Clinical Teratology- A Monster Study

Mrs. Lakshmi Sivasubramaniam

Teratology is  the study of  perceived abnormalities in the natural
world, both real and imagined. A prodigy was a wondrous event or being which
stemmed, in most cases, from a misperception, or creative interpretation of
an actually occurring phenomenon.

This article examines the evolution of teratology through the eyes of physicians,
scholars and philosophers. How have they considered and how have they interwined
different interpretations in their representations and explanations of wonders
from Antiquity to the end of the 19th century?

Ancient times

Monstrosities have attracted notice from the earliest time, and many of the
ancient philosophers made references to them. Monsters possessed of two or
more heads or double bodies are found in the legends and fairy tales of every
nation. Hippocrates, his precursors, Enlpedocles and Democritus, and Pliny,
Aristotle, and Galen, have all described monsters, although in extravagant
and ridiculous language. Greek and Roman authors developed scientific, ethnographic,
and cosmographic interpretations of “the monstrous” that remain influential
until the end of the 17th century.

Ballantyne remarks that the occasional occurrence of double monsters was
a fact known to the Hippocratic school, and is indicated by a passage in De
morbis muliebribus, in which it is said that labor is gravely interfered with
when the infant is dead or apoplectic or double. There is also a reference
to monochorionic twins in the treatise De superfoetatione, in which it is
stated that " a woman, pregnant with twins, gives birth to them both at the
same time, just as she has conceived them; the two infants are in a single
chorion."

The Middle Ages

Many reasons were given for the existence of monsters, and in the Middle
Ages these were as faulty as the descriptions themselves. They were interpreted
as divinations, and were cited as forebodings and examples of wrath, or even
as glorifications of the Almighty. The semi-human creatures were invented
or imagined, and cited as the results of bestiality. We find minute descriptions
and portraits of these impossible results of wicked practices in many of the
older medical books but without a semblance of scientific truth. Natural histories
of the time had a genuinely encyclopedic scope in both coverage of subject
and sources consulted. This desire to mention all the aspects of a plant or
animal led the writers to include both mythical and real monstrous beings.
Medical men, who were also trained in natural philosophy, were the main promoters
and chroniclers of wonders. In Pliny the Elder's ethnographic interpretation,
monsters inhabited distant lands

Rhodiginus speaks of a monster in Italy with two heads and two bodies; Lycosthenes
saw a double monster, both components of which slept at the same time ; he
also says this creature took its food and drink simultaneously in its two
mouths. Even Saint Augustine says that he knew of a child born in the Orient
who, from the belly up, was in all parts double.

With the coming of Christianity, authors interpreted such phenomena as having
been brought forth by God to communicate divine judgments. By the end of the
Middle Ages, unusual natural occurrences were increasingly perceived as “wonders,”
or “prodigies”, terms which all focused on their strange and exceptional character.
Wonders were seen as signs of God’s anger, or a sign of the power of nature,
inspiring fear or admiration depending on the religious and political context.

Renaissance

During the 16th and 17th centuries, interest in the monstrous led to a deluge
of literature about prodigies. In addition to the reprint of classical works
on prodigies, a new genre appeared: the "prodigy book" facilitated by the
invention and development of printing throughout Europe. Published in lavishly
produced books, tales of the monstrous were written for the pleasure of wealthy
audiences. The same prodigies and monsters were also depicted in “cheap print”:
they were a cultural phenomenon shared by heterogeneous populations. In the
16th century, the Protestant reformers Luther and Melanchton substantially
increased the presence of monsters in popular culture with the publication
of a pamphlet depicting monstrous creatures as prophecies of the imminent
ruin of the Roman Church. Monsters were also depicted in broadsides, which
reached more readers than any other type of text.  A crowd would gather
around a broadside, displayed publicly and usually illustrated, as someone
read it aloud. Thus, the broadside appealed to the illiterate as well as to
the reading public through spoken word and image.

Renaissance natural philosophy combined the empirical study of the natural
world i.e today's biology, zoology, geology, and philosophical questions,
such as whether Nature was independent of God.  From the late 14th century
onward, there was a heightened desire to study nature and the unusual (due
to increasing contact with distant countries), which led natural philosophers
to pay significantly more attention to monstrous occurrences.  Wonders
of nature were characterized by their strangeness, as well as by their rarity,
and were attributed to a variety of causes. In Les Observations, Belon, a
French apothecary, described one of his trips to the eastern Mediterranean.
He found the inhabitants exotic, but far from the fantastic beings described
in Antiquity by Pliny the Elder. Partly due to the writings of medical men
such as Cardano and Benivieni, wonders (including monstrous beings) were increasingly
seen as part of the everyday world, rather than on the periphery of the unknown
world. Likewise, illustrations of monsters began to change too. Often represented
in a naturalistic environment, the artist strove for increasing realism, reflective
of the trend toward increasing detailed observation. The shift was not total:
the same book could contain the older style of representing monstrous beings,
as well as more modern, anatomical drawings of abnormalities

Scholars and thinkers continued to track the apparitions of monstrous beings.
An illustration represents a monstrous head found in an egg, said to have
been sent for examination to King Charles at Metz in 1569. It represented
the face and visage of a man, with small living serpents taking the place
of beard and hair. At this time were also reported double hermaphroditic terata,
seemingly without latterday analogues. Rhodiginus speaks of a two-headed monster
born in Ferrari, Italy, in 1540, well formed, and with two sets of genitals,
one male and the other female. Paré gives a picture of twins, born near Heidelberg
in 1486, which had double bodies joined back to back; one of the twins had
the aspect of a female and the other of a male, though both had two sets of
genitals. Many chroniclers tried to explain the existence of such departures
from ‘normal’ by juxtaposing both natural causes (following Aristotle), and
divine responsibility, (following St. Augustine's idea that Nature reflects
the will of God).  Like other chroniclers of prodigies in the 16th and
17th centuries, Lycosthenes introduced monsters in the context of a group
of related terrestrial and celestial natural phenomena. For him, many monsters
and other portents had natural causes, although what they were was often difficult
to determine.  Therefore, he determined that the responsibility of such
monstrous occurences lay with God. Monsters were thus viewed as signs and
portents through which God communicated with man. Especially during the religious
wars of the 16th century, they were often interpreted as political or religious
omens.

The 17th century

The end of the 16th century was marked by profound cultural changes, stimulated
principally by the end of the Wars of Religion. Wonders, and monsters in particular,
began to be interpreted less frequently as bad omens:  they therefore
inspired less horror. Curiosity and admiration of Nature’s products became
predominant, resulting in a more diverse group of scholars writing books about
prodigies and wonders. As one historian has noted, the seventeenth century
was a time when the study of wonders “became a reflection not of ignorance
but of virtuosity and connoirsseurship: the product not only of great experience
and erudition, but also of impeccable taste”.

Although there was an increasing number of books, there were few documented
prodigies, resulting in the repeated use of the same illustrations to accompany
stories of monsters.  Although Renaissance writers were largely inspired
by these works, they were also critical of them, and providing an eschatological
explanation for prodigies. In some instances, such as in Des Prodiges, classical
naturalistic and contemporary eschatological views on prodigies were juxtaposed.

By the end of the 17th century, however, it was only in pamphlets and broadsides
that monsters were still treated as frightening signs of God. Educated classes
were beginning to despise this literature, viewing it as a sign of popular
ignorance and superstition.

The Scientific Era

 By the end of the 17th century, natural philosophy had made an important
shift toward adopting an orderly conception of nature. Scientific societies
started to challenge wonders by questioning the truth of strange phenomena.
The quest for truth and the norm begin to conflict with the love of the marvelous
and unique. As doctors began to specialize, focusing on the medical fields
of anatomy and embryology, by the middle of the 18th century, philosophers
of “enlightenement” boldly set forth new theories that presented the monstrous
as a non-metaphysical phenomenon.

In the first half of the 19th century, teratology became a science free from
considerations of God’s direct interference in natural processes.  It
also limited its area of study to birth defects, therefore eliminating imaginary
monsters.

Anatomists approached the question of monstrosity as a whole and confirmed
that it was a part of the evolution of the foetus. They depicted ‘monstrosity’
as part of a natural process, rather than as an independently produced phenomenon.
Furthermore, they established a distinction between physical anomaly and monstrosity,
and created a specific vocabulary for each of them.

The works of the Geoffroy St. Hilaire family were fundamental in the development
of teratology. Etienne, the father, demonstrated through comparative anatomical
studies that a cause of monstrosity was an interruption in the development
of the foetus. This brought to an end lingering support for the theory that
a pregnant woman’s imagination could influence the development of monstrosities.

Rejecting previous classifications which were limited to a description of
different monsters, Geoffroy de St. Hilaire elaborated a new classification
system emphasizing the character of monstrosity rather than the individual
monster.

The early nineteenth century also witnessed the first attempts by men (Dareste
) to artificially create monstrous deformity in living organisms as a way
to better understand the mechanisms that led to monstrosity.

Frankenstein was first published in 1818.  Its author, Mary Shelley,
was well aware of the medical and other scientific discoveries of her time,
and used them in her novel. Far from describing a ‘freak’, Shelley described
a monster created by science, and in doing so anticipated the more benign
monsters such as those produced by teratologists later.

Teratology

Teratology (from the Greek teras (genitive teratos),
meaning monster, and logos meaning study) is the medical
study of teratogenesis or grossly deformed individuals. Monster is
a a perjorative term for a grossly deformed individual

Teratogenesis

Teratogenesis is a medical term from the Greek, literally meaning
monster making. It has gained a more specific usage for the development
of abnormal cell masses during fetal growth, causing physical defects in the
fetus.

There are a large number of teratogens, such as diethylstilbestrol,
thalidomide and Agent Orange.. The rubella (German measles) virus is also
teratogenic, as is use of large amounts of alcohol during pregnancy (fetal
alcohol spectrum disorder). Isotretinoin (13-cis-retinoic-acid), often used
to treat severe acne, is such a strong teratogen that just a single dose taken
by a pregnant woman may result in serious birht defects. Because of this effect,
most countries have systems in place to ensure that it is not given to pregnant
women, and that the patient is aware how important it is to prevent pregnancy
during and at least one month after treatment.

The term teratogenesis refers to the production of congenital malformations
such as cleft lip and/or palate, anencephaly, or ventricular septal defect,
which are medically serious abnormalities present at birth. The term derives
from teratology, the study of the frequency, causation, and development of
congenital malformations--misleadingly called birth defects

Understanding Birth Defects and Deformity

Severely deformed humans rarely survive, although there have been some celebrated
examples such as Joseph meerick, known as "The Elephant Man". Some cases,
such as conjoined twins, were formerly regarded as monsters, but are now candidates
for surgery.

With greater understanding of the origins of these phenomena, this field
now overlaps other fields of medicine, particularly developmental biology
and embryology.

The birth of malformed fetuses has been well documented and the attitudes
toward the infants and their parents varied according to the cultural state
of the people and ranged from admiration to rejection and hostility.

It was previously believed that the mammalian embryo developed in the impervious
uterus of the mother, protected from all extrinsic factors. However, after
the thalidomide disaster of the 1960's, it became apparent and more accepted
that the developing embryo could be highly vulnerable to certain environmental
agents that have negligible or non-toxic effects to adult individuals. Along
with this new awareness of the in utero vulnerability of the developing mammalian
embryo came the development and refinement of The Six Principles of Teratology
which are still applied today.

These principles were developed by James G. Wilson and are as follows:

·Susceptibility to teratogenesis depends on the genotype of the conceptus
and the manner in which this interacts with environmental factors;

· Susceptibility to teratogenic agents varies with the developmental stage
at the time of exposure;

· Teratogenic agents act in specific ways (mechanisms) on developing cells
and tissues to initiate abnormal embryogenesis (pathogenesis);

· The final manifestations of abnormal development are death, malformation,
growth retardation, and functional disorder;

· The access of adverse environmental influences to developing tissue depends
on the nature of the influences (agent);

· Manifestations of deviant development increase in degree as dosage increases
from the no-effect to the totally lethal level.

Studies designed to test the teratogenic potential of environmental agents
use animal model systems (e.g., rat, mouse, rabbit, dog, and monkey). Early
teratologists exposed pregnant animals to environmental agents and observed
the fetuses for gross visceral and skeletal abnormalities. While this is still
part of the teratological evaluation procedures today, the field of Teratology
is moving to a more molecular level, seeking the mechanism(s) of action by
which these agents act.

Understanding how a teratogen causes its effects is not only important in
preventing congenital abnormalities but also has the potential for developing
new therapeutic drugs safe for use with pregnant women.

Teratogens come from many sources and exposure to these agents while pregnant
may cause congenital abnormalities. Therefore, the best way to prevent birth
defects is through education and research. Researchers are currently investigating
the possible causes of many teratogenic agents to determine their mechanism(s)
and site(s) of action. This field is still in its infancy and continuously
growing in importance.

The Teratogenicity of Anticonvulsant Drugs

Background The frequency of major malformations, growth retardation,
and hypoplasia of the midface and fingers, known as anticonvulsant
embryopathy, is increased in infants exposed to anticonvulsant
drugs in utero. However, whether the abnormalities are caused by
the maternal epilepsy itself or by exposure to anticonvulsant drugs
is not known.

Methods We screened 128,049 pregnant women at delivery to identify
three groups of infants: those exposed to anticonvulsant drugs,
those unexposed to anticonvulsant drugs but with a maternal history
of seizures, and those unexposed to anticonvulsant drugs with no
maternal history of seizures (control group). The infants were
examined systematically for the presence of major malformations, signs
of hypoplasia of the midface and fingers, microcephaly, and small
body size.

Results The combined frequency of anticonvulsant embryopathy
was higher in 223 infants exposed to one anticonvulsant drug than
in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio,
2.8; 95 percent confidence interval, 1.1 to 9.7). The frequency
was also higher in 93 infants exposed to two or more anticonvulsant
drugs than in the controls (28.0 percent vs. 8.5 percent; odds
ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1). The 98
infants whose mothers had a history of epilepsy but took no anticonvulsant
drugs during the pregnancy did not have a higher frequency of those
abnormalities than the control infants.

Conclusions A distinctive pattern of physical abnormalities in
infants of mothers with epilepsy is associated with the use of
anticonvulsant drugs during pregnancy, rather than with epilepsy itself.

Anticonvulsant drugs taken by pregnant women to prevent seizures are
among the most common causes of potential harm to the fetus. In
the 1970s and 1980s, the anticonvulsant drugs used most frequently to
prevent seizures — phenobarbital, phenytoin, and carbamazepine —
were found to cause major malformations, microcephaly, growth retardation,
and distinctive minor abnormalities of the face and fingers in
infants exposed to them during pregnancy.

However, medical textbooks have suggested that these defects
are caused by other factors, such as genetic abnormalities that
cause the mother's epilepsy and are inherited by the fetus. To
elucidate this issue, we conducted a cohort study of three groups
of infants: those whose mothers took anticonvulsant drugs during
the pregnancy, those whose mothers had epilepsy but took no anticonvulsant
drugs during the pregnancy, and those whose mothers had no history
of epilepsy and took no anticonvulsant drugs during the pregnancy
(the control group).

Antiepileptic medication in pregnancy

Exposure to anticonvulsant drugs during pregnancy is one of the
most common potentially teratogenic exposures, occurring in 1 in
250 (0.4%) of pregnancies in a recent study in Boston. The teratogenicity
of these drugs was first postulated in the 1960s, with a consensus
developing in the 1970s that a distinctive anticonvulsant embryopathy
was produced. Two theories developed as to the cause: (1) the mother's
underlying epilepsy and (2) the anticonvulsant drug.

All anticonvulsants marketed up to 1976 have been shown to be teratogenic,
with varied manifestations and degrees of severity. Hopefully some
of the "new" anticonvulsants marketed in the 1990s, for example,
gabapentin (1993), lamotrigine (1994), and topiramate (1996), will
be shown not to be teratogenic.

Patterns of effects

Some effects are apparent at birth and others at older ages. The
most common abnormalities identified in newborn infants are major
malformations, midface and digit hypoplasia, microcephaly, and
growth retardation. Experience has shown the importance of systematic
evaluations for these outcomes, including definitions of the physical
features being looked for, measurements, inclusion and exclusion
criteria for major malformations, and regular assessments of the reproducibility
of the findings.

Major malformations

Theoretically each anticonvulsant drug could produce specific or
distinctive abnormalities; a few have been identified. Five percent
of valproic acid exposed infants in one large study and 1% of carbamazepine
exposed infants had spina bifida; nothing distinctive about the
spina bifida lesion has been reported and the frequency of other
neural tube defects, such as anencephaly, is not increased. Long
bone and preaxial deficiencies in valproic acid exposed infants
have been reported. Stiff, tapered fingers with absent or very
small nails in phenytoin exposed infants, in association with radiographic
changes, for example, coned epiphyses and shortened and hypoplastic
distal phalanges, have been found in phenytoin exposed infants.
Vascular disruption limb anomalies, such as terminal transverse
limb defects with nubbins, have been seen in occasional phenytoin
exposed infants.

Since these associated major malformations are relatively uncommon,
even in infants exposed to these specific drugs, the major malformations
identified most often in anticonvulsant exposed children are those
which also occur in unexposed children: heart defects, hypospadias,
club foot, and cleft lip or palate.

It is usually difficult to know if an infant's major malformation is
"the result of" the fact that his/her mother had taken an anticonvulsant
drug during pregnancy. Theoretically, this could be presumed if
the infant has some of the other features of the anticonvulsant
embryopathy, such as the infant with holoprosencephaly who had
the minor craniofacial and digit anomalies of the phenytoin embryopathy.
In one analysis, the infants with a drug specific feature, such
as the "anticonvulsant face" or midface hypoplasia, were more likely
to have the other features of the embryopathy than control infants.

Microcephaly and growth retardation

Initial reports of children with the hydantoin, carbamazepine, and
phenobarbital embryopathy proposed that microcephaly and growth
retardation were fetal effects of these exposures. But this outcome
could have reflected the effect of polytherapy in some of the children
evaluated. More recent studies of infants exposed to phenytoin,
carbamazepine, and phenobarbital as monotherapy did not identify
an increased frequency of microcephaly. An appropriate comparison group by
race and altitudeis crucial to these analyses.

Midface hypoplasia

The most common features are depressed bridge of the nose, short nose
with anteverted nostrils, and long upper lip. Less common features
are a broad bridge of the nose, thin vermilion, a small mouth,
and a wide philtrum.

Cephalometric radiographs of children who had been exposed to either
phenytoin alone or phenytoin plus phenobarbital have shown significant
changes in the facial bones and the cranial base: decreased length
and height of the maxilla, decreased length of the posterior cranial
base and mandible, altered maxillomandibular relationship, and
shortened nasal bone. These changes persist beyond childhood.

Because two other teratogens, thalidomide and tetracycline, affect
the teeth of children exposed in utero, the size and shape of the
teeth in panoramic radiographs and dental casts from children exposed
to either phenytoin alone or phenytoin and phenobarbital as polytherapy
were analysed. 
An increased frequency of missing teeth and an increase in the
mesiodistal diameter, particularly in the maxillary molars, was
found. It will be important to determine whether other anticonvulsants
produce similar changes in cranial structures and teeth.

Digit hypoplasia

An increased frequency of arch patterns and shortening of the distal
phalanges has been reported in several studies. Changes in the
frequency of other dermal ridge patterns also occur, but are less
common.  The higher frequency of arch patterns could reflect
the fact that the prenatal exposures made the developing pad on
the ends of the fingers lower than the pads associated with developing
whorl and loop patterns.

Hand radiographs of anticonvulsant exposed children show hypoplastic
or malformed distal phalanges, coned epiphyses, pseudoepiphyses,
and shortened metacarpals. In a study of 46 children between the
ages of 5 and 29 years, 14% of the phenytoin and/or phenobarbital exposed
subjects had at least two of these changes. Since the measured
nail sizes of these children in this study were not reduced, it
was concluded that the presence of digit hypoplasia was determined
most consistently from examining dermal ridge patterns and radiographs,
not clinical inspection. The radiographs of the toes of the same
subjects did not show a significant increase in the frequency of
epiphyseal changes.

Cognitive function

Assessments of intelligence have been the most common studies reported
in older anticonvulsant exposed children and teenagers, some of whom have
shown evidence of cognitive dysfunction.

Phenobarbital

Phenytoin

Carbamazepine

The greatest concern about cognitive dysfunction is for children
exposed in utero to valproic acid. Since the reports have come
from case series and not systematic, controlled studies, it is difficult to
know how frequent developmental delay and mental retardation are
in valproate exposed children. An additional concern is the occurrence
of autism in case reports of children exposed to valproic acid
during pregnancy; a systematic study of this very serious potential
fetal effect is needed.

Hopefully future studies will include as many of these confounders as
possible with the detailed analysis of the children and their parents.

Late onset effects

An exposure during pregnancy can also produce fetal effects that
are only apparent when that person is a teenager or young adult.
Two examples from studies of other teratogens are the altered social
behaviour in adult men who had been exposed in utero to diethylstilbestrol
and the higher frequency of diabetes mellitus in adults with congenital
rubella.

Recently, Dessens et al reported an increased frequency of cryptorchidism
in males exposed to phenytoin and/or phenobarbital during pregnancy
and, later, menstrual irregularities in adult women. They identified
an increased frequency of developmental delay, behaviour disorders,
and a diverse group of medical problems that included refractive
errors in vision, joint laxity, and otitis media (only in valproate
exposed children).

Genetic susceptibility

Twenty years ago, David Smith presented his clinical observation that
parents with one child with phenytoin embryopathy had a higher
risk of having a second affected child than the parents whose anticonvulsant
exposed fetus showed no signs of the embryopathy in childhood..

Several hypotheses have been developed to explain why some infants of
mothers taking anticonvulsant drugs have this apparent genetic susceptibility:

(1) decreased function of epoxide hydrolase (EPHX1), an enzyme
which metabolises phenytoin, postulated to be the result of an
autosomal recessive gene in one study and an autosomal dominant
mutation in another

(2) altered distribution of polymorphisms in microsomal EPHXI,
no abnormalities were identified in one study of 16 subjects with
the anticonvulsant embryopathy

(3) production of free radicals by phenytoin

(4) inhibition of potassium channel function, which produces injury
by hypoxia and reperfusion

(5) decreased maternal serum folate, possibly associated with
a deficiency of methylene tetrahydrofolate reductase.

Counselling the pregnant woman taking an anticonvulsant

Because exposure to anticonvulsants is so common among pregnant women,
it is important that all health care professionals be able to inform
her of the potential for fetal effects and her options in her treatment,
which include: take a daily folic acid supplement before conception;
take the anticonvulsant drug as monotherapy, if possible; keep
the dose of the anticonvulsant drug during pregnancy as low as
possible, as the lower the dose presumably the lower the risk of
a harmful fetal effect. Describe the increased risk for the spectrum
of common malformations; do not emphasise an increased risk for
cleft lip and palate, as this has been notable only for phenobarbital
with an odds ratio of about 3. Even when the mother takes phenobarbital,
that risk should be put in the context of the rate in that mother's
ethnic group: if she is white, the baseline risk is about 1:1000
or 0.1% and a three-fold increase makes the risk 1:333 or 0.3%.
This de-emphasis would help make her concerns more realistic.

Future directions

This review highlights the need for more information on many aspects
of the teratogenicity of anticonvulsants. First, hopefully the
"new" anticonvulsants will be shown not to be teratogenic. Second,
determine whether taking folic acid conception reduces the risks
for a harmful fetal effect. Third, do anticonvulsant exposed children
have an increased risk for cognitive dysfunction? Fourth, the "anticonvulsant
face" is a common effect; is its presence associated with an increased
risk for cognitive dysfunction? Fifth, studies are needed to identify
the candidate genes that are associated with the familial clustering
of children with the anticonvulsant embryopathy. One would predict
that each drug will have its own molecular mechanism for conveying
this risk. Hopefully, it will be possible to identify the woman
with a high risk for a teratogenic effect from taking one anticonvulsant
drug and to select a lower risk treatment for her.

 References

1. Woodbury DM, Penry JK, Pippenger CE. Antiepileptic drugs. 2nd ed. New
   York: Raven Press, 1982.


2. Speidel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus
   and the newborn. Lancet 1972;2:839-843.[ISI][Medline]


3. Hill RM, Verniaud WM, Horning MG, McCulley LB, Morgan NF. Infants exposed
   in utero to antiepileptic drugs: a prospective study. Am J Dis Child 1974;127:645-653.[CrossRef]
   


4. Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975;87:285-290.[ISI][Medline]
   


5. Hanson JW, Myrianthopoulos NC, Harvey MA, Smith DW. Risks
   to the offspring of women treated with hydantoin anticonvulsants, with emphasis
   on the fetal hydantoin syndrome. J Pediatr 1976;89:662-668.[ISI][Medline] 
   


6. Seip M. Growth retardation, dysmorphic facies and minor malformations
   following massive exposure to phenobarbitone in utero. Acta Paediatr Scand
   1976;65:617-621.[ISI][Medline] 


7. Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, Ryan
   LM. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132–8
   
8. Monson RR, Rosenberg L, Hartz SC, Shapiro S, Heinonen OP, Slone D. Diphenylhydantoin
   and selected congenital malformations. N Engl J Med 1973;289:1049–52.[Medline]
   
9. Hanson JW, Myrianthopoulos NC, Harvey MA, Smith DW. Risks to the offspring
   of women treated with hydantoin anticonvulsants, with emphasis on the fetal
   hydantoin syndrome. J Pediatr 1976;89:662–8.[Medline]
   
10. Leppig KA, Werler MM, Cann CI, Cook CA, Holmes LB. Predictive value of
    minor anomalies. I. Association with major malformations. J Pediatr
    1987;110:531–7[Medline]
    
11. Holmes LB.
    Need for inclusion and exclusion criteria for the structural abnormalities
    recorded in children born from exposed pregnancies. Teratology
    1999;59:1–2. [Medline]
    
12. Holmes LB, Kleiner BC, Leppig KA, Cann CI, Munoz A, Polk BF. The predictive
    value of minor anomalies. II. Use in cohort studies to identify teratogens.
    Teratology 1987;36:291–7. [Medline]
    
13. Harvey EA, Hayes AM, Holmes LB. Lessons on objectivity in clinical studies.
    Am J Med Genet 1994;53:19–20. [Medline]
    
14. Omtzigt JG, Los FJ, Grobbee DE, Pijpers L, Jahoda MGJ, Brandenburg H,
    Stewart PA, Gaillard HL, Sachs ES, Wladimiroff JW, Lindhout D. The risk
    of spina bifida aperta after first-trimester exposure to valproate in a
    prenatal cohort. Neurology 1992;42:119–25.
    
15. Rosa FW. Spina bifida in infants of women treated with carbamazepine during
    pregnancy. N Engl J Med 1991;324:674–7. [Medline]
    
16. Sharony R, Garber A, Viskochil D. Preaxial
    ray reduction defects as part of valproic acid embryopathy. Prenat
    Diagn 1993;13:909–18. [Medline]
    
17. Lu MCK, Sammel MD, Ryan LM, Holmes LB. Digit effects produced by prenatal
    exposure to antiepileptic drugs. Teratology 2000;61:277–283. [Medline]
    
18. Choulika S, Harvey E, Holmes LB. Effect of antiepileptic drugs (AED) on
    fetal growth: assessment at birth. Teratology 1999;59:388.
    
19. Wong KS, Scott KE. Fetal growth at sea level. Biol Neonate 1972;20:175–88.
    [Medline]
    
20. Orup HI Jr, Holmes LB. Changes in facial soft tissues in individuals exposed
    to antiepileptic drugs in utero. Teratology 1998;57:195–6.
    
21. Orup HI Jr, Holmes LB. Persistence of craniofacial effect of antiepileptic
    drug (AED) teratogenicity into adult years. Teratology 1997;55:34.
    
22. Orup HI Jr, Keith DA, Holmes LB. Prenatal anticonvulsant drug exposure:
    teratogenic effect on the dentition. J Craniofac Genet Dev Biol 1998;18:129–37.
    [Medline] 
    
23. Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975;87:285–90.
    [Medline] 
    
24. Kelly TE, Edwards P, Rein M, Miller JQ, Dreifuss FE. Teratogenicity of
    anticonvulsant drugs. II. A prospective study. Am J Med Genet 1984;19:435–43.
    [Medline]
    
25. Lewis B. Holmes, M.D., Elizabeth A. Harvey, Ph.D., M.P.H., Brent A. Coull,
    Ph.D., Kelly B. Huntington, B.A., Shahram Khoshbin, M.D., Ailish M. Hayes,
    M.D., and Louise M. Ryan, Ph.D, The Teratogenicity of Anticonvulsant Drugs,
    Volume 344:1132-1138
    
26. L B Holmes, The teratogenicity of anticonvulsant drugs:
    a progress report Genetics and Teratology Unit, Pediatric Service, Massachusetts
    General Hospital, Warren 801, 55 Fruit Street, Boston, MA 02114-2696, USA
    
27.  S.J. Moore, P Turnpenny, A Quinn, S Glover, D J Lloyd, T Montgomery
    and J C S Dean, A clinical study of 57 children with fetal anticonvulsant
    syndromes, J. Med. Genet. 20090:37:489-497

About Authors

Madhumathi Seshadri^b, Neha Shah^c and Mrs. Lakshmi
Sivasubramaniam ^a, *

Mrs. Lakshmi Sivasubramaniam

^{* a} Lecturer, Department of Pharmaceutical Analysis, College of
Pharmacy, SRM Institute of Science and Technology, Deemed University, Katangulathur,
Chennai, India.

*^,a Author for Correspondence: Lakshmi Sivasubramaniam,
Lecturer, Department of Pharmaceutical Analysis, College of Pharmacy, SRM Institute
of Science and Technology, Deemed University, Katangulathur, Chennai, India.E-mail:
laxmisiva@rediffmail.com

Madhumathi Seshadri

^b  Department of Chemistry, Pharmaceutical Chemistry unit,
Vellore Institute of Technology, Vellore-632 014, India.

^c Bio medical Genetics, Department of Bio sciences, Vellore Institute
of Technology, Vellore-632 014, India