brief description about the concept of teratogenicity, brief history , drugs that cause the malformations,studies & screening tests related to it, regulations, guidelines and recent updates.

1. PRESENTER – DR. AMITRAJIT PAL
PG GUIDE – DR. R. S. GAMBRE
TERATOGENICITY

2. OVERVIEW
 A BRIEF HISTORY INCLUDING THE THALIDOMIDE TRAGEDY
 INTRODUCTION
 TERATOGENIC MECHANISMS AND DRUG CATEGORIZATION
 DRUGS CAUSING TERATOGENICITY
 STUDIES
 CURRENT SCENARIO
 SCREENING TESTS IN ANIMALS AND PREGNANT WOMEN
 LAWS RELATED TO TRIALS IN PREGNANT WOMEN & FDA GUIDELINES
 RECENT UPDATES, TERMINOLOGY, RECOMMENDATIONS
 CONCLUSION

3. A BRIEF HISTORY
 In 1928 : Exposure to therapeutic radiation during
pregnancy leads to microcephalic baby.
 In 1933 : Deficiency of vitamin A in the 1st month before
pregnancy & during pregnancy leads to anophthalmia.
 In 1941 : German measles (rubella) infection in pregnancy
cause teratogenicity (blindness, deafness, death, mental
retardation).

4.  In 1944 : Malformation due to nutritional deficiency.
 In 1961 : Correlation between Thalidomide (used as
sedative, hypnotic and anti emetic) ingestion in
pregnancy & phocomelia (phoco = seal, melia =
extremities).

5. THE THALIDOMIDE TRAGEDY
 Thalidomide was discovered at Chemie Grünenthal in 1953.
 Researchers at Chemie Grünenthal found that thalidomide
was a particularly effective antiemetic that had an inhibitory
effect on morning sickness. On October 1, 1957, the company
launched thalidomide and began marketing it under the trade
name Contergan.

7.  In November 1961, thalidomide was taken off the market due
to massive pressure from the press and public.
 Estimated death of approximately 2,000 children and serious
birth defects in more than 10,000 children, about 5,000 of
them in West Germany.

11. TERATOLOGY
 Teratology is the study of abnormal prenatal development
and congenital malformations induced by exogenous chemical
or physical agents.
 The term “teratology” was first coined in 1832 by the French
physician Isidore Geoffroy Saint-Hilaire to define a field of
science dedicated to studying developmental anomalies.

12. TERATOGEN
 Teratogen: An agent which produces a permanent alteration
in structure or function of organism exposed during embryonic
or fetal life.

13. TERATOGENICITY
 It is the science dealing with the development of congenital &
developmental malformations in the growing embryo or fetus.

14. OTHER TERMINOLOGIES
 Development toxicity : Involves any adverse effect induced
prior to the attainment of adult life.
 Reproductive toxicity : Represents harmful effects on the
progeny and/or an impairment of male and female
reproductive function or capacity.
 NOAEL : It is the abbreviation for No Observed Adverse
Effect Level and is the highest dose level where no adverse
effects are observed.

16. DRUGS CAN AFFECT THE FOETUS AT 3
STAGES
 Fertilization & implantation – conception to 17 days
 Organogenesis - 18 to 55 days of gestation
 Growth & development - 56 days onwards

19. TERATOGENIC MECHANISMS
 Folate antagonism – Methotrexate, Carbamazepine
 Neural crest cell disruption – Retinoic acid
 Endocrine disruption – Diethylstilboestrol
 Oxidative stress – Thalidomide, Phenytoin, Valproate
 Vascular disruption – Aspirin, Ergotamine,
Pseudoephedrine
 Enzyme-mediated teratogenesis – ACE inhibitors

20. FACTORS THAT DETERMINE
TERATOGENESIS
 Dose reaching fetus.
 Duration of exposure.
 Point in development when drug exposure occurs.
 Environmental factors e.g age or disease of the mother.

21. PROVEN HUMAN TERATOGENS
DRUG ABNORMALITY
Thalidomide Phocomelia, multiple defects
Antineoplastic drugs Multiple defects, fetal death
Androgens Virilization, esophageal and
cardiac defects
Progestins Virilization of female fetus
Tetracyclines Discoloration of teeth, bone
defects
Warfarin Fetal Warfarin Syndrome
Phenytoin Cleft lip/palate, microcephaly,
hypoplastic phalanges

22. Alcohol Low IQ, growth retardation,
fetal alcohol syndrome
ACE inhibitors Hypoplasia of organs, growth
retardation , foetal loss
Lithium Ebstein Anomaly
Anti-thyroid drugs Foetal goitre, hypothyroidism
Indomethacin Premature closure of ductus
arteriosus
Isotretinoin Cranial, cardiac and CNS
defects

23. RETINOIC ACID OR VITAMIN A
DERIVATIVES:
 Even at very low doses
isotretinoin is potent
teratogen
 Malformations include :
 Craniofacial
dysmorphisms
 Cleft palate
 Thymic aplasia
 Neural tube defects
 Critical period of exposure is
from 2nd to 5th week of
gestation.

25. PHENYTOIN

26. ANTICOAGULANTS
 Warfarin (Coumarin) has been associated with
Chondrodysplasia punctata.
 Other malformations like nasal hypoplasia, bone stippling
seen on radiologic examination, bilateral optic atrophy and
mental retardation.

27. THYROID AND ANTITHYROID DRUGS
 Propylthiouracil (PTU) and methimazole both cross the
placenta and may cause some degree of fetal goiter.
 Goal of such therapy during pregnancy is to keep the mother
slightly hyperthyroid to minimize fetal drug exposure.

28. TETRACYCLINE
 Protein synthesis inhibitor.
 Readily cross the placenta.
 Brown discoloration of the
deciduous teeth.
 Hypoplasia of the enamel
and inhibition of bone
growth.
 Critical period of exposure-
2nd & 3rd trimester.

29. MISOPROSTOL
 Moebius Syndrome (MS) is a rare disorder defined by
bilateral congenital paralysis of the abducens and facial nerves
in combination with various odontological, craniofacial,
ophthalmological and orthopaedic conditions.

30. ACE INHIBITORS
 It can cause:
 foetal hypotension
 renal failure
 Hypocalvaria
 Critical Period of exposure 2nd – 3rd trimester

32. #STUDY 1
 A study was conducted in a hospital in Northern India among
405 pregnant women to assess and evaluate the drug
utilization pattern during pregnancy and to evaluate the effect
of the educational and economic status on it.

33. A
28%
B
43%
C
1%
D
27%
X
1%

34.  33.33% (135) women believed that use of certain drugs during
pregnancy is dangerous to both mother and child and 37.03%
(150) believed that drugs are dangerous throughout pregnancy.
 55.55% (225) females advocated the use of iron/folic acid
during pregnancy. 24.69% (100) of women had knowledge
about barrier contraceptives.

36. #STUDY 2
 A questionnaire based study was conducted in KIMS, Bangalore to
analyse the knowledge and attitude of 147 2nd year students on the
various aspects of teratogenicity.
 67.3% of them had knowledge of all the causes.
 58.5% were aware that drugs can act as a teratogen throughout the
pregnancy .
 Only 34.69% were aware of ‘US-FDA foetal risk categories’ though
63.27% and 68.71% of the participants chose correct response for
category A and category X drugs respectively .

37.  Only 27.21% were aware that ‘thalidomide’ is the first known
drug teratogen.
 Post-session improvement in knowledge score emphasizes the
need for early exposure of medical students to the concept of
teratogenicity. Multiple exposures on these aspects will help
the students in the future to decide the safe drug for a pregnant
woman.

38. #STUDY 3
 A retrospective study was conducted in a tertiary care centre in
Northern India to analyse the safety and efficacy of
Levetirecetam (LEV) in 99 pregnant women with epilepsy.

39. Carbamazepine
36%
Levetirecetam
28%
Valproate 15%
Oxcarbazepine
3%
Phenytoin 13%
Lamotrigine 3% Clobazam 2%

40.  It was concluded that LEV is one of the first-line AED during
pregnancy. Future prospective studies using therapeutic drug
monitoring during pregnancy may further help in establishing
its role during pregnancy.

42. #STUDY 4
 A cross-sectional study was conducted to understand the
knowledge of drug dispensers and pregnant women in
Tanzania.
 Out of 200 drug dispensers, 86 (43%) were willing to dispense
artemether - lumefantrine (regardless of the age of pregnancy),
56 (29%) were willing to dispense sodium valproate, 104
(52%) were willing to dispense captopril and 50 (25%) were
willing to dispense tetracycline.

43. THE CURRENT SCENARIO
 According to NFHS 4, 11% of reproductive age group female
was using any forms of tobacco and its usage was almost equal
among pregnant and non-pregnant women.
 Children of women who smoke during pregnancy are found to
have multiple birth defects 1.5-2 times more than expected.
 Alcohol, which is associated with fetal alcohol syndrome,
usage among reproductive age group female was 2.2%.

44. SOME VITAL STATISTICS
 According to study on drug utilization pattern during
pregnancy, exposures to radiation and category X drug occur
in 4% and 5.71% pregnant females respectively during the
first trimester.
 Exposures to other categories of drugs during their first
trimester vary from 55.28% for category A to 6% for category
D drugs respectively.

46. ANIMAL TOXICITY REQUIREMENTS FOR
CLINICAL TRIALS AND MARKETING OF A NEW
DRUG
Toxicity study Human phase for which study
is proposed to be conducted
Segment II
(Teratogenicity Study)
Phase II, III including female
patients of child bearing age
Segment III
(Perinatal Study)
Phase III
 Drugs given to pregnant or
nursing mothers for long
periods
 Drugs with indications of
possible adverse effects on
foetal development

47. TERATOGENICITY STUDY (SEGMENT II)
One rodent (preferably rat)
One non-rodent (rabbit)
Three graded doses
 Highest dose – minimum maternal toxicity
 Lowest dose – proportional tothe proposed dose for
clinical use in humans
 Intermediate dose – logarithmically between two other
doses
Drug administered throughout the period of organogenesis

48. TERATOGENICITY STUDY (SEGMENT II)
Route of administration same as intended for human therapeutic use
Control and treated groups
At least 20 pregnant rats (or mice) and 12 rabbits, on each dose level
All foetuses subjected to gross examination
Skeletal and visceral abnormalities

49. Foetuses
 Total number
 Gender
 Body length
 Weight
 Gross/ visceral/ skeletal
abnormalities
TERATOGENICITY STUDY (SEGMENT II)
Observation parameters
Dams
 Signs of intoxication
 Effect on body weight
 Effect on food intake
 Examination of uterus,
ovaries & uterine contents
 Number of corpora
lutea
 Implantation sites
 Resorption

50. PERINATAL STUDY (SEGMENT III)
One rodent species (preferably rat)
At least 4 groups (including control) each
consisting 15 dams
Dosing at levels comparable to multiples of
human dose by intended clinical route

51. Dams sacrificed and examined
Then, dose that causes low foetal loss should be
continued throughout lactation and weaning
PERINATAL STUDY (SEGMENT III)
Drug administered throughout the last trimester of
pregnancy

52. Pups
 Clinical signs
 Sex- wise distribution in dose
groups
 Body weight
 Growth parameters
 Gross examination
 Survival
 Autopsy
PERINATAL STUDY (SEGMENT III)
Observation parameters
Dams
 Body weight
 Food intake
 General signs of
intoxication
 Progress of gestation/
parturition periods
 Gross pathology

53. IN VITRO TECHNIQUES
 Simple and cost-efficient.
 Can reduce pressure imposed by society to decrease or
replace the number of animals used in research and testing
strategies.

54. FEATURES OF AN IDEAL IN VITRO
TERATOGENICITY TEST SYSTEM
 Simple, easy to perform, yield of interpretable results.
 Rapid, usage of large numbers of samples.
 Giving few false negatives.
 Having relevance to mechanisms of teratogenesis.
 Usable with various types of agents.
 Usage of intact organisms capable to absorb, circulate and
excrete chemicals.

55. IN VITRO TECHNIQUES
 Whole embryo culture test
 Micromass teratogen test
 Embryonic stem cell test
 Dictyostelium discoideum based assay

56. WHOLE EMBRYO CULTURE TEST
Rodent embryo culture (rat or mouse)
 Culturing of whole embryos at early stage of organogenesis.
 Exposure of these to a potential teratogen.
 Endpoints generally used:
 Mortality
 Malformation
 Growth inhibition

57. WHOLE EMBRYO CULTURE TEST
Zebra fish embryo
 Cover the whole period of organogenesis.
 Easy to maintain in large stocks due to their high fecundity.
 Develop rapidly ex utero, with most organs becoming
functional between 3 and 5 days post-fertilization.

58. Fig. Anomalies induced by retinoic acid treatment. The
notochord and tail were normally formed in control group
(A). The treated group (A’) exhibited kinked notochord
(arrow) and kinked tail (arrowhead)

59. Fig. Anomalies induced by retinoic acid treatment. The eyes
and otic vesicles were normally formed in control group (B).
The treated group (B’) exhibited deficiencies of eyes (arrow)
and deficiencies of otic vesicles (arrowhead)

60. MICROMASS TERATOGEN TEST
 Chick, mouse and rat embryo midbrain or limb cell culture.
 Exposed to test compounds for varying times and
concentrations.
 A phase of in vivo embryo exposure will act as a control for
the effects of drug metabolism and pharmacokinetics.

61. In vitro culturing of embryo limb or rather central
neural cells
Differentiation of the cells into chondrocytes or neurons
starting from numerous small aggregates or foci of cells
Observation of cell adhesion, movement,
communication, division and differentiation involving
the new synthesis of tissue specific patterns of
enzymes and structural proteins
MICROMASS TERATOGEN TEST

62. EMBRYONIC STEM CELL TEST
 Pleuripotent embryonic stem cells (ESC) isolated from mouse
blastocytes.
 ESC are able to differentiate into a variety of embryonal
tissues, retain the euploid chromosomal constitution.
 Based on the resemblance between early embryonic stages and
the differentiation of embryonic stem cells in vitro.

63. DICTYOSTELIUM DISCOIDEUM
 Single-cell, eukaryotic microorganism competent to undergo
both vegetative growth and development (fruiting body
formation).
 Cell differentiation leading to the formation of stalk and
spore cells has been shown to be similar, to some extent, to
the development of mammals.

65. CONDUCTING TRIALS IN PREGNANT WOMEN : A
CONCERN
 Possibility of disrupting organogenesis
 Potential long term sequelae in exposed infants
 An introverted restrain from Institutional internal review
boards to approve drug trials in pregnancy
 Lack of financial incentives
 Ethical arguments to justify the exclusion of pregnant women
in drug trials

66. WHAT CAN BE DONE ?
 Studies can be done in pregnant women if pre-clinical &
clinical studies including ones in non-pregnant women have
been conducted.
 Data providing information of no minimal risk to fetus.
 When the purpose of research is development of important
biomedical knowledge that cannot be obtained by any other
means.

67. LAWS GOVERNING TRIALS IN PREGNANT
WOMEN
 Currently there is no legislation that mandates clinical trial
data in pregnant women.
 Despite its deficiency the regulations do stipulate that
sufficient evidence is required to adequately label a drug
product for use, including support for dosage and dose interval
recommended and that any modifications of dose or dose
interval should be identified.

68. FDA GUIDELINES
 2002 – Guidance to Industry : Establishing Pregnancy
Exposure Registries, August 2002
 2004 – Guidance for Industry Pharmaceutics in Pregnancy
 2007 – FDAAmendment Act of 2007

69. FDAAMENDMENT ACT OF 2007
It provided FDA with the authority to require certain post
marketing studies for prescription drugs
To assess a known serious risk related to the use of a drug or a
signal of serious risk related to the drug use
Because pregnant women are usually excluded from
premarketing trials, safety signals seen in pregnancy are
anticipated to arise in post marketing surveillance setting

71. PSYCHOPHARMACOTERATOPHOBIA
 Psychopharmacoteratophobia is the fear or avoidance of
prescribing psychotropic medicine to a pregnant woman on a
given indication in anticipation of foetal malformation.
 It is rooted in the tragedy associated with thalidomide use.

72. THE PROBLEM
 In the Indian setting, the physicians face more challenges as
the majority of the patients may ask them to decide, what is
the best for their health. Most guidelines emphasize more on
what not to do than what to do, and the locus of decision is left
to the doctor and the patient.

73. THE REASON
 Benzodiazepines may increase the incidence (<1%) of cleft
lip or palate, infantile hypotonia, and neonatal abstinence
syndrome.
 Selective serotonin/norepinephrine reuptake inhibitors and
tricyclic antidepressants may increase malformation by 1–3%
compared to the general population.

75.  Mood stabilizers may increase the malformation from the
baseline general population. The increase is <1% for lithium
(Ebstein’s anomaly), <5% for the carbamazepine (neural tube
defects) and lamotrigine (oral clefts), and highest is 5–10% for
valproate (neural tube defects).

76. THE CONSEQUENCE
 Untreated mental illness in pregnant women may adversely
affect the outcome of pregnancy depending upon the
diagnosis, severity, and patients’ physical health status.
 Anxiety disorders have been associated with fetal distress,
spontaneous abortion or preterm delivery or prolong the
labour, assisted (forceps) delivery, decrease developmental
scores, and slow mental development.

77. CHOICE OF DRUGS IN PREGNANCY
After extensive review, National Institute for Health and Care
Excellence provided with medication with a better safety record as
drugs of choice. These medications are:
 Hypnotic and sedative: Zolpidem or promethazine.
 Antipsychotics: Chlorpromazine, haloperidol, and trifluoperazine.
 Antidepressant: Nortriptyline, amitriptyline, imipramine, and
fluoxetine.
 Mood stabilizers: High potency typical antipsychotics may be
considered as a mood stabilizer during pregnancy.

78. THE PROBLEM STILL REMAINS
 Physicians in India are more likely to face
psychopharmacoteratophobia and issues related to this
phenomenon are distinct in India. Clear guidelines are required
to address this issue for Indian setting.

79. ONGOING TREATMENT PROBLEM
 Some women must take medications during pregnancy.
 8% of all pregnant women need to take ongoing medications
for an existing health problem. For example, chronic health
conditions such as epilepsy, high blood pressure, diabetes,
thyroid conditions and asthma require management with
medications.

80. THE REASON
 If a pregnant woman who has asthma stops taking her
medication, there is a risk of slowing the growth of her unborn
baby.
 Stopping anti-epileptic medications, may increase risk of
having seizures and complications to pregnancy and unborn
baby.
 Poorly managed maternal diabetes increases the health risk
for the unborn baby.

81. THE POSSIBLE REMEDY
 The prevalence of deformity is highest with valproate
monotherapy compared to other monotherapies.
 Likewise, the prevalence is higher in polytherapy
combinations that include valproate, compared to
polytherapies that exclude valproate. Deformity rates with
some monotherapies even approximate the rates in the general
population (e.g., levetiracetam, lamotrigine).

82. RECENT UPDATE
 2018 - Dolutegravir is not recommended for use in non-
pregnant women who are trying to conceive or during the
first trimester of pregnancy, due to concerns about a possible
increased risk of neural tube defects (NTDs).

83. POSSIBLE ROLE OF A PHARMACOLOGIST
 The constant experiments and trials keep a pharmacologist
updated on the teratogenic potential of any drug who can
communicate the same to the doctors who are actually
prescribing the drugs to pregnant mothers or they can directly
communicate the same to the patients themselves thus
counselling them from avoiding it.

84.  Staying up to date on the adverse effects through
Pharmacovigilance network is an unmissable opportunity for
a pharmacologist to curb the teratogenic potential of any drug .

85. CONCLUSION
 Understanding the mechanisms of the induction of birth
defects is key to determine how to prevent these effects.
 Further increasing the accuracy of experimental animal
extrapolation will aid in the interpretation of experimental
data in order to more accurately determine the risk of a given
compound to elicit birth defects in humans.

86. A REASON TO PONDER
 The silent cataclysmic reality is slowing growing with little
steps into its magnanimous existence which we as doctors
need to realize fast and take necessary actions as and when
required to curb the inevitability.

87. REFERENCES
 Brunton L, Knollmann B, Hilal-Dandan R. Goodman & Gilman's.
13th ed. New York, N.Y: McGraw-Hill Education LLC.
 Katzung, Bertram G., Susan B. Masters, and Anthony J. Trevor.
2012. Basic & clinical pharmacology. 15th Edition. New York:
McGraw-Hill Medical.
 Kamuhabwa A, Jalal R. Drug use in pregnancy: Knowledge of drug
dispensers and pregnant women in Dar es Salaam, Tanzania. Int Jou
of Pharm, 2011;43(3):345-49

88.  Bansal R, Suri V, Chopra S, Aggarwal N, Sikka P, et al.
Levetiracetam use during pregnancy in women with epilepsy:
Preliminary observations from a tertiary care center in Northern
India. Int Jou of Pharm, 2018;50(1):39-43
 Kumari P, Krishnaiah V, Kumaraswamy G, Tamboli TJ. Impact of
educational session on knowledge and attitude towards
teratogenicity among undergraduate medical students: a
comparative study. Int Jou of Basic & Clin Pharmac,
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