Prenatal Cocaine Exposure and Fetal Vascular Disruption

(1)

Prenatal

Cocaine

Exposure

and Fetal

Vascular

Disruption

H. Eugene

Hoyme,

MD; Kenneth

Lyons

Jones,

MD;

Suzanne

D. Dixon,

MD; Tamison

Jewett,

MD; James

W. Hanson,

MD;

Luther

K. Robinson,

MD; M. E. Msall,

MD; and Judith

E. Allanson,

MD

From the University of Arizona College of Medicine, Tucson, Arizona; the University of

California, San Diego, School of Medicine, La Jolla, California; the University of Iowa

College of Medicine, Iowa City, Iowa; the State University of New York, Buffalo, School of

Medicine, Buffalo, New York; and the Genetics Center, Southwest Biomedical Research

Institute, Scottsdale, Arizona

ABSTRACT. The question of the potential teratogenicity of cocaine has been raised by the increasing frequency of

its abuse in the United States. In previous studies, an increased incidence has been documented of spontaneous abortion, placental abruption, prematurity, intrauterine growth retardation, and neurologic deficits in the infants

of women who abused cocaine. More recently, it has been suggested in studies that fetal vascular disruption

accom-panying maternal cocaine abuse may lead to cavitary

central nervous system lesions and genitourinary

anom-alies. In this article, 10 children born of women who

abused cocaine are described, 9 of whom have congenital limb reduction defects and/or intestinal atresia or infarc-tion. The spectrum of anomalies associated with embry-onic and fetal vascular disruption accompanying mater-nal cocaine abuse is thus enlarged. The specific risk for

congenital anomalies accompanying maternal cocaine

abuse during an individual pregnancy is unknown. How-ever, data from these patients and the available literature suggest that counseling pregnant women concerning

co-caine use should incorporate warnings about the

possi-bility ofassociated embryonic or fetal vascular disruption.

Pediatrics 1990;85:743-747; cocaine, vascular disruption,

drugs in pregnancy, congenital anomaly.

As cocaine use has rapidly increased in the

United States over the past decade, so has maternal

Received for publication May 8, 1989; accepted Jul 5, 1989.

Presented, in part, at the 1988 David W. Smith Morphogenesis and Malformations Conference; Aug 6, 1988; Oakland, CA; and

at the 1988 American Society of Human Genetics Meeting; Oct

14, 1988; New Orleans, LA.

Reprint requests to (H.E.H.) Section of

Genetics/Dysmorphol-ogy, Children’s Research Center, Dept of Pediatrics, University

of Arizona College of Medicine, Tucson, AZ 85724.

cocaine use during pregnancy. It has been estimated

that 10 million Americans have used cocaine at

some time, and that 5 million use cocaine regularly.1 It has been suggested in previous studies that ma-ternal cocaine use during pregnancy may result in fetal vascular disruption of the central nervous

system24 and/or genitourinary system5’6 by means

of vasoconstriction or hemorrhage. The purpose of

this report is to describe 10 children with structural defects born to women who abused cocaine.

Accord-ing to analysis of the types of defects observed,

vascular disruption is suggested as a unifying

path-ogenesis for these anomalies. The nature of the

defects described here further enlarges the clinical

spectrum of fetal vascular disruption observed

fol-lowing prenatal cocaine exposure.

CASE REPORTS

The clinical features of the 10 children are set forth in the Table. These patients were ascertained through five clinical genetics and dysmorphology units throughout the United States. Ascertainment was for children with

con-genital anomalies born to women who used cocaine

reg-ularly throughout pregnancy. The nature of the defects

was analyzed to determine whether they might share a

common pathogenesis.

With respect to gestational timing, four of the children

were born prior to 36 weeks’ gestation. Patient 8 was

delivered prematurely in association with abruption of the placenta. Patient 10 was stillborn at 32 weeks’

esti-mated gestational age. Growth deficiency was seen in

three patients. In each case, growth deficiency was of

postnatal onset, associated with nonduodenal intestinal

infarction or atresia. Microcephaly was noted in two of the children, and developmental delay was documented

(2)

TABLE. Clinical Features of Infants W ith Str uctural Def ects and Prenatal Cocai ne Exposure (n = 10)*

Patient 1 2 3 4 5 6 7 8 9 10 All

Prematurity - - + + - - + - + 4

Growth deficiency - + - - - - + + - - 3

Microcephaly - + - - - - - + - - 2

Developmental delay + + ? ? ? ? + + ? ? 4

Intracranial hemorrhage + + - - - - - - - - 2

Nonduodenal intestinal - + - - - - + + - - 3

atresia/infarction

Limb reduction defects + - + + + + + -

-

+ 7

Cardiac anomalies - - + + - - + + - - 4

Renal anomalies - - - - - - - - + - 1

Aplasia cutis congenita - - - - - - - + - - 1

Hemangiomata - - + + - - + - - - 3

Prenataldrugexposure C,CR,M,

A,CG

C,H C,A,MJ C C,MJ,CG,

A

C,A C,CR,A,CG, MJ,PCP

C C C

* Abbreviations: C, cocaine; CR, crack; M, methamphetamine; A, alcohol; CG, cigarettes; H, heroin; MJ, marijuana;

PCP, phenylcyclidine. Symbols:

+,

present; -, absent;

?,

unknown. Other clinical features were as follows: in patient

1-decreased vision, abnormal visual evoked response; in patient 2-low Apgar scores, ileal and colonic infarction; in

patient 3-vaginal bleeding during weeks 4 to 8 of gestation, bilateral preauricular tags, choanal stenosis; in patient

4-Poland sequence; in patient 6-Robin sequence, nail dystrophy; in patient 8-fetal hydrops, abruptio placentae, tapered fingers; and in patient 10-stillborn, extensive placental infarction.

Intracranial hemorrhage was noted in patients 1 and

2 in the neonatal period. Patient 1 had a posterior fossa

subarachnoid hemorrhage. He was later found to exhibit

decreased vision, an abnormal visual-evoked response,

and developmental delay. Patient 2 exhibited the follow-ing ultrasonographic findings consistent with antenatal cerebral infarction: diffuse echogenic areas anterior and inferior to the ventricles and prominent sulci indicative

of diffuse atrophy. This child was shown to have

devel-opmental delay.

Nonduodenal intestinal atresia or infarction was noted

at delivery in 3 of the 10 children. Patient 2 had a

distended abdomen and absent bowel sounds at delivery.

Radiographically, the abdomen had enlarged loops of

bowel with pneumatosis intestinalis and intrahepatic air. At laparotomy, the bowel was found to be infarcted and necrotic from the terminal ileum to the sigmoid colon, and a resection was carried out. (This child was described elsewhere previously.7) Patient 7 was found to have

atre-sia of the transverse colon following symptoms and signs of bowel obstruction in the newborn period. Finally,

patient 8 was found to have diffuse intraperitoneal cal-cification accompanying ileal atresia and meconium

per-itonitis.

Limb reduction defects were noted in seven of these children. Unilateral terminal transverse limb reduction

defects of the upper extremities just distal to the elbow were found in two children. Unilateral atypical ectrodac-tyly with a missing medial ray of the hand was found in

one. One child was missing the third, fourth, and fifth

digits ofone hand. Two children had bilateral asymmetric

radial ray anomalies, and one child had symmetrical

bilateral reduction anomalies of the arms with only a

single forearm bone and digit present.

Cardiac anomalies have been noted in 40% of these

patients, including a single instance of each of the follow-ing defects: pulmonary atresia, pulmonary stenosis, atrial

septal defect, and ventricular septal defect.

An unusual area of aplasia cutis congenita was noted

on the medial aspect of the forearm in patient 8. Accord-ing to results of placental examination, there was a small

placenta and a single umbilical artery. There was no

evidence of a fetus papyraceus. Patient 9 had congenital

genitourinary anomalies, including right renal agenesis

and left hydronephrosis. Patient 10 was stillborn. Mul-tiple infarctions were seen in placental examination.

Other structural anomalies noted in this series of

pa-tients included one instance of each of the following:

hemangiomas, bilateral preauricular tags, choanal

ste-nosis, the Robin sequence, dystrophic nails, fetal hydrops,

tapered fingers, and a single umbilical artery.

Ofthe 10 children, 4 were exposed prenatally to cocaine

alone, whereas the remaining 6 were exposed to a variety

of other agents including methamphetamine, alcohol,

cigarettes, heroin, marijuana, and phencyclidine. Specific

information regarding the exact dosage and timing of

cocaine use is unavailable; however, these women used

cocaine on a regular basis throughout pregnancy.

DISCUSSION

Cocaine is an amino alcohol base closely related

to “tropine,” the amino alcohol in atropine. It is

structurally similar to the synthetic local

anes-thetics, including lidocaine. Cocaine is obtained

from the leaves of Erythroxylon coca trees

indige-nous to Peru and Bolivia. It has been used in those

countries for centuries to increase endurance and

reduce hunger (by means of central nervous system stimulation).8

Cocaine prevents reuptake of neurotransmitters

(serotonin, epinephrine, and norepinephrine) at

nerve terminals. These vasoactive amines persist

for a prolonged period of time near the receptors of

(3)

Cocaine has several documented pharmacologic effects. Cocaine use leads to central nervous system

stimulation. Effects on the cortex may include

in-creased motor activity, whereas effects on lower

motor neurons may be manifest as tremors and

convulsive movements. Sympathetic stimulation accompanying cocaine use leads to cardiovascular

effects. Tachycardia may result from central

sym-pathetic stimulation. Sympathetic stimulation may

also lead to generalized vasoconstriction.

Hyperten-sion then results from a combination of the

tachy-cardia and vasoconstriction. Hyperpyrexia often accompanies cocaine use as well. Increased core

temperature may follow increased muscular

activ-ity, vasoconstriction and decreased heat loss, and

direct action on hypothalamic temperature-regulat-ing centers.8 In animal models, cocaine has been

shown to lead to decreased uterine and placental

blood flow.9’10

Complications of cocaine use in the adult have

been well-documented, most following

vasocon-striction and the rapid rise of systemic and cerebral

perfusion pressures immediately following cocaine

exposure. Among described complications are

sud-den death, intestinal ischemia, myocardial infarc-tion, seizures, brain infarction, syncope, vascular headaches, and loss of consciousness.”’4

Metabolic factors may potentially lead to an

in-creased vulnerability of the developing human

em-bryo and fetus to the previously described effects

of cocaine. Concentrations of serum cholinesterases

partially responsible for cocaine degradation are

diminished in maternal serum during pregnancy.’5

Therefore, a similar dose of cocaine may result in

a higher, more sustained blood level in the pregnant

as compared with the nonpregnant woman. In

ad-dition, fetal serum has a relative deficiency of cho-linesterases in comparison with adult levels.’5

Complications of maternal cocaine use during

gestation have been documented in a number of

previous studies. In 1985, Chasnoff and colleagues’6 described the outcome of 23 cocaine-exposed

preg-nancies. They found an increase in spontaneous

abortion, placental abruption, and abnormal

neo-natal behavior as measured by the Neonatal Behav-ioral Assessment Scale.’7 In 1987, in an expanded

study of 70 cocaine-exposed pregnancies by the

same researchers,’8 an association was shown with

premature delivery, decreased birth weight, and delivery of small for gestational age infants.

LeBlanc and colleagues’#{176} in 1987 described the

outcome of 38 pregnancies complicated by maternal

“crack” (alkaloidal cocaine) abuse. These authors

noted an increased incidence of prematurity,

intra-uterine growth deficiency, and abnormal neonatal

behavior with tremulousness and irritability. Bingol et al2#{176}in 1987 described an increased

incidence of stillbirth (accompanying placental abruption), growth deficiency ofprenatal onset, and congenital cranial defects (encephalocele, exen-cephaly, and parietal bone defects) in infants born

of women who abused cocaine.

Bingol et al2’ in 1986 and Chasnoff et al5 in 1988

described children with genitourinary

malforma-tions in association with maternal cocaine abuse.

Bingol described 4 such children with the urethral

obstruction malformation (“prune belly”) sequence,

and Chasnoff described 7 children out of 50 ascer-tamed for maternal cocaine abuse who had genito-urinary anomalies. It is of note that 2 ofthe children

in the report by Chasnoff et al also had terminal

limb reduction defects. An additional 2 children in

that study had ileal atresia without genitourinary anomalies. An increased incidence of genitourinary anomalies in infants of mothers who abused cocaine

was also confirmed in epidemiologic studies carried

out in metropolitan Atlanta by researchers at the

Centers for Disease Control.6

Finally, perinatal cerebral hemorrhage and/or

infarction have been noted previously in infants

prenatally exposed to cocaine. In 1986, Chasnoff and colleagues7 described an infant with a perinatal cerebral infarction associated with maternal use of a large amount of cocaine 72 hours before delivery.

Dixon and colleagues3 recently reported that 39%

of 28 children ascertained because of prenatal

co-caine and methamphetamine exposure had

abnor-mal cranial ultrasound study results, with evidence of perinatal hemorrhage and/or infarction.

Although these studies have documented

pen-natal morbidity and mortality associated with

ma-ternal cocaine use, a few prospective studies22’23

indicated that fetal cocaine exposure is not associ-ated with a substantially increased teratogenic risk. In a report23 of 25 prospectively ascertained

preg-nancies associated with first trimester

“recrea-tional” cocaine exposure of less than 10 g total, no

increase was shown in adverse pregnancy outcome.

This discrepancy in outcome may relate to

varia-bility in dosage, timing, and route of cocaine

expo-sure among subjects in previous reports. In

addi-tion, the numbers of cases prospectively studied

may be too small at present to detect a small but

significantly increased teratogenic risk. Larger

carefully controlled studies will serve to delineate individual risk more clearly.

Few animal studies are available with respect to

the potential teratogenicity of cocaine. An

in-creased incidence of cryptorchidism,

hydrone-phrosis, skeletal defects, exencephaly, eye

malfor-mations, and delayed ossification of the skull and

paws followed cocaine administration to gravid

CF-1 mice;24 and decreased fetal weight, increased

(4)

in rats exposed to cocaine in utero.25 Furthermore, Church et al26 noted fetal edema, abruptio placen-tae, and cephalic hemorrhages in fetal rats exposed to cocaine in utero.

Although few animal data exist with respect to

the potential teratogenicity of cocaine, previous

animal studies2729 do indicate significant disruptive

effects in embryos exposed to hypoxia by means

of vasoconstniction. For example, Leist and

Grauwiler29 exposed fetal rats to placental

hypoper-fusion and hypoxia by clamping uterine blood

yes-sels on day 14 of gestation. Among observed

embry-onic and fetal effects were the following: increased fetal mortality, decreased fetal weight, diffuse

hem-orrhages and blistering, bleeding into the amnion

and other fetal membranes, cleft palate, and distal necrosis of snout, fingers, and toes.

Data from the previous human and animal

stud-ies cited indicate that one mechanism by which

cocaine might adversely affect embryonic and fetal development is through vascular disruption. Such

vascular compromise could follow hemorrhage

ac-companying a rapid increase in systemic and

cere-bral blood pressure similar to that noted in exposed

adults.”’3 Hemorrhage might also accompany

hy-perthermia associated with cocaine abuse. It has

been documented in previous studies3#{176}that one of the pathogenetic mechanisms by which hyperther-mia can exert teratogenic effects is by means of hemorrhage. Patient 10, a stillborn infant with unilateral distal digital disruptions, had a placenta with multiple areas of infarction. An additional

mechanism by which structural disruption might

have occurred in this child is by means of placental

emboli interrupting blood flow to a distal extremity.

Alternatively, cocaine may lead to uterine,

placen-tal, embryonic, or fetal vasoconstniction, with

re-sultant hypoperfusion and hypoxia (rather than

overt hemorrhage).9”0 Such vascular compromise

might lead to disruption of existing structures and

incomplete and altered morphogenesis of

develop-ing structures. It is likely that the nature of the

defects associated with vascular disruption

follow-ing embryonic and/or fetal cocaine exposure

re-flects the timing and the location of

vasoconstnic-tion or hemorrhage during the developmental span.

For example, disruption of the superior mesentenic artery in early gestation could lead to infarction

and necrosis of bowel segments distal to the

duo-denum; with time and tissue resorption, nonduo-denal intestinal atresia would result (as noted in

patients 7 and 8). Anatomically similar vascular

disruption in later gestation might result in bowel

infarction and necrotizing enterocolitis being pres-ent in the neonatal period (as described in patient 2).

In the 10 children described here, we hypothesize

that the structural defects noted can be accounted for on the basis of embryonic or fetal vascular

disruption following maternal cocaine use.

Simi-larly, the limb, gastrointestinal, and many of the

central nervous system and renal anomalies

de-scnibed in affected children in the medical literature are best understood in terms of a vascular

patho-genesis. The vascular pathogenesis of the spectrum

of anomalies associated with maternal cocaine use, as set forth in the Table, is borne out by extensive

evidence from experimental animal and human

studies.3’#{176}

It is of note that two of the women in this study

used crack in addition to cocaine. Although

smok-ing crack may lead to a higher overall cocaine

dosage than cocaine hydrochloride powder nasal

insufflation (due to a higher frequency of crack

usage to retain a euphoric state),’9 most authors2#{176} believe that there is no significant pharmacologic or physiologic difference among the forms of co-caine. The role of the additional prenatal drug exposures in these children is unclear. However, in the larger prospective series from the literature,5”9

the presence of exposures in addition to cocaine

(with the possible exception of alcohol4’) has not

apparently altered pregnancy outcome in

compani-son with pregnancies exposed to cocaine alone.

The exact risk to an individual cocaine-exposed

pregnancy is unknown. It was estimated in a few

prospective studies22’23 that the teratogenic risk ac-companying fetal cocaine exposure is small,

espe-cially when exposure is limited in amount and

timing to the first trimester. According to data reported by Dixon and colleagues3 from 28 infants

ascertained because of cocaine present in neonatal

urine screens, however, there was a 39% incidence of peninatal cerebral infarction or hemorrhage. Of

50 infants described by Chasnoff et a15

(prospec-tively ascertained because of the first trimester cocaine exposure), 9 had major anomalies, as com-pared with 1 of 30 control infants born to women who were poly-drug users, not exposed to cocaine. Likewise, according to data from the patients

de-scnibed here, regular cocaine exposure throughout

gestation may have associated risk. Unlike the case

with many teratogens, because vascular disruption

may occur at any point in gestation, potential fetal

damage associated with cocaine exposure may occur

in the second and third tnimesters as well as in

early pregnancy. Clearly, a large, prospective,

well-controlled clinical study is needed to ascertain the

risk to an individual pregnancy more accurately.

SUMMARY

(5)

of vascular disruption associated with prenatal co-caine exposure to include nonduodenal intestinal

atresia or infarction and terminal limb defects.

Although the exact risk to an individual

cocaine-exposed human pregnancy is unknown, it seems

prudent for clinicians caring for such pregnancies

to counsel their patients about the possibility of

associated embryonic or fetal vascular compromise

and to consider recommending maternal serum

a-fetoprotein determination and level II fetal

ultra-sonography to monitor possible vascular disruptive

events.

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1990;85;743

Pediatrics

Hanson, Luther K. Robinson, M. E. Msall and Judith E. Allanson

H. Eugene Hoyme, Kenneth Lyons Jones, Suzanne D. Dixon, Tamison Jewett, James W.