Prenatal Exposure to Drugs: Effects on Brain Development and Implications for Policy and Education

PersPectives

for other relevant reviews), therefore we Science And Society have selected a few examples for which substantial data have been generated. We Prenatal exposure to drugs: highlight clinical findings in humans that parallel many of the findings in model sys tems. Finally, we discuss the complex social effects on brain development and and policy issues involved in providing appropriate support structures for children implications for policy and education exposed to drugs in utero to help improve their neurodevelopmental trajectory. Barbara L. Thompson, Pat Levitt and Gregg D. Stanwood Animal models of prenatal drug abuse Abstract | The effects of prenatal exposure to drugs on brain development are The utility of animal models for understand complex and are modulated by the timing, dose and route of drug exposure. It is ing typical and atypical human development difficult to assess these effects in clinical cohorts as these are beset with problems is well established. Animal models have such as multiple exposures and difficulties in documenting use patterns. This can enabled us to begin to elucidate the complex lead to misinterpretation of research findings by the general public, the media and neurodevelopmental consequences of prena tal drug exposure. Although basic behaviour policy makers, who may mistakenly assume that the legal status of a drug correlates and some aspects of global structure and with its biological impact on fetal brain development and long-term clinical functional neural activity can be studied in outcomes. It is important to close the gap between what science tells us about the humans exposed developmentally to drugs, impact of prenatal drug exposure on the fetus and the mother and what we do the specific neuroanatomical, molecular and programmatically with regard to at-risk populations. cellular consequences that underlie these behavioural changes are not accessible to study in vivo. Welldesigned animal models Chemical neurotransmitters serve important better policy and programme development can therefore be powerful tools for revealing functions in the coordination of the develop to reduce the population of children who the neurobiological alterations that underlie ment of neurons and brain circuits (BOX 1). are exposed to drugs prenatally. Much of later disrupted behaviour. Psychoactive drugs modulate receptors, the human data is being generated by the However, the challenges of developing transporters and other components of neuro National Children’s Study, which aims to appropriate animal models are substantial. transmission, many of which are expressed examine the effects of environmental influ For example, although the orderly assembly during prenatal stages of brain development, ences on the health and development of of the cellular elements that constitute the although here their expression patterns and 100,000 children across the United States. developing nervous system is highly con functions are sometimes quite different from However, logistical issues have made it diffi served across vertebrate species, the timing their more typical roles later in life. Thus, the cult to coordinate and retain the participation and duration of histogenic events and matu presence of these proteins in the developing of the mothers and children. ration of neurotransmitter systems can dif brain underlies the welldocumented impact In this article, we describe findings from fer substantially. Moreover, drug metabolic of prenatal drug exposure on brain architec relevant animal models that illuminate the pathways differ depending on the route of ture, chemistry and neurobehavioural func specific mechanisms by which drugs of exposure and across species; this therefore is tion in clinical cohorts and animal models. abuse, both illegal and legal, affect brain another important variable in recapitulating Many legal drugs, such as nicotine and development. It is not possible to adequately drug exposure patterns in humans. There alcohol, can produce more severe deficien review all drugs and animal models are several key experimental variables to be cies in brain development than some illicit owing to space limitations (see REFS 3–6 considered when designing an animal model drugs, such as cocaine. However, errone ous and biased interpretations of the sci entific literature often affect educational Box 1 | effects of neurotransmitters on brain development programmes and even legal proceedings. For example, a pregnant woman whose Studies beginning almost 50 years ago demonstrated that the capacity to synthesize and degrade neurotransmitters (particularly biogenic amines), many of the receptors through which they signal emergency room toxicology screen revealed and the circuits that utilize them emerge early in embryogenesis100,146,188–192. Because cocaine use was recently jailed and accused neurotransmitters appear well before synapses form, various roles in neurodevelopmental of using a deadly weapon against her unborn processes were postulated but not demonstrated. Modern in vitro approaches and genetic child in Tennessee, United States1. Such pol engineering of mice have facilitated discoveries that highlight the pleiotropic nature of icy decisions may have unintended adverse neurotransmitter signalling in neurodevelopmental processes. To give a few examples of such consequences: for example, they might harm non-synaptic functions, dopamine regulates progenitor cell cycle kinetics and dendritic the fetus through pathophysiological activa growth62,193, serotonin modulates cell proliferation and the response of growing axons to classic tion of the maternal stress response system2 guidance molecules149,194, GABA (γ-aminobutyric acid) activates the migration of developing 195 196 and they might cause pregnant women neurons and glutamate regulates oligodendrocyte precursor survival . Key to these influences addicted to drugs to avoid prenatal medical is the expression, in transient developmental patterns, of subsets of receptors that mediate early neurotransmitter signalling for developmental purposes. This is followed by spatial and temporal (BOX 2) care . reorganization and by the expression of other subtypes that may be involved in modulating or The findings of research in humans and directly inducing synaptic transmission. animal models should be used to inform

Box 2 | criminal prosecution of pregnant women using drugs of abuse advancements in the field. Convergence is often found in translating across larger 16 A study in 1985 reporting damaging effects of cocaine use during pregnancy produced a massive behavioural dimensions, rather than in media response. Based on the media reports, laws were enacted in the United States requiring detailed features of the models. health-care professionals to report pregnant illicit drug users to child-welfare authorities, and Finally, patterns of administration of legislation was pursued to make drug use during pregnancy a criminal offence. The desire to guard fetal health and outcomes is understandable; however, research shows that pregnant women who different drugs vary. Some drugs (such as fear prosecution and the potential loss of their children as a result of using drugs of abuse are less cocaine) are typically used in discrete epi likely to seek essential prenatal and medical care. Thus, the policies that were meant to deter sodes, whereas others (such as nicotine and illegal drug use among pregnant women had unintended consequences, resulting in even greater alcohol) tend to be used chronically. This risk to the fetus197,198. Moreover, the threat of criminal punishment can foster fear and mistrust issue is likely to be important in determining between doctors and their patients, increase maternal stress and endanger the health of women the effects of developmental drug exposures. and their future children. Based on the science, one could argue that this is considerably worse Thus, the effects of various substances may than the drug exposure itself. be reflective of both their inherent neuro South Carolina in the United States has been particularly aggressive in using the court system in toxicity and the patterns with which they are an attempt to deter drug use during pregnancy. At least 90 women have been prosecuted for (ab)used. stillbirths after using drugs or alcohol. Between 1989 and 1994, a prominent hospital in Charleston adopted a policy of informing police of any positive test for cocaine in pregnant women. The patients were informed that an arrest would occur if they failed to successfully complete a drug effects of illegal drugs of abuse programme. If a positive test was obtained at delivery the woman would be immediately arrested Cocaine. Cocaine is a psychostimulant that and charged199. This policy was discontinued in 1994 because of pressures applied by the binds to monoaminergic transporters (with Department of Health and Human Services199 and was found to be constitutionally deficient in a preference for dopaminergic transport 2001 by the Supreme Court200. ers) and prevents the uptake of extracel In May 2008, the South Carolina Supreme Court overthrew the homicide by child abuse lular monoamines into the presynaptic cell. 201 conviction of one of these women, Regina McKnight . They ruled that Mrs McKnight had not This results in excess neurotransmitter in received a fair trial owing to ineffective counsel and the inclusion of unsupported scientific the synaptic cleft and excess stimulation of evidence201. It is not yet known whether she will be re-tried for the charge, but these events dopamine receptors. There are five known suggest that policy may be coming into better accordance with scientific data. dopamine receptors, which can be divided into two groups: D1like receptors (D1 and D5), and D2like receptors (D2, D3 and D4). of prenatal drug exposure: the age of the a situation that differs from that of humans The roles of dopamine and these receptors embryo during exposure, the species to be during late gestation. in reward pathways have been demonstrated used, the frequency and duration of expo Different species can provide distinct in both humans and animal models10,11. sure, the route of administration and the advantages depending on the specific Dopamine receptors are also located in the drug concentration. hypotheses to be tested. For example, if one prefrontal cortex, the hypothalamus, the The timeline for neurodevelopmental wishes to investigate the roles of certain brainstem and even outside the CNS12–15. milestones has been documented in humans genes in mediating the impact of prenatal The dopamine system develops early in and for most animals used as models7–9 drug exposure, genetically engineered mice gestation in all vertebrate species, and might (FIG. 1). Thus, designing animal models of may be most appropriate. This might be therefore be sensitive to exogenous manipu drug exposure during particular stages of weighed against the difficulties in admin lation early in gestation. In fact, some early fetal animal development that correlate istering drugs repeatedly to pregnant mice. reports suggested a severe phenotype in with the timing of exposure during human Selfadministration drug paradigms during children exposed to cocaine in utero16–18. pregnancy is realistic, at least to a first pregnancy may be more imitative of human Children were thought to be emotionally approximation. There are, however, further abuse than experimenteradministered para disrupted, cognitively impaired, less likely to complications when considering how to digms, and rats have been the primary model socially interact, and more likely to die from model human exposure. These include both species for this approach. on the other hand, sudden infant death syndrome. Thus, the nutritional issues and the use of two or more establishing selfadministration in rodents term ‘crack baby’ was introduced to describe drugs in combination. In addition, provid is sometimes problematic and requires other children exposed to cocaine prenatally. ing an environment in which the mother reinforcers to be superimposed on drug However, these original studies were con feels comfortable in disclosing the length of administration. Nonhuman primates most founded by very small sample sizes, use of exposure as well as the amounts and com closely model the temporal domains of multiple drugs, nutritional status and other binations of drugs used is crucial for deter human brain development and behaviour. psychosocial problems. mining clinical profiles and in subsequently However, it is logistically far more difficult We now know that, irrespective of spe using the data to establish accurate animal and expensive to use nonhuman primates cies, the extent to which prenatal exposure models. Furthermore, some processes that for research purposes, and as such this is to cocaine affects brain development var occur during the third trimester of in utero not the ideal approach for rapid mechanistic ies significantly. The assumptions made by development in humans occur postnatally discoveries. Many different models have the public about the biological impact of in rodents and thus might be missed by been used throughout the long history of prenatal cocaine exposure may be based on studies conducted during gestation only. animal model research, and comparison of the severity of symptoms associated with Also, rodent maternal and environmental fundamental discoveries across species has cocaine addiction, and the illegal nature inter actions with the offspring are cru been difficult. Cautious interpretation, in of the substance. In humans, longitudinal cial for their proper social and emotional which one attempts to identify convergent studies have shown that there are longterm development during this postnatal period, findings, is particularly necessary for further consequences of prenatal cocaine exposure;

Human Mouse Neurodevelopmental events Neurotransmitter system development

Cortical pattern established for NA, 5-HT, DA, CTX Synaptogenesis (local tuning) GABA and glutamate 34W–36M P2–P21

Aff Biochemical differentiation

CP Establishment of topography 24–28W E18–P7

Aff Cell death

CP Aggregation Innervation by GABAergic interneurons and 22–34W E16–P0 glutamatergic projection neurons SP Appearance of transient projections

8–15W E16–P0 Aff Aggregation Innervation by VTA, LC and raphe neurons

MZ Migration Generation and migration of GE interneurons and pallium projection neurons 5W E11–17 Proliferation Generation of LC, VTA and raphe neurons PZ Cell death

Figure 1 | Developmental events and ontogeny of drug targets. The peak transporters and so on) are depicted along this same timeline. 5-HT, 5-hydroxy- periods of key neurodevelopmental events are depicted. Reference to the tryptamine (serotonin); Aff, afferents; CP, corticalNature plate;Reviews CTX, | Neur cortex;oscienc DA,e timing of neurotransmitter system development includes the appearance of dopamine; E, embryonic day; GABA, γ-aminobutyric acid; GE, ganglionic receptors, transporters and synthetic machinery. Note that some of these eminence; LC, locus coeruleus; M, months; MZ, marginal zone; NA, noradren- neurotransmitter elements may continue to mature through puberty. aline; P, postnatal day; PZ, proliferative zone; SP, subplate; VTA, ventral teg- Gestational age for both human and mouse are aligned with the arrow to mental area; W, weeks. Figure is modified, with permission, from REF. 202 define the timeline for these events. Emerging drug targets (receptors,  (1995) Elsevier Sciences and REF. 203  (2008) MIT Press. however, the behavioural dysfunction seems closely models the human pharmacokinetic other animal models show that prenatal to be mild19–24. The recreational use of profile38–40. It has been used to delineate a cocaine exposure alters basic processes of cocaine during pregnancy results in a subtle, number of highly specific changes, including neocortical development, including cell pro although dominant, developmental pheno altered GABA (γaminobutyric acid) levels in duction and migration55–60. These findings type that resembles attentiondeficit hyper the cortex, altered expression of Ca2+binding are consistent with recent studies demon activity disorder19–22,25–29. Detailed studies proteins, morphological changes in pyrami strating that dopamine can regulate progeni have shown that prenatal cocaine exposure dal cells and decreased dopamine D1 receptor tor cell proliferation and neuronal migration 41–46 61,62 can have longlasting negative effects on coupling to its cognate G protein, Gsα during prenatal development . cognitive and attention systems, which are (TABLE 1). The most surprising alteration was Behavioural changes in response to mediated by regions such as the prefrontal a permanent reduction in secondmessenger cocaine exposure have been reported in cortex and other higherorder cortical areas coupling, which was found to be due to various animal models. These include that express dopamine receptors and receive abnormal internalization of the D1 receptor. deficits in attention tasks and emotional rich dopaminergic projections from the This suggested that the D1 receptor is not reactivity as well as reductions in the rein midbrain19,24,27,30–32 (TABLE 1). recent data also trafficked properly to the cell membrane, forcing properties of drugs of abuse30–32,63,64. 47 suggest that there is increased likelihood that where it interacts with Gsα . These cellu These findings correspond with the human children exposed to cocaine prenatally will lar and molecular findings were observed clinical literature, which reports distur require special needs programmes33; this, only in dopaminerich cortical areas, which bances in both attention and emotion from both an individual and a societal are intimately involved in cognition and regulation in children exposed prenatally perspective, is expensive. executivefunctioning tasks, including atten to cocaine. Animal models confirm that prenatal tion48–53. These studies have also been able to cocaine exposure results in specific perma directly relate the timing of in utero cocaine Amphetamine and methamphetamine. nent behavioural, cellular and molecular exposure to its deleterious effects in offspring Amphetamine and methamphetamine changes34–37. An intravenous model of and suggest that the second trimester may be are also psychostimulants; however, they prenatal cocaine exposure in the rabbit a particularly vulnerable period54. target the monoaminergic system in a

Table 1 | neurodevelopmental consequences of prenatal drug exposure Age of exposure Drug Neurochemistry involved Neurodevelopmental consequences refs Late early to mid Cocaine DA > NA and 5-HT. Blocks Altered neuroanatomical morphology, 18–37,42– gestation (primarily monoaminergic transporters and disrupted cognition and altered cellular 47,54–59,63– based on animal increases synaptic concentrations of signalling 65,203 studies) monoamines Throughout Alcohol GABA and NMDA. Blocks NMDA receptor Craniofacial dysmorphologies, decreased 113–115,118– gestation activity and increases GABAergic activity birth weight, hyperactivity, cognitive 120,126–132 deficits, cortical dysgenesis, cell death and reduced brain volume Throughout Nicotine Acetylcholine. Activates nAChRs Decreased birth weight, hyperactivity, 82,86–94,96– gestation cognitive disabilities and emotional 98,100– disruptions 105,107,108 Throughout Amphetamine or DA > NA and 5-HT. Reverses the action Low birth weight, decreased arousal, 66,67,70–73, gestation and early methamphetamine of monoaminergic transporters and deficits in learning and decreased volume 76–81 postnatal exposure increases synaptic concentrations of of the hippocampus and striatum monoamines 5-HT, 5-hydroxytryptamine (serotonin); DA, dopamine; GABA, γ-aminobutyric acid; NA, noradrenaline; nAChRs, nicotinic acetylcholine receptors; NMDA, N-methyl-d-aspartate. mechanistically distinct fashion from define the clinical impact of each drug indi (TABLE 1), all of which are highrisk fac cocaine. Both drugs reverse the actions of vidually. rat and mouse models have helped tors for behavioural impairment69,83–85. monoamine transporters and enhance the delineate the specific neurodevelopmental Furthermore, smoking is linked to an release of dopamine, noradrenaline and consequences of prenatal amphetamine and increased risk of sudden infant death syn serotonin in the synaptic cleft, increasing methamphetamine exposure. drome. Numerous studies support a robust their availability to act on postsynaptic Animals exposed to methamphetamine relationship between developmental tobacco receptors. In addition, both drugs can have lower birth weights, increased inci smoke exposure and attentiondeficit dis block the reuptake and degradation of dence of microgyria (smaller and more orders, hyperactivity, antisocial behaviour these neurotransmitters, further increas numerous convolutions in the cerebral and learning disabilities86–94. However, dif ing their concentrations in the synaptic cortex than usual) and deficits in visual ferences in the amount of nicotine and other cleft. The addition of a methyl group allows system development74–76. They also display chemicals in different tobacco products methamphetamine to move through lipid impaired postural motor movements, defi make it challenging to compare findings permeable membranes more easily than cits in specific learning paradigms, increased across ethnic or age groups. Furthermore, amphetamine. Both amphetamine and startle reflexes and decreased prepulse the presence of additional potential neuro methamphetamine are routinely ingested, inhibition76,77. Furthermore, alterations in toxicants and biomodulators in tobacco snorted and smoked. The frequency of use the levels and activities of the noradren smoke makes it difficult to determine the and abuse of amphetamine and metham ergic and serotonergic systems have been specific effects of nicotine exposure. This phetamine has steadily risen in the human demonstrated in animals exposed to either presents a challenge for clinicians who may population, exceeding cocaine use in many amphetamine or methamphetamine78–80. wish to recommend nicotinereplacement regions of the United States65. Some of the functional consequences (such therapy (NrT) to pregnant patients who Because methamphetamine and amphet as impaired sensorymotor coordination) have difficulty terminating smoking. amine use during pregnancy has become of prenatal methamphetamine exposure Although the additional chemicals are prolific only recently, there are few stud are transmitted to the next generation of absent in NrT, high amounts of nicotine are ies defining its longterm consequences. offspring81. These findings demonstrate that still presented to the fetus. Based on animal Children exposed to methamphetamine or prenatal amphetamine or methamphetamine studies (see below), such exposure is likely amphetamine during prenatal development exposure leads to a complex behavioural to lead to longterm disruption of brain show decreased arousal, increased stress, phenotype with similarly complex molecular architecture and chemistry. In fact, transder decreased scholastic achievement, move and cellular roots. malpatch NrT may actually worsen birth ment disturbances and low birth weight outcomes relative to active smoking95,96. one (a highrisk factor for special needs pro effects of legal drugs of abuse possibility, as reviewed recently97,98, is that grammes at school age)66–70. Neurocognitive Nicotine. Nicotine binds to nicotinic acetyl this may be a result of the continuous deliv testing showed that these children score choline receptors (nAChrs), ligandgated ery provided by the patch, which in animal lower on sustainedattention, longterm ion channels that are widely expressed models has been shown to cause fetal brain spatial and verbal memory, and visual throughout the fetal nervous system. nicotine levels to reach up to three times motorintegration tests71. Neuroimaging Nicotine is usually presented to the fetus those of maternal blood levels99. has produced reports of smaller striatum through maternal smoking or environmental Animal studies have provided the most and hippocampus volumes and decreased exposure to secondhand smoke. research compelling evidence that nicotine has numbers of dopamine D2 receptors and has provided unequivocal evidence that a substantial negative effect on neuro dopamine transporters71,72. Use of multiple both can be teratogenic (for a review, see development. Activation of nAChrs affects drugs and other psychosocial risks compli REF. 82), can lead to decreased birth weight morphogenesis, spontaneous neural activ cate these studies70,73, making it challenging to and can increase the risks of preterm birth ity and neuronal survival in rodents100.

In animals, plasma nicotine levels similar In addition, animal models have provided The animal studies are compelling, to those of pregnant women smoking further understanding of the cellular and but epidemiological studies to date do “moderate” numbers of cigarettes produce molecular consequences of prenatal ethanol not provide evidence of an increased risk potent neuro behavioural effects — includ exposure. of birth defects following use of selective ing changes in locomotor activity, reward Animal models of prenatal ethanol serotonin reuptake inhibitors during preg systems, anxiety and cognition — in off exposure have confirmed an increase in nancy155–159. It is important to consider that, spring100–105. Higher doses produce fetal birth defects, including neurological dys even though the rate of overt birth defects hypoxia and substantial growth retarda function3,126–130. exposure during all ges does not increase at typical doses, subtle tion106. Cortical cholinergic systems modu tational periods has dramatic teratogenic yet significant behavioural dysfunctions in late sensory cognitive processing107, and consequences131–133. There are reports of a offspring could occur (similar to the situa prenatal nicotine exposure impairs cognitive decrease in spinal and cranial motor neuron tion with prenatal cocaine exposure). The functions in animal models and in chil production and size, neocortical and hip issues are thus complex and require addi dren100,108. Intriguingly, nicotine inhibits pocampal dysgenesis, increased neuronal tional, detailed studies to inform medical aromatase, an enzyme involved in oestrogen cell death, reduced or delayed neuronal decisions. Healthcare professionals must synthesis in the placenta109; this may inter migration and decreased myelination134–137. weigh the relative neurodevelopmental fere with sexual differentiation of the brain ethanol exposure also disrupts the integrity impact of drug treatment of a psychiatric in males, and changes have been observed of plasma membrane receptors138,139. Thus, in disorder against the potentially negative in the timing of puberty onset in gestation addition to direct antagonism of neurotrans outcomes of untreated illnesses (including ally exposed male adolescents110. Based on mitter receptors, receptor tyrosine kinase increased maternal stress due to depression these findings, reducing smoking by preg signalling is disrupted, leading to altered or neurochemical imbalances). Thus, when nant women and their immediate family modulation of multiple histogenic events by behavioural therapy alone is not effective in members will be very beneficial, whereas the neurotrophic factors. treating depression in a pregnant woman, value of NrT in pregnant women is ques elegant studies have begun to prove the the potential risk of drug therapy must tionable and requires indepth evaluation impact of prenatal alcohol on endocrine be weighed against the risk for relapse of through prospective studies98. function140,141. As well as alcohol’s direct the disorder if pharmacological therapy is effects on the fetus, it also acts directly on interrupted. Alcohol. Alcohol use spans all socioeconomic the hypothalamicpituitaryadrenal (HPA) classes, gender, race, education and cultural axis of both the fetus and the mother. Other prescription medications. Several groups. It is a pharmacological depressant, Modulating the HPA axis during develop prescription medications are used for the blocking NMDA (Nmethyldaspartate) ment can permanently alter its responsive treatment of psychiatric, neurological receptor activity and increasing GABAergic ness to later stressors, setting off a cascade and maternal pregnancy disorders. little activity, thereby decreasing cortical and sub of behavioural, cognitive, and cellular altera research has examined the longterm func cortical activity111,112. Alcohol can also disrupt tions in the adult142. Similarly, alterations in tional implications of these drug treatments, growth factor receptor signalling by disrupt maternal HPA activity could underlie some but new studies are beginning to highlight a ing plasma membrane integrity113,114. GABA of the longlasting consequences of prenatal complex clinical picture. and its receptors are present early in neuronal alcohol exposure. As such, intervention Concerns have been raised regarding the development, and can modulate progenitor and behavioural therapy for these children effects of antipsychotic medications (potent cell proliferation, cell migration and neurite should perhaps include methods used in antagonists of dopamine and serotonin growth115–117. Alcohol crosses the placental clinical populations of children exposed to receptors) taken during pregnancy. Animal barrier at any point during pregnancy and severe stress in utero. studies point to serious potential neuro thus can have a severe impact on numerous developmental risks160–164. However, there histogenic processes (see below and TABLE 1). effects of prescription neurotherapeutics have been few clinical studies165,166, making There is overwhelming basic and clinical Antidepressant medications. A report of a it difficult to draw accurate conclusions evidence regarding the negative neurodevel higher rate of cardiac abnormalities in the regarding longterm impact on fetal devel opmental consequences of prenatal alcohol children of women using selective serotonin opment. As with other psychoactive drugs, exposure. These constitute a disorder rec reuptake inhibitors during pregnancy143,144 an individualized calculation of relative risk ognized by the International Classification has led to enormous public and scientific is important to balance the potential risk of of Diseases and the Diagnostic and Statistical interest. Animal studies have long implicated drug exposure against the risk of a potential Manual of Mental Disorders, fetal alcohol serotonin, the target of many antidepres psychotic episode if pharmacotherapy is syndrome, which is characterized by growth sants, in the development of the brain and suspended. deficiencies, craniofacial dysmorphologies peripheral organs145–147. Serotonin and its Another commonly prescribed drug and CNS damage3,118–121. Prenatal alcohol receptors are expressed in the brain early in is valproate, an anticonvulsant and anti exposure can cause intellectual disability, prenatal development12,148–151 and can modify mania therapeutic that blocks voltage deficits in learning, attention and motor dendritic and axonal differentiation149,152 gated Na+ and Ttype Ca2+ channels and development, and hyperactivity119,120,122–125. (FIG. 1). Although the mechanism remains inhibits the transamination of GABA167. As Although concomitant use of other drugs unknown, early postnatal disruption of a histone deacetylase inhibitor, valproate with alcohol is not unusual, alcohol is serotonin signalling in the rodent (at stages can also regulate the epigenetic modula often used as a solitary drug. This clinical roughly equivalent to third trimester and tion of gene transcription168. Clinical data population provides a less mechanistically neonatal human periods) can permanently demonstrate an increased risk for autism complex picture of the neurodevelopmental increase anxiety behaviours and disrupt spectrum disorder as well as teratogenic consequences of prenatal alcohol exposure. learning153,154. (neural tube defects and craniofacial

dysmorphia) and neurotoxic (apoptosis and and controlled research studies. For it redirects attention away from the default reduced cell proliferation in multiple brain pregnant women who abuse drugs before positions. In part, redefining frames involves areas) effects in individuals exposed to val conception, withdrawal of these drugs identifying values and explanations that proate169,170. rats exposed prenatally have postconception is not without risk to the make the societal, not individual, goals obvi lower sensitivity to pain, increased repeti fetus. Maternal stress can be severe during ous. This can best be done by creating and tive or stereotypiclike activity, higher withdrawal, and general health status may using simplifying models to explain brain anxiety, decreased social interaction and an decline — both severely affecting the brain development, which in turn will assist in increased basal level of corticosterone171,172. development of the fetus. explaining the impact of drugs and stressors Alterations in NMDA receptor expression, We now realize that prescription drug on the process. This provides an opportunity enhanced longterm potentiation and neo treatments for pregnant women with psy for science to explain how current policies cortical hyperconnectivity have also been chiatric and neurological disorders can surrounding drug use may have even more reported173,174. have negative effects on fetal brain develop negative effects on the fetus than the drug Terbutaline and other related drugs were ment and longterm behavioural outcomes. itself, under certain circumstances. These previously commonly used in lateterm However, the underlying maternal patho models thus become vehicles through which pregnancies to reduce premature uterine physiology of untreated disorders can lead science can positively influence policy contractions by stimulating the β2adrenergic to highrisk nutritional and stress status thinking and decisions. receptor175. exposure of neonatal animals for both the mother and the fetus. Perhaps The Frameworks Institute has developed to terbutaline results in neuroinflammation underscoring the level of complexity of the a frame of brain development that captures and longlasting behavioural and cellular maternal—fetal relationship, balancing these the essence of the scientific concept186. deficits176–178. Furthermore, children exposed issues makes formulation of public and According to this frame, the early years of to terbutaline or related adrenoceptor medical policies less straightforward than life matter because early experiences affect stimulants during late gestation may have an generally appreciated. the architecture of the maturing brain. That increased incidence of learning and neuro architecture establishes either a sturdy or a psychiatric disorders179,180. recent clinical Proposals to reduce bias fragile foundation for the development and studies have revealed an increased risk for When considering particular conditions or behaviour that follow. Therefore, similar to the development of autism spectrum dis states, people generally default to frames building a house, getting things right the first order in exposed offspring, consistent with that are most familiar to them. Frames are time is easier than trying to fix them later187. a report of a modest increase in risk due principles that are socially shared and per This explanation of brain development to an allelic variant in the gene encoding sistent over time and that work symbolically reduces the complexity of the problem to a 181 183 the β2adrenergic receptor ; whether this to meaningfully structure the social world . simple, concrete analogy that helps policy genetic predisposition and environmental It is essential for scientists to understand makers, members of the media and the pub risk interact with one another is not yet this concept, because the inadequate com lic organize information into a clear picture. known. In fact, the efficacy of these drugs munication of information causes people to Understanding that the assembly of brain in preventing preterm delivery when used default to these frames. Framing has been architecture starts early, from the bottom up, for maintenance tocolysis is suspect182, and defined as the process of selecting a few ele paralleling the process of skill development in their recognition for such uses has been ments of a perceived reality and assembling a a child imparts a feel for the timedependent withdrawn. narrative that highlights connections among relationship between structure and function. them to promote a particular interpreta This facilitates and stimulates interest in Balancing prenatal drug exposure tion for an individual184. We have already understanding the factors that can influence Basic and clinical research unequivocally mentioned the misnomers that illustrate this the process. For example, discussions of the demonstrate that recreational or prescription concept. The term ‘crack baby’ evolved from more potent influence of alcohol and nico use of drugs during pregnancy negatively social perceptions regarding individuals tine than cocaine on developing brain archi affects healthy development. There is a clear who use crack cocaine, the assumed severity tecture lead directly to the conclusion that conundrum, however, with regard to the of the impact of fetal exposure to an illegal such exposures must also have more pro need to balance exposure (in a clinically drug, and a lack of understanding of the found functional consequences. This reduces prescribed population) with nonexposure complex maternal status that included use of the impact of the default frame (that illegal when considering the longterm functional multiple drugs and malnutrition. The press drugs are more detrimental to fetal develop impact on brain development. The difficul and scientists alike were culpable in ment than legal drugs). likewise, explana ties relate to the fact that high prenatal stress, promoting this image in the absence of tions of the effect of ‘toxic stress’ — such as malnutrition and untreated maternal psychi documented biological and behavioural severe malnutrition — drug exposure, poor atric disorders can themselves increase risk effects. By the time science caught up, the health care or lengthy incarceration on fetal for developmental disabilities in children. frame had been cemented, and it remains brain architecture can lead to discussions With regard to recreational drugs, an influential factor in defining public between scientists and policy makers that human addictive behaviour makes this issue policy (BOX 2). evaluate the factors that may have the great far more complicated than a simple public Fully developed frames perform four est impact on child development187 (BOX 3). policy approach of ‘just say no’. Furthermore, functions: problem definition, causal analy There is thus an attainable goal of eliminating it is clear that the idea that illegal drugs sis, moral judgment and remedy promo default frames and introducing more science are more harmful to the unborn fetus than tion184,185. In order to provide more accurate based simplifying models that can alter the legal drugs is incorrect; this concept, which information for policy makers the original course of social and legal policies to best strongly influences public policy, is not sup concept must be reframed. Initially, the sci manage the difficulties of drug exposure ported by findings from carefully designed ence must be explained in such a way that during pregnancy (BOX 3).

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