Address correspondeUniversity, Schoolblood002@mc.duke

Journal of Midwifery

� 2010 by the AmericIssued by Elsevier Inc.

The Long-Term Effects of Prenatal Nicotine Exposure onNeurologic DevelopmentJane Blood-Siegfried, RN, CPNP, DNSc, and Elizabeth K. Rende, RN, CPNP, MSN

A large body of documented evidence has found that smoking during pregnancy is harmful to both the motherand the fetus. Prenatal exposure to nicotine in various forms alters neurologic development in experimentalanimals and may increase the risk for neurologic conditions in humans. There is a positive association betweenmaternal smoking and sudden infant death syndrome (SIDS); however, the connection between nicotine addic-tion, depression, attention disorders, and learning and behavior problems in humans is not straightforward. Nic-otine’s action on the production and function of neurotransmitters makes it a prime suspect in the pathology ofthese diseases. Nicotine accentuates neurotransmitter function in adults but desensitizes these functions in pre-natally 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 neu-rotransmitter problems while they increase the risk for nicotine addiction. Although nicotine replacement drugsare used by pregnant women, there is no clear indication that they improve outcomes during pregnancy, andthey may add to the damage that occurs to the developing neurologic system in the fetus. Understanding theeffects of nicotine exposure is important in providing safe care for pregnant women, children, and familiesand for developing appropriate smoking cessation programs during pregnancy. J Midwifery Womens Health2010;55:143–152 � 2010 by the American College of Nurse-Midwives.

keywords: attention-deficit hyperactivity disorder, fetal development, nicotine, pregnancy, sudden infantdeath syndrome, smoking

INTRODUCTION

Exposure to cigarette smoking is one of the most modifi-able causes of morbidity and mortality for both a pregnantwoman and her fetus. Damage from maternal smoking hasa direct adverse effect on placental development, which re-sults in a decreased transfer of nutrients and oxygen to thefetus and can result in premature birth, fetal growth restric-tion, and smaller head size.1 Exposure to cigarette smokeduring gestation has also been associated with problemsbeyond the perinatal period that can last well into adult-hood.2,3

Cigarette smoke is made up of more than 4000 com-pounds.4 Nicotine, carbon monoxide, and aldehydes areall likely candidates for causing perinatal damage. In thedeveloping fetus, nicotine crosses both the placental andthe blood–brain barriers, and is found in the fetal compart-ment in a concentration 15% higher than in maternal tis-sues.5 Smoking during pregnancy accounts for as manyas 161,000 perinatal deaths and 4800 infant deaths in theUnited States each year, with more than half of these clas-sified as sudden infant death syndrome (SIDS).3 Maternalsmoking is currently the leading risk factor for SIDS. Al-though paternal smoking and exposure to other forms ofenvironmental tobacco smoke (ETS) have been shownto increase SIDS risk, the risk is highest when the mothersmokes during pregnancy.6

nce to Jane Blood-Siegfried, RN, CPNP, DNSc, Dukeof Nursing, Box 3322, Durham, NC 27710. E-mail:.edu

& Women’s Health � www.jmwh.org

an College of Nurse-Midwives

Much of the current research on the pathophysiology ofnicotine exposure has been performed in animal models.Research in humans has focused primarily on epidemio-logic study of human behaviors. The biggest issue inhuman studies of nicotine exposure is defining and accu-rately assessing maternal smoking status. Both self-reportand past recall of smoking status during pregnancy intro-duces a significant concern of an underreporting bias.The better-designed studies use biologic measures ofsmoking, which may increase reliability but are still sub-ject to underreporting. When pregnant women know inadvance that they will be tested for cotinine (a nicotinemetabolite), they can alter their smoking habits, which inturn changes their blood cotinine levels. Cotinine hasa half-life of 17 to 21 hours in nonpregnant women7 butonly 9 hours in pregnant women between 16 and 40weeks’ gestation.8 Changes in smoking behavior beforecotinine sampling can therefore alter test results.9 Thisalone may explain discrepancies across studies in thereported incidence of maternal smoking, which hasyielded estimates varying from 7%9 to 33%,10 with mostcommonly reported values ranging between 22% and27%, subject to variation by socioeconomic group andmaternal age.11,12

This article reviews animal and human research associ-ated with the effect of nicotine on the developing nervoussystem and the implications for clinical practice. We willfocus on data examining the role of prenatal nicotine expo-sure as a contributing factor to subtle long-term effects onneurodevelopment, learning disorders, attention deficits,addiction, and behavioral changes. Although these out-comes are difficult to attribute to maternal smoking, theaction of nicotine on the production and function of

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1526-9523/10/$36.00 � doi:10.1016/j.jmwh.2009.05.006

neurotransmitters makes it a prime suspect as the underly-ing pathology that contributes to the development of thesedisorders. Other tobacco-related risks for children, includ-ing the irritant effect of ETS and associated increase inchronic otitis media, asthma, and respiratory infections,13

are beyond the scope of this article.

Figure 1. Cerebral cortex and areas of the outer brain. (Reprinted with per-mission from Kailasanath and Fu18).

THE EFFECTS OF NICOTINE ON THE ADULT

Nicotine accentuates neurotransmitter function in adultsbut desensitizes neurotransmitter actions in prenatally ex-posed infants and children. In adults, nicotine directly af-fects the central nervous system (CNS) by stimulating thesympathetic nervous system to release epinephrine fromthe adrenal cortex. This is accomplished through its ago-nist action on the nicotinic acetylcholine receptor(nAChR), resulting in an increase in both blood pressureand heart rate.14 Small, frequent doses of nicotine producealertness and arousal, whereas sustained exposure hasa sedative action, reduces anxiety, and induces euphoria.14

At commonly used doses, nicotine enhances intellectualperformance, decreases depression and anxiety, and acti-vates the dopamine reward system, which is important inthe pathology of nicotine addiction.15–17

THE EFFECTS OF PRENATAL NICOTINE EXPOSURE ON NERVOUSSYSTEM DEVELOPMENT

Central Nervous System Development

In order to understand the effects of cigarette smoking dur-ing pregnancy, it is necessary to describe the processes bywhich the CNS develops and how nicotine exposure canchange that development. During the first and second tri-mesters of pregnancy, neurologic development progressesfrom the spinal cord outward to the brain stem, midbrain,and cerebral cortex. The cerebral cortex is a layer of graymatter that covers the cerebral hemispheres of the frontal,temporal, parietal, and occipital lobes of the brain and isresponsible for voluntary muscle activity, learning, lan-guage, and memory (Figure 1).18 The higher functionsof the brain involving the hypothalamus and associatedstructures of the precortical areas (areas under the cortex),the limbic system, and cerebellar function continue to de-velop during the first few years of postneonatal life in thehuman infant, and during the first 2 weeks of life in the lab-oratory rodent (Figure 2).19 The effect of a neurotoxinsuch as nicotine depends on both the dose and timing ofexposure. Obviously, chronic exposure throughout preg-nancy will affect many different functions in the develop-

Jane Blood-Siegfried, RN, CPNP, DNSc, is an associate clinical professor inthe School of Nursing at Duke University in Durham, NC.

Elizabeth K. Rende, RN, CPNP, MSN, is a pediatric nurse practitioner in theDepartment of Pediatric Neurology at Duke University in Durham, NC, andan instructor for the University of Phoenix.

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ing brain, whereas exposure that is limited to a specifictime of pregnancy may only affect the specific functionsdeveloping during that precise interval.1

Prenatal Nicotine Exposure and Nervous System Development

It has been determined from animal studies thatthe nAChR is functional early in fetal development, bythe time the neural tube is being formed.20 From the stand-point of nervous system development, the most importantphysiologic characteristic of nicotine is its ability to stim-ulate the nAChR and trigger neurodevelopmental eventsthat are normally ascribed to the action of acetylcho-line.21–24 In animal models, it has been shown that acetyl-choline has a very active role in brain development and is

Figure 2. Interior structures of the brain affected by perinatal nicotine ex-posure. (Reprinted with permission from Kailasanath and Fu18).

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responsible for the proliferation, maturation, and differen-tiation of multiple types of brain cells.25,26

Nicotine exposure changes the intensity and timing ofbrain cell development and the programming of neurode-velopmental events on a cellular level. When the timing ofthese events is perturbed, it alters the orderly processes bywhich neurons are replicated and differentiate into func-tional neuronal cells.27 These processes include the initia-tion of axons and dendrites, migration of nerve cells,synapse function, and localization of specific nerve cellpopulations. Later in development, exposure to nicotinechanges higher sensory, memory, and motor functionsthrough its effects on hippocampal, cerebellar, and sensorycortex development.28

EFFECTS OF PRENATAL NICOTINE EXPOSURE ON AUTONOMICNERVOUS SYSTEM FUNCTION

Effects on Autonomic Nervous System Function in Animals

In animal studies, prenatal nicotine exposure alters bothcentral and peripheral autonomic tone, which is impor-tant in the regulation of protective cardiac and respiratoryfunctions in the neonate.24,29,30 Neonatal rat pups ex-posed to nicotine during gestation lose their ability tomount a protective response to a hypoxic challenge.This lack of hypoxia tolerance is assumed to be relatedto nicotine-induced reduction in the ability of the adrenalmedulla to secrete adequate levels of epinephrine andnorepinephrine.30 These catecholamines are responsiblefor heart rate, cardiorespiratory functions of arousal,breathing, apnea response, heart rate variability, and au-toresuscitation.31

In addition to reducing the levels of epinephrine andnorepinephrine, prenatal nicotine exposure delays the de-velopment of beta receptors in the heart that are importantfor increasing heart rate responsiveness to hypoxia andother cardiovascular challenges. Nicotine-exposed ratpups have decreased binding of norepinephrine and epi-nephrine to the cardiac beta receptor; therefore, they donot respond with a protective tachycardia when exposedto 5% oxygen for 10 minutes.32 These animals respondwith an immediate and rapid decrease in heart rate. Thiseffect is related to an increase in inhibitory cardiac M2-muscarinic cholinergic receptors and a down-regulationof the stimulatory beta-adrenergic receptor. Both factorseffectively down-regulate the protective sympatheticresponse to hypoxia.32

Prenatal nicotine exposure appears to change autonomicresponses by decreasing the production of epinephrine andnorepinephrine in the adrenal medulla, and by down-reg-ulating receptor function in the heart. In rats, this alterationin autonomic response persists into adulthood, with de-creased levels of norepinephrine in the brain and an inabil-ity of acute cholinergic stimulation to evoke a normal adultnorepinephrine response.33

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Effects on Autonomic Nervous System Function in Humans

As in animal models, human infants exposed prenatally tonicotine have lower epinephrine and norepinephrine levelsin cord blood at birth when compared to the blood levels ofthese catecholamines in unexposed infants.34 Epinephrineand norepinephrine play a critical role in autonomic re-sponses. Concerns about imbalance in autonomic toneare well documented in the SIDS literature, because thisimbalance may decrease the infant’s ability to respond tocardiovascular and respiratory challenges, resulting indeath.35 Although SIDS is likely to have many causes, in-fants of mothers who smoke have a two- to four-fold in-creased vulnerability compared to unexposed infants.6,36

EFFECTS OF PRENATAL NICOTINE EXPOSURE ONNEUROTRANSMITTERS

Neurotransmitters are chemicals that are critical for brainfunction. Table 1 describes the normal role of neurotrans-mitters and the changes found in animal models followingprenatal nicotine exposure. These changes adversely affectearly fetal development of the synapse between nerve cellswhere these neurotransmitters function. The serotonin sys-tems and the action of other monoamines (e.g., dopamineand norepinephrine) are altered, which results in someneuronal damage, cell death, and the suppression of bothpresynaptic and postsynaptic elements required for neuro-transmission.37

Prenatal Nicotine Exposure and Serotonin in Animals

Serotonin is important for the regulation of mood and de-pression; however, in the brain stem, it also regulates heartrate, respiration, and arousal from sleep.39,43 Fetal nicotineexposure in rats alters the ability of the serotonin transporterto function effectively. This transmembrane protein trans-ports serotonin from the neural synapse back into the pre-synaptic neuron where it can again be recycled for release.Prenatal nicotine exposure affects this transporter systemand results in a significant reduction of serotonin turnoverin many areas of the brain, including vital areas of the brain-stem.37,47 Decreased serotonin turnover ultimately results ina lower level of serotonin in the neural synapse, similar tothe mechanism thought to occur in depression.45

Prenatal Nicotine Exposure and Serotonin in Infants

In human infants, serotonin defects have been best studiedas they relate to SIDS. On autopsy, SIDS infants have a sig-nificantly higher number of serotonin-producing neuronsbut a lower density of serotonin receptor binding sites inregions of the medulla that control some homeostatic func-tions. This pathology in serotonin function in SIDS isfairly extensive within the CNS and includes abnormalneuronal synthesis, release, and clearance of serotonin.35

The damage in the serotonergic system found in some

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Table 1. Neurotransmitters Influenced by Nicotine Exposure During Development

Neurotransmitter Location Function Effect of Prenatal Nicotine Exposure

Acetylcholine Neuromuscular junction of skeletalmuscle, autonomic nerve synapses,CNS, and spinal cord

Important for normal development of thenervous system25

Nicotine is a direct stimulant of thenAChR. Its action on the receptorduring brain development alters theproliferation, maturation, anddifferentiation of brain cells.25,26

Serotonin CNS, spinal cord, and GI tract Regulation of mood and depression38;regulates heart rate, respiration, andarousal from sleep in brain stem39

Causes a significant reduction inserotonin turnover in many areas of thebrain, including vital areas of thebrainstem.37 Decreased serotoninfunction will increase the risk ofdepression and SIDS.39

CatecholaminesEpinephrine Produced in the adrenal medulla and

sympathetic nerve terminals38Diverse effects, but primarily involved in

autonomic responses of ‘‘fight orflight’’; increases blood pressure,pulse, and respiration38

Infants of women who smoke have lowerepinephrine levels in cord blood at birththan infants of mothers who do notsmoke.34 This can change theregulation of autonomic responses.

Norepinephrine Most postganglionic sympathetic fibers,spinal cord, and the adrenal medulla38

Same as epinephrine, plus norepinephrineis involved in the pathophysiology ofinattention and distractibility40,41

Infants of women who smoke have lowernorepinephrine levels in cord blood atbirth than infants of mothers who donot smoke.34 This is important forautonomic function and ADHD.

Dopamine Adrenal medulla, CNS, and autonomicnervous system synapses38

Regulating blood pressure and prolactinrelease; suppressing inappropriatebehavioral impulses39,41; dopamine isimportant in addiction

In animals, prenatal nicotine exposurehas been shown to lower the levels atthe receptor site. This could beimportant for symptoms in ADHD andaddiction.42

ADHD = attention-deficit hyperactivity disorder; CNS = central nervous system; GI = gastrointestinal; nAChR = nicotinic acetylcholine receptor; SIDS = sudden infant deathsyndrome.

SIDS infants is hypothesized to be directly related to ma-ternal smoking, which could support a possible biologicbasis for the association between maternal smoking and in-creased risk of SIDS.3 However, quantifying the relation-ship of dose to outcome for such a pathway is verydifficult.39 Not all SIDS infants have a history of in uteronicotine exposure, and other environmental insults anddifferences in genetic vulnerability are also likely to con-tribute to risk.

Prenatal Nicotine Exposure and Animal Data Support a Role inAttention-Deficit Hyperactivity Disorder

Both norepinephrine and dopamine have been linked tothe etiology of attention-deficit hyperactivity disorder(ADHD).46 They appear to be important in the ability ofthe brain to accept or repress the normal stimulation ofdaily living.39–41 Optimal brain performance requiresa balance between stimulation and suppression of stimulithat varies by function, timing, and need. In animal stud-ies, nicotine exposure during pregnancy reduces levelsof norepinephrine and dopamine in the areas of the brainthat may be important in controlling activity and impulsivebehaviors.37,44 Prenatal nicotine exposure in rat pups sig-nificantly increases hyperactive behavior; however, moresophisticated studies of hyperactivity and learning prob-lems are difficult to perform in an animal model.47

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Prenatal Nicotine Exposure and Human Data to Support a Rolein Attention-Deficit Hyperactivity Disorder

In studies of children with ADHD, the aberrant focus ap-pears to be in subcortical pathways of the brain that arenormally rich in dopamine and norepinephrine.46 Thefrontal cortex is important in regulating impulse control,executive functions, and the modulation of reward path-ways. Affected children have a wide range of symptomsinvolving some degree of inability to ignore the environ-ment and suppress input.46

A systematic analysis of 24 studies of children whowere prenatally exposed to substances of abuse found anincreased risk for ADHD-related disorders among chil-dren whose mothers smoked during pregnancy.2 Childrenwith a specific polymorphism (genetic variation) in the do-pamine transporter and exposure to maternal smokinghave a significantly higher incidence of hyperactivity im-pulsivity than children without this combination of envi-ronmental and genetic risk.40 These studies provideevidence of an association and a glimpse into the complexinteraction of factors involved in risks associated with ma-ternal smoking.

Medications that increase the activity of dopamine andnorepinephrine in the neural synapse reduce ADHD symp-toms by blocking the reuptake of these neurotransmit-ters.46 Nicotine treatment and cigarette smoking can also

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decrease the symptoms of ADHD and other psychiatricdisorders, which may explain the prevalence of nicotineself-medication in adolescents and adults with ADHD ordepression.48–50 Deficiencies in content and turnover ofthese two neurotransmitters were found in the midbrainin adolescent rats that were prenatally exposed to nico-tine.42 The midbrain is an area of the brain that is mostclosely associated with addiction.

Addiction

Although smoking addiction has been blamed on the so-cial influences of familial smoking and peers, the currentthinking is that there is also a biologic basis for these be-haviors.51,52 There is a high correlation between smokingbehavior and symptoms of depression, inattention, and hy-peractivity in both adolescents and adults.51,52 Thesesymptoms are often intensified during nicotine depriva-tion.50,53,54 Nicotine use in adolescents and adults appearsto partially correct for the symptoms caused by chronicnicotine exposure to the fetus.

As indicated earlier, animal studies of prenatal nicotineexposure have found that the function of several neuro-transmitters are decreased at birth.55–59 This decreasedfunction resolves somewhat in the first few months oflife only to recur during adolescence.55,59 When adoles-cent rats are given the opportunity, those exposed prena-tally to nicotine will self-administer larger amounts thannonexposed rats, with the effect being more pronouncedin female rats.56–59 If a comparable pattern occurs in hu-mans, it could explain both the increase in smoking prev-alence in adolescents at risk for depression and ADHD andthe increased risk that these adolescents will develop nic-otine addiction.60

BEHAVIOR, LEARNING, AND SENSORY DEVELOPMENT

The hippocampus is an important area of the brain respon-sible for short-term memory and sequential learning, aswell as a part of the limbic system that has been associatedwith pathology in ADHD. The cerebellum plays a role inthe integration of sensory input and coordination of motorcontrol.38 Damage to these two areas of the brain canchange how a person perceives and responds to his/herenvironment. Such damage can also alter the developingsensory cortex, inducing changes in visual, somatosen-sory, and auditory function.61,62 Changes in the hippocam-pus are likely to affect memory, behavior, and both motorand cognitive functioning.63

Prenatal Nicotine Exposure, Hippocampal, and CerebellarDamage in Animals

In rats, neonatal nicotine exposure during the developmentof the hippocampus and cerebellum induces changes re-lated to increased motor activity as the rats mature.47

Chronic neonatal nicotine exposure causes cell death and

Journal of Midwifery & Women’s Health � www.jmwh.org

changes in cell morphology in the hippocampus and cere-bellum, damage that lasts well into adulthood.28,64 Theseareas are important in learning and the integration ofhigher functions of mental capacity. Damage to thesestructures in animals from prenatal nicotine exposurecould indicate damage to these same higher functions inhumans.

Prenatal Nicotine Exposure, Hippocampal, and CerebellarDamage in Humans

Because the hippocampus develops near the end of preg-nancy and postnatally in the first few years of life, damagefrom environmental exposures, including maternal smok-ing, may also continue after birth.19 Some exposed adoles-cents have been shown to have an increased incidence ofauditory-cognitive deficits that cause problems with un-derstanding speech and verbally presented information,particularly in noisy settings. They may be unable to telldifferences between similar sounds, although their hearingis not impaired. Auditory processing problems are mostprominent in males; females demonstrate both auditoryand visual cognitive impairments.65

There is compelling evidence that the children ofwomen who smoke may be more likely to develop cogni-tive and learning deficits in addition to ADHD, impairedattention and orientation, and poor impulse control66;however, the literature is mixed with studies that also as-cribe these changes to the detrimental effects of impairedsocial and environmental factors.67 The role of prenataland neonatal nicotine exposure in causing neurodevelop-mental damage is subtle and highly likely to be associatedwith other complex risk factors. At this time, there is a greatdeal known about the effect of prenatal nicotine exposurein animals, and somewhat less about the effect of prenatalnicotine exposure in humans. However, there are somewell-documented associations, and there is evidence thatprenatal nicotine exposure affects physiologic functionand may be an etiologic factor in the pathology of severalbrain disorders.

CHALLENGES OF SMOKING CESSATION PROGRAMS

Reducing tobacco use by pregnant women is a publichealth priority because of nicotine’s contribution to poorpregnancy outcomes.68 Smoking cessation during preg-nancy can counteract some of the risks to the fetus, butsuccessful compliance with cessation protocols is chal-lenging and can often be as problematic as active smoking.The risk from prenatal nicotine exposure is additionally in-creased because women who smoke often live in socialsituations where smoking is common, thereby increasingtheir chronic exposure to environmental tobacco smoke,which can make quitting more difficult.

The standard prenatal practice of brief behavioral coun-seling at a prenatal visit produces only a modest rate of

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smoking cessation.68 In an attempt to increase efficacy,prenatal treatment has incorporated the use of smokingcessation medications such as bupropion or nicotine re-placement therapies (NRTs).68 In a sample of 296 women,only 29% reported that their obstetric provider discussedusing cessation medication during pregnancy, whereas46% reported being offered a nonpharmacologic cessationaid, booklets, or referral to a smoking cessation program.These practice patterns appear to be consistent with clini-cal guidelines that recommend considering medication forheavier smokers and for smokers who fail nonpharmaco-logic methods.68 When medications were discussed, nico-tine replacement was talked about more than twice as oftenas bupropion. Of the women offered a pharmacologictreatment, only 10% actually used medication during theirpregnancy.68

Pharmacologic Treatments for Smoking Cessation

Bupropion and varenicline are commonly used medica-tions for smoking cessation in the general adult popula-tion. There are no human data to support the use ofvarenicline during pregnancy; however, bupropion ap-pears to have no more side effects in the fetus than theselective serotonin reuptake inhibitor (SSRI) medicationsused for depression. The Bupropion Registry examined1597 pregnancies with exposure in one or more trimes-ters. The prevalence of malformations associated with1213 first-trimester exposures was 2.3%. Outside of thefirst trimester, the prevalence of malformations was2.2%.69 This report suggested that there is no increasein birth defects over the baseline 3% reported for theUnited States; however, the use of bupropion—as withany medications used during pregnancy—should be rec-ommended only if the potential for benefit outweighs thepotential unknown risk.70

NRTs in pregnancy have been studied more extensivelythan the pharmacologic therapies described above. How-ever, there are few large, randomized control studies,and the data on safety and efficacy are inconclusive. A re-cent study of NRT use during pregnancy was terminatedearly because of an increase in adverse events in the treat-ment group.71 The data safety monitoring board reportedthat these adverse events were likely not associated withNRT use, but they were potentially serious: preterm birth(<37 weeks’ gestation), low birth weight (<2500 g),preeclampsia, placental abruption, placental previa, neo-natal intensive care unit admission, fetal demise, and in-fant death.71 The assumption of the monitoring boardthat these events were likely unrelated to NRT use wasbased on the lower cotinine levels in women using NRTthan those found among women actively smoking, andon the higher proportion of women in the NRT arm havinga previous history of preterm birth.71 The numbers of par-ticipants included were relatively small, so further studyon the safety of NRT in pregnancy is indicated.71

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A similar study examining the use of NRT during preg-nancy found that the use of nicotine gum did not increasesmoking cessation rates but did increase birth weight andprolonged gestational age in the infants of mothers whosmoked.72 In contrast, another study concluded that therisks of low birth weight and preterm birth were highestin women using NRT.73 It must be kept in mind thatheavier smokers, who have the most difficulty with cessa-tion, are also more likely to use NRT, which can confoundcomparisons between these studies. In order to establisha significant connection between NRT during pregnancyand subtle outcomes, it will be important to have largernumbers of participants, longer follow-up periods, andgood information on potential confounding factors.

There has been some discussion that NRT may be lesshazardous than active smoking during pregnancy.74 Thisassumption raises several questions. A smoker’s dose ofnicotine is intermittent; however, when nicotine is admin-istered in the form of a patch, the dose is continuous, sothat the total dose of nicotine delivered to the fetus ishigher than the amount delivered by actual smoking. In an-imal studies using continuous delivery methods, levels ofnicotine in the fetal rat brain are about 2.5 times higherthan in the mother’s blood.75 Nicotine appears to accumu-late in the fetal compartment in higher concentrations thanin maternal tissues.5 This suggests that continuous nico-tine exposure could be more hazardous than intermittentsmoking, although there are no direct data to prove or dis-prove this assumption.

The author of Drugs in Pregnancy and Lactation recom-mends that counseling is the preferred treatment for smok-ing cessation during pregnancy and lactation.76 Bupropionappears to be the least toxic of the cessation drugs, is as ef-fective as NRT, and does not expose the fetus to nicotine.76

When NRT is used during pregnancy and lactation, inter-mittent dosing is most likely better than continuous use.Nicotine replacement therapies should probably beavoided in the first trimester and used with caution forthe remaining duration of pregnancy. Removal of the nic-otine patch at night will decrease the nicotine exposure tothe fetus. Gum, lozenges, or nasal spray also decrease theamount of nicotine exposure to the fetus; however, theyhave been associated with problems of decreased compli-ance because of poor taste and oropharyngeal irritation.76

Nonpharmacologic Treatments for Smoking Cessation

Nonpharmacologic treatments for pregnant women in-clude cognitive behavioral therapy (CBT), support groups,self-help aids, and hypnosis. Hypnosis is one of the morepopular nonpharmacologic aids, although its effectivenessis not well established.68 CBT is felt to be of some benefitduring pregnancy, but the literature is mixed regarding itseffectiveness. CBT should be considered as the first choicebecause it does not increase the risk of nicotine exposure tothe fetus and has been shown to have few side effects.

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Unfortunately, the greatest success in smoking cessationhas been obtained with a combination of both CBT andpharmacologic treatment.71

The Adolescent and Smoking Cessation During Pregnancy

Most importantly, an adolescent female who smokes oftenbecomes an adolescent mother who smokes. In the UnitedStates, 17% of pregnant adolescents between 15 and 19years of age smoke.77 The majority (60–80%) of these ad-olescents continue to smoke throughout their pregnancies.In many instances, smoking behaviors actually increase asthe pregnancy advances.78

The smoking cessation interventions used for adoles-cents are the same as for adults.78 Cognitive behavioralstrategies in adolescents directed at decreasing smokingbased on peer-enhanced concepts of social support andtherapeutic relationships, addressing goal setting, reeduca-tion, and urge control have been the most effective. How-ever, the use of peer-enhanced programming has not beenshown to sustain smoking cessation beyond the postpar-tum period.78 These results are similar to those seen instudies of adults, who also often return to smoking afterpregnancy.71 Additional factors that make dealing withthe adolescent particularly difficult are the issues of peerinfluence, cognitive development in regards to risk-takingbehavior, and testing of independence.78

For all age groups, further consideration should be di-rected toward pursuing smoking cessation in women be-fore pregnancy or immediately postpartum. Thesewomen are usually healthy and often receive regular med-ical care. A formal, aggressive approach to providing cog-nitive behavioral support and smoking cessationmedication could improve outcomes, by increasing theproportion of women who quit smoking before theybecome pregnant again.

SMOKING DURING LACTATION

Nicotine is excreted in breast milk, in a dose-dependentmanner, with breast milk levels 2.9 times higher than ma-ternal plasma.79 Nicotine has also been shown to lowerprolactin levels, which could decrease milk supply insome women and may account for the lower incidenceof breastfeeding among women who smoke.80 Giventhat women who smoke are less likely to intend to breast-feed,81 it cannot be assumed that the relationship betweensmoking and duration of breastfeeding is purely a physio-logic one. There is a wide variation in breastfeeding ratesamong mothers who smoke. Therefore, psychosocial fac-tors are likely to contribute to the lower rates of breastfeed-ing found in women who smoke.81

CONCLUSION

A large body of documented evidence shows that smokingduring pregnancy is harmful to both the mother and fetus.

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Controlled animal studies have confirmed some of themechanisms of pathology. In animals, prenatal exposureto nicotine has been shown to alter autonomic functioningand protective responses that could be involved in thepathophysiology of SIDS. Significant epidemiologic datain humans support the potentially devastating effects ofnicotine on fetal growth and development. In humans,there is evidence that prenatal nicotine exposure is associ-ated with subtle changes in learning and behavior prob-lems. Nicotine addiction is also increased in people whowere exposed to nicotine in utero.

Understanding the effects of nicotine exposure on neu-rologic development and the consequences for long-termoutcomes is the direct responsibility of providers caringfor pregnant women and children. Childhood and adoles-cent morbidity from cognitive difficulties, ADHD, con-duct disorders, behavioral problems, depression, andother smoking-related concerns are a significant publichealth issue.

The authors thank Elizabeth P. Flint, PhD, for her time and considerableeffort editing this manuscript.

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