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Passive Addiction and Teratogenic Effects
Drugs can exert major effects on the developing central nervous system (CNS). In the broadest sense, drugs may disturb specific developmental events in the brain and, in turn, produce teratogenic effects. In addition, maternal ingestion of certain drugs can result in passive addiction of the fetus, and postnatally lead to a neonatal withdrawal or abstinence syndrome. The capacity for teratogenicity was first recognized in the late 1950s and early 1960s with the recognition of the adverse effects of thalidomide. Believed to be safe, thalidomide was prescribed to large numbers of pregnant women as a treatment for morning sickness but was later found to result in a number of birth defects. The most notable of these was phocomelia, in which the bones of the arms and, in some cases, other limbs were extremely shortened or absent. With this medical tragedy came an increased awareness of the potential teratogenic risks of fetal exposure to prescribed and recreational drugs.
Evidence suggests that prenatal exposure to both licit and illicit drugs can have short-term and long-lasting effects on the structure and function of the developing CNS. These effects vary in severity, from profound effects on morphological structure to more subtle but nonetheless clinically significant neurological effects. Some of the latter may include a striking neonatal abstinence syndrome (NAS) or include a range of neonatal neurobehavioral difficulties ( Table 42.1 ). Further, few of these effects are transient, with most persisting in some form into childhood and adolescence. Multiple systems are often affected spanning cognition, motor function, language, and behavior. Fig. 42.1 provides a conceptual overview of the factors and processes involved in the effects of drug exposure in utero on child neurological development.
TABLE 42.1
Nature of Outcomes Related to Intrauterine Drug Exposure
| OUTCOME | ALCOHOL | AEDs | STIMULANTS | OPIOIDS | SSRIs | MARIJUANA |
|---|---|---|---|---|---|---|
| Congenital malformations | X | X | ||||
| Neonatal abstinence | X | X | X | X | X | |
| Newborn neurobehavioral difficulties | X | X | X | X | X | |
| Global cognitive deficits/delay | X | X | X | X | ||
| Executive function | X | X | X | X | X | |
| Language problems | X | X | X | X | X | |
| Attention problems | X | X | X | X | ||
| Externalizing problems | X | X | X | |||
| Internalizing problems | X | X |
AEDs , Antiepileptic drugs; SSRIs , selective serotonin reuptake inhibitors.
Schematic model of factors involved in the effects of drug exposure in utero on child neurological developmental outcome.
CNS , Central nervous system.
MAJOR FACTORS INVOLVED IN NEUROLOGIC DISTURBANCES ASSOCIATED WITH INTRAUTERINE DRUG EXPOSURE
Almost all drugs unbound to protein move across the placenta by passive or facilitated diffusion, enter the fetal bloodstream, and can affect fetal brain development, either directly or indirectly ( Fig. 42.2 ). The direct effects of a drug on the developing brain will vary depending on the type of drug, the gestational timing of exposure, dose, the extent of drug distribution, and the number of drugs. The developmental stage of the fetus at the time of exposure, as well as the sensitivity of different brain regions to different chemical agents, also likely plays a role. For prescribed drugs, information about timing and extent of exposure is typically known, whereas for alcohol and other illicit drugs, such information is harder to obtain accurately, thereby posing additional challenges for clinical assessment and diagnosis.
In addition to these direct effects, drugs can have indirect effects on fetal brain development via their effects on other organ and physiological systems. Numerous drugs impact fetal blood flow and nutritional exposure. For example, cocaine impairs fetal oxygen and nutrient transfer via profound vasoconstriction of the umbilical vein. Acutely, these alterations may contribute to cerebral infarction and intracranial hemorrhage. Chronically, these perturbations may contribute to the documented effects of cocaine on cortical neuronal migration and differentiation.
It is also increasingly recognized that maternal and fetal genotypes may interact with a drug exposure to determine phenotypic effects ( Fig. 42.1 ). Functional polymorphisms in alcohol metabolism may best exemplify this phenomenon. The offspring of individuals with normal metabolism experience long-term impacts from in utero alcohol exposure, whereas the offspring of rapid metabolizers avoid these effects. Fetal genetic susceptibility has also been observed, with concordance in the manifestations of fetal alcohol spectrum disorder (FASD) between monozygotic twins but not dizygotic twins. Finally, there is also growing evidence to suggest epigenetic influences on outcome. These epigenetic modifications may even be transgenerational, placing subsequent generations at increased risk of drug dependence, even in the absence of direct exposure during gestation.
In addition to these drug and fetal factors, several other maternal and environmental factors may play a role in determining the clinical presentation of an infant and are therefore important to consider. Comorbid physical and mental health conditions in the mother, combined with the underlying disease state necessitating drug exposure, may complicate the interpretation of prenatal drug effects and exacerbate risks for the infant. In addition, maternal lifestyle factors, such as poor nutrition and social disadvantage, which are correlated with substance use, may also contribute to later risks, including poor growth and neurodevelopmental impairment in the infant.
DEVELOPMENTAL CONSEQUENCES FOR THE INFANT
As a result of the various factors noted previously, considerable heterogeneity in the nature and severity of outcomes may be observed, including death, malformations, neurodevelopmental disability, and impaired neurobehavioral functioning (see Table 42.1 ). A distinction can also be made between drugs that are associated with congenital malformations in the newborn infant versus those that have more subtle but nonetheless clinically significant neurobehavioral effects, with or without withdrawal symptoms that may require medical management ( Table 42.2 ). In this chapter we discuss fetal exposure to alcohol, antiepileptic drugs (AEDs), stimulants, opioids, selective serotonin reuptake inhibitors (SSRIs), sedatives, anesthetics, and marijuana.
TABLE 42.2
Major Drugs Associated With Teratogenic Effects, Congenital Malformations, and Neonatal Neurobehavioral Effects
| Teratogenic effects |
| Alcohol |
| Antiepileptic drugs such as valproate, hydantoins, barbiturates, and carbamazepine |
| Stimulants (cocaine, amphetamines) |
| Neonatal neurobehavioral effects (including neonatal abstinence syndrome) |
|
Alcohol
FASD includes a range of possible diagnoses that may result from a woman drinking alcohol during pregnancy. These diagnoses, which vary in the severity of later abnormalities or impairment, include fetal alcohol syndrome (FAS), partial FAS, alcohol-related birth defects, alcohol-related neurodevelopmental disorder (ARND), and neurobehavioral disorder associated with prenatal alcohol exposure. At the severe end of the spectrum is the clinical diagnosis of FAS, which was described in a thesis by Rouquette of Paris in 1957 followed by the first published cohort in 1968 by Lemoine of Nantes, France, and then reported in further detail by Jones and colleagues in Seattle. This disorder refers to a specific constellation of neural and extraneural anomalies that include abnormal facial features ( Fig. 42.3 ), poor body growth, and CNS abnormalities that are in turn associated with later cognitive, learning, and behavioral impairments. However, even in the absence of the full features of FAS, it is now also recognized that prenatal alcohol exposure can result in a range of less pronounced dysmorphic, cognitive, and behavioral effects of varying severity, termed fetal alcohol effects (with specific diagnostic terminology noted previously).
Prevalence
The prevalence of maternal alcohol use during pregnancy and FASD varies with the drinking patterns of a population. The accurate estimation of these rates is hindered by a number of methodological problems. These include (1) reliance on maternal recall and underreporting because of stigma and a fear of potential punitive consequences; (2) limitations of toxicological measures, such as urine and meconium; and (3) differences in the diagnostic criteria used to define FAS and FASD. Nonetheless, findings suggest that in the United States, approximately one-half of all women of childbearing age report having consumed alcohol in the past month, with 18% likely to have had a binge-drinking episode, defined as more than five standard alcoholic drinks on at least one occasion. Although most women reduce their alcohol intake during pregnancy, 14% continue to drink and 5% binge drink. Even higher rates of drinking during pregnancy are reported in the United Kingdom, Ireland, Australia, and New Zealand, with prevalence estimates ranging from 20% to 80%. Importantly, these rates were pervasive across all social groups. Finally, Africa has highly variable rates of alcohol consumption by region, with binge drinking reported by as many as 1 in 4 women of childbearing age and up to 20% of all pregnant women in some regions.
The prevalence of FAS in the United States ranges from 6 to 9 cases per 1000 live births in the general population, with the risk increasing to 1% to 2% for infants from socioeconomically disadvantaged families and infants in foster care. Rates of FASD, which are more common but harder to detect because of their more subtle presentation, are even higher in the United States, ranging from 11 to 50 cases per 1000 live births or up to 5% of all live-born infants. The global prevalence of FASD varies widely; for example, a high prevalence was reported in South Africa (71 to 158 cases per 1000 live births), whereas many European countries report an incidence comparable to the United States. It is important to note that these rates are widely regarded to underestimate the extent of this problem for the methodological reasons listed previously, as well as difficulties with both misdiagnosis and underdiagnosis.
Clinical Features
The diagnostic features of FAS are distinctive and include growth disturbance, characteristic facial anomalies, and neurological abnormalities. Growth disturbance is the hallmark of the disorder, with microcephaly present in nearly all cases. At birth, infants have a distinct pattern of growth restriction, with length often affected more than weight, which is a pattern different from that expected with intrauterine undernutrition. This poor growth persists postnatally, but weight gain is more disturbed than linear growth.
For a diagnosis of FAS, three criteria must be met: (1) prenatal and/or postnatal growth deficiency; (2) the presence of three key facial features—short palpebral fissures, hypoplastic philtrum, and a narrow vermilion lip border (see Fig. 42.3 ); and (3) evidence of structural or functional CNS impairment (discussed later). Confirmation of prenatal alcohol exposure through maternal report or infant toxicology strengthens, but is not required, for an FAS diagnosis. As with all recreational drugs, it is also important to clarify the extent of prenatal exposure to other drugs, such as tobacco, illicit substances, and any prescribed medications. The possibility of other genetic and environmental conditions that share similar dysmorphic features with FAS (e.g., Williams syndrome, fetal hydantoin syndrome, and trisomy 21) or present at older ages with a similar behavioral phenotype (e.g., attention-deficit/hyperactivity disorder [ADHD]) should also be considered.
In addition to the three previously noted defining criteria, a number of other clinical features may also aid FAS diagnosis ( Table 42.3 ). For example, a variety of limb anomalies can be observed in around one-half of these infants. These include abnormal palmar creases and minor joint abnormalities, such as an inability to completely extend the elbows, camptodactyly, and clinodactyly. Cardiac lesions occur in approximately one- half, but these lesions are usually not severe and mostly consist of septal defects, with atrial defects more common than ventricular defects. Minor ear anomalies occur in approximately one-fourth of the children, and hearing loss, primarily conductive and of a mild nature, occurs in 75% of infants. Optic nerve hypoplasia affects 75% of infants, but disturbances of visual acuity are not marked. Other less common anomalies include strabismus, ptosis, micrognathia, cleft palate, or railroad track ears (prominent horizontal crus of the helix with prominent and parallel inferior crus of the antihelix).
TABLE 42.3
Clinical Features of the Fetal Alcohol Syndrome
| CLINICAL FEATURES | APPROXIMATE FREQUENCY (%) |
|---|---|
| Growth | |
| Prenatal growth deficiency | 95 |
| Postnatal deficiency | 95 |
| Central nervous system | |
| Microcephaly | 95 |
| Developmental delay | 90 |
| Facial | |
| Short palpebral fissures | 90 |
| Epicanthal folds | 50 |
| Midfacial hypoplasia | 65 |
| Short, upturned nose | 75 |
| Hypoplastic long or smooth philtrum | 90 |
| Thin vermilion of upper lip | 90 |
| Limb | |
| Abnormal palmar creases | 55 |
| Joint abnormalities | 50 |
| Cardiac | |
| Cardiac defects | 50 |
| Other | |
| Ear anomalies | 25 |
| Conductive hearing loss | 75 |
| Sensorineural hearing loss | 10 |
| Optic nerve hypoplasia | 75 |
| External genital anomalies | 30 |
| Cutaneous hemangioma | 25 |
Numbers are rounded off to nearest 5%.
The less severe FASD conditions are more difficult to diagnose because only some of the classic features are present. For example, ARND requires confirmation of prenatal alcohol exposure and evidence of structural or functional CNS impairment, such as learning and/or behavior problems, but not facial anomalies. When prenatal alcohol exposure is confirmed but all other criteria for FASD are not met, an infant can be described as exhibiting partial FAS or fetal alcohol effects. These diagnoses may be needed to ensure that a child receives ongoing developmental surveillance in view of high rates of neurodevelopmental impairment in children exposed to alcohol in utero.
Neurodevelopmental Consequences
The nature of a child’s later neurobehavioral problems and their manifestation varies depending on a number of factors. These include (1) the extent of prenatal alcohol exposure (dose, timing) and the severity of the condition (i.e., FAS or fetal alcohol effects); (2) the presence of other developmental risk factors in the child, mother, or family situation; and (3) the age of the child at the time of evaluation. Genetic factors also likely play a role. Nonetheless, reasonable consensus exists regarding the neurobehavioral profile of children with FASD. These problems span a number of developmental domains, including (1) cognition and executive impairment; (2) language; (3) behavioral and regulatory problems, especially ADHD; and (4) motor and visuospatial deficits . The most disabling of these subsequent problems are the intellectual and behavioral impairments. A brief description of the neurobehavioral profile of children with FASD across each impairment domain is provided next.
Cognition and Executive Functioning
Children exposed prenatally to alcohol typically have intelligence quotient (IQ) scores in the low average to borderline range. Children with more dysmorphic features tend to have lower IQ scores, but cognitive problems are not limited to this group. Of those with FAS, around 25% to 50% will experience severe cognitive delay (IQ score < 70), with the pooled prevalence of cognitive disability being 97 times higher in infants with FAS than the general population. Challenges in math, spelling, and reading are common at school age. In addition to global cognitive impairment, deficits in executive function and memory are also evident on neuropsychological testing. Executive deficits include problems with planning and organization, cognitive flexibility/set shifting, working memory, and behavioral inhibition, with parents reporting the greatest difficulty with inhibitory control and problem solving. In terms of memory deficits, problems encoding or memorizing information appear more prominent than problems with recall, although nonverbal learning and recall are affected by heavy prenatal alcohol exposure. Not surprisingly, given this constellation of cognitive impairments, learning problems are very common at school, even after controlling for IQ.
Language Development
Children with FASD are characterized by delays in the acquisition of language and understanding of spoken language. Common difficulties include word comprehension, grammatical ability, naming ability, phonological processing, speech production, and articulation errors, resulting in poorer performance on tests of both receptive and expressive language development.
Behavior and Regulatory Problems
Virtually all infants with FASD exhibit serious attentional and behavioral problems, with 50% subsequently meeting clinical criteria for a diagnosis of ADHD. The next most common condition is oppositional defiant/conduct disorder, with children with FASD showing less guilt after misbehaving, less behavioral maturity for their age, and higher levels of antisocial behavior, including cruelty and stealing. High rates of expulsion and/or school dropout complicate assessment of cognition. Longer-term substance abuse and mood disorders, such as anxiety and depression, are also common. For example, relative to the general population, adults with FASD have more hospital admissions for alcohol abuse (9% vs. 2%) and psychiatric disorders (33% vs. 5%), and are also more likely to be prescribed psychotropic medications (57% vs. 27%).
Motor and Visual Function
Finally, deficits in both fine and gross motor development have been reported in children with FASD and include tremors, weak grasp, poor hand-eye coordination, and impaired postural balance. Visuospatial performance indicates poorer saccadic control, which results in the processing of visual stimuli in a disorganized way.
Neuropathology
The essential nature of the neural disturbance in FASD is an impairment of brain development ( Table 42.4 ). Several aspects of the developmental program appear to be involved, on the basis of neuropathological analysis of brain tissue from children with FAS who died in infancy. In keeping with the microcephaly, micrencephaly is common. The most striking additional abnormalities reported appear to involve neuronal and glial migration. Thus in the series of infants studied by Clarren and colleagues, the most frequent abnormality was a leptomeningeal neuroglial heterotopia that took the form of a sheet of aberrant neuronal and glial cells covering portions of the cerebral, cerebellar, and brainstem surfaces ( Fig. 42.4 ). Aberrations of brainstem and cerebellar development, in large part related to faulty migration, also have been particularly frequent. Schizencephaly and polymicrogyria are other migrational disturbances observed. In addition, disordered midline prosencephalic formation (e.g., agenesis of the corpus callosum, septooptic dysplasia, and incomplete holoprosencephaly) has been documented. Other developmental defects have included anencephaly, lumbar meningomyelocele, lumbosacral and sacral meningomyelocele, absent olfactory bulbs or arrhinencephaly , and disturbances of dendritic development.
TABLE 42.4
Major Neuropathological Features of Fetal Alcohol Syndrome a
| In order of decreasing frequency: |
|
Thus it appears that multiple aspects of CNS development can be affected in severe cases. In chronological order, these include neurulation, canalization and retrogressive differentiation, prosencephalic development, neuronal proliferation, neuronal migration, and organizational events (see Chapter 1, Chapter 2, Chapter 3, Chapter 4, Chapter 5, Chapter 6, Chapter 7 ). The time periods of the most frequently reported occurrences (i.e., disorders of neuronal proliferation and migration and of midline prosencephalic development) range from the second to the fifth months of gestation, suggesting that teratogens could be acting either during these time periods or, of course, earlier.
Advanced magnetic resonance imaging (MRI) techniques have helped further define the neuropathology of FASD in the human infant ( Table 42.5 ). Key findings from studies using different imaging modalities are summarized next. However, it is important to note that almost all studies have been conducted in older children, thus limiting information about structural and functional brain abnormalities during infancy, or the way in which prenatal alcohol exposure affects the developing brain over time and age.
TABLE 42.5
Major Central Nervous System Alterations Defined by Magnetic Resonance Imaging in Fetal Alcohol Spectrum Disorders
|
Volumetric MRI studies indicate both global and regional disturbances in cortical and subcortical development, alterations in cortical thickening, and specific regional vulnerability of the corpus callosum, cerebellum, and basal ganglia, especially the caudate nucleus. Findings confirm smaller brain size, with both white and gray matter volumes affected. In terms of regional abnormalities, a highly consistent finding across studies is the altered shape and area of the corpus callosum, further supporting the vulnerability of midline brain structures to the effects of alcohol. Abnormalities include partial or complete agenesis, underdevelopment, and corpus callosal thinning, particularly in the splenium, which is involved in communication between the parietal and temporal lobes. Fig. 42.5 illustrates several examples of corpus callosum abnormalities. These imaging abnormalities relate to motor function, attention, verbal learning, and executive function. Other subcortical structures affected by prenatal alcohol exposure include the cerebellum and caudate nucleus, which may help explain deficits seen in balance, bimanual coordination, memory, and attention among children with FASD.
At the microstructural level, diffusion tensor imaging studies indicate that white matter abnormalities also extend to other brain regions beyond the corpus callosum, including the anterior-posterior fiber bundles and the cerebellum. White matter abnormalities have also been seen in the frontal and temporal lobes, as well as several subcortical structures (e.g., globus pallidus, thalamus, and putamen), suggesting more widespread impacts on white matter integrity. Although these abnormalities may contribute to the attention, executive function, and other neurobehavioral impairments of children with FASD, studies addressing these links are, as of yet, rare and insufficient to draw clear conclusions.
Taken together, these findings suggest prenatal alcohol exposure has global and regional effects on the development of the CNS. These abnormalities appear to reflect both the adverse effects of alcohol on different organizational events during fetal development, but also the cascading effects of early brain abnormalities on brain growth, myelination, and pruning, suggesting an altered trajectory of brain development in children with prenatal alcohol exposure.
Pathogenesis
The pathogenesis of these disturbances of CNS development has been studied in both clinical and experimental models—primarily the latter. Findings indicate that the adverse effects of alcohol and acetaldehyde, its major metabolite, likely result from some combination of (1) effects on fetal blood flow, (2) fetal malnutrition, (3) direct deleterious molecular effects, and (4) genetic/epigenetic alterations within the rapidly developing CNS. A brief review of each of these processes is given in the following sections.
Fetal Blood Flow
Maternal alcohol exposure has a variable impact on uterine blood flow, depending on the gestation of the fetus and the pattern of exposure. However, there is converging evidence to suggest that alcohol alters the development of new blood vessels and vascular remodeling, which are both essential to normal uteroplacental circulation during gestation. There is also evidence that alcohol may alter cerebral oxygen and glucose consumption in the fetus near term gestation, but these effects do not appear earlier in gestation. Further studies are needed to better understand how alcohol consumption affects uteroplacental hemodynamics during different maturational periods of pregnancy.
Fetal Malnutrition
The quality of maternal nutrition and the direct physiological effects of alcohol on the fetus are also likely involved in the pathogenesis of FASD. Specifically, poor maternal nutritional status and vitamin deficiencies are common comorbidities of chronic alcoholism. Alcohol also interferes directly with the absorption, digestion, and utilization of nutrients. Retinol (vitamin A), folate, and zinc, three nutrients that are important for fetal brain development, have been shown to be directly affected by maternal alcohol use. First, retinoic acid, the oxidized form of retinol, plays a pivotal role in the development of the nervous system, as well as limb morphogenesis. Alcohol competitively inhibits the oxidation of retinol in the liver. In mouse models, deficiencies in retinoic acid early in gestation alter the expression of the sonic hedgehog gene, resulting in the classic craniofacial and corpus callosum abnormalities characterizing severe FAS. Second, folic acid has numerous roles in the developing nervous system, especially neural tube closure (see Chapter 1 ). Alcohol interferes with folic acid absorption, inhibits its metabolism, and increases excretion. Clinical research has shown a significant reduction in fetal-to-maternal folate ratios associated with chronic maternal alcohol use. Third, zinc is necessary for neurogenesis, neuronal migration, and synaptogenesis. Alcohol induces the zinc binding protein metallothionein in the maternal liver, which sequesters zinc and results in fetal deficiency. Although other primary and secondary nutritional deficiencies may exist in the fetuses of mothers who consume alcohol during pregnancy, the relative importance of these perturbations in the overall pathogenesis of FASD requires additional investigation.
Molecular Effects
Major contributors to the cascade of developmental damage associated with fetal alcohol exposure include (1) excessive cell death (apoptosis), (2) deficient cell proliferation, (3) impaired cell migration, and (4) altered differentiation. In experimental models, neuronal and oligodendrocyte degeneration is a prominent feature of prenatal alcohol toxicity. In particular, alcohol induces two types of cell death in the developing fetal brain. These include apoptosis and necrosis. Necrosis appears to represent a minority of cell death associated with alcohol exposure, typically occurring after binge drinking or alcohol withdrawal. Even low levels of alcohol exposure early in gestation appear to promote apoptosis, via elevation of phospholipase C activity, promotion of intracellular calcium transit, and repression of the transcriptional effector, β-catenin. This is an abnormal process during this stage of development. Later in gestation, apoptosis naturally occurs in approximately one-third of postmitotic neurons. However, in experimental models, alcohol exposure may increase the extent of apoptosis, most likely through N -methyl- d -aspartate (NMDA) receptor blockade and hyperactivation of γ-aminobutyric acid type A (GABA A ) receptors.
Experimental models of fetal alcohol exposure during the equivalent of the human second trimester demonstrate a profound impact on neuronal proliferation, migration, and differentiation. Organization of neural circuitry relies on ongoing electrochemical activity, allowing firing neurons to locate and synapse with other cells as part of activity-dependent network formation. Neurosuppression via NMDA antagonism/GABA A agonism depresses electrochemical activity, suppressing neurogenesis and triggering apoptotic neuronal death in the developing brain. In addition, alcohol impairs the function of insulin-like growth factor receptors, potentially via inhibition of cyclins and cyclin-dependent kinases. This inhibition may help explain delays in progression through the neuronal cell cycle that have been observed in experimental models. Alcohol induces errors in neuronal migration, perhaps through disruption of L1 cell adhesion molecule and interference with glial fibers. Alcohol phosphorylates the cytoplasmic domain of L1 cell adhesion molecule, thus altering the conformation and function of the extracellular domain. These changes not only affect neuronal migration, but also promote aberrant dendritic morphology.
Genetic and Epigenetic Alterations
Maternal and fetal genetics play a prominent role in susceptibility to FASD. Alcohol is metabolized in the liver to acetaldehyde by alcohol dehydrogenase (ADH). Functional polymorphisms in the locus encoding the beta subunit of the Class I ADH (ADH1B) alter the rate of alcohol metabolism. Alcohol is more rapidly metabolized in individuals with the ADH1B*3 allele (15% to 20% of African Americans) compared with individuals with the more common ADH1B*1 allele. This finding appears to have functional significance because prenatal alcohol exposure has been associated with increased attention problems and externalizing behavior in adolescents born to mothers with two ADH1B*1 alleles. In contrast, these differences were not observed in adolescents whose mothers had at least one ADH1B*3 allele.
Fetal genetic differences may also play an important role in outcome . After prenatal alcohol exposure, monozygotic twins are more concordant in outcome than dizygotic twins. Neuronal nitric oxide synthase (nNOS) and oxyguanine glycosylase 1 (OGG1) protect the developing brain from injury induced by alcohol. Mice homozygous for null nNOS or OGG1 have more severe neuronal damage and functional deficiencies after alcohol exposure compared with wild-type mice. In contrast, homozygous mutation of the tissue plasminogen activator and Bax genes are protective against the effects of alcohol on fetal brain development. Importantly, alternate or coexisting genetic syndromes may occur in children with a diagnosis of FASD, emphasizing the potential importance of genetic testing even in the setting of clear exposure. Further research is required to determine the array of genes that influence the spectrum of fetal alcohol disorders.
Changes in gene expression after prenatal alcohol exposure represent a relatively new field of study. However, there is evidence to suggest that alcohol alters the sequence of genes involved in DNA methylation, chromatin remodeling, protein synthesis, and mRNA splicing. Alcohol also promotes epigenetic changes, including alterations in methylation and acetylation, that give rise to phenotypic changes in animal models. As noted earlier, there is also evidence that epigenetic modifications associated with prenatal alcohol exposure may be transgenerational, placing subsequent generations at increased risk of alcohol dependence. Further study of the mechanisms underlying these important transgenerational effects is needed; the role of imprinted genes is an emerging focus with significant promise.
Prevention
Consensus guidelines recommend that the safest choice for a woman is not to drink alcohol during pregnancy. Given that malformation risks are greatest when the fetus is exposed to alcohol during the first weeks and months of gestation, it is critical that women be advised about the risks to their infant as early as possible in the pregnancy. Indeed, advice should ideally be given before pregnancy because most women do not begin prenatal care until after the first important weeks of pregnancy have passed. As discussed previously, most women of childbearing age in the United States consume alcohol, and a small percentage continue during pregnancy. Reduction or cessation of alcohol consumption during any stage of pregnancy benefits the developing fetus. When this cessation is initiated very early in pregnancy, malformations and cognitive and motor impairment may be avoided or at least minimized. When it is carried out in midpregnancy, although malformations are not prevented, growth retardation is clearly diminished. Thus there is benefit to be gained, even if cessation of drinking is delayed.
Supplementation to correct the nutritional deficiencies of the fetus (discussed previously) has been investigated. Supplementation with retinoids reduces alcohol-induced ocular phenotypes in experimental models. Similarly, folic acid supplementation may prevent alcohol-induced cardiac defects. Supplementation with other vitamins having a vital role in normal human development also may hold promise, despite the unknown direct impact of alcohol on these molecules. Choline, a B-complex vitamin, has been considered, given that it is the methyl donor for DNA methylation and the precursor for acetylcholine and essential cell membrane constituents. Alcohol induces hypermethylation in the hippocampus and prefrontal cortex, resulting in reduced brain size and long-term functional abnormalities; choline may be helpful in competitively reducing these effects. Vitamin E (α-tocopherol) encourages antioxidant activity, with deficiencies in vitamin E having an established role in developmental and behavioral deficits. Oxidative stress has a well-established role in the teratogenic effects of alcohol, promoting caspase-3 activity and subsequent cell death. In multiple experimental models, supplementation with vitamin E reduces cell loss within the brain after prenatal alcohol exposure. Importantly, however, none of the interventions described previously independently eliminates the full spectrum of fetal alcohol effects. In addition, the identification of at-risk women and the challenges of compliance in this population limit the feasibility of these interventions.
Treatment
Newborns with FASD represent a complex, high-risk population. Nutritional supplementation after fetal alcohol exposure has been proposed. As noted earlier, postnatal choline supplementation reduces cognitive deficits and behavioral outcomes in experimental models. Recently, Wozniak and colleagues demonstrated similar effectiveness in a randomized controlled trial (RCT) in 2- to 5-year-olds with FASD. Optimizing an infant’s postnatal experiences, educating parents, engaging social support, and mobilizing developmental and educational interventions may improve outcomes. These interventions demonstrate promise in mitigating some of the negative effects of fetal alcohol exposure.
ANTIEPILEPTIC DRUGS
AEDs are among the most common teratogenic drugs prescribed to women of childbearing age. Their primary use is in the treatment of epilepsy, but over half of AED prescriptions are for neuropathic pain, migraine headaches, and psychiatric disorders. A large number of drugs fall into this class, and prescription patterns have changed considerably in the last 2 decades as knowledge about the teratogenic effects of AEDs on the developing fetus and child have increased. Older drugs, such as valproate, phenytoin, phenobarbital, and carbamazepine, have declined in use among women of childbearing age and increasingly have been replaced with newer therapies, such as gabapentin, lamotrigine, levetiracetam, and topiramate. Because all of these drugs are still in use, and with more neonatal and outcome data available for such older drugs as valproate, we review these as exemplars. However, drugs such as trimethadione and paramethadione, which are no longer in clinical use because of their severe teratogenic effects, are not considered.
Prevalence
Approximately a third of individuals treated with AEDs are women of reproductive age. In the United States alone, recent estimates suggest that 20 to 35 per 1000 pregnancies occur with AED exposure, resulting in 70,000 to 130,000 exposed newborns born annually. Of these, 5% to 10% involved AED combination therapy . Contrary to historic data, the use of valproate in pregnancy has declined and this medication is commonly discontinued during pregnancy; however, the use of newer AEDs like lamotrigine and levetiracetam is increasing, and these agents are most often continued throughout pregnancy. In fact, there is evidence to suggest that AED prescriptions during pregnancy are increasing. In the United States AED prescriptions more than tripled from 1996 to 2007 and have continued to rise at a slower rate in the last decade. This change was driven primarily by an increase in the number of prescriptions for newer AEDs. The use of older AEDs such as valproate has slowly declined, which is expected given contraindications for use in pregnancy. In contrast, use of topiramate and lamotrigine has doubled and levetiracetam and gabapentin tripled in recent years, highlighting the importance of considering the potential teratogenic effects of both established and novel AEDs in modern neonatal neurology.
Clinical Features
Maternal-Fetal Effects
In addition to the risks of major congenital malformations (see later), a meta-analysis of 38 studies across both low- and high-income countries found that infants born to pregnant women who were treated with AEDs for epilepsy had increased odds of preterm (<37 weeks gestation) birth (odds ratio [OR] = 1.16, 95% confidence interval [CI] 1.01 to 1.34) and fetal growth restriction (OR = 1.26, 95% CI 1.20 to 1.33). Fetal and neonatal mortality are not consistently increased, although marked variability exists between geographical regions/economic status. More research is needed to examine neonatal neurobehavioral outcomes, as well as the extent to which these risks vary by AED, dose, epilepsy type, and therapy regimen (monodrug vs. polydrug exposure).
Major Congenital Malformations
AED exposure in pregnancy results in a constellation of fetal and developmental effects that range in severity from major congenital malformations to subtle variations in normal development. Early, large-scale retrospective studies in the 1970s and 1980s were the first to document the teratogenic effects of AEDs on the developing fetus. Findings suggested a more than twofold increased risk of major malformations in offspring of epileptic women on AEDs versus those not on medication or nonepileptic women. Subsequent studies in the 1990s supported this initial work. These studies focused largely on fetal valproate syndrome and fetal hydantoin syndrome; the latter is a syndrome associated with phenytoin exposure or structurally similar agents, such as phenobarbital, carbamazepine, and oxcarbazepine. The clinical features of these syndromes are reviewed in Table 42.6 and Figs. 42.6 and 42.7 .
TABLE 42.6
Clinical Features of 63 Cases of the Fetal Hydantoin Syndrome
Data from Hill RM, Verniaud WM, Horning MG, McCulley LB, Morgan NF. Infants exposed in utero to antiepileptic drugs. Am J Dis Child . 1974;127:645–653; and Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr . 1975;87:285–290.
| CLINICAL FEATURES | PERCENTAGE AFFECTED a |
|---|---|
| Growth | |
| Prenatal growth deficiency | 19 |
| Postnatal growth deficiency | 26 |
| Central nervous system | |
| Microcephaly | 29 |
| Developmental delay or mental deficiency | 38 b |
| Craniofacial | |
| Large anterior and posterior fontanel | 42 |
| Metopic ridging | 27 |
| Medial epicanthal folds | 46 |
| Ocular hypertelorism | 23 |
| Broad and/or depressed nasal bridge | 54 |
| Cleft lip and/or palate | 5 |
| Limb | |
| Nail and/or distal phalangeal hypoplasia | 32 |
| Fingerlike thumb | 14 |
| Other | |
| Short neck with or without low hairline | 18 |
| Inguinal hernia | 14 |
| Bifid or shawl scrotum | 33 |
| Cardiac defect | 8 |
a Data are expressed as percentage of those patients for whom information is available.
More recently, given the increased use of AEDs and a growing awareness of adverse effects on the cognition and behavior of children born to treated women, a number of new important data sources have been established. These include (1) large registries of pregnant epileptic women in North America, Scandinavia, the United Kingdom, Ireland, India, and Australia; (2) pharmaceutical company registries for specific drugs; (3) the European Surveillance of Congenital Anomalies database across 14 countries; (4) the U.S. National Birth Defects Prevention Study; and (5) prospective cohort studies of pregnant women treated with AEDs and their infants. Although not without methodological challenges, including limited information on newer AEDs, insufficient follow-up data, and variable methods used, these efforts have helped advance understanding of the neonatal and longer-term effects of AED exposure during pregnancy.
It is clear from this work that several factors have an influence on the teratogenic effects of AEDs ( Table 42.7 ). First, fetal effects differ for each AED . Valproate (relative risk [RR] 5.69, 95% CI 3.33 to 9.73) appears to be the most teratogenic, followed by topiramate (RR 3.69, 95% CI 1.36 to 10.07) and phenobarbital (RR 2.84, 95% CI 1.57 to 5.13), which carry moderate risks. Newer drugs, at least based on current evidence, appear to be generally less harmful (specifically lamotrigine and levetiracetam), although not all are completely risk-free ( Table 42.8 ). Second, the dose of drug has been found to influence outcome. Higher maternal doses tend to carry more risk. Third, the timing of AED exposure during pregnancy is also important. First trimester exposure poses the highest risk for congenital malformations, whereas third trimester exposure may be most detrimental to neurodevelopment. This observation correlates with the natural progression of fetal development, given that neural tube closure occurs between weeks 3 and 4 of gestation and systemic organogenesis between weeks 4 and 10, whereas extensive myelination and synaptogenesis occurs in the third trimester. Fourth, the type of epilepsy can further complicate outcomes for the fetus. Specifically, breakthrough seizures during pregnancy may result directly in fetal hypoxia, and consequent falls may increase the risk of premature labor and fetal death. Fifth, the presence of other comorbid conditions , such as psychiatric and endocrine disorders, lower maternal level of education, and the potential for polypharmacy (e.g., antidepressants) may further increase the risk for the infant born to a woman with epilepsy. Sixth and relatedly, fetal effects can vary depending on whether one or multiple AEDs are prescribed . Delineation of the teratogenic potential of each drug or drug combination is very difficult based on current evidence, especially for newer drugs. Emerging evidence suggests that the specific AEDs included in a regimen have tremendous effects on the RR of polytherapy. For example, high-dose valproate monotherapy appears to pose greater risk to the fetus than a combination of low-dose valproate and another AED (most commonly, carbamazepine). Additional evidence is needed to characterize the impacts of different polytherapy combinations, to assist the clinical management of women (and their infants) when monotherapy is ineffective for seizure control. Finally, there is increasing evidence to suggest that maternal genetic factors relating to the cerebral disorder underlying the epilepsy or other heritable conditions in the family increase the risk of congenital malformations. For example, a parental history of major congenital malformations increases the fetal risk more than fourfold, and the birth of a previous child with malformations when on the same AED increases the risk 17-fold.
TABLE 42.7
Factors Influencing Teratogenic Effects of Antiepileptic Drugs
|
TABLE 42.8
Relative Risk of Major Malformations Associated With Different Antiepileptic Drugs Used During Pregnancy
Adapted from Veroniki AA, Cogo E, Rios P, et al. Comparative safety of antiepileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med . 2017;15:95.
| AGENT | RELATIVE RISK OF MAJOR MALFORMATIONS COMPARED WITH UNEXPOSED |
|---|---|
| Valproate ( N = 4455) | 2.93 (2.36–3.69) |
| Hydantoins and agents with similar structure | |
| Phenytoin ( N = 2237) | 1.67 (1.30–2.17) |
| Phenobarbital ( N = 1709) | 1.83 (1.35–2.47) |
| Carbamazepine ( N = 8437) | 1.37 (1.10–1.71) |
| Oxcarbazepine ( N = 372) | 1.32 (0.72–2.29) |
| Newer agents | |
| Topiramate ( N = 599) | 1.90 (1.17–2.97) |
| Lamotrigine ( N = 6290) | 0.96 (0.72–1.25) |
| Levetiracetam ( N = 1015) | 0.72 (0.43–1.16) |
| Gabapentin ( N = 329) | 1.00 (0.47–1.89) |
With respect to individual AEDs, though the data are not perfectly consistent, several conclusions appear justified regarding the malformation and neurobehavioral risks associated with AED exposure during pregnancy. The most common major malformations reported in recent large series are neural tube defects, cardiac anomalies, oral clefts, hypospadias and other genitourinary anomalies, gastrointestinal anomalies, and skeletal malformations ( Table 42.9 ). The incidence of these malformations ranges from 2% to 11%, depending on the AED used, in contrast to a malformation rate of 1% to 3% in the general population.
TABLE 42.9
Types of Major Congenital Malformation by Antiepileptic Drugs
Adapted from Veroniki AA, Cogo E, Rios P, et al. Comparative safety of antiepileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med . 2017;15:95.
| DRUG | HYPOSPADIAS a | CLUB FOOT | CARDIAC ANOMALIES | ORAL CLEFTS |
|---|---|---|---|---|
| Valproate | 2.58 (1.24–5.76) | 3.26 (1.43–8.25) | 1.54 (0.98–2.37) | 3.26 (1.38–5.58) |
| Hydantoins and agents with similar structure | ||||
| Phenytoin | 1.12 (0.51–2.66) | 2.73 (1.13–6.18) | 0.99 (0.60–1.57) | 3.11 (1.31–7.72) |
| Phenobarbital | 1.53 (0.60–3.84) | 1.38 (0.51–3.42) | 1.54 (0.96–2.57) | 5.75 (2.41–14.08) |
| Carbamazepine | 1.09 (0.53–2.61) | 1.64 (0.68–3.62) | 0.93 (0.62–1.43) | 1.39 (0.56–3.15) |
| Newer agents | ||||
| Lamotrigine | 0.66 (0.23–2.26) | 0.70 (0.12–2.89) | 0.55 (0.32–0.95) | 1.21 (0.45–3.20) |
| Levetiracetam | 0.29 (0.00–2.56) | 0.26 (0.00–3.80) | 0.25 (0.03–0.96) | 0.48 (0.07–2.18) |
| Topiramate | 3.52 (0.77–15.72) | 0.0 | 0.66 (0.16–2.11) | 6.12 (1.89–19.05) |
Neonatal Effects
In relation to the neonatal effects of AEDs, neonatal withdrawal has been described. This has been reported most extensively with phenobarbital. Onset generally occurs around 7 days of age, which is understandable in view of the slow elimination of phenobarbital in the immediate neonatal period due to its half-life of several days. The major features consist primarily of CNS phenomena, including jitteriness, overactivity, disturbed sleeping, excessive crying, hyperreflexia, and disturbed sucking. Overt gastrointestinal phenomena, such as diarrhea, may occur but usually are not prominent. The symptoms may appear after the infant is discharged from the hospital, and the infant’s irritability may be mistaken for colic or some other extraneural cause. Symptoms often worsen over several weeks and persist for several months .
Neonatal withdrawal from other AEDs has been less extensively described. Recent reports describe withdrawal symptoms after prolonged in utero exposure to gabapentin both in the setting and absence of in utero opioid exposure. Symptoms developed within 24 hours of life include sneezing, irritability, jitteriness, and loose stools. Given the increasing use of other novel AEDs, withdrawal should remain in the differential diagnosis for exposed infants presenting with similar symptomatology.
An additional potential complication for the newborn infant associated with maternal AED treatment using a select group of AEDs is neonatal hemorrhage . The drugs incriminated are hepatic enzyme inducers and have included hydantoins, barbiturates, primidone (which is metabolized to phenobarbital in vivo), and carbamazepine . In one series of 111 infants born to epileptic women treated with phenytoin or phenobarbital, 8 exhibited severe bleeding. In this syndrome, the infant developed hemorrhage shortly after birth. This early onset is unlike hemorrhagic disease of the newborn secondary to vitamin K deficiency. Sites of hemorrhage are, in order of decreasing frequency, skin, liver, gastrointestinal tract, intracranial sites, and thorax. Intracranial hemorrhage has been reported in 20% to 25% of the cases with any bleeding. The course may be fulminating, and approximately 40% of reported infants have died. Clotting studies demonstrate diminution of the vitamin K–dependent clotting factors (factors II, VII, IX, and X), with prolongation of either the prothrombin time or partial thromboplastin time, or both. Vitamin K levels in cord blood are depressed, as evidenced by the presence of PIVKA-II (protein induced by vitamin K absence-II), an incompletely carboxylated, functionally defective form of factor II (prothrombin). Indeed, in one study of 24 infants born to mothers on antiepileptic therapy during pregnancy, 13 (54%) had detectable levels of PIVKA-II, and of the four infants exposed to valproate (none of whom had detectable levels of PIVKA-II), the incidence was 65%. Moreover, vitamin K levels also were depressed in the infants. These findings suggested increased degradation of vitamin K with impaired action of vitamin K on hepatic production of prothrombin. The latter occurs because of insufficient carboxylation of the glutamic acid residues of prothrombin, a posttranslational event that requires vitamin K. The pathogenetic mechanism by which some AEDs lead to vitamin K deficiency may relate primarily to increased degradation of vitamin K by fetal hepatic microsomal mixed-function oxidase enzymes, known to be inducible by phenytoin, phenobarbital, primidone, and carbamazepine. The similarity in structure of these so-called enzyme-inducible AEDs is shown in Fig. 42.8 . Nevertheless, in recent years this disorder appears to have become rare . Three reports ( n totals = 105, 204, and 662) have shown no increased incidence of hemorrhagic complications among women treated with various combinations of phenobarbital, phenytoin, primidone, and carbamazepine during pregnancy. The women were not treated with vitamin K during pregnancy, although the infants did receive vitamin K at birth. Whether the decline in incidence in this disorder relates to the diminishing use of polytherapy or increasing use of carbamazepine or related factors is unclear.
Neurodevelopmental Consequences
The body of longitudinal follow-up data describing the longer-term outcomes of children exposed prenatally to AEDs has grown in recent years. As illustrated in Table 42.10 , historic sample sizes tended to be small for individual AEDs and especially some newer AEDs. Although newer studies have expanded our knowledge of outcomes in infants and children exposed to newer AEDs, outcomes remain incomplete, with an emphasis on early global cognitive development assessed using the Griffith and Bayley Scales, and/or general intelligence at later ages. Though helpful in evaluating general function and risk, these measures provide no or limited information about other important aspects of neurodevelopmental functioning, such as executive function, memory, attention, and language, at least until recently. With this in mind, existing research relating to each outcome domain is summarized as follows.
TABLE 42.10
Impact of Antiepileptic Drugs on Early Childhood Development and Intelligence Quotient
Data from Bromley R, Weston J, Adab N, et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcome in the child. Cochrane Database Syst Rev . 2014;CD010236.
| EARLY CHILDHOOD DEVELOPMENT | SCHOOL AGE INTELLIGENCE QUOTIENT | |||||
|---|---|---|---|---|---|---|
| N | N | N | N | |||
| DRUG | DRUG EXPOSED | NOT DRUG EXPOSED | MEAN DIFF (95% CI) | DRUG EXPOSED | NOT DRUG EXPOSED | MEAN DIFF (95% CI) |
| Valproate | 42 a | 230 | −8.00 (−12.79 to −3.21) | 76 | 552 | −8.94 (−11.96 to −5.92) |
| Hydantoins and agents with similar structure | ||||||
| Phenytoin | 20 | 44 | −0.12 (−7.54 to 7.30) | 5 | 201 | 4.80 (−4.10 to 13.70) |
| Phenobarbital | – | – | – | 14 | 201 | −6.80 (−12.90 to −0.70) |
| Carbamazepine | 50 a | 79 | −5.5 (0.34–10.83) | 150 | 552 | −0.03 (−3.08 to 3.01) |
| Newer agents | ||||||
| Levetiracetam | 51 a | 97 | 1.09 (−2.81 to 4.99) | – | – | – |
| Lamotrigine | 34 a | 230 | −1.0 (−5.75 to 3.75) | 29 | 210 | −4.0 (−8.32 to 0.32) |
| Monotherapy | 138 a | 230 | −4.00 (−6.86 to −1.14) | 182 | 391 | −1.30 (−4.12 to 1.51) |
| Polytherapy | 30 a | −6.00 (−13.27 to 1.27) | 105 | −8.57 (−11.77 to 5.38) | ||
Intelligence quotient was assessed with age-appropriate standardized measures of intelligence.
a General development assessed with either Griffiths or Bayley depending on measure used most commonly across studies, with the largest N . Measure is Bayley unless otherwise marked.
Cognition and Executive Functioning
Prospective studies have consistently documented the negative effects of valproate on cognitive development, with an 8- to 9-point IQ decrement. Of note, significant effects appear to relate largely to high-dose valproate exposure (>800 mg daily). The NEAD study also found that higher doses of valproate exposure during pregnancy were associated with poorer memory and executive function in offspring at age 6. Similarly, a Danish population-based cohort study documented worse performance on standardized language and mathematics tests at age 13 in children exposed to valproate compared with unexposed children or those exposed to lamotrigine; carbamazepine was not linked to school performance deficits, a finding congruent with historic studies. Limited data exist regarding newer AEDs. Available studies suggest that lamotrigine does not affect infant or early childhood cognitive development. The MONEAD study, a continuation of the NEAD study, recently reported no difference in 2-year cognitive outcomes between infants exposed to lamotrigine and/or levetiracetam during pregnancy and unexposed controls, supporting preliminary conclusions from other cohorts. These findings help reframe historic evidence consistently suggesting that monotherapy may be less harmful than polytherapy, as historically polytherapy has generally included valproate (see Table 42.10 ). As previously discussed, the individual components of polytherapy appear to influence both risk of malformations and long-term neurological deficits, and some polytherapy regimens (lamotrigine and levetiracetam) appear to be safer than specific single drugs (high-dose valproate).
Language Development
There is some suggestion that, based on IQ, verbal abilities may be more impaired than nonverbal abilities in children born to mothers treated with valproate. Of note, lower doses of valproate appear to be associated with less severe effects, although performance is still negatively affected compared with controls. Carbamazepine appears to exert similar negative effects as lower doses of valproate. In contrast, studies suggest that language abilities are comparable to control children for other AEDs, including phenytoin, lamotrigine, topiramate, gabapentin, and levetiracetam. However, these conclusions are based on studies with small sample sizes and unstandardized language measures.
Behavior and Regulatory Problems
A small series of studies suggest that children exposed prenatally to valproate are at increased risk of behavior problems based on screening measures, such as the Vineland Adaptive Behavior Scales and Strengths and Difficulties Questionnaire. Less is known about specific risks for mental health problems, such as ADHD and anxiety disorders. Fetal valproate exposure has been linked to ADHD in the NEAD study. Additionally, two population-based studies have linked valproate to an increased risk of autism spectrum disorder (ASD). Concerning preliminary data exist regarding children exposed to lamotrigine or levetiracetam, with documentation of a higher incidence of parent-reported defiance/conduct difficulties at 6 to 8 years compared with population norms, although behavioral problems appear to be significantly less prevalent and severe compared with valproate exposure.
Motor and Visual Function
The large prospective NEAD study ( N = 229) suggests that prenatal AED exposure (carbamazepine, lamotrigine, phenytoin, valproate) is not associated with later motor problems, at least on global measures of psychomotor development. However, small series suggest the potential relevance of this domain. A small study of 56 AED-exposed (predominantly carbamazepine or polytherapy) and 77 nonexposed newborns found that exposed infants had lower limb and axial tone, and were less irritable than nonexposed infants. Specifically, valproate, lamotrigine, and topiramate exposure have been associated with poorer motor skills in small cohorts of exposed children. In contrast, levetiracetam appears to have fewer effects on early childhood gross motor skills, locomotor function, and hand/eye coordination. Even less data exist describing visual outcomes of children exposed to AEDs, although this domain represents an important area of future study given the known interactions between many AEDs and vision.
Neuropathology
The nature of the neural disturbance associated with intrauterine AED exposure in the human infant has yet to be well characterized. Experimental models have shown decreased brain weight after phenobarbital, phenytoin, valproic acid, or benzodiazepine exposure. In contrast, these morphological effects have not been observed after exposure to clinically relevant doses of carbamazepine, lamotrigine, or levetiracetam. Neuroimaging studies with human infants or older children exposed prenatally AEDs have not been reported. A recent study examining early cortical activity with electroencephalography (EEG) in a small series of AED-exposed newborns ( N = 56; predominantly oxcarbazepine/carbamazepine monotherapy or polytherapies containing these agents) found both individual alpha oscillatory bouts and wider band spectra in these infants, as well as differences in interhemispheric synchrony, suggesting that functional brain networks may be altered as a result of prenatal AED exposure.
Pathogenesis
As with alcohol exposure, direct effects on fetal perfusion, fetal malnutrition, and direct molecular effects of individual agents or their metabolite(s) are all likely contributors to the developmental anomalies associated with intrauterine exposure to AEDs ( Table 42.11 ). These effects may be further modulated by genetic factors. Whereas the mechanisms of adverse effects of older agents, such as phenobarbital and phenytoin, have been evaluated extensively, less insight exists regarding newer agents, such as levetiracetam and lamotrigine, which are now more widely used in the management of epilepsy during pregnancy.
TABLE 42.11
Pathogenesis of Anomalies Associated With Intrauterine Exposure to Antiepileptic Drugs
| Valproate |
|
| Hydantoins and agents with similar structure (phenytoin, phenobarbital, carbamazepine, oxcarbazepine) |
|
| Newer antiepileptic drugs (lamotrigine, levetiracetam, topiramate, gabapentin) |
|
Fetal Blood Flow
AEDs have been found to have direct cardiotoxic effects in fetal experimental models. Phenytoin and phenobarbital, specifically, inhibit the potassium channel IKr at clinically relevant concentrations. Via this mechanism, phenytoin induces bradycardia and transient ventricular arrhythmias in experimental models. These fetal cardiac effects may result in episodic hypoxia, leading to hemorrhage and necrosis of developing tissues. Preliminary data suggest lamotrigine has similar potential. In fact, recent experimental studies have documented cardiac toxicity from both valproic acid and lamotrigine, with rapid impact on cardiac function in animals exposed to high-dose lamotrigine. The relevance of this adverse effect for other AEDs requires further investigation.
Fetal Malnutrition
There is also a suggestion that nutritional deficiencies may potentially modulate the teratogenic effects of AEDs. As discussed previously, hepatic enzyme inducers, including phenytoin, phenobarbital, and carbamazepine, have been implicated as a risk factor for neonatal hemorrhage. This effect may relate to increased degradation of vitamin K by fetal hepatic microsomal mixed-function oxidases inducible by these agents.
Women with epilepsy and abnormal pregnancy outcomes also have significantly lower blood folate concentrations. Valproic acid functions as a noncompetitive inhibitor of cellular folate receptors and increases methylenetetrahydrofolate reductase activity, which is a crucial determinant of folate utilization in the methyl cycle. Phenobarbital and carbamazepine decrease the expression of reduced folate carrier (RFC), potentially reducing folate uptake and transfer to the fetus. Newer AEDs also alter folate uptake and transfer. Specifically levetiracetam and lamotrigine decrease placental expression of RFC and folate receptor α, respectively. In rodent models of fetal valproic acid or hydantoin exposure, treatment with folate reduces the risk of congenital malformation. Observational studies in women with epilepsy suggest periconceptional folic acid supplementation improves childhood behavior and cognition compared with later initiation of folic acid. In this context, preconceptional folic acid supplementation is recommended in a similar fashion as it is for all women of childbearing age for the prevention of neural tube defects (0.4 to 0.8 mg/day; see Chapter 1 ). The role of higher doses in women with epilepsy has yet to be determined, although some experts recommend at least 1 mg/day of folic acid for all women of childbearing potential taking AEDs, and up to 5 mg/day in women who require carbamazepine or valproic acid therapy.
Molecular Effects
Several AEDs induce widespread neuronal apoptosis in a manner similar to fetal alcohol exposure. As described in detail earlier, the mechanism of alcohol-induced apoptotic neurodegeneration is likely mediated through NMDA receptor blockade and hyperactivation of GABA A receptors . Similar neuronal apoptosis has been described in newborn rodents after exposure to phenytoin, phenobarbital, diazepam, and valproic acid, all of which directly activate GABA A receptors or increase levels of GABA through sodium channel blockade or inhibition of catabolism. Of concern, recent in vitro data suggest similar potential with oxcarbazepine. Interestingly, although carbamazepine appears to exert antiepileptic activity through a similar mechanism, apoptosis is only augmented in rat pups exposed at postnatal day 7 at concentrations that far exceed those used in clinical practice. Notably, AEDs with a less clear impact on GABA, including levetiracetam and lamotrigine, appear to induce little to no apoptosis in experimental models. However, with the exception of levetiracetam, these safer agents do potentiate cell death when used in combination with proapoptotic AEDs.
An additional mechanism of teratogenesis may be the generation of reactive oxygen species (ROS). Experimental models demonstrate the ability of fetal peroxidases to rapidly bioactivate hydantoin derivatives (phenytoin and carbamazepine) to free radical intermediates that initiate the formation of ROS. Valproic acid also increases the formation of ROS in embryos, an effect that may be inhibited by coadministration with antioxidants. In vitro models demonstrate ROS generation in astrocytes after exposure to gabapentin, oxcarbazepine, and topiramate, but minimal effects from levetiracetam and lamotrigine. ROS generation interferes with development by direct oxidative damage to cellular macromolecules, including DNA and RNA. In addition, ROS generation leads to dysregulation of signal transduction, thereby triggering apoptotic or necrotic cell death.
Later in gestation, the fetus develops an additional ability to generate toxic metabolites via the cytochrome P-450 enzyme system ( Fig. 42.9 ). Several AEDs, including phenytoin, phenobarbital, carbamazepine, lamotrigine, and valproic acid, undergo metabolism in multiple phases. The first phase is generally a two-step hydroxylation catalyzed by cytochrome P-450. The first step produces a highly reactive epoxide that can bind nucleic acids and impair developmental processes. Multiple systems exist to detoxify harmful epoxides, including epoxide hydrolase, resulting in a hydroxylated molecule. Glucuronidation of these molecules in a later phase produces a highly water-soluble metabolite suitable for urinary excretion. Increased exposure to epoxides in experimental models increases the risk of teratogenesis. For example, exogenous inhibition of microsomal epoxide hydrolase produces a higher incidence of fetal demise and anatomical abnormalities after phenytoin exposure in mice. Importantly, several AEDs (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, valproic acid, topiramate) induce the cytochrome P-450 system, increasing the generation of reactive epoxides, and valproic acid specifically inhibits microsomal epoxide hydrolase (see Fig. 42.9 ). Many investigators have proposed these interactions as a potential explanation for the increased incidence of teratogenesis observed with polytherapy regimens including valproic acid compared with monotherapy. Of note, inhibitors of the cytochrome P-450 system decrease the incidence of teratogenesis in experimental models. Importantly, this modulatory effect of polytherapy does not occur when using agents with no effects on the cytochrome P-450 system.
However, recent evidence suggests apoptosis may not be the fundamental mechanism of neurodevelopmental alterations from AEDs. These experimental models in mice highlight the importance of neocortical dysgenesis through alteration of proliferation and differentiation of neural progenitor cells. Specifically, valproic acid inhibits histone deacetylase, alters the expression of G1-phase regulatory proteins, inhibits neural progenitor cells from exiting the cell cycle during neocortical histogenesis, and increases the production of projection neurons in superficial neocortical layers. These findings highlight our incomplete understanding of the fundamental mechanisms underpinning well-described syndromes associated with valproic acid and other AEDs.
Genetic Factors
Genetic factors appear to mediate the incidence and severity of anomalies after prenatal AED exposure. Syndromic features are dramatically more likely to recur in children born to mothers with a previously affected offspring compared with mothers whose previous offspring showed no observable effects. The most frequently investigated and implicated gene is responsible for encoding MTHFR , the rate-limiting enzyme in the folate-activating methyl cycle. Maternal metabolic variability may also contribute. Cytochrome P-450 polymorphisms are common and result in more rapid production of toxic epoxides in some individuals. In addition, epoxide hydrolase exhibits polymorphisms that result in large variability in the capacity to detoxify metabolic intermediates. Observational studies of pregnant females taking phenytoin have found that lower epoxide hydrolase activity correlates with fetal hydantoin syndrome in offspring ( Fig. 42.10 ). However, the fact that these reactive hydrophilic metabolites most likely do not cross the placenta raises questions regarding these associations. In this case, maternal genetics may represent a proxy for fetal genetics, which clearly play a role in the risk of adverse outcomes associated with prenatal AED exposure. Children with major congenital anomalies after phenytoin exposure are also characterized by abnormal metabolite detoxification in experimental tests conducted in vitro after birth. Additional fetal genetic factors may include a sensitivity to the cardiac effects of AED exposure.
Prevention
As described, AED exposure during pregnancy increases the risk of congenital anomalies. However, maternal seizures put both the mother and fetus at risk for physical injury. Therefore preconception planning is ideal to allow careful consideration of the risks and benefits of transitioning the mother to a less teratogenic treatment plan. Expert recommendations suggest the avoidance of valproic acid, phenytoin, and phenobarbital. In addition, the avoidance of AED polytherapy is recommended if possible. However, experts emphasize that polytherapy may be preferable to monotherapy with valproic acid and may be necessary with newer AEDs to achieve seizure control. Based on available evidence, it appears levetiracetam and lamotrigine are the preferred AEDs in women of childbearing age with epilepsy, followed by carbamazepine, oxcarbazepine, or zonisamide.
Treatment
Newborns with withdrawal from phenobarbital respond well to postnatal phenobarbital therapy, starting on a dose of 3 to 5 mg/kg per day and then tapering very slowly, over months, as symptoms are controlled. Postnatal gabapentin at a dose of 5 to 10 mg/kg per day has been described as a successful intervention when withdrawal occurs secondary to prenatal gabapentin exposure with or without concomitant opioid exposure. As discussed previously, the incidence and treatment of withdrawal from other AEDs is less clear. Similar to newborns with FASD, newborns exposed to any AED in utero may benefit from developmental care.
The management of newborn infants whose mothers have been on AEDs during pregnancy to prevent neonatal hemorrhage has previously been recommended as follows: (1) consideration of delivery by cesarean section if a difficult or traumatic delivery is anticipated, (2) administration of oral vitamin K (10 mg/day) to the mother before delivery during the last month of pregnancy (parenteral vitamin K should be administered as soon as possible after the onset of labor if oral vitamin K was not given), (3) administration of vitamin K to the infant intramuscularly immediately after birth, (4) administration of fresh frozen plasma to the infant if clotting studies are distinctly abnormal, and (5) consideration of exchange transfusion if hemorrhage ensues. Oral supplementation of vitamin K 1 to the mother for 2 to 4 weeks before delivery prevented neonatal coagulation defects in one study. However, in view of the recent studies showing no increase in the risk of hemorrhage in infants whose mothers did not receive vitamin K during pregnancy, its use has been questioned. A more selective approach may be preferable, such as in pregnancies where there is a higher likelihood of hemorrhage due to trauma, prematurity, or other related risk factors. At least based on current evidence, prenatal vitamin K appears to pose no risks to the fetus but may have potential benefits.
Stimulants
Two classes of stimulants that are used recreationally and have been shown to affect fetal development are discussed here. These include cocaine and methamphetamines . The effect of cocaine on the fetus became an important issue during the crack cocaine epidemic of the 1980s. Cocaine is benzoylmethylecgonine, an alkaloid derived from the leaves of the Erythroxylon plant species. It is available in two forms: cocaine hydrochloride and highly purified cocaine alkaloid (free base). The latter is derived from the former principally by alkali extraction. Cocaine hydrochloride is heat labile but water soluble, and therefore is generally administered by nasal insufflation, orally, or intravenously. Cocaine alkaloid is heat stable but highly water insoluble and therefore is generally administered by inhalation (smoking). The cocaine alkaloid preparation is also called crack because of the popping sound made by the heated crystals.
In response to early concerns about the possibility of a “crack baby” syndrome, several large prospective longitudinal studies were initiated. These clinical studies, as well as experimental observations, have helped inform understanding of the neurological and developmental effects of prenatal cocaine exposure on the developing fetus and infant. Findings from these studies demonstrate that cocaine has the potential to cause, directly and indirectly, alterations in brain structure and associated behavioral functions in the child. However, in general, these effects were more subtle than first suggested. These longitudinal studies were also very important for the field in general because they helped advance methods and models of studying prenatal drug effects. Specifically, these studies helped (1) develop improved strategies for addressing the effects of confounding polydrug use and lifestyle factors; (2) establish more reliable and valid measures of drug exposure(s) and child outcomes assessments; (3) highlight the importance of postnatal environmental influences; and (4) emphasize the need for a life course perspective.
Because prenatal methamphetamine abuse is relatively recent, less is known about the outcomes of newborns after methamphetamine (Desoxyn in medical use; “meth” in the illicit setting) or amphetamine (Adderall, Dexedrine, Dextrostat, and Vyvanse in medical use; “speed” in the illicit setting) exposure. In contrast to cocaine, fewer studies have examined the effects of prenatal methamphetamine exposure on pregnancy, infant, and child outcomes. With the exception of a Swedish cohort ( n = 66 exposed infants) and the U.S.–New Zealand Infant Development, Environment, and Lifestyle (IDEAL) study ( n = 204 exposed and 208 unexposed infants), most research in this area is cross sectional and/or based on retrospective chart review. Thus especially for longer-term outcomes, conclusions are heavily dependent on one, if not two, longitudinal studies (see later). The mechanism of action of methamphetamine is similar to cocaine, promoting dopamine release through inhibition of reuptake transporters. However, there are also several important differences between the two drugs. First, the half-life of methamphetamine is nearly four times longer than cocaine, resulting in a greater window of drug exposure for the fetus during pregnancy. Second, although both amphetamines and cocaine exert their effect by blocking the reuptake of dopamine, amphetamines also increase the release of dopamine . Despite these differences and based on available information, there appears to be significant overlap between the pathological and developmental effects observed after exposure to these agents.
Prevalence
The exact prevalence of crack/cocaine use in pregnancy is not known, although estimates suggest a recent resurgence in the use of stimulants, including cocaine, methamphetamine, and prescription agents. Estimates vary widely depending on the method used to assess drug exposure, with hair and meconium analysis yielding higher rates than either self-report (which is susceptible to underreporting) or urine analysis (which captures only a short window of time during the pregnancy). For example, 11% of women self-reported illicit drug use in a large local cohort of 3000 urban women in Detroit in the early 1990s; however, a 31% prevalence of cocaine was detected on the basis of infant meconium analysis shortly after delivery. These rates and discrepancies were not confined to urban areas ( Table 42.12 ). More recent studies suggest the current national burden of cocaine exposure approximates rates in the early 2000s (~10% prevalence by meconium; ~7.5% by self-report), demonstrating that cocaine remains a common drug of abuse, especially in some urban areas of the United States.
TABLE 42.12
Incidence of Cocaine Use in a Suburban U.S. Hospital
Data from Schutzman DL, Frankenfield CM, Clatterbaugh HE, Singer J. Incidence of intrauterine cocaine exposure in a suburban setting. Pediatrics . 1991;88:825–827.
| PRIVATE ( n = 366) | CLINIC ( n = 134) | |
|---|---|---|
| Cocaine use (meconium) | 6.3% | 26.9% |
| Cocaine use (maternal report) | 0% | 4.0% |
Although amphetamine-based stimulants have a long history of use for fatigue and weight loss, it was not until the 1990s and early 2000s that methamphetamine abuse became a public health problem. This largely occurred as a consequence of the advent of illicit home manufacturing of the drug. Commonly known as ice or crystal , this crystallized form is heated and inhaled as a vapor, intensifying the euphoric (and addictive) effects of the drug. These home-based manufacturing laboratories initially emerged on the West Coast and in deprived rural areas of the United States, but then quickly spread across the North American continent and to regions of Southeast and East Asia, Australasia, South Africa, and parts of Europe, such as the Czech and Slovak Republics.
Limited information exists regarding the prevalence of methamphetamine use during pregnancy. Estimates in the United States vary by geographical region, with rates as high as 1% in the rural West. Importantly, many of these women are also subject to high levels of social and psychological disadvantage. For example, a large study of United States ( n = 127) and New Zealand ( n = 97) women, who either reported using methamphetamine during pregnancy or whose infant’s meconium tested positive for the drug, found that social disadvantage, single motherhood, and delayed prenatal care were relatively common. A large proportion also had comorbid psychiatric (48% United States, 43% New Zealand) and other substance abuse disorders (71% in both United States and New Zealand women), highlighting the complex presentation of these women and infants.
Clinical Features
Maternal-Fetal Effects
Cocaine use during pregnancy has deleterious effects on both the mother and the fetus. The specific features and the magnitude of these effects are relatively consistent across studies. A meta-analysis of 31 studies found that cocaine use during pregnancy was associated with significantly higher odds of preterm birth (OR = 3.4), low birth weight (LBW) (OR = 3.7) and being born small for gestational age (SGA) (OR = 3.2), with similar effects observed in nine studies specific to crack cocaine ( Table 42.13 ). On average, cocaine-exposed infants were born 1.5 weeks earlier and were almost 500 g lighter than nonexposed infants. Findings are mixed as to whether these infants catch up in growth, with one study finding no differences in the height and weight of exposed children between the ages of 1 and 6 years, and another reporting that they were in fact heavier at age 13 months, potentially indicating some postnatal compensation for intrauterine growth deficiencies.
TABLE 42.13
Odds of Selected Neonatal Outcomes Associated With Intrauterine Cocaine and Methamphetamine Exposure
Data from Tronick EZ, Frank DA, Cabral H, Mirochnick M, Zuckerman B. Late dose-response effects of prenatal cocaine exposure on newborn neurobehavioral performance. Pediatrics . 1996;98:76–83; and LaGasse LL, Wouldes T, Newman E, et al. Prenatal methamphetamine exposure and neonatal neurobehavioral outcome in the USA and New Zealand. Neurotoxicol Teratol . 2011;33:166–175.
| COCAINE | AMPHETAMINE | |||
|---|---|---|---|---|
| N INFANTS (EXPOSED AND NOT EXPOSED) | OR (95% CI) | N INFANTS (EXPOSED AND NOT EXPOSED) | OR (95% CI) | |
| Birth characteristics a | ||||
| Preterm birth (<37 weeks gestation) | 39,860 | 3.4 (2.7–4.2) | 62,070 | 4.1 (3.1–5.6) |
| Low birth weight (<2500 g) | 38,796 | 3.7 (2.9–4.6) | 26,132 | 4.0 (2.5–6.4) |
| Small for gestational age (<10th percentile for weight) | 28,098 | 3.2 (2.4–4.3) | 4383 | 5.8 (1.4–24.1) |
| Neurobehavioral features b | ||||
| 123,101 |
|
291,268 |
|
|
OR , Unadjusted odds ratio (95% confidence interval).
a Data from Gouuin K, Murphy K, Shah PS. Effects of cocaine use during pregnancy on low birthweight and preterm birth: systematic review and metaanalyses. Am J Obstet Gynecol . 2011;204:340.e1–e12; and Ladhani NN, Shah PS, Murphy KE. Prenatal amphetamine exposure and birth outcomes: a systematic review and metaanalysis. Am J Obstet Gynecol . 2011;205:219.e211–e217.
b Based on NBAS (Tronick et al) and NNNS (LaGasse et al) exam. Findings reported are after adjustment for covariates.
Similarly, a recent meta-analysis of five studies found that methamphetamine exposure during pregnancy was associated with increased risks of preterm birth (standardized mean difference = −0.613), LBW (standardized mean difference = −0.348), shorter body length (standardized mean difference = −0.198), and smaller head circumference (standardized mean difference = −0.479; see Table 42.13 ). The approach to confounders varies by study, with the most common consideration being prenatal consumption of alcohol, tobacco, and/or marijuana. Studies controlling for covariates showed that although risks were lower (OR range = 1.3 to 2.5), they remained statistically significant and consistent with unadjusted findings.
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