TERATOGENIC DRUGS

✓ Definitions:

1. Teratogenicity: The ability of exogenous agents to cause foetal abnormalities when

administered to the mother at any stage of pregnancy.

2. Teratogen: Any substance, agent or exposure given to pregnant woman that can induce

anatomical, structural or developmental defects in foetus.

3. Teratogenic drugs: The drugs having ability to cause foetal abnormalities when

administered to the mother at any stage of pregnancy.

✓ Types of teratogens:

1. Physical agents:

e.g., Heat, ionizing radiations, etc.

2. Environmental chemical agents:

e.g., Organic mercury compounds, polychlorinated biphenyl (PCB), etc.

3. Infections:

e.g., rubella, cytomegalovirus, HSV, varicella, etc.

4. Drugs:

e.g., Alcohol, Warfarin, Thalidomide, etc.

5. Metabolic conditions:

e.g., maternal PKU, diabetes mellitus, PIH, etc.

✓ Factors affecting effect of teratogens:

1. Placental barrier: non-polar, lipid soluble drugs cross rapidly

2. Amount of exposure: higher dose and increased frequency

3. Duration of exposure: longer duration, maximum risk

4. Gestational age at the time of drug exposure: Maximum risk during first trimester when

organogenesis occurs.
✓ Effects of teratogens on foetus during pregnancy:

1. Fertilization and implantation: (From conception to 17 days)

e.g., Failure of pregnancy

2. Organogenesis: (18 to 55 days)

MOST VULNERABLE PERIOD
e.g., Congenital malformations

3. Growth and development: (56 days and onwards)

e.g., Developmental & Functional abnormalities

✓ Mechanisms for drug induced teratogenicity:

- Teratogens that interact with an embryo during the period of development causes errors

in genetic programming based on deviations in genotype of the embryo or low

probability for error of normal genotype.

Mechanisms Drugs involved

Folate Antagonism Methotrexate, Carbamazepine

Neural crest cell disruption Retinoic acid

Endocrine disruption Diethylstilboestrol

Oxidative stress Thalidomide, Phenytoin, Valproate

Vascular disruption Aspirin, Ergotamine

Enzyme-mediated teratogenesis ACE Inhibitors

✓ Pregnancy and lactation labelling rule:

As per pregnancy and lactation labelling rule, drugs were categorized as follows:

Category Risk Examples

A Controlled human studies shows no risk Folic acid, Thyroxine

B No confirmatory evidence of risk in humans Amoxicillin, Ondansetron

C Risk cannot be rule out Fluconazole, Metoprolol

D Positive evidence of risk Phenytoin, Lithium

X Contraindicated in pregnancy Methotrexate, Warfarin

✓ New Pregnancy and lactation labelling rule, 2015:

✓ Pregnancy risk letter categories eliminated

✓ Sections for Pregnancy & Lactation combined

✓ New section “FEMALES AND MALES OF REPRODUCTIVE POTENTIAL” added

8.1 Pregnancy 8.2 Lactation 8.3 Females and males of

reproductive potential
✓ Pregnancy registry ✓ Risk summary ✓ Pregnancy testing
✓ Risk summary ✓ Clinical ✓ Contraception
✓ Clinical considerations ✓ Infertility
considerations ✓ Data
✓ Data

• Diagnostic testing for teratogenicity:

- Teratogenicity testing came into being since the Thalidomide tragedy of 1961, resulting

into >2000 deaths, >10000 babies born with deformities after use of R-Thalidomide by

mother for morning sickness.

- High demand for a rapid, reliable and cost-effective method for detection of

teratogenic toxicity
✓ First trimester screening:

- Done between 11 to 13 weeks of pregnancy

- Maternal blood test: Human chorionic gonadotropin (hCG) and Pregnancy associated

plasma protein A (PAPP-A)

- Ultrasound: Nuchal translucency

✓ Second trimester screening:

- Done between 15-20 weeks of pregnancy

- Maternal serum screen: Triple (AFP, hCG, Estriol) and Quadruple (AFP, hCG,

Estriol, Inhibin A)

- Foetal echocardiogram: For heart defects

- Ultrasound: Also known as Anomaly scan

✓ Diagnostic tests:

- Chorionic villus sampling (10-12 weeks of gestation)

- High resolution ultrasound (15-18 weeks of gestation)

- Amniocentesis (18-20 weeks of gestation)

✓ Post-natal testing:

- Unnoticed and noticed on evaluation for other conditions

• Prevention of teratogenicity:

✓ Patient education: Educate about planning of pregnancy and hazards of teratogens and

preventable causes of teratogenicity.

e.g., Alcohol and smoking.

✓ Past medical and family history: History of diabetes mellitus, hypertension,

hereditary disorders, past history of congenital birth defects, miscarriage leading to high

risk.

e.g., Causes of previous loss of pregnancy should be ruled out.

 ✓ Management of pre-existing conditions: Treatment of diseases and hazards of

medications should be explained to patients and management of adverse drug reactions

before planning pregnancy.

e.g., Treatment of Hypertension to prevent IUGR, prematurity, etc.

✓ Medications: If patient is on any medication, then it should be informed to treating

doctors so teratogenic effects of drug can be minimised.

e.g., Isotretinoin used for Acne treatment may result into pregnancy loss.

• Teratogenic drugs:

A Teratogenic drug is an agent that can disturb the development of the embryo or foetus by

halting the pregnancy or producing congenital malformations. This is a list of teratogenic drugs.

Drug class Drugs Effects Recommendations

Angiotensin Captopril, Teratogenic: Renal Avoid in all

converting Enalapril, agenesis, pulmonary trimesters of
enzyme (ACE) Ramipril, hypoplasia, Acalvaria pregnancy
inhibitors Lisinopril Fetopathic:
Oligohydramnios,
Hypo calvaria, patent ductus
arteriosus, neonatal
hypertension, anuria, renal
failure
Alcohol Alcohol Intellectual disability, Do not use during
IUGR, microcephaly, foetal pregnancy
alcohol syndrome
(maxillary hypoplasia,
congenital heart defects)
Androgenic drugs Ethisterone, Ambiguous external Avoid prior and
Testosterone, genitalia, masculinisation of during pregnancy
Norethisterone female foetus especially in especially in 1st
1st trimester trimester
Antimicrobials Tetracycline Yellow staining of teeth and Avoid during 2nd and
diminished growth of long 3rd trimester
bones
Nitrofurantoin Haemolytic effects on new Avoid at term
born if used in last trimester
Streptomycin Ototoxicity in new born Avoid during 2nd and
3rd trimester
Anticoagulants Warfarin Causes bleeding in foetus Avoid during 1st and
leading to spontaneous 3rd trimester of
abortion, stillbirth, neonatal pregnancy
death and preterm birth.
Birth defects: blindness,
intellectual disability
Anticonvulsants Carbamazepine Neural tube defects ✓ Avoid during
Phenobarbital Cleft palate, delayed motor pregnancy
✓ Contraceptive
development advice to women
Phenytoin Foetal Hydantoin syndrome: of reproductive
IUGR, microcephaly, age receiving
anticonvulsants
intellectual disability
✓ Change in
Valproate Neural tube defects: spina therapy if woman
bifida willing to get
pregnant
✓ High dose Folic
acid
Antifungal Fluconazole Malformed bones, head, Avoid during
heart, face – if used in high pregnancy
doses
Antidepressants Lithium Ebstein anomaly Avoid during
pregnancy – if used
then monitoring for
Lithium
concentration is
advised
Antithyroid drugs Carbamazole, Choanal atresia Avoid during 1st
Methimazole trimester of
pregnancy
Chemotherapeutic All Stunted growth, cleft palate, Avoid during
agents missing brain parts pregnancy
Folate antagonist Methotrexate Neural tube defects ✓ Avoid during
pregnancy
✓ Contraceptive
advice to patients
receiving
Methotrexate and
3 months after
treatment in
males & females
Lipid lowering Statins Malformations like ✓ Avoid during
agents vertebral, anal, cardiac, pregnancy
✓ Contraceptive
tracheal, oesophageal, renal,
advice to patients
deficient limb, IUGR receiving Statins
and 1 month after
treatment
Prostaglandin Misoprostol Club foot, cranial nerve Avoid during
analogues anamolies, absence of finger pregnancy
Nicotine Nicotine IUGR, foetal hypoxia Avoid during
leading to impaired pregnancy
development and premature
delivery
NSAIDs Naproxen, Miscarriage, patent ductus Avoid during
Aspirin, arteriosus and persistent pregnancy
Celecoxib, pulmonary hypertension in
Diclofenac, newborn
Ibuprofen,
Indomethacin
Opioids Morphine, Neural tube defects, Avoid during
Codeine, respiratory depression and pregnancy
Oxycodone, withdrawal symptoms
 Hydrocodone,
Hydromorphone
Radiations Ionizing Chromosome injury Avoid during
radiations pregnancy
Tranquillisers Thalidomide Phocomelia, congenital ✓ Avoid during
heart defects, limb pregnancy
✓ Contraceptive
abnormalities, absence of
advice to patients
external ears receiving
Thalidomide and
1 month before &
after treatment
Vitamin A Retinoic acid (at Neural tube defects, cleft Avoid during
derivatives very low doses) palate, thymic aplasia pregnancy