Alcohol and Drugs of Abuse in Pregnant Women: Effects on the Fetus and Newborn, Mode of Action, and Maternal Treatment

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.

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