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Column: Drugs and side effects
A.A. Ivanova1, A.V. Mikhailov2, 3, A.S. Kolbin4
1
St. Petersburg State University, Russian Federation
2
SFHI “Maternity Hospital №17”, St. Petersburg, Russian Federation
3
Mechnikov North-West State Medical University, St. Petersburg, Russian Federation
4
Regional Centre for Drug Monitoring and Safety, St. Petersburg, Russian Federation
Teratogenic properties of drugs. Background information.
Author affiliation:
Ivanova Anna Aleksandrovna, postgraduate student at the faculty of medicine, St. Petersburg
State University
Address: 8a, 21st Line, Vasilyevsky Island, St. Petersburg, 199026, tel.: +7 (921) 759-04-49
Article received: 10.09.2012, accepted for publication 15.01.2013.
The article presents the most significant steps in the development of ideas about drugs’ effects
on fetus. It features the thalidomide tragedy and features of thalidomide teratogenic properties,
as well as data on thalidomide syndrome prevention relevance in the 21st century. The article
covers teratogenesis principles and gives information about the discovery of teratogenic
properties and their manifestation in several other major teratogens: retinoids, carbamazepine,
valproic acid, diethylstilbestrol.
Keywords: pregnant women, teratogenic properties, drugs, teratogenesis principles,
thalidomide, retinoids, carbamazepine, valproic acid, diethylstilbestrol.
Abundant experience indicating the possibility of negative influence of a range drugs in
the perinatal period of human development has been gathered. Any unfavorable consequences
caused by drug intake in a developing body until puberty belong to developmental toxicity [1].
The study of such unfavorable effects of different factors, including drugs, is the sphere of
developmental toxicology [2]. Developmental toxicity is subdivided into embryo- and
fetotoxicity; correspondingly, any toxic effects on embryo or fetus due to prenatal influence of
particular unfavorable factors belong to them [3]. There are 4 main classes of fetal
developmental toxicity manifestations: fetal death (including spontaneous abortion),
dysmorphogenesis (structural anomalies), growth disorders (usually – intrauterine growth
retardation, although the fetus may be large) and malfunctions (any deviations from normal
physiological or biochemical parameters, psychomotor development, learning capability and
memory, behavioral peculiarities and reversible functional postnatal effects – sedative,
withdrawal syndrome, bradycardia, hypoglycemia) [1, 3]. In a range of cases chromosomal and
genetic disorders, prematurity and carcinogenesis are also rated as developmental toxicity.
Teratogenicity is one developmental toxicity manifestations, a particular case of embryo- and
fetotoxicity manifesting itself in structural anomalies [3]. Teratogenic effect is an important, but
not the only manifestation of unfavorable consequences for fetus of a woman who took drugs
during pregnancy [2, 4]. A term “functional teratogenesis” has been established in literature in
recent years – malfunctions of organs and systems under influence of a teratogen on the fetal
ontogenetic stage with no morphological alterations [5].
Congenial maldevelopments and their causes (both in animals in humans) have for a
long time interested humankind. There is evidence that people in ancient times already
suggested the possibility of influence of different chemical substances on fetal development.
E.g., in Carthage newlyweds were forbidden to drink alcohol due to its unfavorable influence
on fetal conception and development [6]. Before embryology and comparative anatomy,
congenital malformations raised a wide range of possible causes: supernatural forces, coitus
with animals (hybrid theory), coitus during menstruation, “maternal impressions”, i.e.
unexpected and powerful impressions of a pregnant woman. Such explanations were in use not
only among the ancient, but also the Renaissance researchers, including Paracelsus and
Ambroise Paré [7]. E.g., Sebastian Münster described the etiology of a sensational birth of
craniopagus twins Wormer in the famous world chronicle “Cosmography” (1544) in the
following way: “Two women were walking, one of them was pregnant, then a man came and
bumped their heads against each other, the pregnant woman became frightened and in the end
gave birth to girls, whose heads fused” [8].
Knowledge of teratology considerably widened with the beginning of systematic use of
morphological method when examining corpses and fetuses (W. Harvey, 1651; T. Bartholinus,
1654, C. Wolil, 1759; L. Morgagni, 1761; J. Meckel, 1812). These studies allowed describing
many maldevelopments, which were determined only morphologically; this underlay the theory
of developmental termination together with the results of using comparative anatomy methods
[7]. In this period famous anatomists, such as F. Ruysch (1638-1731) in Amsterdam, C.
Bartholin the Younger (1655-1738) in Copenhagen, J. Lieberkühn (1711-1756) and J. Meckel
the Elder (1724-1774) in Berlin, described congenital anomalies in fetuses and infants and
gathered unique collections of drugs [8]. A period of experimental teratology came instead of
the “golden age of descriptive teratology” in the middle of the XIX century, and accents of
studies shifted from the description and classification of congenital malformations towards the
attempts of their experimental reproduction in laboratory animals [8, 9]. Many issues of
etiology and pathogenesis of congenital malformations were studied using experimental method
on chick embryos: father and son Etienne and Isidore Geoffroy Saint-Hilaire studied the effect
of mechanical factors on chicken eggs (1822, 1832-1837), C. Dareste – the effect of shaking,
temperature factor and chemical substances (1855) and P.I. Mitrofanova – the effect of oxygen
starvation in the same objects (1894) [7, 9]. In 1919 congenital malformations were for the first
time obtained by ionizing radiation by W. Baldwin [7]. These were among the first proofs that
external factors may disturb embryonal development [9]. One of the most important results of
experimental method development in teratology was the definition of teratogenesis principles –
propositions, which define the understanding of the main regularities of how external factors,
including drugs, affect fetus. The first researcher to define these propositions was C. Dareste,
who relied on the results of his own experiments. The foundation of scientific teratology was
laid in the age of Gregor Johann Mendel (1822-1884), the “father” of genetics; it was, without
any doubt, influenced by Mendel’s ideas [10]. In 1871, Dareste defined the first principles of
scientific teratology in the publication “Recherches Sur La Production Artificielle Des
Monstruosités, Ou, Essais De Tératogénie Expérimentale” [11].
Adapted to modern terminology, these 5 principles are as follows:
1.
Identical anomalies may be caused by different agents.
2.
Development of particular embryos may be disturbed individually under
influence of an unfavorable factor.
3.
Differences are caused by a unique combination of hereditary capabilities
and exogenous influence.
4.
Defect type depends on the intensity and time of the unfavorable
impulse’s activity.
5.
The smaller the defect, the later it is revealed [10].
Although Dareste emphasized: “Do not prolong my studies endlessly; I
restricted myself only to one species. Chicken eggs are an easy [object] for analyzing normal
and anomalous development, as everyone may obtain in any amounts… The time will show
whether the results that I obtained studying only one species are actually applicable to the
whole class of vertebrate mammals” [cited by: 11], these principles have not lost their value.
Moreover, they implicitly admitted and absorbed the later (in 1921) discovered concept of
critical periods (C. Stockard) and an interrelation dose-effect [10].
Since Middle Ages until the middle of the XX century an opinion that placenta
does not allow toxic substances to penetrate fetus had been widespread, despite the proofs
obtained by the end of the XIX century that the human placenta is penetrable for a range of
chemical substances [12]. In 1874 a study conducted by B. Zweifel showed that chloroform
penetrates through human placenta [13]. In 1912 the experiments on dogs confirmed that the
amount of chloroform in fetal blood is the same as in maternal blood if it used during labor
[14]. A case of revealing sodium salicylate, which was prescribed to mother 30 minutes before
labor, in her child’s urine was made public in 1878. These were the first suggestions of the
possibility of chemical substances’ penetration through placenta in scientific literature. Later
there appeared evidence of alcohol, morphine and quinine (used for labor stimulation)
penetrating through the placenta and affecting fetus [13]. By 1930s there were enough proofs to
disprove the myth that placenta is a safe barrier. It has been known since 1955 that any
substance with molecular mass of less than 1,000 atomic units may penetrate fetal blood
through placenta [12]. However, this knowledge and achievements of teratology often remained
within the narrow circle of specialists of laboratory academies and research institutes [15].
Works of teratologists were mainly published in journals for a limited, narrowly defined
readership; this may have been one of the reasons why a wide range of medical workers did not
think about the possible danger of using drugs during pregnancy. That is why the major part of
medical community was convinced until the middle of the XX century that placenta safely
protects fetus from exposure to external factors and is impenetrable for toxic substances,
excluding large doses, which could result in mother’s death. Recommendations of doctors did
not include advice to patients on careful use of alcohol, drugs and other chemical substances
[6]. Achievements of teratology were not accounted by healthcare organizations, which were to
watch over public health and safety; there were no standardized techniques of testing whether
drugs are safe or not in experiments on pregnant animals [15]. It is known that such studies
were conducted in big pharmaceutical companies, but were not obligatory [12].
Thalidomide disaster was the event that made the medical community to
reconsider views on placenta and assess the data gathered by experimental teratology in a new
way [6, 7].
Thalidomide disaster
Thalidomide is a drug that caused one of the most dramatic catastrophes in the history of
medicine [6]. It was one of the first drugs which clearly showed its teratogenicity in human. Its
use led to a bigger number of severe anomalies in infants than any other drug [16]. Thalidomide
was synthesized in 1954 in West Germany as an anticonvulsant; however, no anticonvulsant
action was revealed during studies; instead a pronounced sedative effect was identified [12, 17].
Thalidomide first appeared in the market in November 1956 as a part of a compound drug
Grippex for respiratory infections, and in a year it was represented by a sedative drug
Contergan. Market appearance of Contergan was accompanied by massive advertising, which
laid the main stress on its safety [12]. The idea of Contergan’s safety was based on the fact that
it is almost impossible to commit suicide using this drug [6]. It was considered so safe that it
was widely used even in pediatrics, and by 1961 Contergan became the bestselling sedative in
Germany [12, 18]. Thalidomide was also efficient for treating morning sickness in the pregnant
[6]. Later, it was registered under different trade names in 46 countries around the world [17].
It is still unclear whether the manufacturer conducted adequate experiments on pregnant
animals [12]. As “Grünenthal” records were destroyed, we will never know how thalidomide’s
safety was studied [13]. It is known that the Food and Drug Administration (USA) experts
considered data given by the manufacturer on the drug’s safety obtained in experiments on
animals insufficient and unconvincing. The drug was not allowed to sell in the USA [19]. At the
same time, the thalidomide action peculiarities revealed later in experiments on animals of
different species show that even if such studies had been conducted to the full extent, they
would still have not revealed any unfavorable effects for a fetus. Moreover, there is a possibility
that these effects would not be suspected even in case the drug underwent all the accepted
modern preclinical studies.
A strange “epidemics” started in Germany soon – children with severe reducing
anomalies of extremities, which had been registered before many times as rarely, were born
with unparalleled frequency. There were a lot of theories explaining the cause of this
phenomenon. It was suspected to be connected with water pollution, nuclear tests or unknown
toxin. As most cases were registered in West Germany and were almost absent in East
Germany, it was also suspected that the reason for this was the use of a secret chemical weapon
by the Soviet bloc [19].
In December 1961 journal “The Lancet” published a letter from an Australian
obstetrician-gynecologist W. McBride who reported the increase in the number of cases of
congenital anomalies connected with the use of thalidomide. He wrote that in the latest months
he had been observing cases of multiple severe anomalies (polydactylies, syndactylies, reducing
malformations of extremities due to anomalously short femoral and radial bones) in children
born by women taking thalidomide on the level of almost 20% [20]. “The Lancet” published a
response to McBride’s story by doctor W. Lenz in January 1962. Lenz reported to have
observed such malformations and to have received information about them form other doctors
from different places. Lenz suggested that 2,000-3,000 children, who suffered from
thalidomide, had been born in West Germany since 1959 [21]. Later, a connection of
thalidomide with the development of such malformations as anotia, microtia, anophthalmia,
microphthalmia and with anomalies of heart, urogenital system and gastrointestinal tract was
registered, apart from the reducing malformations of extremities [17]. On the basis of these
facts thalidomide was withdrawn from the market in Germany and several other countries in
1961-1962. The problem was that thalidomide was sold around the world under different trade
names. As there had not yet been international cooperation in the sphere of drug safety,
Contergan and Distaval referred to in articles by Lenz and McBride were withdrawn (from
West German and Australian markets, accordingly), but other thalidomide drugs remained in
the market in other countries for longer [19]. By that time ca. 10,000 children who had suffered
from this drug were born in the world [17].
A lot of attempts to model the development of malformations in animals and explain the
mechanism of thalidomide’s teratogenic action were made later [22]. However, congenital
malformations in embryos of rats, mice, rabbits, dogs, hamsters, primates, cats, guinea pigs,
pigs and polecats were extremely rare. Relying on these facts, it was hard to believe that
thalidomide is dangerous in embryonal period of human development [13, 22]. Thalidomide
caused reducing malformations of extremities only in New Zealand rabbits, although the
teratogenic effect identification required doses, which exceeded therapeutic doses 150 times.
Later it became known that some kinds of primates are also susceptible to thalidomide [12].
The results of such studies resulted in a proposition that direct transfer of data on drugs’ safety,
obtained in experiments on animals, on a human is faulty [22]. Moreover, 2 peculiarities
connected with thalidomide’s teratogenic properties were revealed. The first was that
thalidomide’s teratogenic effect took place in case of its intake in an extremely short pregnancy
period. Developmental anomalies occurred only when using the drug on days 35 through 50
from the first day of the latest menstruation – days 21 through 36 of embryonal development.
Thalidomide intake outside this 2-week period did not cause any teratogenic consequences in a
human fetus. Another peculiarity of thalidomide’s teratogenic action is the exceptionally small
drug doses capable of leading to fetal development disorders. It was established that typical
anomalies occurred when taking 25mg TID or 100mg OD for 3 days in the sensitive period,
which is equivalent to an extremely small dose of 1mg per kg of mother’s body weight.
Interestingly, doses leading to developmental disorders were manifold smaller in humans than
in thalidomide-susceptible experimental animals [18].
The story of thalidomide embryopathies did not finish in the XX century. New properties
of this drug were discovered several years after the thalidomide disaster. In 1965, Israeli
dermatologist Sheskin reported thalidomide’s efficacy in treating erythema nodosum leprosum
(ENL) [17]. It appeared that thalidomide is an inhibitor of tumor necrosis factor (TNF) α, the
content of which is extremely high in ENL patients; TNF considerably reduced at this drug’s
intake [23]. Proved efficacy in these parameters increased common interest towards the
possibility of therapeutic use of thalidomide for treating other conditions, especially after
discovering its new properties – antiinflammatory, immunomodulatory and antiangiogenic [17].
Series of clinical studies showed thalidomide’s efficacy in treating HIV wasting syndrome,
hereditary hemorrhagic telangiectasia, ENL, multiple myeloma and Behçet's disease [23]. At
present, thalidomide is approved in many countries for treating mainly ENL, skin diseases and
several cancer types with strict contraindication to use during pregnancy [17]. Brazil is one of
the countries endemic to leprosy, and thalidomide has been used there to treat ENL since 1965.
In 2011 a study, which analyzed cases of thalidomide syndrome in 2000-2008 in this country,
was published. Despite the fact that the drug is not commercially available and is spread only
via special Ministry of Health programs, the scientists revealed that these measures are not
sufficient. Birth frequency of children with thalidomide embryopathy phenotype rose in 20002008 in comparison with the period of 1982-1999. Thus, out of 793,177 of assessed births from
1982 to 1999 152 infants had signs of thalidomide syndrome (1.92 per 10,000 births (95%
confidence interval [CI] – 1.60-2.20), while in 2000-2008 out of 352,037 births 109 infants had
signs of thalidomide embryopathy (3.10 per 10,000 births (95% CU – 2.50-3.70) [17]. This
indicates the relevance of preventing thalidomide today, too.
It may be said in conclusion that no drug that would exceed thalidomide in teratogenic
effect has been known [2].
Lessons of thalidomide disaster. The study of drugs’ efficacy nowadays
The idea of uteroplacental barrier’s reliability as the protection of fetus against toxic
substances, which had prevailed in medical community, changed after thalidomide disaster and
a need in obligatory testing of drugs for fetal safety before allowing its use during pregnancy
became evident. Regulating organs controlling drugs’ safety formed in many countries; in 1968
the World Health Organization launched a Drug Monitoring Program. In compliance with the
existing requirements, all new pharmacological preparations are tested for teratogenicity in
experiments on animals before they are allowed for use in clinical practice [4]. Teratogenic
properties are studied on not less than 2 kinds of animals [24], however, a perfect kind has not
yet been determined. Most frequently drugs’ teratogenic effect is studied on pregnant rats and
mice, and on rabbits (out of animals of other orders). Probably, the optimal experimental
animals may be primates due to their anatomic and physiologic similarity to humans; however,
high cost of such studies is an obstacle to using primates in laboratory research [25]. Moreover,
their behavior is not always a guarantee of the analyzed drug’s safety for humans [4]. It is
proved by the fact that the effect of most teratogens was first revealed in humans – not in
experiments on animals. Exceptions to the rule are only androgens, several antimitotic drugs,
sodium valproate and retinoids [3]. Discovery of the drug’s teratogenic effect in clinical
conditions is hindered by a certain natural setting of fetal maldevelopments linked to other
reasons (viral infections, ecology, parental alcoholism etc.). It is obvious that the discovery of
drugs’ teratogenic properties is most possible when the congenital anomalies they cause occur
frequently, are unusual or severe. It is much more difficult to reveal such anomalies if they are
rare or are manifested with insignificant disorders. As a result, teratogenic effect of several
drugs may remain unnoticed and unaccounted for a long time [4]. In 2002 W.Y. Lo and J.M.
Friedman revealed that teratogenic risks are not defined for 91.2% of drugs, which had been
approved in the USA from 1980 to 2000. There was no adequate information, whether the
benefit of most drugs introduced in the latest 20 years exceeds teratogenic risks of their use
[26]. Pregnant women are principally excluded from clinical studies conducted before the
drugs’ registration (I-III) for ethical reasons, excluding cases of analyzing drugs intended for
pregnant women, when necessary information may only be obtained in clinical studies on
pregnant women assuming all necessary measures to exclude any harm to a pregnant women
and fetus [27, 28]. The largest amount of information of drugs’ safety is obtained only after its
release in a pharmaceutical market. Usually, teratogenic properties and the connection between
action
and
pregnancy
outcome
are
revealed
in
the
course
of
case-control
pharmacoepidemiological prospective cohort studies and retrospective studies; in some
countries there are registers on using drugs during pregnancy and registers on congenital
maldevelopments [2, 27, 29]. Unfortunately, the description of drugs’ safety data accessing
mechanisms, including registers, has not yet been given in Russian legislation [30].
Apart from the conclusions made after the thalidomide disaster, other peculiarities were
noted in observations of the possible teratogenic effect of other drugs. Gradually, the data
accumulation led to reformulation of teratogenesis principles 100 years after general
regularities of teratogenic factor effect on embryo were first described by Dareste. James
Wilson became the authors of regularities, which became classic for modern teratology; he
published them in 1977 in the “Handbook of Teratology”, written together with F. Fraser [10].
6 teratogenesis principles describing typical cases were formulated [31].
1.
Susceptibility to teratogenesis depends on fetal genotype and how it interacts
with the unfavorable environmental factors. On the one hand, this rule explains the different
action of drugs on human and animal bodies (species-specific action is determined by the
species’ genotype; e.g., the study of thalidomide’s teratogenic properties); on the other hand, it
indicates that the genetically determined susceptibility to teratogens is different in different
people [2]. E.g., more than a half of the children were not affects, 1/3 developed certain
congenital anomalies and only 5-10% of them develop fetal hydantoin syndrome (heart
diseases, lip/jaw/clefts and urogenital system’s disorders) at the same intrauterine effect of
phenytoin [2, 29]. The teratogenic effect realization may depend on both mother’s and fetus’s
genotype; this may lead to differences in cellular sensitivity, transport through placenta,
metabolism, binding with proteins and drug’s spread in the body. A range of different outcomes
is possible even when patients take the same doses in the same pregnancy periods [29].
2.
Susceptibility to teratogenic agents changes depending on the development
stage at the moment of unfavorable factor’s influence. This principle is based on a C.
Stockard’s theory of critical development periods in ontogenesis (1921); it is also connected
with the concept of teratogenic termination periods, first defined by G. Schwalbe in 1909 [32].
During the first critical period of intrauterine development (end of the 1st – beginning of the 2nd
pregnancy week (from the moment of impregnation to the formation of a blastocyst)) there is a
maximal risk of embryotoxic action of drugs, which most often manifests itself with embryonic
death before pregnancy is ascertained [5]. The period of maximal susceptibility to teratogens –
the second critical period – is days 15 through 56 (weeks 3-8) of prenatal development, when
organogenesis takes place (formation of organs and tissues) [29, 32]. In this period anomalies of
organs and systems are most frequent [2]. Starting from week 9, there is a considerable
reduction in the developing fetus’s susceptibility to drugs’ influence [32]. Unfavorable factors
affecting a fetus during the fetal period, when fine differentiation of organs and tissues and
quick growth of the future child occur, provoke the development of fetopathies, which are
characterized not by morphological anomalies, but by diseases and functional disorders of
organs and systems, behavioral disorders [5].
Teratogenic termination period is the time limit, until which a teratogen may cause a
certain maldevelopment of one or another organ in prenatal ontogenesis. Therefore it should be
understood that every organ has its own termination period, after which a congenital anomaly
cannot develop. E.g., teratogenic termination period for cor biloculare is limited by 34 days of
prenatal development, for ventricular septal defect – by 44 days, for atrial septal defect – by 55
days, etc. [32].
3.
Teratogenic agents affect developing cells and tissues in specific ways
(mechanisms) in order to initiate the succession of anomalous events in development
(pathogenesis). When S. Wilson formulated teratogenesis principles, molecular action
mechanisms had not been known in toxicology [2]. Modern scientific achievements allowed
deepening the understanding of teratogenesis mechanisms – epigenetic control of gene
expression, damaged cytoskeleton, territorial matrix disorders, effects of small regulatory RNA
molecules etc. [10]. Understanding of action mechanism is conductive of the development of
maldevelopment prevention measures. Thus, e.g., the discovered connection of folate deficit
with the development of neural tube defects (NTD) and the proved protective effect of the
additional intake of folic acid allows conduction population NTD prevention by prescribing
folic acid (400 mcg/day) when planning pregnancy and in its first 8 weeks. It has been
established that some drugs (valproic acid, carbamazepine, phenytoin, phenobarbital, primidon,
cholestyramine etc.) are folate antagonists and affect its absorption and metabolism, that is why
the folic acid dosage should be increased up to 4-5 mg/day when they are used [2, 33].
4.
4 manifestations of developmental disorder: death, maldevelopment, growth
impairment and malfunctions. Other outcomes were discovered after C. Wilson described the
aforementioned variants. One of them is transplacental carcinogenesis. Fetal tissues are
characterized by a heightened susceptibility to the action of carcinogenic factors due to high
level of cellular proliferation. This phenomenon was showed in experiments on rats, mice,
hamsters, rabbits, pigs, dogs and primates [3]. However, the only proved case of transplacental
carcinogenesis in human was connection with diethylstilbestrol’s (DES) (synthetic non-steroid
drug with estrogenic activity) fetal effect. Diethylstilbestrol was proposed to treat threatened
abortions and restrict excessive growth in girls [2]. Ca. 2-3 mn. of pregnant women received
DES from 1948 to 1971 only in the USA. Aggressive drug’s advertising aided its wide use all
over North America, Europe, Latin America, Africa, Middle East and Asia [34]. In 1971 A.
Herbst discovered that the vaginal clear cell adenocarcinoma developed with heightened
frequency in adolescence in girls, whose mothers received DES during pregnancy [2, 34, 35].
One of the names that DES received was “clockwork toxic bomb” [34]. However, no
heightened malignization frequency was revealed in male posterity [35].
Another unfavorable influence’s outcome, discovered later and not described by Wilson,
was the sex cell mutations that cause defects after a generation. This action was established in
animals and is not excluded in human. Sex cell mutations are caused by the fact that oocytes
develop on the early embryogenesis stages and stop growing before birth, which is why foreign
substances are capable of disturbing their maturation negatively affecting the next generation’s
fertility during early pregnancy.
5.
Access of unfavorable effects to developing tissues depends on the nature of
effect (agent). Influence of unfavorable factors on a developing embryo may be direct or
indirect. The examples of direct influence are ionizing radiation, microwaves, ultrasound,
which spread unaltered directly through maternal tissues and interact with an embryo. The best
known substances affecting embryonal development (including drugs) reach it indirectly. They
are subject to metabolic alterations (e.g., liver biotransformations), distribution, uptake and
excretion in maternal organism, which either reinforces or weakens their damaging potential
[36].
6.
Frequency and degree (severity) of developmental deviations’ manifestations
are in direct proportion to the dosage – from no effect to fatal outcome [31]. Drug’s effect
also depends on the dosage, frequency and duration of use. All teratogens have a threshold; if it
is not crossed, there are no unfavorable reactions [29]. Retinoids are an example of this
principle. The study of how vitamin A deficiency affects animals in 1930-40s led to the
understanding of this nutrient’s importance for normal embryogenesis [18]. Retinoic acid
functions in body as a growth factor; it is present in all cells and connects with specific retinoid
receptors. Retinoic acid is especially important during the embryonal development phase, as it
regulates brain and spine development, along with other effects. However, manifested
teratogenic properties of retinoids were later found in experiments on animals. Fortunately, it
took place before these drugs were introduced into human treatment practice. At present,
retinoids are considered to be the worst human teratogens after thalidomide [2]. Gal was the
first to assume that large vitamin A quantities may lead to human developmental anomalies.
Her colleagues and she conducted a retrospective study of vitamin A plasma content in mothers
of children with NTD. It was revealed that vitamin level in them was higher than in mothers of
healthy children. Separate cases of children’s birth with various craniofacial, cardiovascular,
urogenital and other anomalies to mothers who took enormous vitamin A doses (60,000 IU and
more) during pregnancy have been observed in the following years. These messages led to
Shepard’s publishing in 1986 of a warning of potential teratogenic vitamin A megadoses’
danger [18]. An ample amount of information on risks connected with the use of retinoids and
vitamin A megadoses (more than 25,000 IU) during pregnancy has been gathered thus far:
increase in the risk of spontaneous abortions, characteristic retinoid syndrome (defects of ear
anlages, including agenesis and acoustic meatus stenosis, palatal and facial malformation,
micrognathia, cardiovascular system defects, thymus and central nervous system development
disorders – from neurological disorders involving eyes and internal ear to hydrocephaly) [2].
Thus, even the drug that is necessary for normal fetal development may in large doses disturb it.
Dose-dependent effect is observed at alcohol intake. In small doses alcohol intake
during pregnancy is connected with little body weight reduction at birth. In large doses it affects
fetal neurological development, while at constantly large doses it causes microcephaly and
other visible anatomic effects [29].
The accumulated experience of revealing effects unfavorable for fetal development
indicates the need in continuing collecting information even about the drugs with wide
application experience. Thus, e.g., teratogenic activity was revealed in carbamazepine and
valproic acid.
Carbamazepine has been used as an anticonvulsant since 1962. Considered safe, it later
became the drug of choice in different medical spheres [16, 18]. Carbamazepine was first
suspected of teratogenic properties in 1986 when small-scale craniocerebral anomalies and
finger alterations were accidentally revealed in children of neonatal age. Other studies
considerably extended the list of possible small-scale anomalies caused by the use of this drug
[18]. A definition of specific carbamazepine syndrome was suggested; it consists of small-scale
craniocerebral anomalies, hypoplasia of nail bones and developmental delay [2, 16]. The
possibility of severer carbamazepine effects was discovered in 1991 by Rosa, who revealed 1%
spina bifida risk [18].
Valproic acid, the anticonvulsive properties of which were discovered in 1963, had been
considered safe to use in pregnant women until 1981 [2, 16]. In 1981 it was recommended to
use sodium valproate or carbamazepine as the drug of choice for certain epilepsy types in
women who may become pregnant. Although since 1980 results of experiments on animals
have allowed suspecting that valproic acid may be a potential teratogen, a description of the
only unconfirmed case of its teratogenicity for human was published in 1969-1976 – in a fetus
which was also affected by at least 2 other anticonvulsants. The other published cases of
valproic acid’s intrauterine action before and after 1980 described cases of successful birth of
healthy term infants. Moreover, committee of the American Academy of Pediatrics decided in
1982 that data on the valproic acid’s teratogenic potential for human were inadequate and
recommendations for or against its use during pregnancy cannot be given. The first confirmed
report on a child with congenital malformations caused by valproic acid appeared in 1980. A
child with signs of intrauterine development delay, facial dysmorphia, diseases of the heart and
extremities was born to a mother who took 1,000mg of valproic acid per day throughout the
pregnancy. The child died at the age of 19 days. This report was followed by a range of studies
and descriptions of birth cases of children with developmental anomalies due to valproic acid
treatment in monotherapy or in combination with other anticonvulsants [16]. It is obvious, that
both carbamazepine and valproate (and also the aforementioned diethylstilbestrol) were
considered safe and used to treat pregnant women.
Diethylstilbestrol is another example of a drug, the effect of which manifested itself not
right after the birth, but in many years. Functional, and especially psychoemotional and
behavioral disorders may not be visible right after birth. The latter are studied by a separate
developmental toxicology branch – behavioral teratology. Thus, e.g., specialists link child’s
autism to mother’s use of valproates, thalidomide, misoprostol and alcohol [2].
At present only a limited range of drugs with teratogenic effect has significantly been
revealed. The major of them are thalidomide, retinoids, vitamin A (more than 25,000 IU/day),
diethylstilbestrol,
carbamazepine,
androgens,
antimetabolites,
lithium,
misoprostol,
penicillamine, cumarin derivatives, phenytoin, phenobarbital/primidon and trimethadione.
Monotherapy using one of the listed drugs in trimester I does not necessarily result in
embryonal damage. Risk of defect development is less than 10% (excluding the strongest
teratogens – thalidomide and retinoids). The high-risk group also includes women receiving
comprehensive therapy for severe epilepsy. At the same time, the application safety of most
drugs during pregnancy has not yet been defined [2, 3, 37].
Conclusion
Sufficient amount of actual data has been gathered throughout the period of observing
drugs’ effect on a fetus; this allowed reconsidering the concept of impenetrable placental safe
fetal protection against hazardous substances; the necessity of testing drugs’ safety for fetus
was admitted; teratogenesis principles were formulated; notions of teratogenesis mechanisms
and variants of drugs’ influence on a fetus are being developed.
It is evident that further improvement of drug teratogenic effects’ study methods is
necessary; it is also important to trace various effects not only in fetuses and infants, but also
possible remote consequences for human development in the form of pharmacoepidemiological
prospective cohort and retrospective studies. It is important to keep registers on the application
of drugs during pregnancy.
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