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; Shiono 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; Shiono 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; Shiono 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; Shiono 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).

Maternal cocaine use during pregnancy was a.s.sociated with significantly shortened mean gestational periods and increased frequencies of preterm labor (Chasnoff et al et al., 1985, 1989a; Chasnoff and MacGregor, 1987; Cherukuri et al et al., 1988; Chouteau et al et al., 1988; Cohen et al et al., 1991; Dixon and Oro, 1987; Keith et al et al., 1989; Kliegman et al et al., 1994; Little et al et al., 1989b, 1999; MacGregor et al et al., 1987; Neerhof et al et al., 1989; Oro and Dixon, 1987; Ryan et al et al., 1986, 1987a, 1987b; Zuckerman et al et al., 1989). This drug is significantly a.s.sociated with an increased frequency of precipitous labor (Bateman et al et al., 1993; Chasnoff et al et al., 1987), but in a study of 1220 gravid women no decrease in duration of labor was a.s.sociated with cocaine use (Wehbeh et al et al., 1995). Gestation length and frequency of preterm delivery among women who used only cocaine during the first trimester were not found to be significantly different from women who did not use cocaine during pregnancy (Chasnoff et al et al., 1989a). Others have found no a.s.sociation with preterm labor or low birth weight when other obstetric complications were controlled (Miller et al et al., 1995; Shiono et al et al., 1995).

In a meta-a.n.a.lysis, increased risks for abruptio placentae and premature rupture of membranes (PROM) were statistically related to cocaine use. However, other risks (birth defects, low birth weight, prematurity, decreased length, and lower head circ.u.mference) were said to be related to polydrug use, and could not be attributed to cocaine use (Addis et al et al., 2001).

Cerebrovascular accidents and related cocaine toxicity Fatalities following adult cocaine use have frequently been reported. However, only four cases have been doc.u.mented that involve pregnant women (Burkett Fatalities following adult cocaine use have frequently been reported. However, only four cases have been doc.u.mented that involve pregnant women (Burkett et al et al., 1990; Greenland et al et al., 1989; Henderson and Torbey, 1988), although many have occurred among pregnant women and have not been published. Of the published cases, two were due to subarachnoid hemorrhage resulting from ruptured aneurysms and a third case involved a pregnant woman admitted to the hospital in a comatose condition after about 1.5 g of cocaine had been placed in her v.a.g.i.n.a. She was maintained on life-support systems and eventually died approximately 4 months later, never having regained consciousness. The fourth maternal death was attributed to cardiac ischemia and arrhythmia (Burkett et al et al., 1990). Among more than 4 million women studied in California, the risk of maternal mortality was more than doubled among women who used cocaine during pregnancy (Wolfe et al et al., 2005). This is a large, reliable study whose findings are important.

Pregnancy-induced hypertension and cocaine Two studies have reported an increased frequency of pregnancy-induced hypertension a.s.sociated with cocaine use (Chouteau et al et al., 1988; Little et al et al., 1989b). Other factors, Cocaine abuse during pregnancy Cocaine abuse during pregnancy 313.

such as maternal age, race, and use of multiple substances of abuse, may have accounted for this difference, but a causal a.s.sociation seems likely. Finally, one study reported hepatic rupture during pregnancy as a result of severe pregnancy-induced hypertension a.s.sociated with cocaine use (Moen et al et al., 1993).

Cocaine and embryofetal development INTRAUTERINE GROWTH.

Fetal growth r.e.t.a.r.dation, cerebrovascular accidents, and congenital anomalies are frequently observed in pregnancies complicated by maternal cocaine use (Box 16.4). A number of studies have found that in utero in utero cocaine exposure adversely affects fetal growth parameters such as birth weight, length, and head circ.u.mference (Bateman cocaine exposure adversely affects fetal growth parameters such as birth weight, length, and head circ.u.mference (Bateman et al et al., 1993; Bauchner et al et al., 1987, 1988; Bingol et al et al., 1987a,b; Chasnoff and MacGregor, 1987; Chasnoff et al et al., 1985, 1987, 1989b; Cherukuri et al et al., 1988; Chouteau et al et al., 1988; Dixon and Oro, 1987; Donvito, 1988; Eyler et al et al., 1994; Fulroth et al et al., 1989; Hadeed and Siegel, 1989; Keith et al et al., 1989; Little et al et al., 1988a; MacGregor et al et al., 1987; Madden et al et al., 1986; Neerhof et al et al., 1989; Oro and Dixon, 1987; Pet.i.tti and Coleman, 1990; Ryan et al et al., 1986, 1987a, 1987b; Zuckerman et al et al., 1989).

Box 16.4 Fetal complications reported to be a.s.sociated with antepartum cocaine exposure antepartum cocaine exposure Bradycardia Fetal heart rate abnormalities Brain cavitations Growth r.e.t.a.r.dation Brain growth r.e.t.a.r.dation Intracerebral hemorrhage/infarction Cardiac arrhythmias Meconium staining Cerebral ischemia Prematurity Congenital anomalies Tachycardia Importantly, head circ.u.mference is significantly reduced among infants exposed to cocaine prenatally (Chasnoff et al et al., 1992; Bateman et al et al., 1993; Bateman and Chrirboga, 2000).

Head circ.u.mference was reduced proportionately more than birth weight among 80 infants whose mothers used only cocaine during pregnancy, exhibiting a pattern of brain growth similar to that observed in 67 infants whose mothers had used only alcohol during pregnancy (Little and Snell, 1991a). This is an ominous sign because head circ.u.mference is a rough indicator of brain growth, and this pattern of growth is statistically similar to that observed among infants with FAS, and infants exposed to other human teratogens.

Serial ultrasound examinations (two to four) were used to evaluate fetal growth, and reduced head circ.u.mference and biparietal diameter were found, although estimated birth weight was not significantly reduced (Mitch.e.l.l et al et al., 1988).

CONGENITAL ANOMALIES.

Cocaine abuse during pregnancy has been a.s.sociated with numerous congenital anomalies (Box 16.5). The most consistent a.s.sociation between cocaine use and fetal malformations involves the genitourinary tract (Buehler et al et al., 1996). In publications from 314 314 Substance abuse during pregnancy Box 16.5 Congenital anomalies a.s.sociated with cocaine use during pregnancy during pregnancy Absent digits 3 and 4 on hand Ambiguous genitalia, absent uterus and ovaries a.n.a.l atresia Atrial septal defect Bilateral cryptorchidism Blepharophimosis Cardiomegaly Cleft palate Cleft palatea Club foot Complete heart block Congenital hip dislocation Cryptorchidism Cutis aplasia Duplex kidney Esophageal atresia Exencephalyb Facial skin tags Horse shoe kidney Hydrocele Hydrocephaly Hydronephrosis, bilateral Hydronephrosis, bilateral, prune belly syndrome, patent ductus arteriosus Hydronephrosis, unilateral, contralateral renal infarct Hydronephrosis, unilateral, incompetent ureteral orifices Hydroureter Hypertelorism, maxillary hypoplasia, high palate, holoprosencephaly with agenesis of corpus callosum Hypoplastic right heart Hypospadias Hypospadias with accessory nipple Hypospadias, one with chordee Ileal and colonic infarction Ileal atresia Inguinal hernia Intracranial hemorrhage Intraparietal encephalocele Limb reduction/amputation Mid-colonic atresia Multiple ventricular septal defects Necrotizing enterocolitis Oro-orbital cleft, unilateral Parietal bone malformation Patent ductus arteriosus continued Cocaine abuse during pregnancy 315.

PierreRobin anomalyc Poland sequence,d ulnar ray deficiencies Polydactyly Prune belly syndrome with urethral obstruction Ptosis and facial diplegia Pulmonary atresia Pulmonary stenosis Renal agenesis Renal and ureteral agenesis, unilateral, ambiguous genitalia, unilateral ectopic fallopian tube and ovary, gastroschisis, eventration of abdominal contents, hypoplastic gall bladder, spina bifida, hydrocephalus, postural scoliosis, asymmetric chest, congenital dislocation of a hip, clubfoot, flexion deformity of knee joints, arthrogryposis of a lower limb Renal tract dilation Sacral exostosis and capillary hemangiomas Sirenomelia Transposition of great vessels Transverse limb reduction, unilateral Unilateral hemimelia (absent right hand and right leg below the knee) Ventricular septal defect Bader and Lewis, 1990; Bingol et al., 1987a, 1987b; Dominguez et al., 1991; Hoyme et al., 1988, 1990; Isenberg et al., 1987; Kobori et al., 1989; Little and Snell, 1991b; Little et al., 1988; Little et al., 1989; Madden et al., 1986; Neerhof et al., 1989; Oriol et al., 1993; Porat and Brodsky, 1991; Puvabanditsin et al., 2005; Ricci and Molle, 1987; Sarpong and Headings, 1992; Sehgal et al., 1993; Shanske et al., 1990; Telsey et al., 1988; Teske and Trese, 1987 aa.s.sociated with Trisomy 13 and causation by cocaine is not plausible.

bProbably really encephalocele.

cPierreRobin anomaly is cleft palate and severe micrognathia.

dPoland sequence is defect of pectoralis muscle with syndactyly of hand.

1985 to 2006, numerous isolated congenital anomalies have been described (Box 16.6).

These include ileal atresia in two infants (with bowel infarction in one) and genitourinary tract malformations in nine infants (Chasnoff et al et al., 1985; 1987, 1988, 1989a; MacGregor et al et al., 1987; Sarpong and Headings, 1992; Sheinbaum and Badell, 1992; Spinazzola et al et al., 1992; Viscarello et al et al., 1992), prune belly syndrome with urethral obstruction, bilateral cryptorchidism, absent digits 3 and 4 on the left hand in two infants, and hypospadias, female pseudohermaphroditism, hydronephrosis with ambiguous genitalia and absent uterus and ovaries, a.n.a.l atresia, clubfoot, limb-body wall complex, limb deficiencies, secondary hypospadias, and bilateral hydronephrosis and unilateral hydronephrosis with renal infarction of the contralateral kidney.

No congenital abnormalities were observed in four studies of infants born to women who used cocaine during pregnancy (Cherukuri et al et al., 1988; Doberczak et al et al., 1988; LeBlanc et al et al., 1987; Townsend et al et al., 1988). Among 114 infants born to women who used cocaine during pregnancy, the frequency of congenital anomalies (major or minor) was not increased after controlling for other substances of abuse used and maternal characteristics known to adversely affect pregnancy outcome (Zuckerman et al et al., 1989).

316.

Substance abuse during pregnancy Box 16.6 Perinatal complications a.s.sociated with prenatal cocaine exposure cocaine exposure Asphyxia Bradycardia Brain lesions Cardiac arrhythmias Cerebral ischemia Cerebrovascular infarction/hemorrhage Congenital heart block Congenital infections [syphilis, cytomegalovirus (CMV), human immunodeficiency virus (HIV), hepat.i.tis]

Decreased cardiac output Hyperbilirubinemia Increased vascular resistance Meconium aspiration syndrome Myocardial infarction Myocardial ischemia Neurobehavioral abnormalities Neurovascular ischemia Respiratory depression Seizures Stillbirth Tachycardia Tachypnea Withdrawal symptoms (unrequietable, shrill cry, opishotonic posturing, hyperirritability, hyperresponsiveness, poor feeding behavior) Bauer et al., 2005; Chasnoff et al., 1985, 1986, 1987, 1989a; Cherukuri et al., 1988; Dixon and Bejar, 1988, 1989; Dixon and Oro, 1987; Dixon et al., 1987; Doberczak et al., 1988; Geggel et al., 1989; Hadeed and Siegel, 1989; Kapur et al., 1991; Keith et al., 1989; Kobori et al., 1989; Little et al., 1989; MacGregor et al., 1987; Madden et al., 1986; Miller et al., 1995; Neerhof et al., 1989; Oro and Dixon, 1987; Ryan et al., 1986, 1987a, 1987b; Spence et al., 1991; Sztulman et al., 1990; Telsey et al., 1988; Tenorio et al., 1988; van de Bor et al., 1990a, 1990b; w.a.n.g and Schnoll, 1987a, 1987b.

The bulk of evidence supports the a.s.sociation between prenatal cocaine exposure and isolated major congenital anomalies. Mechanisms of embryonic and fetal effects appear to be vascular disruption, hypoperfusion, hemorrhage, and vascular occlusion, parallel-ing the known effects of cocaine on adults.

Cocaine syndrome It was suggested that a cocaine syndrome exists. Facial defects observed among 10 of 11 infants in a case series of infants exposed to cocaine during gestation included ble-pharophimosis, ptosis and facial diplegia, unilateral oro-orbital cleft, PierreRobin anomaly, cleft palate, cleft lip and palate, skin tags, and cutis aplasia (Kobori et al et al., Cocaine abuse during pregnancy Cocaine abuse during pregnancy 317.

1989). All of the infants had major brain abnormalities, cavitations, holoproscen-cephaly, and porencephaly. One additional study reported unusual facies among cocaine-exposed infants similar to fetal alcohol syndrome, and speculated whether or not a cocaine syndrome may exist (Fries et al et al., 1993). We found no evidence of a syndrome in a matched casecontrol study of 50 infants chronically exposed to cocaine prenatally (Little et al et al., 1996). Fetal growth r.e.t.a.r.dation was the only significant finding in that study, although it is clear that an increased risk of isolated congenital anomalies occurs during the first trimester, and outside the first trimester. Recently, investigators rea.s.sessed a possible cocaine syndrome and concluded that physical growth deficits were a.s.sociated with prenatal cocaine exposure. However, they confirmed our earlier study that no systematic pattern of congenital anomalies (i.e., a syndrome) characterized children who were exposed to cocaine prenatally (Minnes et al et al., 2005). Hence, the existence of a cocaine syndrome is not generally accepted.

Perinatal distress and cerebrovascular accidents with prenatal cocaine exposure cocaine exposure Perinatal complications (tachycardia, bradycardia, respiratory problems, jaundice, elevated bilirubin, etc.) are significantly increased among infants born to cocaine abusers (Box 16.6).

Thus, maternal cocaine use is a.s.sociated with major neuropathology of the fetus and newborn. The mechanisms of brain injury may be vascular accidents or ischemia, or a combination of these effects. The a.s.sociation of cocaine abuse and cerebral palsy has not been established, but it is a plausible a.s.sociation that is likely causal.

Neurobehavioral abnormalities in the perinatal period Newborn infants exposed to cocaine Newborn infants exposed to cocaine in utero in utero appear to have significant neurobehavioral impairment in the neonatal period including: increased irritability, tremulousness and muscular rigidity, vomiting, diarrhea, seizures, EEG abnormalities, and behavioral abnormalities on the Brazelton a.s.sessment (Chasnoff appear to have significant neurobehavioral impairment in the neonatal period including: increased irritability, tremulousness and muscular rigidity, vomiting, diarrhea, seizures, EEG abnormalities, and behavioral abnormalities on the Brazelton a.s.sessment (Chasnoff et al et al., 1985, 1987, 1989a,b, 1992; Cherukuri et al et al., 1988; Dixon et al et al., 1987; Doberczak et al et al., 1988; Feng, 1993; Kandall, 1988; LeBlanc et al et al., 1987; Little and Snell, 1991b; Little et al et al., 1989b; Nair and Watson, 1991; Neerhof et al et al., 1989; Oro and Dixon, 1987; Ryan et al et al., 1986, 1987a,b) Perinatal mortality among cocaine-exposed babies Increased perinatal mortality in comparison to controls has been reported (Bauchner et et al al., 1988; Chasnoff et al et al., 1987, 1989a; Critchley et al et al., 1988; Davidson et al et al., 1986; Kandall et al et al., 1993; Neerhof et al et al., 1989; Ryan et al et al., 1987a,b).

Neonatal hospital stay in days was significantly increased in infants born to women who used cocaine during pregnancy (Neerhof et al et al., 1989). This may be biased because precautionary actions were taken by physicians who were knowledgeable of prenatal drug exposure.

318.

Substance abuse during pregnancy Box 16.7 Summary of follow-up studies of cocaine-exposed infants infants Decreased cognitive function (correlated with reduced head circ.u.mference) Delayed mental and motor development Delays in all domains (f.a.gan test) Language development impairments Lower IQ Lower verbal reasoning Mental and psych.o.m.otor development delay Motor performance deficits Poor perseverance Reduced height and weight School performance poor Small head circ.u.mference Angelilli et al., 1994; Azuma and Chasnoff,1993; Chasnoff et al., 1992; Ernhart et al., 1987; Frank et al., 2005; Griffith et al., 1994; Gross et al., 1991; Hack et al., 1991; Hurt et al., 2005; Lewis et al., 2004a, 2004b; Miller-Loucar et al., 2005; Nulman et al., 1994; Singer et al., 2004; VanBeveren et al., 2000.

Postnatal follow-up of infants whose mothers used cocaine during pregnancy pregnancy The number of studies that reported long-term effects of prenatal cocaine exposure on child development is limited, but they have a common finding of growth and development delays and intellectual deficits (Box 16.7).

Animal models of cocaine Animal models of the possible teratogenicity of cocaine have yielded inconsistent results.

Summary of cocaine during pregnancy In summary, the epidemic use of cocaine during pregnancy has resulted in an alarming number of individuals with serious adverse outcomes in mothers, fetuses, and newborns.

The use of cocaine is often compounded by frequent concomitant heavy use of other illicit drugs and alcohol. Women who use cocaine during pregnancy are at significant risk for no prenatal care, shorter gestations, premature rupture of membranes, premature labor and delivery, spontaneous abortions, abruptio placentae, decreased uterine blood flow, and death. The fetuses of these women who use cocaine are growth-r.e.t.a.r.ded or severely distressed, and have an increased mortality risk. Fetal and maternal cerebrovascular accidents, with attendant profound morbidity and mortality, occur in a.s.sociation with maternal cocaine use during pregnancy. Major congenital anomalies involving the brain, genitourinary tract, bowel, heart, limbs, and face occur with significantly increased frequency among infants whose mothers used cocaine during gestation.

Use of hallucinogens during pregnancy 319.

Hence, cocaine use during pregnancy is very probably teratogenic and fetotoxic. The mechanisms of cocaine's adverse effects are vascular disruption and hypoperfusion for gross abnormalities, but molecular level mechanisms are yet to be determined.

USE OF HALLUCINOGENS DURING PREGNANCY.

Psychedelic drugs produce visual hallucinations through a disruption of higher central nervous system function. Most hallucinogens are actually functional a.n.a.logs of neurotransmitters (e.g., LSD resembles serotonin). Some hallucinogens are a.s.sumed to exert their effect by displacing this or other neurotransmitters, but the molecular basis for the action of hallucinogens is not established. Tolerance of hallucinogens is rapidly developed and chronic users must increase doses rapidly over the course of the drug's use to maintain desired effects (Carroll, 1990).

Hallucinogens or psychedelic drugs are not nearly as popular in 2006 as they were 30 or so years ago. Less than 2 percent of the general population uses psychedelic drugs, based upon data that are not part.i.tioned by s.e.x, ethnicity, or pregnancy status. Among pregnant women at a large urban hospital in Dallas, Texas, it is estimated that approximately 1 percent used psychedelic drugs (LSD, mescaline, psilocybin) during gestation.

Specific hallucinogens LYSERGIC ACID DIETHYLAMIDE.

Lysergic acid amides (cla.s.sically known as lysergic acid diethylamide or LSD) or lysergides are amine alkaloids obtained only through chemical syntheses and have a variety of street names. Under medical supervision lysergide has been used to treat psychiatric illness, and ergotamine is a closely related drug. LSD stimulates the sympathetic nervous system, often producing increased heart rate and blood pressure, and a rise in body temperature. LSD used recreationally also has powerful hallucinogenic effects for which it is well known. The hallucinations usually last 836 h, depending upon dose.

The published studies of LSD use during pregnancy are of medically unsupervised use of this cla.s.s of drugs, although some clinical experiments in nonpregnant adults have been published.

Congenital anomalies among infants born to mothers who used LSD before or during pregnancy are highly heterogeneous and show no consistent pattern of anomalies (Cohen and Shiloh, 1977/78; Long, 1972). Congenital anomalies among many children reported in the literature to be a.s.sociated with maternal LSD exposure are unlikely to be caused by use of the drug during pregnancy. The most frequently observed malformation among exposed infants are limb defects, but the defect types were highly variable (i.e., lacked a pattern). Among 86 infants born to women who used LSD at undetermined times during gestation, eight infants had a variety of congenital anomalies (Jacobson and Berlin, 1972). Of these eight infants, five had central nervous system defects, but two were exposed to LSD during embryogenesis (2/86 or 2.3 percent). No convincing evidence has been published that LSD is a human teratogen. However, lifestyle practices a.s.sociated with drug abuse during pregnancy are probably harmful to intrauterine development. In one clinical series, the frequency of growth deficits and 320 320 Substance abuse during pregnancy neurological impairments among children born to LSD users was not increased in frequency compared to drug-free controls (Julien, 1988).

Three investigators found increased frequencies of chromosomal breakage in somatic cells of individuals who used LSD (Cohen and Shiloh, 1977/78; Hulten et al et al., 1968; Long, 1972). Other investigators have reported negative results. Notably, chromosomal aberrations in somatic cells have no clinical relation to the risk of congenital anomalies in the children of parents who used LSD or to the inheritance of chromosomal abnormalities.

Importantly, illegally produced LSD may contain lysergic acid with no amination, and this can lead to peripheral neuropathy, gangrene, and necrosis that resembles toxic shock syndrome. Human toxic exposures to lysergic acid are rare, but among cattle and sheep that consumed wheat grain affected with the fungus Claviceps pupurea Claviceps pupurea, which produces lysergic acid, peripheral neuropathy, gangrene, and necrosis were observed. As with most illegal drugs, no quality control or a.s.surance measures are taken to a.s.sure drug purity.

MESCALINE.

Mescaline is a naturally occurring hallucinogenic alkaloid that is concentrated in the 'b.u.t.tons' of the peyote cactus, Lophophora williamsii Lophophora williamsii. Flattened dried seed pods from this plant, called 'b.u.t.tons' or 'peyote,' are ingested for recreational use and are used in Native American religious rituals. Members of the Native American Church use mescaline legally in their ceremonies. Naturally mescaline is often contaminated with strychnine and is a.s.sociated with severe nausea and vomiting. Mescaline may also be synthesized chemically. Mescaline effects are similar to the effects of LSD, but with much more vivid and intense hallucinations. Some users report that mescaline is a.s.sociated with auditory hallucinations, while LSD is reportedly not. The user also often experiences episodes of severe vomiting and nausea following ingestion of the drug. The hallucinogenic effects usually last about 12 h and sometimes much longer (2040 hours) depending upon dose.

No published studies of congenital anomalies in infants born to mothers who used mescaline during pregnancy are available. In an animal study, neural tube defects were increased in frequency among the offspring of hamsters whose mothers were given mescaline during pregnancy at one-tenth to one-fifth the dose usually ingested by humans, but the effect was not dose related (Geber, 1967). Neonatal weight was decreased among hamsters born to mothers injected with mescaline during pregnancy (Geber and Schramm, 1974). Moreover, no such abnormalities were seen in animal studies by other investigators who employed doses three to six times those used by humans (Hirsch and Fritz, 1981). Intrauterine death was increased in exposed pregnancies in both animal studies.