1. Teratogenic Drug & Antibiotic for pregnancy
Dr. Jarir At Thobari, PharmD, PhD 1,2
1Dept. Pharmacology and Pharmacotherapy
2Clinical Epidemiology & Biostatistic Unit
Fac. Medicine Universitas Gadjah Mada

2. Thalidomide ( )
Some remedies are worse than the disease” Publilius Syrus, Roman writer, 1st century BC.

3. Fetal Development: Period of High Susceptibility
Period of greatest concern begins at days when organogenesis begins
Reaches a peak at 30 days postconception
Susceptibility decreases until days and becomes minimal through day 90

6. General approach Virtually all drugs cross to some degree
We really don’t know much about what a given drug can or cannot do
Use any drug only when necessary, when risk/benefit indicates, and then only in minimal effective dose

7. Maternal/Fetal Transfer
Maternal/Fetal blood flow
Placental binding
Maternal, Placental,& Fetal metabolism
Diffusion capacity
Maternal & Fetal protein binding
Maternal Dose/Drug Uptake

8. Placental drug transfer
Depends upon:
Physical and chemical properties of drug
Characteristics of maternal, fetal, and placental circulations
Anatomy and physiology of the placenta

9. Placental Transport Molecular weight Lipid solubility Ionization
Concentration gradient
Protein binding
Changes in maternal physiology
Route of delivery

10. Documented Teratogenic
ACE Inhibitors
Mercury
Alcohol
Phenytoin
Androgens
PPIs (some evidence)
Antithyroid drugs
Radiation (>5 rad)
Carbamazepine
Streptomycin/kanamycin
Chemotherapy agents
Isotretinoin (Accutane)
Cocaine
Tetracycline
Coumadin
Thalidomide
Diethylstibestrol
Trimethadione
Lead
Valproic acid
Lithium
Vit A derivatives (Retinoic acid)

11. Teratogen
Is an agent that can disturb the development of the embryo or fetus
Teratogens halt the pregnancy or produce a congenital malformation
Include radiation, maternal infections, chemicals, and drugs

12. Teratogenic drugs
directly or indirectly, causes a structural or functional change in the fetus or child if it is administrated to pregnant mother
If mother is taking this drug, It can be either stopped, switched or reduced to the lowest dose possible
typically during sensitive periods of fetal development
Depending on the particular teratogenic process and target organ

13. Teratogenesis
Birth defects are known to occur in 3-5% of all newborns.
They are the leading cause of infant mortality in the United States, accounting for more than 20% of all infant deaths.
They can do direct damage to the fetus, causing abnormal development.
They can compromise the function of the placenta, often by constricting blood vessels and reducing the supply of oxygen and nutrients from the mother to the fetus. This can lead to underdevelopment or low birth weight, which are risk factors for birth defects.
They can trigger forceful uterine contractions, potentially injuring the fetus or prompting premature birth.

14. DRUGS PREGNANCY CATEGORIES
CATEGORY A
failed to demonstrate a risk to the fetus in the first trimester of pregnancy
no evidence of risk in later trimesters
CATEGORY B
failed to demonstrate a risk to the fetus
no adequate and well-controlled studies in pregnant women.
CATEGORY C
shown an adverse effect on the fetus
no adequate and well-controlled studies in humans
potential benefits may warrant the use of drug despite potential risks.
CATEGORY D
positive evidence of human fetal risk based on adverse reaction data
potential benefits may warrant use of the drug in pregnant women despite potential risks
CATEGORY X
demonstrates fetal abnormalities
positive evidence of human fetal risk based on adverse reaction data
the risks involved in use of the drug in pregnant women
CATEGORY N
FDA has not classified the drug.

15. POSSIBLE SITES OF ACTION OF TERATOGEN
DIRECT TOXIC ACTION
INDIRECT TOXIC ACTION
FETUS: -Direct toxicity. -Metabolites toxic. -Indirectly toxic, e.g. anti-metabolites, anti-vitamin. -Pharmacodynamic actions, e.g. on cardiovascular system. -Endocrine balance altered
FAETOPLACENTAL UNIT: -Umbilical cord, e.g. spasm. -Amniotic fluid volume change. -Faetal or maternal placental blood flow. -Placental transfer of nutrients, e.g. decreased active transport
MOTHER: -Nutritional changes, e.g. vitamin or mineral deficiencies. -Biochemical changes with secondary effects on the foetus, e.g. hyperglycaemia. -Endocrine balance
FATHER: -Sperm changes
Cause malformation -interfering with faetal metabolism
Drugs: -folic acid antagonists -antiepileptic drugs

16. TERATOGENIC MECHANISMS OF DRUGS
Folate antagonism
Neural crest cell disruption
Endocrine disruption
Oxidative stress
Vascular disruption and specific receptor
Enzyme-mediated teratogenesis

17. Teratogenic Drug (TERATOWA)
Thalidomide
Epileptic drugs (valproic acid/phenytoin)
Retinoid (Vitamin A)
ACE-inhbitors/ARC
Third element (lithium)
Oral contraceptives - hormone
Warfarin
Alcohol

18. Analgesic (aspirin) Gastroschisis
Decrease prostaglandin  decrease uterine contraction delayed onset of labor & prolonged period of pregnancy
During delivery severe bleeding because aspirin decrease platelet aggregation

19. Anticonvulsant Fetal hydantoin syndrome : cranio facial malformation:
-Cleft lip and palate
-Broad nasal bridge
-Ocular hypertelorism
-Abnormal ears
congenital heart disease
limb malformation
mental and growth retardation

20. Anticoagulant (Warfarin-coumadin)
Fetal wafarin syndrome:
-Nasal hypoplasia
-Bone stippling
-Bilateral optic atrophy
-Mental retardation
Respiratory distress syndrome
Fetal and maternal hemorrhage

21. Antidepressant (imipramine)
Cleft palate
Defect in abdomen
Adrenal hypoplasia
Cardiovascular defect

22. Antithyroid
Fetal goiter

23. Vitamin A (Retinoic acid)
Cranio-facial dysmorphism
Cleft palate
Thymic aplasia
Neural tube defect ( spina bifida cystic )

24. Metal Toxic (Lithium) Hypotonia (floppy baby syndrome) Cyanosis
Lethargy
Poor respiratory

25. Sedative-hypnotic (diazepam)
Cleft lip and palate
Inguinal hernia
Congenital heart disease
Pyloric stenosis
Breathing difficulties

26. Cardiovascular Drugs Agent Mechanism of action Dosage Benefits
Side Effects
Notes
ACE inhibitor
Blocks the conversion of angiotensin I to angiotensin II
Variable
5-40 mg/d
Do not use in pregnancy
Fetal teratogen
Screen for ACE inhibitor use in pregestational diabetic patients and stop before conception
Angiotensin receptor blocker
Blocks angiotensin II receptor sites
Variable mg/d
Screen for angiotensin receptor blocker use in pregestational diabetic patients and stop before conception
Aspirin
Cyclo-oxygenase inhibitor
mg/d
Maternal and newborn hemorrhage, increased perinatal mortality, intrauterine growth retardation, and teratogenic effects
In one case-controlled study, 3 of 14 newborn exposed to aspirin within 1 week of delivery had minor hemorrhaging compared with 1 of 17 controls(10). In two retrospective studies, mothers of 1,291 malformed infants were foiund to have consumed aspirin during pregnancy more frequently than mothers of normal infants (11:12)
HMG-CoA reductase inhibitors
Decreases synthesis of cholesterol in the liver
Possible teratogen
In a surveillance study of lovastatin exposures during pregnancy, normal outcomes were 85% congenital anomalies 4.0% spontaneous abortions 8.0% and fetal deaths/ stillbirths 1.0% (9)

27. Antiemetics
Ondansetron

28. Significant findings re: cleft palate

29. Conflicting data
Danish registry covering from (897,018 pregnant women). In contrast to earlier studies from same registry, found a 2-fold increased risk of cardiac malformations with ondansetron (odds ratio 2.0; 95% confidence interval 1.3–3.1), leading to an overall 30% increased risk of major congenital malformations. To rule out confounding by indication, also examined metoclopramide taken for morning sickness, detecting no increase in teratogenic risk.
Andersen, J.T., Jimmenez-Solem, E., and Andersen, N.L. Ondansetron use in early pregnancy and the risk of congenital malformations. Int Soc Pharmacoepidemiol. 2013;

32. Antibiotics Penicillins, cephalosporins, EES: OK
Sulfonamides: compete with bili for albumin binding
Tetracycline: OK, except for teeth
Aminoglycosides

33. Tetracycline IN PREGNANCY….. dental discoloration in children
maternal hepatotoxicity with large Parenteral doses

34. Chloramphenicol
Intravenous chloramphenicol use has been associated with Gray Baby syndrome
This occur in newborn infants because they liver enzymes not yet fully developed
chloramphenicol remains unmetabolised in body

35. Aminoglycoside Pregnancy category D
Fetal otoxicity: Auditory or vestibular nerve damage

36. Trimethoprim- Sulfamethoxazole
NEONATAL HAEMOLYSIS
METHAEMOGLOBINAEMIA

37. Approved
Arch Gynecol Obstet (2011) 283:7–18

38. Restricted
Arch Gynecol Obstet (2011) 283:7–18

39. Restricted
Arch Gynecol Obstet (2011) 283:7–18

40. Contraindications
Arch Gynecol Obstet (2011) 283:7–18

41. Take home messages Be careful in taking drugs during pregnancy
All physicians including pharmacists are reponsible to counsel patients with complete accurate and current information on the risks and benefits of using medication during pregnancy.

42. All things are poison and nothing is without poison, only the dose permits something not to be poisonous."
~Paracelcus

43. THANK YOU