Part 36 (1/2)

The diagnostic features of FAS are: (1) prenatal and postnatal growth deficiency (Faden and Graubard, 1994; Greene et al et al., 1991; Larroque et al et al., 1993); (2) mental r.e.t.a.r.dation (Autti-Ramo et al et al., 1992a; Jacobson et al et al., 1993); (3) behavioral disturbances (Coles et al et al., 1987); and (4) typical recognizable facial appearance (Box 16.2) (Autti-Ramo et al et al., 1992b; Lewis and Woods, 1994). The most frequent congenital anomalies are heart defects (Loser et al et al., 1992) and brain anomalies (Mattson et al et al., 1992), but other major congenital anomalies (e.g., spina bifida, limb defects, genitourinary defects, eye anomalies, airway obstructions, renal hypoplasia) also occur (Carones et al et al., 1992; Froster and Baird, 1992; Hinzpeter et al et al., 1992; Lewis and Woods, 1994; Taylor et al et al., 1994; Usowicz et al et al., 1986).

Absence of the full syndrome but presence of mild to moderate mental and physical growth r.e.t.a.r.dation, and are known collectively as fetal alcohol effects (FAE) (Jones, 1989).

Box 16.2 Features of fetal alcohol syndrome Craniofacial anomalies Major anomalies Absent-to-hypoplastic philtrum Brain defects Broad upper lip Cardiac defects Flattened nasal bridge Spinal defects Hypoplastic upper lip vermillion Limb defects Micrognathia Genitourinary defects Microphthalmia Short nose Short palpebral fissures Effects on postnatal development In one study, children born to women who abused alcohol during pregnancy had physical growth delays of 2 years or more reported as the long-term consequences of intrauterine alcohol exposure on the child's physical and cognitive development. The investigators found that at 5 years of age the children whose mothers had continued drinking during pregnancy showed more alcohol-related deficits than non-alcohol-exposed children or children whose mothers stopped drinking in the second trimester of pregnancy. Transient withdrawal symptoms, including tremors, hypertonia, and irritability, were reported among infants born to women who chronically drank alcohol late in pregnancy (Coles et al et al., 1984), and we have also observed similar findings at Parkland Memorial Hospital (Little et al et al., 1990a).

Children continually exposed to alcohol had smaller heads, lower IQs, other deficits in intellectual functioning (short-term memory and encoding), problems in preacademic Amphetamine abuse during pregnancy Amphetamine abuse during pregnancy 307.

skills, including abstraction, arithmetic, and speech (Autti-Ramo and Granstrom, 1991; Becker et al et al., 1990; Caruso and ten Bensel; 1993; Coles et al et al., 1991; Spohr et al et al., 1993; Streissguth et al et al., 1985, 1991a, 1991b).

Factors other than alcohol abuse that may have an etiologic role in FAS include poor protein-calorie nutrition, vitamin deficiencies, and alcohol contaminants (e.g., lead). In addition, there is genetic polymorphism for alcohol dehydrogenase, implying a pharmacogenetic etiologic role in the severity of effects.

COUNSELING.

It is clear that women who abuse alcohol during pregnancy should be counseled to stop drinking completely. Importantly, medical and psychological support for cessation of drinking should be offered. Since many of these women may also abuse other substances, they should also be advised to stop using these agents.

Alcohol summary Fetal alcohol syndrome is one of the three leading causes of mental r.e.t.a.r.dation.

Importantly, FAS is the only one that is potentially preventable. In addition, this syndrome is a leading cause of poor pregnancy outcome and childhood morbidity (congenital anomalies, including mental r.e.t.a.r.dation). Advice against any use of alcohol during pregnancy cannot be overemphasized. Even maternal consumption of less than three drinks per day has been a.s.sociated with mild to moderate lowering of IQs among infants (Streissguth et et al al., 1981) and with prenatal growth r.e.t.a.r.dation (Larroque, 1992; Larroque et al et al., 1993).

AMPHETAMINE ABUSE DURING PREGNANCY.

Dextroamphetamines (D-amphetamine, amphetamine) and methamphetamines are sympathomimetic agents used medically during pregnancy to treat narcolepsy. They are also used illicitly as stimulants and have a number of street names. Approximately 6 percent of pregnant women tested positive for methamphetamines at delivery in one study (Little et al et al., 1988a; Ramin et al et al., 1994) and the majority of such women were White (Little et et al al., 1988a, 1988b). No studies are available regarding the illicit use of amphetamines during pregnancy. Several factors complicate extrapolation of these results to illicit use or abuse: (1) dose regimens in illicit use are not controlled; (2) they likely involve amounts much greater than those used therapeutically; and (3) harmful impurities (e.g., dilutants) may be present in illicit amphetamines or methamphetamines.

Methylphenidate (Ritalin), dextroemphetamine (Dexedrine) and a c.o.c.ktail of amphetamine salts (Adderall) are stimulants with potential for abuse that are often represented as amphetamine or methamphetamine by those who distribute illegal drugs.

Amphetamines HUMAN CONGENITAL ANOMALIES.

The frequency of congenital anomalies was not increased among 69 infants whose mothers abused amphetamines during the first trimester. However, preterm delivery and 308 308 Substance abuse during pregnancy perinatal mortality were increased in frequency (Eriksson et al et al., 1981). Follow-up of these children found that 15 percent were delayed in academic achievement in school, but other adverse effects were not reported (Eriksson et al et al., 2000).

Medically supervised use of amphetamines during pregnancy is not convincingly a.s.sociated with an increased frequency of congenital anomalies among several thousand infants exposed during the first trimester (Heinonen et al et al., 1977; Milkovich and van den Berg, 1977; Nelson and Forfar, 1971; Nora et al et al., 1967, 1970) ANIMAL STUDIES OF AMPHETAMINES ANIMAL STUDIES OF AMPHETAMINES Cardiac, eye, and a variety of other congenital anomalies were increased in frequency at maternally lethal doses among mice whose mothers were treated with ma.s.sive doses of amphetamines during pregnancy (Nora et al et al., 1965). The relevance of these findings to human amphetamine use is unknown.

Methamphetamines HUMAN CONGENITAL ANOMALIES.

Methamphetamines are sympathomimetics and are potent central nervous system stimulants. They are prescribed medically to treat obesity and narcolepsy. Illegal methamphetamines are known as 'designer drugs' because they are synthesized by methylating novel sites along the carbon chain and ring in a one-step reduction process. This 'design'

creates molecules so different from pharmaceutical forms of the drug that they were technically legal in the USA for several years in the mid-1980s. They are a popular cla.s.s of recreational drug. Sometimes methamphetamines are used to 'cut' or dilute other illicit drugs (cocaine). In 2006, they are called 'club drugs' because they are available in night clubs, and are used in parties called 'raves' that may last 24 hours or longer. The stimulant effects of methamphetamines keep the party-goers awake, although some varieties of this drug may cause hallucinations or other altered states of consciousness.

The prevalence of methamphetamine use during pregnancy was 5.2 percent in one large cohort in a public hospital and was used predominately by White women who were single, had fewer prenatal visits than the general obstetric population, and were dependent on public health care (Arria et al et al., 2006), consistent with findings in other studies of pregnant methamphetamine abusers (Cantanzarite and Stein, 1995; Ho et al et al., 2001; Little et et al al., 1988b). Notably, the prevalence of methamphetamine use has not decreased over the past decade (Buchi et al et al., 2003), or 15 years (unpublished data from Dallas, Texas).

We reported 52 pregnancies complicated by methamphetamines finding that symmetric fetal growth r.e.t.a.r.dation was increased above controls. The frequency of congenital anomalies was not significantly increased (Little et al et al., 1988b). Perinatal infant abnormalities and maternal pregnancy complications were not increased in frequency. The small sample size of the metamphetamine-exposed groups limits the ability to extrapolate these findings.

Methamphetamines and cocaine use in pregnancy were a.s.sociated with lower birth weight but not with anomalies (Oro and Dixon, 1987; Chomchai et al. et al. , 2004), as we found in another study of 863 infants (Ramin , 2004), as we found in another study of 863 infants (Ramin et al et al., 1994). Fetal growth r.e.t.a.r.dation was a.s.sociated with methamphetamine use throughout pregnancy, but when drug use was discontinued after the second trimester no difference in birth weight was found (Smith et al et al., 2003).

Cannabinoid use during pregnancy 309.

Lower birth weight was a.s.sociated with maternal methamphetamine use during pregnancy among 47 infants in a study from Thailand (Chomchai et al et al., 2004).

Medically supervised use of methamphetamines among 89 infants born to women who took the drug during the first trimester reported a frequency of congenital anomalies no different from controls. Among 320 infants born to women who used the drug after the first trimester there were no abnormalities (Heinonen et al et al., 1977). The relevance of medically supervised use of methamphetamines to abuse employing much higher doses is not possible to a.s.sess.

INTRACEREBRAL HEMORRHAGE.

Intracerebral hemorrhage and other cardiovascular accidents are markedly increased in frequency among methamphetamine abusers and their fetuses/infants (Catanzarite and Stein, 1995; Dixon and Bejar, 1989; Keogh and Baron, 1985; Sachdeva and Woodward, 1989), often resulting in maternal and/or infant death (Perez et al et al., 1999; Stewart and Meeker, 1997).

LONG-TERM EFFECTS OF PRENATAL AMPHETAMINE EXPOSURE ON CHILD DEVELOPMENT.

Children whose mothers took amphetamines during pregnancy followed postnatally had slightly lower IQ scores, were more aggressive, and were delayed in academic achievement (Billing et al et al., 1985; Cernerud et al et al., 1996; Eriksson and Zetterstrom, 1994; Eriksson et al et al., 2000).

ANIMAL STUDIES.

At doses of methamphetamine similar to those prescribed for narcolepsy, no congenital anomalies were found among nonhuman primates (macaque monkeys) (Courtney and Valerio, 1968). Frequencies of congenital anomalies (brain, anencephaly, eye, cleft palate) were increased among mice and rabbits whose mothers were given methamphetamines during pregnancy at doses up to 20 times the therapeutic adult human dose (Kasirsky and Tansy, 1971; Martin et al et al., 1976; Yamamoto et al et al., 1992).

Summary of amphetamine/methamphetamine use Medically supervised use of amphetamines and methamphetamines during pregnancy does not seem to pose significant risks for increased frequencies of congenital anomalies or maternalfetal complications. Risks for congenital anomalies and pregnancy complications for those who abuse this cla.s.s of drugs may exist and probably involve serious complications secondary to vascular disruption and other cardiovascular accidents.

CANNABINOID USE DURING PREGNANCY.

More than 12 million people in the USA use marijuana or its derivatives [hash, hash oil, Thai sticks, tetrahydrocannabinol ( (THC)] regularly. Fifty percent or more of users are women of reproductive age. An estimated 3 percent of the population uses marijuana daily and as many as 1015 percent of Americans use the drug on a monthly basis (NIDA, 2004). Estimated prevalence rates of cannabinoid use during pregnancy vary widely, ranging from 3 to more than 20 percent of gravidas.

310.

Substance abuse during pregnancy Maternal effects Preterm labor was increased in frequency among women who smoked marijuana during pregnancy in several investigations (Fried et al et al., 1984; Gibson et al et al., 1983; Hatch and Bracken, 1986), but other investigators have failed to confirm this observation (Fried, 1980; Hingson et al et al., 1982; s.h.i.+ono et al et al., 1995; Tennes, et al et al., 1985; Zuckerman et al et al., 1989). Prolonged labor and meconium-stained amniotic fluid apparently increased in frequency in one uncontrolled study of 35 women who smoked marijuana late in pregnancy (Greenland et al et al., 1982), but not replicated in several other controlled studies with large sample sizes (Fried et al et al., 1983; Greenland et al et al., 1983; Witter and Niebyl, 1990).

Perinatal infant effects Significantly lowered birth weights have been reported among infants whose mothers used marijuana during pregnancy in three studies (Cornelius et al et al., 1995; Hingson et al et al., 1982; Zuckerman et al et al., 1989), but not in others (Fried, 1980; Greenland et al et al., 1983; Linn et al et al., 1983; s.h.i.+ono et al et al., 1995; Witter and Niebyl, 1990). Among more than 1200 infants whose mothers smoked marijuana during pregnancy, 137 during the first trimester, the frequency of major congenital anomalies was not increased (Linn et al et al., 1983).

Although not generally accepted, a syndrome (fetal growth r.e.t.a.r.dation, craniofacial and other minor dysmorphologic features) was proposed in a clinical case series that included five infants born to women who used two to 14 joints (cigarettes) of marijuana daily throughout pregnancy (Qazi et al et al., 1985). The infants probably had fetal alcohol syndrome and this finding has not been replicated.

Many studies of marijuana and THC have been performed in pregnant rats, mice, hamsters, and rabbits (Abel, 1980; Schardein, 1985). Most animal teratology studies of marijuana are negative, particularly if dosing (amount, route of intake) was comparable to the human situation.

Withdrawal symptoms Among infants born to women who used marijuana near the time of delivery, certain neonatal neurobehavioral abnormalities (tremulousness, abnormal response stimuli) were found (Fried, 1980; Fried and Makin, 1987), but other studies found no differences (Tennes et al et al., 1985).

Summary of cannabinoid use Mild fetal growth r.e.t.a.r.dation and maternal lung damage are the only untoward outcomes that can reasonably be attributed to marijuana use during pregnancy.

Importantly, woman who use marijuana during pregnancy frequently use other substances know to be harmful substances (i.e., alcohol and/or cocaine) (Cornelius et al et al., 1995; s.h.i.+ono et al et al., 1995) because illicit substance abuse is often a polydrug use (Little et al et al., 1990c).

Cocaine abuse during pregnancy 311.

COCAINE ABUSE DURING PREGNANCY.

Cocaine use is widespread, and not limited to Western society as it has been detected in the urine of people from around the world, and in areas as remote as the Arctic. It is an epidemic that began in the mid to late 1970s and has reached users of virtually every age, s.e.x, ethnic, and socioeconomic subgroup. At least half of these users are women of reproductive age (GAO, 1990).

The use of cocaine is accepted to be dangerous to intrauterine development and can cause birth defects (not a syndrome), fetal growth r.e.t.a.r.dation, and transient withdrawal symptoms. Postnatal intellectual development also seems to be adversely affected by the drug.

Cocaine use among pregnant women We first estimated the prevalence of cocaine use during pregnancy at 9.8 percent in one of the nation's largest hospitals (Little et al et al., 1988a). Survey results in public hospitals range from 11 to 31 percent (Brody, 1989; Nair et al et al., 1994; Ostrea et al et al., 1992) and an incredibly high rate of 48 percent was reported in a San Francisco public hospital (Osterloh and Lee, 1989). Much of the professional community was unprepared to deal with the large number of cocaine-exposed fetuses over the last decade (Landry and Whitney, 1996; Kuczkowski, 2005). In one study, approximately 77 percent of pregnant cocaine abusers at a large public hospital used other drugs of abuse and/or alcohol (Little et al et al., 1990d) and in another study, 90 percent of female cocaine users were of reproductive age (Kuczkowski, 2005).

We found that cocaine crosses the placenta and is metabolized in the placenta through plasma cholinesterase to ecgonine methyl ester, a major active metabolite (Roe et al et al., 1990). Actions of cocaine on the vasculature precipitate a number of serious effects.

Coronary artery vasospasm and arrhythmias occur at even very low doses of cocaine (Lange et al et al., 1989). Chronic cocaine use can lead to myocardial infarction, congestive heart failure, dilated cardiomyopathy, or severe ischemic events in the heart or brain (Box 16.3). In more severe situations, cocaine can aggravate vascular weakness and cause serious vascular accidents (intracerebral infarctions and hemorrhages, acute ischemic brain events). Death from cocaine toxicity is usually preceded by hyperpyrexia, shock, unconsciousness, respiratory/cardiac depression. Chronic cocaine use is a.s.sociated with epileptogenic seizures and cerebral atrophy (Pascual-Leone et al et al., 1990; Karch, 2005).

Box 16.3 Complications among pregnant women who use cocaine Abruptio placentae Abruptio placentae Premature rupture of membranes Hepat.i.tis Preterm labor Intracerebral hemorrhage Ruptured ectopic pregnancy Placental vasculitis s.e.xually transmitted diseases Pregnancy-induced hypertension Spontaneous abortion Premature delivery (shortened gestation length) 312.

Substance abuse during pregnancy The literature is replete with reports regarding the increased frequency of abruptio placentae after intravenous or intranasal cocaine use (Acker et al et al., 1983; Bingol et al et al., 1987a, 1987b; Chasnoff and MacGregor, 1987; Chasnoff et al et al., 1985, 1987, 1989a; Cherukuri et al et al., 1988; Collins et al et al., 1989; Cregler and Mark, 1986; Dixon and Oro, 1987; Dusick et al et al., 1993; Hladky et al et al., 2002; Keith et al et al., 1989; Little et al et al., 1988a; Miller et al et al., 1995; Neerhof et al et al., 1989; Oro and Dixon, 1987; s.h.i.+ono et al et al., 1995; Townsend et al et al., 1988; Witlin and Sibai, 2001), although some investigators did not observe any cases (Chouteau et al et al., 1988; Doberczak et al et al., 1988).