use.3 For this reason, clonidine should not be used to aid nicotine withdrawal in pregnant patients.
Lobeline Lobeline is a partial nicotine agonist derived from the leaves of an Indian tobacco plant. It has not been shown to be effective in aiding smoking cessation, therefore its use cannot be justified during pregnancy.
Mecylamine No reports of the reproductive toxicity of the nicotine antagonist mecyclamine were located. Thus, its use cannot be recommended for use in pregnant patients.
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The authors are from the National Teratology Information Service (NTIS), Wolfson Unit, Claremont Place, Newcastle upon Tyne NE2 4HH. Correspondence to Dr McElhatton