Early Human Development,

31 (1992) l-24

Elsevier Scientific Publishers Ireland Ltd.

EHD 01338

Cocaine and development: mechanisms of fetal toxicity and neonatal consequences of prenatal cocaine exposure Jeannine L. Gingrasa, Debra E. Weese-Mayerd, Roderick F. Hume, Jr.’ and Karen J. O’Donnellb “Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, bDepartment of Psychiatry University, Duke University Medical Center, Durham, NC 27710, cDepartment of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710 and dDepartment of Pediatrics, Rush-Presbyterian St. LukeS Medical Center, Rush Medical College, Rush University Chicago, IL 60612 (USA)

(Received 25 November 1991; revision received 15 June 1992; accepted 29 June 1992)

As cocaine use during pregnancy has become increasingly recognized, there also has been increased concern about the toxic and teratogenic properties of cocaine on the fetus. A significant literature exists describing the adverse fetal and neonatal outcomes associated with in utero cocaine exposure. However, specific causality by cocaine on outcome in the human is difficult to ascertain because of multiple confounding variables associated with substance abuse including social factors and polydrug use as well as diff%zulty in confirming timing, dose and frequency of cocaine exposure. Most literature suggests that prenatal cocaine exposure is associated with developmental risk to the fetus. What is currently unknown is the extent of risk, the additive and/or synergistic factors contributing to cocaine’s toxicity and the reversibility of the injury. In this paper we review the pharmacologic properties of cocaine as related to a model of mechanisms for developmental injury secondary to cocaine exposure and the published literature on the adverse fetal and neonatal outcomes associated with cocaine use during pregnancy. Specific attention has been focused on the structural, neurobehavioral and respiratory control teratogenesis. Key words: cocaine; developmental cocaine exposure

Correspondence

injury; prenatal cocaine exposure; in utero

to: J.L. Gingras, MD, Duke University Medical Center, Box 3179, Durham, NC 27710,

USA. 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

0378-3782/92/$05.00

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Cocaine A summary of the pharmacology and toxicology of cocaine use during pregnancy, review of the associated adverse fetal and neonatal outcomes and a model of developmental injury. Cocaine and teratogenesis Approximately 40% of Americans who use cocaine regularly are between the ages of 20 and 30 [1,31,108,117], prime childbearing years. Although the overall prevalence of cocaine use has decreased slightly from its peak in the mid 1980s recent statistics continue to support similar trends in age distribution [ 114,115]. Alarmingly, the risk of initiating cocaine use is also greatest between the ages of 20 and 30 [127] thus increasing the probability of first time use during child bearing years; a phenomenon different from any other illicit drug including alcohol, cigarettes and marijuana [ 1311. A 1989 survey of 18 hospitals performed by the Select Committee on Children, Youth and Families (106) reported cocaine as the drug of choice in pregnant substance abusers. Further, among an inner-city population, 17% of pregnant women used cocaine at least once during their pregnancy [54]. Use in pregnancy crosses socioeconomic lines [24]. Recent attention has been focused on the outcome of infants exposed prenatally to cocaine. Cocaine use in pregnancy has been reported in association with an increased incidence of abruptio placentae [2,17,18,66], in utero fetal death, [12,66] spontaneous abortions, [9,12,18,33,66,13 11, premature labor and delivery [12,17, 98,103], intrauterine growth retardation [ 12,25,57,88,98,13 1,172], adult and neonatal intracranial events including hemorrhage and cystic lesions [ 19,36,37,61,101, 1621, markers of fetal stress such as meconium staining [12,17,25,57,66,103,131], altered neonatal behavior including altered state regulation [ 17,18,22,116], abnormal neonatal sleep patterns [118] and poor feeding [118]. Reports also suggest that infants exposed to cocaine in utero demonstrate transient neurological findings [22,38,88,118], altered cerebral flow characteristics [ 1541, respiratory pattern abnormalities [4,23,58,122,158] and possibly an increased risk of sudden infant death [ 17,125,130,156]; although the latter association is controversial [6,56,96]. Although prenatal cocaine use during pregnancy appears detrimental to the fetus, a causal effect has not been documented. Specifically, published reports have not clarified the effects of poor health practices, poverty, environment, undernutrition, or multidrug use on infant outcome. Many of the early studies are limited in design; comparison groups are often lacking; population size is often too small for statistical power to be achieved; recruitment strategies often add biases that limit the validity of the study results; and the lack of documentation and verification of the pattern, dose and timing of drug use allow for group misclassification [ 16,105,169,170]. For example, a positive urine toxicology at birth does not offer information on the frequency of cocaine use during pregnancy, on the pattern or timing of use, or on the amount taken at each use. In contrast, a one-time negative urine screen does not verify a drug free pregnancy. Maternal drug histories are often unreliable [711 and other confounding variables such as polydrug abuse and associated medical and

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obstetrical complications are likely contributory to cocaine’s reported effects on the fetus and newborn. The purpose of this review is threefold: first, to provide a model for cocaine’s mechanism of injury: a model developed by correlating the known physiologic and pharmacologic properties of cocaine with associated neonatal outcomes identified in the literature. Details of the pharmacology of cocaine’s action have recently been reviewed [49] and are summarized only as relevant to the model. Second, we elaborate, through a review of the literature, on the three major teratogenic properties of cocaine: (1) structural teratogenesis, (2) neurodevelopmental teratogenesis, and (3) respiratory control teratogenesis. Third, we discuss the social and environmental confounding variables that may be synergistic and/or additive in the neonatal outcomes associated with cocaine abuse. Cocaine and teratogenesis: a model of developmental injury Fetal embryopathy is a function of the interactions between a specific drug and three separate but closely related compartments: mother, placenta and fetus. This model is diagrammed in the compartmental model presented in Fig. 1; the nature of the embryopathy is dependent on the toxicity and pharmacologic properties of the drug, frequency and dose of drug exposure, the gestational timing of drug exposure, the maternal/fetal drug pharmacokinetics [73,136,140,149] and genetic vulnerability. This model is particularly applicable to prenatal cocaine exposure. Importantly, maternal and fetal vulnerability to cocaine induced injury is enhanced during pregnancy secondary to altered metabolism. During pregnancy, women demonstrate COMPARTMENTAL

MODEL

Nwrodevelopmantal effwta

ADULT-

/

Fig. 1. Diagram of the compartmental model of drug interactions during pregnancy

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decreased plasma cholinesterase levels although cholinesterase levels may be increased or unchanged in some [46,123,146]; cholinesterase levels are also decreased in the fetus [108]. Since cocaine is detoxified to its inactive metabolite, ecgonine methylester by cholinesterase mediated hydrolysis [146,147], it is likely that the mother and- fetus may both have increased and prolonged exposure [5,18,108,113] and toxicity [163] to cocaine’s effects during pregnancy. Indirect effects of cocaine on the developing fetus

Cocaine increases circulating catecholamine levels, in particular the level of circulating norepinephrine, by inhibiting norepinephrine uptake at the nerve terminal [126]. In the peripheral nervous system this results in increased amounts of norepinephrine in the circulation and at the noradrenergic receptor resulting in the physiologic sequelae of vasoconstriction [34], accelerated heart rate and hypertension [52]. These effects alter maternal and placental physiology, thereby indirectly placing the embryo/fetus at risk (Fig. 2). The placental vasculature is not spared the vasoconstricting effects of the catecholamines and other vasoactive substances. Recently, investigators have suggested that other vasoactive neurotransmitters may be implicated in the fetal and maternal cardiovascular responses to cocaine [39]. In fact, Moore et al. [109] reported a dose-dependent decrease in uterine artery blood flow following administration of cocaine to pregnant ewes. In these animals, cocaine infusion decreased uterine blood flow by 36 to 42%, depending on the maternal dose, for a duration of 15 min. In addition to confirming the dose-dependent increase in maternal blood

Cocaine: Indirect Fetal Effects

EMBRYONIC; FETAL MILIEU Fetal tachycardia Fetal hypertension ??4 0 2 content and O2 pressure ??Fetal catecholamlnes

??

??

@? Abruption Stillblrth ??Prematurity ??Growth retardation ?? Cerebral infarct

??

??

Fig. 2. The compartmental model depicting the indirect effects of maternal cocaine, fetal responses and possible neonatal outcome.

pressure and decrease in uterine blood flow following maternal cocaine injection, Woods, Plessinger and Clark [164] showed that these maternal responses were accompanied by fetal hypoxemia. They showed that decreased fetal oxygen content occurred only after maternal cocaine injection and not after direct infusion of cocaine into the fetal compartment supporting the concept of placental compromise as the etiology of fetal hypoxemia. Decreased uterine blood flow and compromised oxygen delivery to the fetus, then, could result in altered fetal somatic and fetal brain development. Additionally, the study by Woods et al. [164] showed that the fetus experienced hypertension and tachycardia after both maternal and fetal cocaine administration possibly via an indirect effect of hypoxia induced increase in fetal catecholamines. Abrupt increases in fetal blood pressure could result in vascular accidents, as has been documented in adult users [61,162]. In one study, in utero cerebral infarction in an infant whose mother used cocaine 15 h prior to delivery [ 191 is suggested to have resulted from an in utero hypertensive-mediated vascular insult. This is a high probability model given the fragile nature of the fetal cerebral circulation and germinal matrix. These mechanisms of decreased placental blood flow and compromised oxygen delivery are consistent with the findings of cocaine use associated with cardiac arrhythmias, hypertension and cerebrovascular accidents in adult users; abruptio placentae and increase in the number of spontaneous abortion in pregnant users; and in the incidence of prematurity, growth retardation, cerebral infarcts and altered neurodevelopment in infants exposed in utero to cocaine. Direct effects of cocaine on the developing fetus Cocaine exerts direct effects on both the fetal central and peripheral nervous systems; it crosses the placenta by simple diffusion [ 108,109,136] and is concentrated within the fetal/embryonic milieu [49,110,136,137] achieving peak levels in the fetal circulation by 3 min [145,164,165]. Figure 3 summarizes the direct effects of cocaine on the developing fetus. Once in the fetal compartment, circulating cocaine also directly blocks reuptake of the catecholamines, resulting in the physiologic effects in the fetus of increased heart rate and blood pressure. Woods et al. [ 164,165] demonstrated that direct infusion of cocaine into the fetus of pregnant ewes resulted in fetal tachycardia and hypertension; the magnitude of this fetal hypertensive response, however, was less with direct fetal infusion than with maternal infusion [164]. These findings suggest that the fetal cardiovascular response is mixed: there is an indirect effect of placental hypoperfusion, fetal hypoxia, and subsequent fetal catecholamine release as well as a direct cocaine effect at the fetal noradrenergic nerve terminal. In fact, prenatally cocaine exposed infants may demonstrate altered catecholaminergic system postnatally [ 107,159]. The fetal cardiovascular response was not completely abolished by pretreatment with phentolamine, an adrenergic blocker [log], supporting the concept that cocaine may also act through non-adrenergic mechanisms [39]. Cocaine also alters neurotransmitters in the central nervous system by blocking the re-uptake of the biogenic amines: serotonin, dopamine and norepinephrine [55,84,121], thereby increasing the availability of these transmitters to bind with their receptor sites. Increased receptor binding acutely increases neuronal excitabil-

Cocaine: Direct Fetal Effects EMBRYONIC; FETAL . Lowchollnestarare actlvlty

Low molecular wt.

. Time dspandant vulnarablllty A I

Low cholnastarrss actlvlty

!

??

Naurodavalopman

A

Ylcrocaphaly Abnormal nourodovalopmsnt ?? Abnormal motor dsvolopmant ?? Rarplratory control dlrordarr . SIDS ??

??

Fig. 3. The compartmental model depicting the direct fetal effects of cocaine during development and the possible neonatal outcome.

ity, thereby producing the cocaine ‘high’. With chronic cocaine usage, post-synaptic receptors may, in fact, be down-regulated and a dampening effect produced. This has been shown for both alpha and beta adrenergic receptors in the placenta [ 120,124] and for dopaminergic receptors in the central nervous system [ 1431. The brain/plasma ratios of cocaine between rat dams and fetuses after intravenous injection are similar (mean 2.36) [ 1421suggesting rapid penetration of cocaine across the placental and the fetal blood-brain barrier [l lo]. Wiggins et al. reported that cocaine appears in the fetal brain at a rate of 109-151% of the concentration in the dam’s blood [161]. Since neurotransmitters act as trophic factors early in development [87], the fetus may be particularly at risk for abnormal development of important neurotransmitter systems, abnormal neuronal growth and differentiation, altered migrational events, or abnormal glial cell function if cocaine exposure occurs during these vulnerable periods [32,80,86,87]. In fact, omithine decarboxylase, a marker of CNS (central nervous system) cell growth and differentiation, is altered by in utero cocaine exposure [10,60]. In utero exposure to a number of environmental disturbances and pharmacologic agents has been documented to result in long-term behavioral and chemical changes long after the prenatal exposure [ 102,148,155,167]. Recently, Dow-Edwards, Freed and Milhorat [40,41] reported altered brain metabolism in the motor, limbic, and sensory systems of adult rats who were exposed to cocaine at a period of CNS development comparable to the third trimester in the human fetus. This study suggests that in utero cocaine exposure may not only produce immediate effects, but also may have long-term effects on brain structure and function. It is probable that the association between in utero cocaine exposure and small head circumference and

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altered neurobehavior, at least in part, is secondary to altered neurotransmitter development at critical periods of brain growth and differentiation. Confounders of cocaine exposure

In addition to multiple methodologic issues previously described such as recruitment bias, difficulty in defining pattern of use, dose and timing [ 15,16,105,169,170], numerous associated social, medical, environmental, economic, demographic and psychological factors influence the subsequent neurobehavioral and developmental outcomes for infants exposed in utero to cocaine. For instance, maternal depression symptoms, independent of other confounding variables, have recently been implicated to be highly associated with altered neurodevelopmental outcome in cocaine exposed newborns [171]. Lifestyle and health characteristics may be independent risk factors for a given outcome: smoking and SIDS (sudden infant death syndrome) [67,84], alcohol and teratogenesis [83], smoking and placental dysfunction [112] and secondary exposure from crack smoking [5] as well as transfer of cocaine from breast milk [26] offer additional exposure risk for the newborn. Also, in an animal model of cocaine exposure, alcohol was found to be interactive with cocaine [30] emphasizing the importance of controlling for polydrug use. Developmental and behavioral outcomes in this group of children must therefore be studied and interpreted in the light of ongoing transactions with the caregiving context [ 1351. Development in utero is subject not only to cocaine exposure but also to poor maternal nutrition, possible lack of or inadequate prenatal care [53] and increased obstetrical complications such as preterm labor, prematurity, abruptio placentae [12,103]. Additionally, many of the neonates are behaviorally disorganized, have difficulties with arousal and alertness and are poor interactive partners for their caregivers. Many caregivers, in turn, are affected by their own illicit drug use either medically or psychologically [171]. Further drug exposure for the infant may continue through nursing [26], passive exposure [5], or by accidental ingestion [128]. Subsequent problems with behavior and development undoubtedly reflect some of the main effects of cocaine exposure (e.g. neuronal damage) as well as the interactions and complex transactions among these numerous lifestyle and physiologic events. Figure 4 lists prenatal and postnatal influences that may be synergistic in the ‘developmental and medical outcomes of infants exposed in utero to cocaine. The potential influences of these multiple confounders on structural, neurodevelopmental and respiratory control outcomes will be discussed within each section. Summary

Cocaine has powerful vasoconstrictive properties that may alter the maternal, placental and fetal function. Fetal drug induced injury, then, may result indirectly from maternal and/or placental compromise secondary to its vasoconstrictive property or from direct injury of the developing embryo/fetus. Cocaine-induced injury may also be exaggerated, enhanced, or potentiated by the associated high risk medical, environmental, and social factors associated with cocaine use. Studies designed to address developmental injury from in utero cocaine exposure must consider this constellation of biologic, social and environmental factors.

Confounders of Cocaine Exposure Poor Prenatal

Maternal Education

Lack of Support Resources

Lack of Resources Dysfunctional

Family 2

Poor Nutrition

Fig. 4. Diagram of multiple maternal and postnatal socioenvironmental development.

factors that may impact

Cocaine and teratogenesis: specific considerations Cocaine and structural teratogenesis

The specific timing of an insult during gestation is an important determinant of embryopathy [78,140,149]. Insults, for instance, during the embryonic period or the first 2 months of gestation, the period of organogenesis, can result in major structural malformations such as neural tube defects. Insults occurring during the fetal period or histogenesis (day 60 to birth and postnatally), a period during which time cellular differentiation and acquisition of system function occur, can result in more subtle abnormalities of growth, development and behavior. Although early studies suggested that cocaine exposure during development was devoid of structural abnormalities [48,99], subsequent studies have reported in utero cocaine exposure to be associated with defects in multiple structures: skull and skeletal, eyes, genitourinary tract, cardiac and CNS [9,20,27,36,42,48,64,79,92,100]. Our group has made additional observations of anomalies with cocaine exposure, identified in utero by ultrasound and confirmed postnatally: meconium peritonitis, gastroschisis, radial hypoplasia and complex choroid plexus cysts [74]. That cocaine is directly responsible for structural teratogenesis is supported by both animal and human observations of increased fetal anomalies after in utero cocaine exposure. Bingo1 et al. [9] reported an increase in skull defects including exencephaly, encephalocele and parietal bone defects in infants exposed in utero to cocaine when compared to polydrug abusers and a group of drug-free women. All

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groups were reported to use tobacco with equal frequency. Urogenital abnormalities were reported by Chasnoff et al. [20] and in a larger, case control study by Chavez et al. [27]. In these studies, cocaine use was determined by urine toxicology and by maternal report, respectively; some of the cocaine using women in the second study were also on methadone maintenance. Neither study controlled for alcohol use. Although all women abused cocaine, these studies did not address the effects of other drugs particularly the possibility of synergistic or additive effects of polydrug abuse, in particular alcohol [30,82], marijuana [91] and cigarettes [67,83,132], which are all known human teratogens, environmental factors, or of familial recurrence patterns associated with specific malformations. In an attempt to reproduce structural teratogenesis in an experimental animal model, Mahalik, Gautieri and Mann [ 1001designed treatment paradigms to examine critical periods of susceptibility to cocaine exposure. The abnormalities detected in fetal mice paralleled the period of ontogenesis for these structures and support a direct teratogenic property for cocaine. The recent studies by Church et al. [29] in the Long-Evans rat, by Finnell et al. [51] in two strains of mice and by Webster, Brown-Woodman [160] in the Sprague-Dawley rat all report increases in the incidence of malformations in pups prenatally cocaine-exposed. This consistent reporting of structural anomalies in pups exposed in utero to cocaine in the studies using different species and strains, different routes of administration and different dosing schedules (Table I) supports the concept that cocaine is capable of altering normal development. The malformations reported by Finnell et al. [51] were observed in the absence of altered maternal weight gain during pregnancy strongly indicating that the anomalies were directly related to cocaine and not secondary to maternal toxicity. Although it is more difficult to test for a direct association of teratogenesis with cocaine versus other adulterants in human studies, we have been able to correlate, in the human fetus, the time of cocaine exposure obtained by self report and similar associated malformations, suggesting specific periods of vulnerability for structural anomalies and cocaine exposure [74]. The mechanisms of injury resulting in structural defects includes deformation, malformation and vascular disruptions [63,81]. Cocaine’s specific mechanism of injury is unknown although most studies suggest a vascular disruption teratogenesis. Vascular insults or interruptions at specific critical periods during development may result in vascular-induced teratogenesis [72]. These insults can occur as late as the second or third trimesters [ 1l] as has been supported by the recent work of Webster, Brown-Woodman [160]. These authors administered cocaine to pregnant rats in midgestation and observed congenital malformations that mimic the vascular disruptive phenomena that have been reported in humans [9,10,27,42,72,150] suggesting that cocaine’s teratogenic properties occur by disrupting previously established structures. Vascular disruption has also been shown to occur after hypoxia in other models [11,152]. Vasoconstriction leads to a hypoxic response, either locally or in the placental-fetal unit, resulting in edema and hemorrhage in the fetus with subsequent tissue damage [ 11,160]. In a recent animal study, cocaine has been reported to induce reduction deformities comparable to that reported in humans [ 1601. Cocaine’s pharmacologic effect of vasoconstriction could disrupt blood flow to specific organs in

60 Daily during organogenesis 60 Time specific injection 40-90 Split daily doses 20, 40, 60 40-80 Single dosing Double dosing

Rat Sprague-Dawley Mice Swiss-Webster Mice CF-1 Rat Mice DBA/2J SWV Rat

Fantel et al. (1982) [48]

Mahalik et al. (1980) [ 1001

Church et al. (1988) [29]

Finnell et al. (1990) [51]

Webster et al. (1990) 1601

No differences between groups 1,2,7,10 3,4,9,11,12 (260 mg/kg) 10 (90 mg/kg) 1,5,6,7,8,13: cleft lip and palate, open eyes deformities Dose dependent 3, 4, sacrifice on GD 16 5 sacrifice on GD 21

IP

SQ SQ

IP

IP

Findingsa

Route

sobserved anomalies indicated as follows: urogenital (I), skeletal (2), edematous fetus (3), hemorrhagic fetus (4), reduction deformities (5) GI (6) neural tube deficit (7), cardiovascular (S), decreased maternal weight gain (9), decreased fetal weight gain/growth delay (lo), resorption (ll), placental abruption (12) others (13).

Sprague-Dawley

Long-Evans

Dose (m&g)

Species

Study

Structural teratogenesis in animal models.

TABLE I

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the fetus resulting in infarction and vascular disruption teratogenesis. Limb reduction anomalies have been reported in association with in utero cocaine exposure [20,72,74] supporting this model. The vascular disruption model is further supported by a growing literature documenting various anomalies such as gastroschisis [73], meconium peritonitis [95], neural tube defects [ 1441 and limb defects [ 1531 with vascular disruptions. The association of ocular defects that resemble retinopathy of prematurity [151] as well as the suggested association of necrotizing enterocolitis [42,150], also could be explained by vascular disruption at critical periods in morphogenesis. These studies have typically not been prospective nor well controlled but are supportive documentation of cocaine-induced structural teratogenesis. Cocaine and neurodevelopmental teratogenesis Current studies approach maternal cocaine use and infant outcome from the perspective of neurodevelopmental injury, that is, the effects of in utero exposure on the developing fetal central nervous system as evident in subsequent behavior and development. Although various methodological issues [ 15,16,85,105,169,170,] and likely confounding variables discussed in this manuscript render findings inconclusive at best, many studies support the hypothesis that cocaine exposure presents some degree of neurodevelopmental risk. In particular, the increased incidence of microcephaly [22,57,66,118,166,172] in cocaine exposed infants, neurofunctional abnormalities such as prolonged auditory evoked responses [ 1341 suggesting delayed myelination and altered DNA synthesis [3] make a strong case for the concept that cocaine produces injury to the developing fetal brain that could compromise behavioral and developmental outcome. Early studies of the effects of prenatal cocaine exposure in the newborn were focused on whether these infants experienced withdrawal or ‘addiction’ as determined by either a formal scoring system [50,57,93] or subjective observations of behavior such as tremors, irritability, hyperreflexia, increased muscle tone and tachypnea [50]. Findings are mixed; these behaviors have been observed in human infants by some investigators [ 12,22,57,88] as well as in an animal model of in utero cocaine exposure [ 131, while other investigators report no or mild withdrawal symptoms [28,50,58,66,99] with cocaine exposure. The apparently conflicting results may be understood by the methodological differences between studies. However, even if behavioral and physiologic features of withdrawal are present in cocaine exposed infants, it is difficult to determine whether these behaviors index acute effects of cocaine (intoxication) or if they are markers of more global disruptions of neuronal development and function. Our own data [75] and those of others [18,22] suggest that a key feature of the newborn infant’s behavior relevant to developmental injury is the differentiation and regulation of behavioral state. It is important to note that study designs using informal neurologic assessments that do not quantify state organization as an independent outcome measure report mild or no difference between exposed and nonexposed groups [99]. Significant differences for cocaine exposed infants, however, are found in studies in which formal, blind assessments with the Neonatal Behavioral Assessment Scale (NBAS) are used [ 18,221. We recently studied developing behavioral states in cocaine-exposed fetuses from

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36 weeks gestation using real time ultrasonography [75]. In an assessment designed to observe the unperturbed fetus and efforts at behavioral regulation after perturbation with acoustic stimulation, we were able to document an increased likelihood of delayed or disorganized state behavior in fetuses exposed to cocaine. Behaviorally disorganized fetuses were found among both acutely intoxicated fetuses and those exposed to cocaine earlier in pregnancy. The measure of fetal disorganization also successfully predicted poor state organization in the neonate as assessed by the NBAS. In addition, a significant number of these exposed fetuses exhibited poor state organization as neonates when compared with controls. Many of these infants seemed to have ‘all or nothing’ behavioral states: deep sleep or hyperarousal; quiet alertness was difficult for them to attain and maintain. These results are similar to other studies using the NBAS. Chasnoff et al. [ 181, for example, reported less optimal orientation to stimuli and state organization in cocaine-exposed neonates. They noted, in particular, the infants’ poor consolability and an inability to reach an alert state. With more participants in 1989, the same group reported that cocaine-exposed infants also had abnormal motor functioning and an increased number of abnormal reflexes [22]. Recently, Eisen et al. [45] reported decreased habituation in infants exposed prenatally to cocaine as well as a tendency for cocaine exposed infants to display more stress behaviors. What is still unclear is whether the behavioral effects represent transient neurologic dysfunction or mark a permanent CNS injury with resultant disrupted development. Transient behavioral effects to cocaine exposure have been suggested by three studies. In one study, newborn tremulousness, irritability and muscular rigidity were present in the newborn period compared to controls but resolved by 3 to 3.5 months of age [22]. In another human study [38], abnormal EEG and behavioral findings appeared to be normalized between 3 and 12 months of age. The third study [ 1341 reported increased brainstem transmission times in neonates and young infants exposed to cocaine suggesting altered myelination. The abnormalities appeared to resolve by 1 year of life. Whether these neurologic signs and their aberrant physiologic underpinnings truly resolve or produce lasting subtle developmental and behavioral difficulties is presently unknown. The fact that first trimester cocaine exposure alone results in abnormal newborn behavioral exams [22] suggests a direct and permanent injury early in the development of the CNS. Animal studies of prenatal cocaine exposure reporting decreased markers of cell growth and differentiation such as altered DNA synthesis [3] and ornithine decarboxylase activity [10,60], altered behavioral indices and neurotransmitter levels [3,60,143], as well as studies of neuronal cell cultures [104] support the concept that the abnormal behavioral findings represent direct CNS injury that may be long term [70]. To date, very few published studies report long term findings regarding behavioral and developmental outcome. In a 2-year follow-up of over 100 in utero-exposed children [21], weight remained lower than control infants to 12 months. No group differences in the global Bayley development scores for mental or motor areas were shown at 3,6, 12, 18, or 24 months; however, a greater number of cocaine exposed infants scored 1 S.D. below the Bayley means suggesting that differences do, in fact, exist between groups. Head circumference stayed relatively small, again supporting the potential for the long-term sequelae of prenatal developmental injury. In fact,

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Harvey et al. [69] in a study of term intrauterine growth retarded (IUGR) infants with slow head growth, demonstrated delayed cognitive index, motor ability and perceptual performances at 3 to 7 years of age in this IUGR population. Recently, Lester et al. reported abnormal cry characteristics in infants exposed prenatally to cocaine [go]. Since acoustic characteristics of cry are thought to reflect the neurophysiologic status of the newborn, these authors suggest that the alterations in cry characteristics secondary to cocaine exposure represent the effect of cocaine on the developing nervous system. Previously, they have shown that cry characteristics are related to developmental outcome in preterm and growth retarded infants [89,168]. They suggest that altered cry characteristics secondary to cocaine exposure may be an early marker of disrupted CNS development with potential for long term developmental consequences. The impact of cocaine exposure on the immediate and long term developmental outcome is not completely known, In addition to the methodological considerations previously outlined, two other important caveats must be considered when evaluating developmental outcome studies. The first caveat, i.e. the importance of subset scoring and analysis, was highlighted by Griffith et al. who, when reporting findings from their 3-year data, showed no group difference on overall developmental test scores [65]. However, when scores were analyzed for specific subset areas, group differences were found in specific domains, such as language development. Similarly, in another study assessing cocaine exposed infants with the NBAS, habituation was compromised to a greater degree than other domains assessed by this testing strategy [45]. Reporting overall scales could possibly overlook this specific effect. It is important, therefore, to critically identify the specific functions or areas to be targeted in the developmental evaluation of the infant exposed prenatally to cocaine. Also, it is important to identify the salient behaviors for assessment. For instance, prenatally cocaine exposed infants may score within the normal range for structured tests such as the Bayley, but show individual behaviors reflective of a disorganized state such as low threshold to frustration, neonatal stress indicators [45] and altered play characteristics [ 1291. Another important consideration when interpreting results from developmental testing is taking into account the definition used to define normal and abnormal. For instance, in the 2-year follow-up study by Chasnoff et al. [21], cocaine-exposed and non-exposed infant groups were not considered significantly different on developmental assessment scores. For both groups, however, global scores were in the low range of normal; a finding that may reflect an impact of environment greater than cocaine. Also, although global scores for both drug groups were not different, the cocaine exposed infants showed a higher rate of scores more than 1 S.D. below the test mean. Critical evaluation of data, therefore, is necessary for proper interpretation of data and for the development of appropriate intervention strategies. In summary, the literature suggests both acute and possible long-term sequelae of in utero cocaine exposure. There may be moderate to severe developmental sequelae secondary to structural malformations in the CNS, to perinatal conditions presenting risk to the CNS (e.g. prematurity, abruptio placentae) and the direct cocaine toxicity. Additionally, there may be transient and long-term problems in more subtle

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dimensions of developmental functioning, such as motor skills or language development. Difficulties with behavioral regulation may be present as irritability, sleep and feeding problems and difficult temperament in the young infant. Milestone-oriented or intelligence tests may not be adequate to reflect the range of outcomes of developmental injury incurred by the fetus exposed to maternal cocaine use. Cocaine and respiratory control The true impact of in utero cocaine exposure on postnatal respiratory control and

SIDS risk remains unknown. In a retrospective study of three groups of infants: 50 exposed to cocaine and methadone, 50 exposed to methadone alone and 50 controls, Ryan et al. [133] reported a 4.0% incidence of SIDS among infants born to cocaine and methadone using women, demonstrating a 20-fold increase over the general population incidence of 0.2% [ 1471. The deaths in this series included two of 50 cocaine/methadone-exposed infants versus zero of 50 methadone-exposed and 50 control infants. Since the mean methadone use and the frequency of other drugs of abuse were ‘approximately equal’ in the two drug groups, the authors concluded that the groups differed only by cocaine exposure. Combining the results of the experience in two demographically separate programs, a subsequent retrospective study by Chasnoff et al. [ 171described a 15% incidence of SIDS among infants born to cocaine-using women demonstrating a 76-fold increase over the general population. The deaths in this series included 10 of 66 infants who were exposed to cocaine. Information regarding use of other illicit substances was not provided but eight of 10 mothers smoked cigarettes and three of 10 mothers used alcohol. Additionally, by combining the results of two demographically separate programs, potential population and selection bias further limited this study. Thus, both of these early studies were limited by polydrug abuse, selection and population bias and retrospective design. Since these reports, other published studies have supported [125,130,139,156] or challenged [6,56,96] the concept of an increased incidence of SIDS in infants exposed to cocaine prenatally. In 1988, for instance, Bauchner et al. [6] prospectively evaluated 175 infants born to women who had used cocaine during pregnancy as determined by prenatal or postpartum urine screens. Of these mothers, 15% also used opiates, 86% smoked cigarettes and 79% used alcohol. Only one infant died of SIDS providing a SIDS incidence of 0.57%; an incidence not significantly higher than the 0.49% incidence in their control population. All women were recruited during pregnancy therefore suggesting that poor prenatal care is an intervening variable in cocaine’s effect on SIDS risk [35]. An alternate interpretation of this data could support that, compared to the national SIDS figure, results of this study represent a two- to threefold increase above the overall population risk of 2.2 per 1000 [146]; in other words, even their control population was at a higher than national risk. These results may indicate that other albeit related factors may increase the incidence of SIDS in a specific population (e.g. poverty, stress, family stresses) [156]. The spectrumof reported SIDS incidence, therefore, is very broad and has varied from zerofold increased risk [6,56,96] to a 76-fold increased risk [17]. All studies, however, dift& by design (retrospective versus prospective), patient population (clinic-based versus population-statistics), screening methods (maternal history,

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maternal urine, infant urine) and, importantly, use of other illicit substances. Such differences can minimize the interactive effects of secondary drugs with cocaine, introduce recall bias in case-control studies, or recruitment bias depending on recruitment strategies. Self-report is unreliable [71,172] and reliability of urine toxicology studies are influenced by the sensitivity of the screening methods, sample collection technique [37,62,119] and timing of collection [68]; all have potential for exposure misclassification thus biasing the validity of the exposure data. The complexities of controlling for polydrug abuse, nutrition and life style in any study evaluating the incidence of SIDS in infants born to cocaine-abusing women make it doubtful that the true incidence of SIDS will be determined unless carefully controlled, prospective clinic and population studies are undertaken. Even then, the effect of clinic intervention in maternal care may disguise the true incidence [7]. The most comprehensive study to date is that of Ward et al. [ 1561. This population-based study on 2143 infants exposed to illicit substances (Infants of Substance Abusing Mothers, ISAM) reported an overall SIDS rate in the ISAM population of 8.87 deaths per 1000 compared to the non-ISAM population (1.22 deaths per 1000 live births). Of the 1674 infants exposed to cocaine, the relative SIDS risk was 6.87 times that of the non-ISAM group; the SIDS rate being 8.36 per 1000 live births. This rate is consistent with the population-based experience of Durand et al. who reported a SIDS incidence of 8.8 per 1000 live births [43]. In the study of Ward et al. [156], the infants were categorized as cocaine-exposed by either positive drug history from the mother, suspected drug history by the physician, or positive urine toxicology from the mother or infant. Unfortunately, the study design did not allow for distinction between cocaine and cocaine with opiate or other drug exposure. Smoking, an independent variable for SIDS risk [68,84], was not reported in either study. Nonetheless, this population-based study is important since some investigators have raised concern that program clinic-based studies may exert a negative bias on the true incidence of SIDS in cocaine-exposed infants. The exact pathophysiology of SIDS is unclear, although many studies support the concept of abnormal CNS regulation of breathing as the final mechanism [76]. Altered brainstem neurotransmitter content [8] and antecedent hypoxia [I 1I] have been reported in human infants with SIDS. Cocaine alters the central biogenic amines; important respiratory control neurotransmitters. Preliminary data from our laboratory suggests that prenatal cocaine exposure may also alter the relationship of respiratory neuromodulators such as ME and SP [60]. Alternatively, cocaine may disrupt brain structures essential to respiratory regulation through its direct pharmacologic property of inducing hypertension with potential resultant CNS infarcts or indirectly through repeated episodes of hypoxia secondary to cocaine’s vasoconstrictive effects on the placental vasculature [123,146]. That prenatal cocaine exposure is associated with altered respiratory control is suggested by Ward et al. 11561who, in a population-based study of 2143 infants of substance abusing mothers including 1674 cocaine exposed infants, reported an increase in symptomatic apnea in the ISAM population compared to the non-ISAM group. Abnormal patterns of breathing have also been associated with in utero cocaine exposure. In the human fetus, our group has reported on two abnormal patterns of breathing demonstrated in infants exposed in utero to cocaine; sustained,

16

regular, hyperpneic breathing and repetitive yawning [59]. Few studies have systematically examined breathing patterns in infants of cocaint -abusing mothers; all are limited to some extent by unknown histories of polydrug abuse, selection bias and high attrition rates. However, the observations of Chaney, Franke and Wadlington [14] suggest that cocaine indeed alters respiration in infants. They described an infant with irregular respiration, gasping and cyanosis after cocaine ingestion during breast feeding contaminated with topical cocaine powder used by the mother. Further, recent reports show that pneumocardiograms are abnormal in some infants exposed in utero to cocaine. The abnormalities have included apnea greater than 15 s [ 1221, increased episodes of bradycardia [ 1391 and increased incidence of periodic breathing and short apneas [23]; the incidence ranging between 11 and 33%. The significance of these studies on SIDS risk and altered respiratory control remains unclear. In the report of Chasnoff et al. [23] no baby with an abnormal pneumogram died of SIDS, although all were treated with theophylline. In another abstract, two of 51 cocaine-exposed infants who had apparent life threatening events had normal pneumograms [125]. Thus, the relationship of periodic breathing and short apnea to subsequent SIDS has not been supported by these or other studies [141,157], and the link between these respiratory pattern abnormalities and SIDS remains unsubstantiated. Again, cocaine use in mothers is also associated with independent risk factors for SIDS such as cigarette smoking and poor prenatal care. Indeed, animal models to study brainstem mechanisms involved in respiratory control and large scale, multicenter, human studies are needed. Conclusions and directions for the future

Evidence supports the concept that cocaine is a true teratogen, an agent capable of inducing structural and neurologic injury in the fetus [44,77] and data derived from both animal and human studies suggest that prenatal exposure to cocaine is associated with functional consequences to the fetus and infant. In a recent analysis of factors associated with the poor perinatal outcome with cocaine exposure, the single best predictor of outcome was, in fact, cocaine use [47] even after controlling for socioeconomic status [77]. Unfortunately, abuse of illicit substances is complicated by other factors such as polydrug abuse, poverty, poor nutrition, dysfunctional families, poor medical care, maternal depression, all of which can affect the developmental and respiratory control outcomes of infants exposed in utero to cocaine. Relative contribution of these multiple factors can only be weighed by large, multicenter studies and multivariant analytic techniques. Region and population based epidemiologic studies could address the interaction of biologic and environmental forces on structural and neurodevelopmental outcome. As recent studies suggest that the developmental outcome for in utero cocaine exposed infants is variable, attention should be focused on intervention paradigms to test whether early maternal rehabilitation and early access to health care can improve neonatal outcomes as suggested by MacGregor et al. [97] or if improved parenting behaviors could enhance infant behavior and development outcomes in exposed groups. Longitudinal studies of growth and development with specific attention to regulation of state and modulation of behaviors are necessary to evaluate longterm outcome and the effects of socioenvironmental factors. Complex research

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designs and linear modeling techniques, both requiring a large sample, should assist in identifying relative contributions and the interaction aspects of behavioral competence and CNS integrity. For example, a young child could respond within normal limits within a structured one-to-one testing situation but exhibit disorders of attention and self regulation in a preschool classroom setting. An important goal for research in this area is the development of measurement strategies to better quantify dimensions of behavioral organization likely to index neurofunctional processes such as arousal and attention and to implement this measurement across studies. Additionally, animal models to control for confounding variables should be developed to address the questions of time specific vulnerability, control of breathing and the direct teratogenic properties associated with cocaine. Maturation of behavioral reflexes as well as learning and memory paradigms could be evaluated in these animal models free of confounders. Questions such as ‘how much’, ‘when’, ‘how often’, could and should be addressed. Acknowledgments

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