Maternal Smoking and Conduct Disorder in the Offspring
Authors: Theodore A. Slotkin
Journal: JAMA Psychiatry (2013)

Although there iswidespread consensus thatmaternal smoking during pregnancy has adverse, long-term effects on neurobehavioral development in the offspring, it has been surprisingly difficult to prove that there are specific behavioral problems that can be incontrovertibly attributed to prenatal tobacco smoke exposure. It is now 16 years since a relationship was first postulated between maternal smoking and conduct disorder in the offspring,1 and in the intervening years, there havebeennumerous studies in support of acausal relationship, aswell as studies claiming thatother confounds obscure any role of tobacco. The article by Gaysina et al2 resolves this issue once and for all by examining the connection in 3 distinct, longitudinally followed up cohorts, incorporatingnotonly thestandardbatteryof covariables insuch studies, but also involving genetically related and unrelated families with children raised by biological or adoptive parents. Therefore, theirmeta-analysis controls for perinatal and postnatalconfounds includingdifferences inchild-rearingpractices or thehomeenvironment. Thus, the conclusion is incontrovertible: prenatal tobacco smoke exposure contributes significantly to subsequent conduct disorder in the offspring. Considering the relationship of conduct problems to poor school performance, social isolation, and juvenile and adult incarceration, the negative impact on the affected individuals’ quality of life and, ultimately, on society as whole, cannot be underestimated. The definitive findings of this study come after 30 years of basic and clinical research on the adverse effects of tobaccoon thedeveloping fetus.Upuntil themid-1980s, the entire focus had been on growth retardation, preterm delivery, and the impact on perinatalmorbidity andmortality. Indeed, the surgeon general’s cigarette-pack warnings about pregnancy, implemented in 1985, say that tobacco use can “complicate pregnancy” and can cause “fetal injury,” but the latter is specificallypresented in relation to“prematurebirthand low birthweight.”Twobreakthroughs, one technical andoneheuristic, repositioned animal studies to focus instead on longterm neurobehavioral damage. The first was the development of the implantable, osmotic minipump, which enabled researchers to deliver nicotine to animals on a continuous basis so as tomaintainplasma levels in the range found in smokers, devoid of the confounds of repeated stress from injections, and the peaks and valleys of nicotine levels because of the faster metabolism of nicotine in rodents.3 With injection models, each dose of nicotine produced an acute episode of hypoxia/ischemia, followed by withdrawal stress in between doses. Continuous infusion models eliminated all these confounds and allowed research to focus on the biological activity of nicotine in the developing brain. The second breakthrough was the recognition that brain assembly is regulated in largemeasure by neurotransmitters, which in the developing brain act as morphogens,4 a function that evolved from the role of these same smallmolecules in embryogenesis of lower organisms.5 Because neurotransmitter receptors, includingnicotiniccholinergic receptors,arise early in embryonicdevelopment, agents suchasnicotinehave enormouspotential todisrupt thecomplexprocessofbrainassembly. The trophic role of neurotransmitters in normal brain development involvesa careful coordinationof cell-to-cell signals,whichhave tooccur ina specified sequence,with thecorrect intensityandspatial distribution.Withexposureof thedeveloping brain to nicotine, the same receptors are stimulated continuouslyandat a constant intensity,without regard toany temporal or spatial requirements. An analogy is that you are trying to play a piano piece where each key has to be played in coordination with other keys at a specific volume and in a designated sequence; nicotine exposure is like someone coming along and depressing an entire series of keys with a piece of wood, preempting your playing of the necessary and appropriate notes. Consequent to theseadvances, animal studiesduringa20year period detailed the critical prenatal period and developmental processes bywhichnicotine leads toneuronal cell loss and miswiring of brain circuits.6 Early on, the effects of prenatal nicotine exposure onbrainmorphology appear to be appalling, and itmay seem surprising that, later on, the damage is evident only at thequantitative,microscopic level, and that brain structures appear grossly normal; these types of defects areunlikely tobedetectable at the level of standardmagnetic resonance imaging. In part, this is a tribute to the enormous plasticity of the fetal brain, which can generate new neurons to replace lost ones. However, there is a more sinister reason:maternal smoking evokes a large increase in spontaneous abortion during the first trimester, so that the most affected fetuses are never carried to term.7Whenwe observe adverse neurobehavioral effects in the offspring, we are thus seeing a reduced impact because of a survivor effect. Accordingly, at the basic science level, there is little doubt that at least one componentof tobacco smoke,nicotine, is sufficient to disrupt brain development and to evoke subsequentbehavioralabnormalities.Theproblemhasbeentotranslate theeffects inanimals toparallel effects inhumans.Animal studies involve populations that are as genetically uniformas possible and the experimenter has control over any environmental factors thatmay interact with the toxicant. Thus, animal models are inherently more sensitive in detecting toxiRelated article page 956 Opinion