Introduction
Several drugs and chemicals are known to be teratogenic to the human embryo when administered throughout pregnancy, especially during the period of organogenesis. The evidence for their teratogenicity has been shown by human epidemiologic and clinical studies as well as in studies carried out in animals such as rats, mice, rabbits, and primates. The most important disadvantage of the animal models used is the interspecies differences in toxicity and teratogenicity. These teratogenic insults occurring during embryonic life may be present immediately after birth, at infancy, or even later in life, especially if the damage involves the central nervous system. Moreover, many of the insults to the central nervous system occur in the second and third trimesters of pregnancy, when most other organs have already passed the stage of active organogenesis. Briefly, the main stages of human central nervous system development are the formation of the neural folds, their closure to form the neural tube that closes completely toward the end of the fourth week postfertilization, and the formation of the main brain vesicles during weeks 5 and 6, with the medulla, pons, and midbrain undergoing much of their active development during that time. However, the cortical plate starts to develop mainly during weeks 8–9 postfertilization, and the cerebellar cortex develops even later, mainly during the second and third trimesters of pregnancy. The cerebral cortex continues to develop actively throughout gestation and even in the early postnatal life, mainly by forming the different cortical layers, neuronal growth and sprouting, synapse formation, and myelinization. It is therefore expected that psychotropic agents such as ethanol, opioids, cannabis, and cocaine, as well as different psychotropic drugs, may affect the development of the central nervous system almost throughout the entire pregnancy. Hence, such late effect will not necessarily be manifested by distinct morphological changes in the central nervous system but rather by more subtle changes in intellectual capacity, learning ability, attention span, and behavior. Often, slight pathological changes in different regions of the brain can be demonstrated by using newer brain imaging methods.
In this chapter, we discuss only the possible effects of ethanol, opiates, cannabis, and cocaine use during pregnancy on the human embryo and fetus. We survey studies concerning substance-abusing women either throughout pregnancy or following sporadic use. In addition, we discuss some animal studies, especially those related to mechanism of action. Unlike other drugs that impact the central nervous system or other organs, all drugs of abuse may affect both the mother and embryo, inducing mainly, but not exclusively, behavioral and psychiatric problems and intellectual deficits.
Effects of Maternal Alcohol (Ethanol) Consumption During Pregnancy
History of Alcohol Effects in Pregnancy
The history of maternal alcoholism and development of the offspring goes back to the Bible and to early Greek mythology. Samuel the prophet forbids Samson’s mother from drinking wine during her pregnancy because she is going to give birth to an exceptional child blessed by God with special power, and the bridal couple, in Carthage, was forbidden to drink wine on the wedding night to prevent the birth of a defective child. In 1834, a report to the House of Commons (by a select committee investigating drunkenness) indicated that some of the alcoholic mothers gave birth to infants with “a starved, shrivelled and imperfect look.” Later, in 1900, the earliest suspicion of the teratogenic effects of alcohol came from Sullivan, who reported an increase in the rate of abortions and stillbirths as well as increased frequency of epilepsy among live-born infants of chronic alcohol-abusing women. The teratogenic effects of ethanol on human fetuses were first reported by Lemoine et al. in 1968. The authors described a common pattern of birth defects in 127 children born to alcoholic mothers in France that included growth deficiency, psychomotor retardation, low IQ, and atypical electroencephalogram. Alcohol was used at the time to prevent premature labor, and its use was so widespread that if any causal correlation existed between prenatal alcohol use and birth defects, it should have been recognized and reported long before 1968. The adverse/harmful effects of alcohol use during pregnancy have been suggested for decades, and despite the numerous case reports, the implication of alcohol as a teratogen was greeted with skepticism by the medical community. Furthermore, it was rather difficult to document or diagnose formally the constellation of problems observed in these children until guidelines for fetal alcohol syndrome were established.
Effects on the Developing Embryo and Fetus
Fetal Alcohol Spectrum Disorder
It is well known that alcohol in pregnancy may lead to a variety of damaging effects on the fetus. Hence, the general term for alcohol disruptive effects is fetal alcohol spectrum disorder (FASD). Basically, there seem to be several categories of prenatal exposure to ethanol related to quantity (amount of alcohol used), modality (whether continuous or binge drinking), and fetal age at exposure (whether pre- or postorganogenesis). Exposure to heavy drinking (more than 100 g of ethanol/day), which may cause the full-blown fetal alcohol syndrome (FAS), exposure to moderate drinking (between 50 and 100 g of ethanol/day), which may result in fetal “alcohol effects” (the differences between these categories are not sharp), and binge drinking-occasions with intakes of four to five drinks of ethanol (altogether more than 100 g of ethanol in each of such occasions. , Additional factors such as maternal age, weight, and genetic makeup of the mother and fetus play an important role. Most investigators are in agreement that binge drinking may also cause damage to the developing fetal brain. The amount of alcohol ingested, the length of the period of alcohol use, and the developmental stage of the embryo and fetus at exposure mediate the effects of ethanol intake on the developing fetus. It is important to note that a meta-analysis of reports on the incidence of fetal malformations in moderately alcohol-abusing women during pregnancy did not show an increase in congenital defects. Alcohol drinking, even in moderate amounts, also is associated with an increased risk of spontaneous abortions, especially in the first trimester of pregnancy, and with infertility in males and females.
It has been demonstrated by many investigators that high alcohol consumption during pregnancy may seriously affect the embryo. The severity of the malformations ranges from FAS, which is evident in 4%–6% of infants of heavy-drinking mothers with the typical clinical picture of facial dysmorphism, mental retardation, and disruptive behavior, to minor effects, such as low birth weight, intrauterine growth retardation, a slight reduction in IQ of the infants, and an increased rate of congenital anomalies and behavioral emotional changes.
Alcohol consumption during pregnancy was associated with a variety of abnormalities in the newborn. However, the more serious and specific syndrome FAS has been described only for regular/daily alcohol users. Fig. 8.2). a Recognition of the syndrome was made by Drs. David Smith and Kenneth Jones in 1973 based on the evaluation of eight children born to mothers who were defined as chronic alcoholics. The principal features were determined as prenatal and postnatal growth deficiency, short stature, developmental delay, microcephaly, fine-motor dysfunction, and facial dysmorphism manifested by short palpebral fissures, long smooth philtrum, thin vermilion border of upper lip, and maxillary hypoplasia. In addition, there may be cleft palate, joint anomalies, altered palmar creases, and cardiac anomalies. Many of these children also show disruptive behavior, such as severe ADHD, oppositional defiant disorder (ODD), conduct disorder (CD), and autism spectrum disorder (ASD)–like behavior. Many of them also need appropriate medication for their disrupted behavior. The above-described facial dysmorphism tends to improve with the advancement in age of the affected individuals.
Anomalies of Organs Other Than the Brain
Alcohol is known to affect not only the central nervous system but also organs that are developmentally related to central nervous system derivatives, including those developmentally dependent on neural crest cells like the craniofacial complex and the heart.
Orofacial Clefts
A number of reports addressed potential correlation between alcohol consumption and oral clefts. However, effect estimates were often unstable due to numbers of the cases studied. In a case-control surveillance study, Meyer et al. collected 5956 live-born infants with cleft palate, cleft lip, or both. Based on the maternal report of alcohol use during the first 4 months of pregnancy, the authors failed to link low levels of alcohol use and oral clefts. Even the highest level of alcohol consumption (three or more drinks per week, three or more drinks per drinking day, and maximum daily consumption of five or more drinks) did not result in a higher number of infants born with a cleft than did the use of less than one drink per week or less than one drink per drinking day. In addition, folic-acid–supplemented multivitamins used by some of the women did not modify the association between oral clefts and ethanol consumption. Contradictory results were reported by Romitti et al. based on the data from the National Birth Defects Prevention Study. The authors found a weak correlation between average periconceptional alcohol consumption and all orofacial clefts (combined and isolated clefts). A moderate link was identified for multiple clefts and for Pierre-Robin syndrome. Estimates for this latter phenotype, however, were based on small numbers, reflecting the study criteria to exclude cases of known etiology. An increased risk of orofacial clefts was observed among infants born to binge-drinking (five or more drinks per occasion) mothers exposed in the first trimester of pregnancy. Maternal binge drinking may be particularly harmful, since it results in a greater peak of blood ethanol concentration and, therefore, a prolonged alcohol exposure. In contrast, Bell et al. in their recent review and meta-analysis of 33 studies (from 737 publications) did not find any increase in oral clefts, with odds ratios near 1.00.
Cardiac Anomalies
There is sparse literature dealing with the effects of alcohol abuse in pregnancy on cardiac anomalies. It is accepted that about one-third of children with alcohol embryopathy will also have congenital cardiac problems. Krasemann and Klingebiel retrospectively reviewed electrocardiographic and echocardiographic data of all patients with clinical signs of alcoholic embryopathy between the years 1976 and 2003. Electrocardiographic and echocardiographic measurements often showed slightly altered values in individuals with alcoholic embryopathy, resulting in the conclusion that alcohol abuse during pregnancy as a primary toxin can lead to minor cardiac abnormalities, even without structural congenital cardiac defects. Conotruncal cardiac defects are among the more common serious cardiac anomalies following periconceptional use of alcohol, but the extent of their increase following alcohol use in pregnancy is in debate.
Reduced Fetal Growth
Intrauterine growth restriction is a well-known feature of alcohol embryopathy. There is a growing mass of data demonstrating postnatal long-term height and weight deficits among children born to ethanol-using women. Furthermore, Covington et al. found a moderating effect of maternal age on children’s weight at age 7, as children born to women over 30 years of age at the time of birth had significantly lower weight compared with those born to younger women. Nykjaer et al. found that alcohol drinking, mainly in the first trimester of pregnancy, is associated with reduced birth weight and increased prematurity.
Behavioral and Developmental Changes
1. Attention-deficit/hyperactivity disorder (or ADHD): Alcohol is considered one of the risk factors for ADHD, independently of prenatal nicotine exposure or other familial-hereditary risk factors. One study showing a positive correlation between alcohol and ADHD included 26 prenatally alcohol-exposed children. Of the 24 children followed up, 10 were diagnosed with ADHD, two with Asperger syndrome, and one with mild mental retardation. The severity of the disorder correlated in a linear pattern with the amount of alcohol used by the mother during pregnancy. This effect was reversible, since discontinuation of alcohol consumption by the 12th week resulted in normally developed children. Moreover, consumption of less than one alcoholic drink per day in the last 3 months of pregnancy, despite heavier drinking earlier, did not result in increased rate of ADHD, learning disabilities, or cognitive impairment at the age of 14 years.
It has been difficult to define and characterize developmental risks associated with binge drinking or moderate drinking in pregnancy, and some studies have failed to demonstrate an association between alcohol exposure and sustained attention performance in school-aged children.
2. Intellectual impairment: Alcohol in pregnancy may affect intellectual ability, which, together with attention span and behavior, is considered a higher function of the cerebral cortex. Children with the complete FAS generally have different degrees of mental retardation, occasionally moderate to severe retardation. Studies in 7-year-old school children following prenatal exposure to moderate amounts of alcohol show a decrement of 7 points in IQ. Binge drinking was also associated with poorer achievements at school compared to children of nondrinking mothers. On the other hand, drinking relatively low amounts of alcohol (1-2 drinks/week) did not result in any increased risk of cognitive or behavioral difficulties.
3. Cerebellar changes: Alcohol may affect the cerebellum. In the human cerebellum, Purkinje cell migration is completed and dendritic outgrowth begins around gestational week 26, extending to the third trimester of pregnancy. Consequently, a period of enhanced vulnerability of Purkinje cells to binge alcohol exposure in humans would be predicted near the end of the second trimester and may extend over the first half of the third trimester. Cerebellar developmental disorders and disproportionate reduction in the anterior cerebellar vermis have been identified by magnetic resonance imaging (MRI) in children who were exposed prenatally to alcohol during each trimester of pregnancy. Decreased cerebellar growth and decreased cranial-to-body growth in fetuses of alcohol-abusing mothers were also observed on fetal ultrasound performed in the 18th week of gestation. If the mothers stopped drinking at the beginning of pregnancy, cerebellar growth was normal.
Mechanisms of Alcohol Teratogenicity
The exact mechanism(s) of the teratogenic effects of alcohol on the developing embryo and fetus are not yet well established. However, the extent of damage depends on the dose, duration, and developmental stage at exposure. Different mechanisms have been offered to explain the teratogenic effects of alcohol on the developing embryo. They stem from results of different experimental studies and include the following: (1) increased oxidative stress; (2) disturbed metabolism of glucose, protein, lipid, and DNA; (3) epigenetic changes; and (4) effects on neurons: impaired neurogenesis and increased cellular apoptosis, especially of neural crest cells.
Oxidative Stress
One process implicated is an alteration in the reduction-oxidation reaction status in the central nervous system. This hypothesis was supported by studies demonstrating that ethanol mediated changes in the production and/or activity of endogenous antioxidants in various organs, including the cerebellum and placenta.
Oxidative stress has been increasingly recognized as one of the mechanisms underlying ethanol toxicity. Ethanol can induce oxidative stress directly by formation of free radicals, which react with different cellular compounds, or indirectly by reducing intracellular antioxidant capacity, such as decreased glutathione peroxidase levels. The levels of oxidative stress markers were studied in placental villous tissue following 2 hours of ethanol perfusion. The results demonstrated a significant increase in oxidative stress, primarily involving the nitric oxide pathway in the trophoblast and DNA damage in the villous stromal cells. Alcohol-induced oxidative stress was also found to increase lipid peroxidation and damage protein and DNA.
Disturbed Metabolic Pathways: Prostaglandin Synthesis
Alcohol is known to affect prostaglandins, hence influencing fetal development and parturition. When mice were treated with aspirin (a prostaglandin synthesis inhibitor) prior to alcohol exposure, aspirin pretreatment reduced by 50% the alcohol-induced malformations in comparison with mice treated with aspirin after alcohol exposure.
Effects on Neurons
Several studies in rats and mice have shown that in utero exposure to alcohol caused structural defects in the hippocampus, cerebellum, and neural crest cells, with increased cell death. Similar changes in the brain of affected children were also described.
Epigenetic Changes
Epigenetic changes manifested by changes in gene expression, DNA methylation, histone modification, and changes in micro RNA have been observed in children with FASD. Recently, Laufer at al. have found changes in DNA methylation in six children with FASD. These DNA methylation changes, observed in DNA obtained from buccal swabs, are influenced by sex and medication exposure. Masemola et al. studied the methylation of DNA samples obtained from blood or buccal cells in 73 children with FAS compared to 50 control children, and they found, by using pyrosequencing, hypomethylation at KvDMR1 and PEG3 DMR genes, which are maternally imprinted loci. Changes in DNA methylation are responsible for changes in gene expression, which might induce a variety of long-term behavioral and molecular changes in the brain. Similar epigenetic changes were also observed in mouse models of FASD.
In light of these different mechanisms of action, it is reasonable to presume that alcohol-induced teratogenicity is probably the result of injuries caused by several mechanisms.
Prevention and Treatment
Prevention
Because the diagnosis of FAS in young children is often difficult, the first challenge is identification and follow-up of children at risk. The second challenge is to prevent this disorder by preventing alcohol drinking. Unfortunately, there are only a few reports demonstrating success in reducing drinking of alcohol in pregnancy, and these reports even declined from 1995 to 1999. The rate of binge drinking apparently remained stable, and chronic heavy drinking remained unchanged, suggesting that the education programs were not effective. Preventing alcohol abuse must therefore start with educational programs in schools and later during academic studies. Prevention programs need to be addressed primarily toward high-risk individuals and groups.
Treatment During Pregnancy
Assuming that oxidative stress is one of the major routes of ethanol-induced damage, it is reasonable to supplement with antioxidants in an effort to attenuate this damage. Antioxidants, such as vitamin C, vitamin E, folic acid, beta-carotene, and flavonoids can be supplemented by food, therefore reversing other nutritional deficits common among this population. However, to our knowledge, only a few, if any, such programs exist.
Treatment of the Child With Fetal Alcohol Spectrum Disorder
There is no effective treatment for children with FASD. However, treatment of the behavioral and emotional symptoms as well as special educational methods are helpful in improving the neurobehavioral function of the affected children. Stimulants can be used for the treatment of ADHD, inducing improvement in more than 80% of the children with ADHD. Aggression and defiant behavior can best be treated with low doses of risperidone or other neuroleptics. These can be given even in children treated with stimulants (i.e., methylphenidate, dextroamphetamine, and so on) because of ADHD symptoms.
Lactation
Because alcohol is transferred to human milk, reaching levels similar to those in maternal serum, women drinking high amounts of alcohol should refrain from nursing their infants. Moreover, nursing infants suckle lower amounts of alcohol-containing milk. If nursing mothers drink only small-to-moderate amounts of alcohol, they should wait 2–3 hours before nursing their infants. In infants fed on milk from mothers who drank heavily, the sleep patterns of their nursing infants were disturbed.
Prevention and Treatment of Alcohol-Exposed Pregnant Animals
Alcohol-exposed C57BL/6 J mice were injected twice with 2.9 g/kg, 4 hours apart, of EUK-134 (a potent synthetic superoxide dismutase plus catalase mimetic) on their ninth day of pregnancy. EUK-134 supplementation induced a notable reduction in cell death of the apical ectodermal ridge of the newly forming limb buds in ethanol-exposed embryos and reduced the forelimb malformations by about half (67.3%–35.9%).
Further support for the efficiency of antioxidants in attenuating the teratogenic effects of alcohol consumption throughout pregnancy comes from Wentzel et al., who studied the effects of 5% vitamin E added to food on the outcome of ethanol-exposed rat pregnancies, showing a reduced rate of malformed or dead fetuses, but no change in the alcohol-induced reduction of body weight.
Animal Models for Alcohol-Induced Embryopathy
The growth spurt of the human brain is mainly during the third trimester of pregnancy, continuing into postnatal life. In rats, the brain growth spurt takes place almost entirely in the postnatal period. Therefore, rats must be exposed to alcohol during the equivalent periods of the brain development in humans, which is in the early postnatal life. The reduced Purkinje cell number demonstrated by Goodlett et al. supports the contention that a significant amount of pathological loss of postmitotic Purkinje cells occurs, yet it is dependent on the time of alcohol exposure. Hamre and West found in newborn rats that postnatal days 4–6 were the most sensitive period for cerebellar Purkinje and granule cell loss following binge alcohol exposure.
Alcohol exposure of pregnant rats, equivalent to all three trimesters of human pregnancy, was shown to reduce cerebellar Purkinje cell numbers compared with the group that was exposed only in the third or first and second trimesters equivalent. In contrast, exposure to alcohol in the third trimester equivalent yielded a decrement in the olfactory bulb mitral cell numbers as compared with other timing groups (first or second trimester).
Similar results were demonstrated by Ramadoss et al., utilizing an ovine model to determine the critical period of vulnerability of fetal Purkinje cells following prenatal alcohol abuse, mimicking a human binge pattern during the first and third trimesters of pregnancy. In these animals, unlike the rat model, the entire brain development occurs in utero. They found that the fetal cerebellar Purkinje cells are sensitive to alcohol throughout gestation. The short- and long-term effects of ethanol were studied by Dembele et al. in 7-day-old and 3-month-old rats following alcohol exposure. They found that prenatal ethanol exposure led to hypothalamic oxidative stress persisting into adult life and being significantly higher among the group of older rats, implying long-term damage of ethanol consumption during pregnancy.
In a meta-analysis of 22 studies using different strains of rats and one study on mice, Chotro et al. found in 18 of 22 studies that prenatal exposure to ethanol increased ethanol intake among the offspring. The four remaining studies failed to show any effect whatsoever, a result interpreted and explained as the age of testing, 120 days and over. Simpson et al. have shown that alcohol exposure in rats decreased fetal body weight and bone length and delayed skeletal ossification. These effects persisted postnatally, leading to growth plate abnormalities and decreased skeletal maturity scores at 2–4 weeks of age. FAS-like craniofacial malformations were demonstrated by Rogers et al. following treatment of pregnant C57 BL/6 J mice with methanol on GD-7 during gastrulation. These malformations included anophthalmia, microphthalmia, holoprosencephaly (in varying degrees), and ear and jaw malformations. The involvement of ethanol in cardiac anomalies was also studied in rats. Alcohol administration during pregnancy reduced cardiac mass and depressed function, evidently, due to microstructural changes of the myocytes, even when affected animals reached adulthood.
The exposure of Xenopus laevis frog embryos to alcohol during gastrulation has shown that alcohol competes with retinoic acid retinaldehyde dehydrogenase 2, interfering with retinoic acid signaling pathway. Thus interference in such an early phase in this important pathway may explain many of the observed injuries in FASD. Whether this mechanism is also operating in humans is as of yet unknown, but we have to remember that the damaging effects of alcohol are not confined only to the early phases of embryonic development, as initiation of alcohol ingestion in the second half of pregnancy is also teratogenic in humans.
Recently, epigenetic changes have been described in the brains of mice exposed in utero to alcohol. Specific changes were observed in the PTEN/P13K/AKT/mTOR pathway, which is responsible for alterations in cell adhesion and proliferation, inducing long-lasting changes in cortical regions of the brain.
Conclusions
Maternal alcohol ingestion in pregnancy may have deleterious effects on the central nervous system and other organs of the developing embryo and fetus, depending on the dose and duration and on the developmental stage of the embryo at exposure. These embryotoxic effects of alcohol were observed in many animal species. It is therefore important to reduce alcohol drinking during pregnancy to a minimum. However, as of today, it is still difficult to define the minimal dose that will affect the developing embryo and the exact dose-response relationship. Animal studies are helpful in understanding the pathogenesis of FASD but do not help in the delineation of the exposure level that may be safe in pregnancy.
Heroin-Dependent Mothers in Pregnancy
Pregnant mothers who are heroin dependent often belong to one of the following three categories: (1) women treated with opiates (i.e., methadone and in recent years also buprenorphine or naltrexone) and who carefully follow the treatment regimen, (2) women treated with opiates but who on occasion also use heroin or other street drugs, and (3) women addicted to heroin or other opiates and who hence use heroin, depending on availability. These women also have periods without drugs, a fact that may result in withdrawal symptoms in the mother and the fetus. In many cases, these mothers also use other psychotropic drugs such as benzodiazepines, phenothiazines, or barbiturates. Rarely, they may also use cocaine. Many of these women also smoke cigarettes and/or ingest different amounts of ethanol (alcohol). Moreover, they often do not seek medical care and suffer from medical neglect even during pregnancy. The addicted mothers are at increased risk for various acute and chronic serious infections, such as hepatitis B, hepatitis C, and HIV.
Relation Between Substance Abuse and Attention-Deficit/Hyperactivity Disorder
Several studies have found an association between ADHD and substance abuse. The prevalence of substance abuse is therefore much higher among persons with ADHD, which was found to be common among opioid (heroin) abusers. It is more difficult to treat opioid-dependent individuals with ADHD than it is to treat those without it. Moreover, stimulant treatment of adolescents with ADHD can effectively reduce the rate of substance abuse. In addition, there seem to be specific differences between drug abusers with and without ADHD. Drug abusers with ADHD report an earlier start to using the substances; their substance abuse is more severe, and they may also need treatment for their ADHD to achieve abstinence. Similar types of genetic polymorphism to genes related to dopamine metabolism have been found among individuals with ADHD and those who are heroin dependent. For example, several investigators have shown in heroin-dependent individuals, or those with other substance abuse, a polymorphism to the catechol- O -methyl transferase gene, to the dopamine D4 receptor, or to the mu-opioid receptor gene. Similar gene polymorphism was also observed in individuals with ADHD.
Effects of Heroin and Opiates on the Fetus and Newborn
Although several reports of children with congenital anomalies born to heroin-dependent mothers have been published, there is no consistent pattern of anomalies, and heroin is not considered to be a teratogenic agent and, in contrast to cocaine, is not considered to cause intrauterine fetal bleeding or placental abruption. a
a References 36, 86, 87, 121, 136, 139, 143.
However, heroin (and opiate) use during pregnancy is associated with increased prematurity, low birth weight, small head circumference, and increased neonatal and perinatal mortality. Withdrawal symptoms may also develop in 40%–80% of the newborns; a high incidence of sudden infant death syndrome during the first year of life was also described, although this is subject to some debate. The use of methadone during pregnancy seems to be much safer for the developing embryo and fetus, with relatively few side effects, but withdrawal symptoms are frequent in the offspring of methadone-treated mothers to the same extent as with heroin.Effects on Postnatal Development
Developmental delay, as well as behavioral and emotional problems, was often encountered in children born to opiate-dependent mothers using heroin or methadone during pregnancy. b
b References 36, 86, 87, 121, 136, 139, 143.
Some investigators have demonstrated an improvement of the developmental scores in these children with the advancement of age, but others have not. A high proportion of children demonstrated inattention, hyperactivity, aggressiveness (ADHD), and lack of social inhibition. cc References 20, 37, 102, 107–109, 129.
The environment in which a child is raised seems to be one of the most important factors that determine his or her developmental outcome. In children born small for their gestational age, the parental socioeconomic status influences the development, especially during the early years of life, with children in families from lower socioeconomic status failing to show developmental recovery. In fact, the relative impact of the clinical and biological factors of these children seems to be overshadowed by the family factors. A similar phenomenon was described repeatedly in very-low-birth-weight infants, where the major factors affecting cognitive development of the children were the home environment and their neurological status.
In studies describing the development of children born to heroin-dependent mothers, often there may be many confounding factors influencing the results. They are often influenced by the fact that they suffer from significant neglect. Therefore the outcome is the result of interaction between in utero exposure to heroin and the postnatal environment. Hence it is important in evaluating the outcome of these children to compare them with relevant controls.
We had the opportunity to study the developmental outcome of children born to heroin-dependent mothers who were either raised at home or sent for adoption (or foster homes) immediately after birth or at a very young age. Because there is evidence of a correlation between socioeconomic status and cognitive functioning of children, and most adoptions are into middle or high socioeconomic status environments, adoption should have a positive effect on cognitive functioning. Indeed, most adopted children score in the normal range on assessment of cognitive and emotional development. This enabled us to isolate the prenatal effects of heroin on neurobehavioral development from the postnatal possible impact of environmental deprivation, which is so common in families of drug addicts.
Comparison groups were composed of children born to heroin-dependent fathers; children with severe environmental deprivation born to nonaddicted parents of low socioeconomic status; and a group of normal, age-matched children. About 400 children from 6 months to 12 years of age were studied.
A lower birth weight and a shorter gestation were recorded for children born to heroin-dependent mothers and, to a lesser degree, for children born to heroin-dependent fathers when compared with the other groups. The head circumference and height at examination were lower for children born to heroin-dependent mothers raised at home in comparison with controls. There was no difference in the weight at examination among the different groups of children.
Intellectual Developmental Outcome
We have found that children of preschool age born to heroin-dependent fathers, thereby not being exposed in utero to heroin, function as poorly as children born to heroin-dependent mothers. However, paternal drug use in and of itself did not have a more deleterious effect on school-age children than parental low socioeconomic status, and children born to nonaddicted parents who had environmental deprivation performed even less well than children born to heroin-dependent fathers or to mothers with nonaddicted fathers. Finally, when children of preschool-age born to heroin-dependent mothers were adopted at a young age and hence raised in a stable environment, their intellectual function was similar to that of control children. These results show that in utero exposure to heroin per se does not affect the cognitive ability of preschool-age children, and that most harm to those children is caused by their unstable postnatal environment because the mother is a heroin addict. However, there was a high rate of children with behavioral problems among those born to heroin-dependent mothers when the children were raised at home.
We then studied similar groups of children aged 6–12 years who attended regular school. At that age, the children born to heroin-dependent mothers had a very high rate (54%) of inattention and hyperactivity (ADHD). The rate of ADHD was reduced to 24% in the heroin-exposed adopted children, whereas 24% of those born to drug-dependent fathers (and not exposed to heroin) had ADHD. It is important to add that 21% of the children with environmental deprivation had ADHD, whereas none of the control children had it, as evidenced from the abbreviated Conner’s Questionnaire. We also studied their arithmetic and reading abilities and found that they were poor in the children born to heroin-dependent fathers, in those born to heroin-dependent mothers when children were raised at home, and in the children with environmental deprivation. However, the adopted children at that age had slightly lower cognitive abilities compared with controls, although the difference was not statistically significant. Their arithmetic and reading abilities were also lower.
Because it is possible that the high incidence of inattention, hyperactivity, and behavioral disorders found in the children in our study is related to a high incidence of ADHD among their parents who were therefore prone to substance abuse more than the general population, we used the Wender-Utah questionnaires to assess for maternal ADHD. We indeed found a high rate of ADHD among drug-dependent mothers. However, there was no correlation with the rate of ADHD in their children, implying that in utero heroin exposure is responsible, at least partially, for the high rate of ADHD among the heroin-exposed children, whether raised at home or adopted. This is in line with other studies showing a high rate of ADHD among the offspring of heroin-dependent parents.
We also studied the development of these groups of children at 12–17 years of age. The findings were similar to those observed in children at school age, with a high rate of ADHD and learning and behavioral problems in the heroin-exposed children. Moreover, adolescents born to heroin-dependent mothers who were raised at home performed less well than adolescents with environmental deprivation, implying that heroin might have affected some of the higher cortical functions that are related to learning abilities and attention span. In that context, we should mention that other investigators have found that exposure to multiple risk factors is associated with poor developmental outcomes. Therefore in utero heroin exposure and postnatal poor environment may have a multiple and long-lasting deleterious effect.
The beneficial effects of a good postnatal environment on the intellectual and behavioral outcome of children born to heroin-dependent mothers emphasize the importance of the social and educational services for improving the outcome of children of drug-dependent parents, as well as of children from low socioeconomic status families.
Polymorphisms in dopaminergic and serotonergic genes such as DAT1 , 5HTTLPR , D4DR4 , and MAO – A have been linked to ADHD and also to susceptibility to opiate addiction. We investigated in opiate-addicted parents and their children the rate of ADHD and genetic markers that could predict susceptibility to ADHD and/or opiate addiction. A total of 64 heroin-addicted, methadone-maintained parents and their 94 children who had or had not been exposed prenatally to opiates were studied. DNA was extracted from mouthwash and assessed for genetic polymorphism for six polymorphic sites of four different genes. Study subjects also filled a variety of questionnaires assessing the rate of ADHD in the parents and children, and the children’s Intelligence Quotient (IQ). Children of opiate-dependent mothers had a higher rate of ADHD compared to children of the opiate-dependent fathers, without correlation with the presence of ADHD in their parents, demonstrating again that intrauterine exposure to heroin increases the rate of ADHD. Opiate-dependent parents have a high risk of being carriers of most risk alleles examined, except DRD4EX3 (allele7). There was no difference whether the addicted parents did or did not have ADHD. From these studies, it seems that serotonergic and dopaminergic risk alleles seem to be related mainly to opiate dependence with no effect on the occurrence of ADHD. Hence people carrying those polymorphisms are susceptible to opioid addiction and not necessarily to ADHD.
Because in many cases where the mother is drug dependent it is expected that the father will be addicted as well, it is important to mention that children born to drug-dependent fathers were also shown to be at risk for developmental problems as well as for ADHD, further demonstrating the importance of the postnatal environment. Sowder and Burt found that children born to heroin-dependent fathers were at high risk for early school behavioral and learning problems. Similarly, children born to drug-free parents of a similar underprivileged environment and low socioeconomic status were also at risk for early school problems, but to a lesser extent. These results are similar to our findings in school-age children. Herjanic et al. found slow mental development in 44% of children born to heroin-dependent fathers. By age 12, conduct disorders and behavioral problems were common among these children. Behavioral problems, attention deficit disorder, and ADHD were also described in the offspring of cocaine-using mothers. Thus whenever both parents are addicted, their children seem to be at higher risk than when only the mother is addicted.
Treatment of the Pregnant Mother
The most common approach for treating opiate addicts, whenever weaning is unsuccessful, is methadone treatment. Because it is not accepted to wean pregnant women from heroin, methadone is the preferred treatment in pregnancy. The daily doses vary and range from 10–20 mg up to 100 mg or even more, according to individual needs. Pregnancy outcome in women who are on strict methadone treatment throughout the entire pregnancy and attend antenatal care seems to be good, with very little long-term effects on the infants except neonatal abstinence symptoms that are common and necessitate transfer to neonatal special care units. However, there seems to be no correlation between the presence of withdrawal symptoms and developmental outcome, even in children born to heroin-dependent mothers. Although methadone treatment during pregnancy seems to be relatively safe, more recent studies show that women treated with methadone have similar complications of pregnancy as those that are heroin dependent, although to a lesser degree. Relatively low amounts of methadone are transferred to milk and therefore women on methadone maintenance can nurse their infants.
In the last few years, there have been two additional successful approaches to treatment, using either buprenorphine (an opiate with agonist-antagonist properties) or naltrexone (an opiate antagonist) in low, intermediate, or high doses. In some cases, buprenorphine was administered through slow-release implanted devices. Both of these methods are successful in maintaining normal pregnancy outcomes, but they do not seem to be superior to methadone in terms of maternal retention of treatment. However, it is possible that these new modes of therapy are superior to the traditional methadone treatment for the fetus, as prematurity, fetal weight at birth, withdrawal symptoms, and other pregnancy complications were apparently lower than with methadone maintenance. However, in one study of 25 children born to heroin-addicted mothers who were treated with buprenorphine, there was a higher rate of inattention and memory problems at 5 and 6 years compared to controls. The few data that exist on the specific effects of naltrexone on the developing fetus seem to be reassuring.
Lactation
Because heroin and other opiates are transferred to human milk, reaching relatively high levels, women using heroin or other opiates might be advised to refrain from nursing their infants, depending on the dose. This is because of the depressive effects of large amounts of opiates on the central nervous system, including the possibility of causing respiratory depression in the suckling infants. As stated above, nursing is permitted in women treated with methadone, depending on the daily dose. Both naltrexone and buprenorphine are excreted in human milk but lactation is permitted, depending on the dose.
Animal Models for Heroin- and Opiate-Induced Fetal Damage
There are not too many studies on the effects of heroin on pregnancy in animals. This stems from the fact that in the absence of structural anomalies following exposure to heroin and opiates in experimental animals, it is difficult to use animal models that mimic the behavioral changes observed in men. However, several studies were carried out on pregnant mice and rats, demonstrating functional and pathological changes in various parts of the brain in the offspring. Such studies have used in pregnant rats osmotic mini-pumps with opiates or opiate antagonists-buprenorphine, naloxone, and methadone-demonstrating changes in mu-opioid receptor G protein in the offspring, with male offspring showing more sensitivity than female offspring. Slotkin et al. found in mice that administration of heroin during pregnancy causes changes in the hippocampal cholinergic neurons of the offspring, as it induced a deficit in muscarinic cholinergic receptor-induced translocation of protein kinase C gamma. These authors also demonstrated changes in adenylyl cyclase, the latter changes also occurring in the cerebellum, where there are only few cholinergic neurons. Changes in signaling proteins distal to neurotransmitter receptors were proposed by the authors as a general mechanism related to several neuroteratogens. Whether these changes are relevant to the human situation is currently unknown.
Of special interest is the fact that grafting of neural progenitor cells into the hippocampus of these mice offspring at adulthood reversed the behavioral deficits observed in non-treated, heroin-exposed mice .
Conclusions
Heroin exposure in utero seems to have little effect on the intellectual ability of young children if they are raised in a supportive environment. However, it induces a high rate of ADHD, which seems to be attributed to the direct effect of heroin on the fetal brain as well as to genetic and environmental factors. Moreover, ADHD and opiate addiction share several common issues like similar genetic polymorphism and the relation to the dopaminergic brain systems. We should try to improve the home environment of the children born to heroin-dependent mothers and thus minimize the damaging effects of maternal drug addiction. It is important to develop adequate social and educational services to improve the outcome of children of drug-dependent parents as well as of children from low socioeconomic status families. Appropriate treatment of children with ADHD might reduce the rate of addiction to drugs in general and to opiates specifically.
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