Environmental Health Perspectives Volume
102, Supplement 2, June 1994
[Citation
in PubMed] [Related
Articles]
Developmental Neurotoxicity Induced by Therapeutic and Illicit Drugs
Charles V. Vorhees
Division of Basic Science Research, Children's Hospital Research Foundation,
and the Departments of Pediatrics and Environmental Health, University of
Cincinnati, Cincinnati, Ohio
Abstract
The developmental neurotoxicity of phenytoin, isotretinoin, and methamphetamine
has been reviewed to illustrate effects from both therapeutic and illicit
drugs to which people are exposed and which either induce or show the potential
for inducing learning disabilities following in utero exposure. In
each case both human and experimental animal data are presented and compared
where possible. The findings point to several conclusions. First, some drugs
in current use induce developmental neurotoxicity, and it cannot safely
be assumed that there are not more as yet unidentified. Second, of the types
of neurotoxicity induced by drugs, learning disabilities figure prominently.
Third, the effects observed are dependent on both the drug's mechanism of
action and the period of brain development during which exposure occurs.
Fourth, with the exception of CNS teratogens, it is not yet possible to
predict which periods of brain development are the most vulnerable for the
induction of learning disabilities, as seen by the different patterns of
critical periods for phenytoin and isotretinoin compared to methamphetamine.
Fifth, as seen with isotretinoin, existing drugs that cause developmental
neurotoxicity are not the only problem; new drugs with such effects are
still being introduced. Sixth, only a small fraction of the drugs currently
in use have ever been examined for developmental neurotoxicity; hence, the
full scope of the problem cannot even be accurately estimated based on current
information. It is concluded that prevention of new cases caused by drugs
such as isotretinoin should be a high priority for future regulatory action.
-- Environ Health Perspect 102(Suppl 2):145-153 (1994).
Key words: developmental neurotoxicity, phenytoin, isotretinoin,
methamphetamine, behavioral teratogenicity of drugs
Address correspondence to Dr. Charles V. Vorhees, Division
of Basic Science Research. (Rm 5007A), Children's Hospital Research Foundation,
Elland Ave. at Bethesda, Cincinnati, OH 45229-2899. Telephone (513) 559-8622.
Fax (513) 475-3912
Introduction
The purpose of this paper, as the title implies, is to review evidence
that there are established examples of both therapeutic and illicit drugs
that induce prenatal neurotoxicity. While suspicions about such effects
have been gathering for many years, a more complete link between specific
drugs and developmental neurotoxicity which extends from experimental animals
to humans has only emerged in the last 15 years.
Rather than present a list of all the drugs proven or suspected of inducing
developmental neurotoxicity, I have selected three examples that illustrate
what I believe to be the most common pattern by which this kind of finding
is revealed. The pattern begins with clinical case reports, in which a small
number of cases are identified, and the suggestion is made that the effects
seen in the affected children are related to a particular intrauterine drug
exposure. Next, experimental animal research tests this hypothesis. In the
cases presented below, such data showed a direct cause-effect relationship
in animals between the drug in question and various neurological and behavioral
abnormalities in the offspring. The animal data also usually establish dose-effect
and exposure-effect relationships, provide control over potential confounding
factors such as undernutrition and changes in postnatal rearing environment,
identify sites of brain injury, and ultimately, uncover mechanisms of drug
action. Following the studies in experimental animals, the final phase is
the conduct of epidemiologic studies in humans. These are usually prospective
and are controlled by matching comparison subjects to cases and by using
statistical methods of adjustment for covariates known or suspected to be
confounders. Epidemiologic studies are not necessarily triggered by the
animal experimental studies, but they nevertheless constitute the culmination
of a process that when positive, implicates the drug in question to adverse
effects. This, of course, is an idealized three-step process, and it seldom
runs true to course. Nevertheless, it fits sufficiently well to use it to
provide structure to this review.
The three drugs I have selected for review are the anticonvulsant phenytoin
(Dilantin), the antiacne drug isotretinoin (Accutane), and, for the illicit
drug example, the centrally acting stimulant methamphetamine (street names
rock, ice, meth, or speed).
The Drugs and Their Actions
Phenytoin
Phenytoin is associated with the fetal hydantoin syndrome (FHS). FHS
was first described by Hanson and Smith in 1975 (1). This was not
the first time an anticonvulsant drug had been linked to developmental toxicity,
that had first been suggested by Meadow (2), who suggested a link
between anticonvulsants, including phenytoin, and certain congenital malformations.
However, Hanson and Smith (1) were the first to suggest a syndrome
associated with hydantoin exposure and the first to suggest that an integral
part of the syndrome was a neurotoxic effect. The features Hanson and Smith
(1) described for FHS involve the CNS including developmental delay
and mild mental subnormality; craniofacial structures, including midfacial
hypoplasia, hypertelorism, flattened philtrum, and shortened nose; growth
effects, in this case growth retardation; and limb development, including
distal phalangeal hypoplasia and small nails.
It is important to note that FHS did not occur in isolation. The fetal
alcohol syndrome had been described just 2 years earlier by the same group,
and in 1975 this group also described a fetal trimethadione syndrome (3).
Actually, their paper was predated by a paper by Hill et al. (4),
although the effects described by Hill et al. were not characterized as
a syndrome per se. Shortly thereafter, a possible fetal barbiturate
syndrome was described (5). Subsequent reports were to describe a
fetal primidone syndrome (6), a fetal valproate syndrome (7),
and most recently a fetal carbamazepine syndrome (8).
Following the initial case reports of FHS, a series of experimental animal
investigations were published. These may generally be categorized as of
two types. First were those attempting to link phenytoin to congenital malformations.
I will not review those here. Second were those attempting to link phenytoin
to developmental neurotoxicity; I will highlight some of these.
The investigators in this area approached the issue of possible developmental
neurotoxic effects from a perspective of trying to eliminate the concomitant
influence of malformations on the exposed progeny. This was done to more
clearly determine if there were CNS effects of intrauterine phenytoin exposure
that were separate and distinct from those attributable to dysmorphogenesis
of major organ systems. Therefore, these experiments administered phenytoin
at subteratogenic doses.
Only those neurotoxic effects seen in the offspring of phenytoin treated
dams that have been replicated numerous times will be presented here. During
early postnatal development, rats exposed to phenytoin in utero exhibit
heightened locomotor movement, primarily pivoting. This is illustrated in
Figure 1 and is taken from Vorhees and Minck (9). The pattern is
always consistent. The progeny appear normal on day 7, but become more active
than controls on day 9 and subsequent days. As the progeny grow older, their
hyperactivity becomes more pronounced. Figure 2 illustrates this for the
same progeny as shown earlier in life in Figure 1. The apparatus is a figure-eight-shaped
activity monitor; but the effect appears equally clearly in circular and
square open-fields, and in hold-board chambers. Note in the right of Figure
2 that accompanying the hyperlocomotion of the phenytoin-exposed offspring
is a reduced rearing frequency. Animals that ambulate more, rear less. Perhaps
this inverse relationship is a function of competing responses, such that
rearing is crowded out of the animal's response repertoire by the press
to ambulate. However, an alternative explanation is that these rats rear
less because they are unstable. We later found that phenytoin-exposed animals
have balance and righting reflex abnormalities that lend credence to the
latter interpretation (below).
Figure 1. Mean
(± SEM) early locomotor activity counts on each day and summed across
test days (inset). *p<0.05; **p<0.01. From Vorhees and
Minck (9).
Figure 2. Mean
(± SEM) locomotor activity counts on each day of testing in the figure-eight
activity monitor (left) and rearing counts under the central canopy averaged
across test days (right). **p<0.01. From Vorhees and Minck (9).
As evidence that phenytoin offspring have balance abnormalities, Elmazar
and Sullivan (10) reported that rats exposed prenatally to this drug
show large delays in the normal developmental acquisition of the air-righting
reflex. In rats, this reflex develops rapidly during the second week of
postnatal life and once attained gains additional speed during the third
week of life. We have replicated Elmazar and Sullivan's (10) air-righting
effects in rats prenatally exposed to phenytoin in several experiments,
one of which is illustrated in Figure 3 (11). As can be seen, regardless
of the scoring criterion used, phenytoin offspring were not only delayed
in the acquisition of the air-righting reflex, they never attained the speed
of response seen in controls. The data in Figure 3 also include groups exposed
to two other hydantoin anticonvulsants and to the inactive hydantoin core
molecule itself. These other hydantoins produced no delays resembling those
seen the phenytoin group. This illustrates an important point: it is risky
to rely too heavily upon structure-activity relationships in making predictions
about which drugs are capable of inducing developmental neurotoxicity and
which ones are not.
Figure 3. Mean
proportion of animals in each group successfully righting themselves by
the 2/3 (left) and the 3/3 (right) trial criterion based on visual scoring
of righting by two observers. *p<0.05; **p<0.01. From
Minck et al. (11); reprinted with permission.
One of the most striking effects of prenatal phenytoin is that when the
offspring reach 40 to 50 days, a percentage begin to exhibit a neurological
abnormality. This takes the form of exessive circling movements. It is different
from the kind of circling seen in normal animals because of its speed and
repetitive nature. However, it is not seen if the animal is placed in an
open arena. It is most conspicuous in confined spaces where the walls are
close to the animal, such as when the animal is first returned to its home
cage, and in the narrow channels of a maze. Under these circumstances, the
affected individuals will episodically exhibit bouts of circling in which
they will turn several times in a row. As they turn they often tilt their
head in the direction of the turn with the inside ear lower than the outside
one. However, we have been careful to rule out middle ear infection as a
possible cause of this symptom.
Prenatal phenytoin exposure also affects another complex reflex, the
startle response. An example of phenytoin's effects on startle is shown
in Figure 4 (9). Phenytoin-exposed offspring show a reliable reduction
in startle amplitude to either an acoustic or tactile stimulus as adults
(as reflected in their maximum, Vmax, and average responses),
but no change in the latency to their maximum response (Tmax).
One of the most striking effects of prenatal phenytoin exposure is its
effects on offspring learning. We have relied upon two well-established
tests of learning: The Morris hidden platform maze and a complex multiple-T
water maze, termed the Cincinnati maze. These tests were chosen because
existing evidence suggests that they measure different (although perhaps
somewhat overlapping) aspects of learning. The Morris maze is a test of
spatial navigation, which relies upon the use of distal cues (12).
This test is known to be sensitive to hippocampal damage (13). The
complex multiple-T water maze is a test of what is termed "dead-reckoning"
navigation, which relies upon the use of proximal cues and vector estimation
(14). The brain region to which this test is sensitive is not as
well-established as it is for the Morris maze, but current evidence suggests
that cortical lesions and probably frontal cortex is the zone that has the
greatest effect on complex maze problem solving following lesion induction
(15).
Figure 4. Mean
(± SEM) startle amplitude (left two panels) and latency to peak response
(right panel) averaged across 50 trials (25 acoustic and 25 tactile stimulus
trial types). **p<0.01. From Vorhees and Minck (9).
The effects of prenatal phenytoin exposure on Morris maze learning are
shown in Figure 5 (9). As can be seen, the phenytoin-exposed animals
took significantly longer to navigate to the hidden platform than controls.
Figure 5. Mean
(± SEM) latency (sec) to find the goal in the Morris hidden platform
maze in phenytoin and control offspring under place test conditions. Extinction
refers to time spent in the goal quadrant. Shift refers to relocation of
the goal to the opposite quadrant. +p<0.10; *p<0.05.
From Vorhees and Minck (9).
As clear as the effect on Morris-maze acquisition is, the effect of prenatal
phenytoin exposure on the Cincinnati water maze is even greater. An example
is shown in Figure 6 (11). As can be seen, all phenytoin-exposed
offspring make many more errors than controls. Another aspect evident in
Figure 6 is that there are two distinct subgroups of phenytoin-exposed offspring.
Those that exhibit abnormal circling behavior are the most severely affected
(Figure 6,group PHT-C ) and show little improvement in performance across
trials. By contrast, those phenytoin-exposed offspring that do not exhibit
abnormal circling (Figure 6, group PHT-NC) show impaired learning, but they
eventually succeed in learning the maze; the difference is that the latter
animals learn at a slower rate than controls or animals exposed to other
hydantoins.
Figure 6. Mean
(± SEM) number of errors committed on each trial in the Cincinnati
water maze (path B). **p<0.01 from control. PHT-C, phenytoin-exposed
animals exhibiting circling; PHT-NC, phenytoin-exposed animals not exhibiting
circling; MPH, mephenytoin-exposed group; ETH, ethotonin-exposedgroup; HYD,
hydantoin-exposed group: CON, control group.
To bring things full circle, consider the recent prospective study by
VanOverloop et al. (16) of children exposed prenatally to phenytoin
alone or in combination with one of several other anticonvulsants. They
report that such children exhibit significant reductions in full-scale IQ,
reduced scores on the Visual Motor Integration test, and reduced counts
on a measure of locomotor activity when the children were assessed at between
4 to 8 years of age compared to controls. Controls were children identified
at the same time in the study's prospective enrollment process and were
selected because they were born in one of the target hospitals with three
or more minor congenital anomalies. On the verbal portion of the Wechsler
tests of intelligence (WPPSI or WISC-R, depending on their age), the most
affected subscales among the phenytoin-exposed children were those for Similarities
and Comprehension. However, the most striking differences occurred on the
performance subscales. Three performance subscales showed significant reductions
in the phenytoin-exposed children: Block Design, Mazes, and Animal House
Retreat. In terms of the size of the differences, the largest effect by
far was on mazes, and this would appear to be the task most analogous to
the animal data showing severely impaired complex maze learning. VanOverloop
et al. (16) also found a number of other differences that were nearly
statistically significant. Overall, their data suggest that while phenytoin-exposed
children may not be at risk for mental retardation, they may be at risk
for specific learning disabilities. Since approximately 0.5% of the population
has epilepsy, and over 95% of epileptics are treated for their disorder
with medication and phenytoin is the most widely prescribed of these medications,
it stands to reason that thousands of exposed infants are born in the United
States per year with the potential of phenytoin-induced learning disorders.
If even 10% of those exposed prenatally to phenytoin are learning disabled,
then this one anticonvulsant alone is inducing more than a thousand learning
disabilities per year in the United States and thousands more in the rest
of the world. While this is small from a national perspective, disabilities
such as these are not only a lifelong struggle for those affected and their
families, they also carry a lifetime financial burden to society. If these
could be prevented by policies designed to avoid certain anticonvulsants
during pregnancy, the benefits would be substantial.
Retinoids
The next example comes from the retinoids, of which vitamin A (retinol)
is the most familiar. Retinol's teratogenicity in animals has been recognized
since the early 1950s, but its developmental neurotoxicity was not demonstrated
experimentally until the 1970s.
In the 1980s Hoffmann-LaRoche developed a congener of retinoic acid (RA),
13-cis-retinoic acid. This compound exhibited a high degree of therapeutic
efficacy for severe cystic acne, a disorder for which highly efficacious
alternative treatments are not available. The company's own preclinical
animal experiments demonstrated that 13-cis-RA (isotretinoin, Accutane)
was teratogenic. However, the company conducted no developmental neurotoxicity
testing because it was not required by the US Food and Drug Administration
(FDA). Accordingly, the company sought FDA approval as a category X drug
(contraindicated during pregnancy). The drug was approved in September 1982.
Because of the nature of the laws in the United States, once the drug was
on the market it could be prescribed by any physician for any purpose, not
just for those purposes for which it was originally indicated. Furthermore,
under current US law, the FDA has no legal authority to restrict is use.
This drug, however, was not only highly efficacious for cystic acne, it
was also effective for acne, and by 1985 an estimated 160,000 women of childbearing
age had taken the drug. Since nowhere near this number of women has cystic
acne, the obvious had happened: physicians were over-prescribing the drug.
It did not take long for isotretinoin-associated malformation cases to begin
to appear. In 1985, Lammer et al. (17) collected all the known retrospectively
ascertained cases plus a cohort of prospectively ascertained cases. In both
groups he demonstrated unequivocally a human malformation syndrome caused
by isotretinoin. The affected children showed craniofacial, cardiac, thymic,
and CNS malformations in those born, and increased malformations among those
that never reached term. Even without these data, it was possible to predict
that isotretinoin would also be a developmental neurotoxin (18).
Indeed, the company could have predicted this had it attended to the scientific
literature. The prediction could be based on the substantial series of already
published animal experiments. I have summarized these in Table 1.
Animals exposed to retinoids during organogenesis exhibit a variety of
dysfunctions in the absence of malformations, but the most reliably reported
effect was a deficit in complex maze learning. Given this, it was a somber
but compellingly straightforward prediction that isotretinoin-exposed children
would be mentally retarded or learning disabled and further, that such effects
would be seen not only among those malformed, but also among exposed children
who were otherwise completely normal in appearance (18). Regrettably,
this scientific prediction proved to be only too correct. Recently, Adams
and Lammer (19) have completed a neuropsychological evaluation of
31 prospectively ascertained cases and a similar number of matched controls.
The psychometric findings are summarized in Figure 7. As can be seen, the
exposed children show a striking downward shift in their IQ distribution
on the Stanford-Binet IV test of intelligence. Figure 8 shows only the isotretinoin-exposed
children's IQ data coded for malformation type. Two observations stand out
from these data: First, those children with severe CNS malformations are
the ones with the most severe mental retardation. This confirms one of the
basic principles of developmental neurotoxicity developed from animal experiments,
that CNS teratogens (i.e., agents that induce gross malformations of the
brain) are reliably developmental neurotoxins at lower doses (doses that
do not cause neural tube defects) (20). The second observation is
that some children with moderate or milder degrees of IQ reduction had no
malformations whatsoever. This reveals the principle that one cannot predict
developmental neurotoxicity based on the presence or absence of malformations
alone (21).
Figure 7. Mean
performance on the Stanford-Binet IV test of 5-year-old children exposed
to isotretinoin in utero and controls. From Adams and Lammer (19);
reprinted with permission.
Figure 8. Number
of cases with malformations by IQ range and showing the relationship between
major malformations and general mental ability in 5-year-old children exposed
to isotretinoin in utero and controls. From Adams and Lammer (19);
reprinted with permission.
This brings the case of isotretinoin full circle. It began with human
collected case reports and a small prospective cohort in which isotretinoin's
embryopathic effects were described, then the drug's developmental neurotoxicity
was predicted based on already extant animal data, and finally its developmental
neurotoxicity was proven in a human prospective study. The latter data represent,
beyond any doubt, the most clear-cut human developmental neurotoxicity data
ever obtained.
Methamphetamine
Methamphetamine (MA) is the N-methylated congener of amphetamine. Its
pharmacology is the same as that of amphetamine except that MA is two to
three times more potent as a CNS stimulant. Amphetamines have been abused
for their neurostimulant effects for many years, but following the emergence
of the free base use pattern of cocaine, it was not long before users discovered
that MA could also be smoked, if it was sufficiently pure. The smoking of
MA has led to a resurgence of illicit use of this drug and along with it,
a concern for infants born to women using MA.
Several studies have appeared on the possible effects of MA on infants
following intrauterine exposure. Three of these are worth noting. In the
first, Oro and Dixon (22) described a group of infants born to women
using MA, cocaine, or both. Oro and Dixon found that the stimulant group
showed intrauterine growth retardation and altered neonatal behavior. The
latter included lethargy, poor feeding, tremors, and abnormal sleep, among
others, compared to a narcotic-exposed group or a non-drug-exposed control
group. Subsequently, Dixon and Bejar (23) reported an increased incidence
of intraventricular hemorrhages, echodensities, and cavitations seen on
cranial ultrasonographs of stimulant exposed infants. About one-third of
the infants were exposed to MA and the remainder were exposed to cocaine
or cocaine and narcotics. The abnormal sonograms were found in all stimulant-exposed
groups compared to the comparison group. There were no differences in abnormal
sonogram findings between infants exposed to MA and those exposed to cocaine.
In between the two reports by Dixon (22,23) and Little et al.
(24) reported on 52 women and their infants exposed to MA. Little
et al. reported that these infants were intrauterinely growth retarded,
but that no increase in birth defects occurred. They conducted no behavioral
testing.
Unlike the situation with isotretinoin, the animal data available on
prenatal MA were not adequate for making predictions of human developmental
neurotoxicity. Therefore, we sought to improve the situation by developing
a high-dose early exposure model. This was at variance with the existing
published data, which were entirely devoted to a constricted portion of
the dose-response range, i.e., low doses.
In one experiment d,l-MA (50 mg/kg, twice a day) was administered to
rats on days E7 to E12 of embryonic development. The offspring exhibited
reduced olfactory orientation to their home-cage scent, reduced pivoting
locomotion early in life, and heightened acoustic-tactile startle reactivity
as weanlings. The latter may be seen in Figure 9 (25). However, when
these same offspring were tested on a complex water maze, they showed no
learning deficits. By comparison, rats exposed later in development to d-MA
also exhibited heightened startle (Figure 10) and they committed more errors
in a complex water maze (Figure 11) (26,27).
Figure 9. Mean
(± SEM) peak startle amplitude (left panel), average amplitude (center),
and latency to peak response (right) averaged across 50 acoustic startle
trials. +p<0.10; *p<0.05; **p<0.01.
MA, prenatal methamphetamine-treated group; Con, controls.
Figure 10. Mean
(± SEM) maximum amplitude of the acoustic startle response averaged
across test ages and trials for females. *p<0.05; **p<0.01
compared to control. From Vorhees et al. (26,27).
Figure 11. Mean
(± SEM) number of errors committed in the Cincinnati water maze averaged
across trials. +p<0.10 compared to control. From Vorhees
et al. (26,27).
Figure 12. Mean
(±) time (sec) to find the hidden platform during each phase of testing
in the Morris navigation test. Acq: acquisition phase, consisting of 24
trials (8 trials/day); test: memory phase, consisting of 4 trials with the
platform removed (for this measure the ordinate represents the time spent
in the goal quadrant); re-acq: reinstatement phase, consisting of 4 trials
with the platform in its original location; shift: new learning phase, consisting
of 8 trials with the platform moved to a location in the opposite quadrant
of the tank. *p<0.05; **p<0.01 compared to controls.
From Vorhees et al. (26,27).
Note, however, that the effect on errors of commission in the complex
water maze was relatively small and occurred only in those rats exposed
during the second of the two exposure periods examined. More striking than
this is the effect MA exposure had on the development of learning in the
Morris hidden platform maze. As can be seen in Figure 12, the later-exposed
group showed a significant delay both in initial learning and in learning
a new goal position when the platform was shifted to another location (26,27).
This shows just how sensitive the developing brain is as a function of the
stage of ontogeny when the exposure occurs. It is clear that effects on
learning can be induced by one drug at one stage of brain development, but
at another stage by a different drug (compare phenytoin vs MA)
Discussion
The developmental neurotoxicity of three drugs has been reviewed in order
to illustrate effects from both therapeutic and illicit categories of drugs
to which people are exposed and which either induce or show the potential
for inducing learning disabilities following in utero exposure. In
each case both human and experimental animal data were presented and compared
where possible. The findings point to several conclusions. First, drugs
in some current use appear to induce developmental neurotoxicity; therefore,
it is not correct to assume that the current pharmacopoeia of approved drugs
is free of developmental neurotoxins. Second, among the types of neurotoxicity
these drugs induce, learning disabilities are prominent, sometimes the most
prominent, effect observed. Third, the effects observed are dependent on
both the drug's mechanism of action and the period during brain development
when exposure occurs. Fourth, it is evident that simple predictions about
critical periods during brain development that are most vulnerable for the
induction of learning disorders are not yet possible, as seen by the different
patterns of critical periods for phenytoin and isotretinoin compared to
methamphetamine. Fifth, it is evident from the example of isotretinoin,
that we not only face the problem of attempting to identify and correct
cases of drugs already on the market that induce developmental neurotoxicity,
but our society continues to introduce new developmental neurotoxins that
must be uncovered. In this regard, the government's stated position that
its current testing is adequate is obviously incorrect, otherwise the isotretinoin
case would never have happened. Sixth, current research expenditures only
permit us to assess a small percentage of the drugs currently in use and
to detect only the most serious types of developmental neurotoxicity; we
know almost nothing about this aspect of toxicity for most drugs and we
know even less about more subtle types of developmental neurotoxicity. This
is a source of concern, because we appear to have only scratched the surface
when it comes to knowing all the types of CNS damage prenatal drugs are
capable of inducing.
Nevertheless, one promising avenue is now becoming feasible for dealing
with some of these drug-induced problems: prevention. Most instances of
developmental neurotoxicity could be prevented with current techniques of
assessment if these were incorporated in preclinical testing for all drugs
and other agents to which people are exposed in significant quantities.
The only thing standing between us and this benefit is the Federal government.
The scientific basis for regulatory action exists already. Proof of this
is to be found in regulatory actions already taken by the US Environmental
Protection Agency. Other agencies can follow suit anytime they choose to
do so.
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