1. Drugs in Pregnancy and Lactation Max Brinsmead MB BS PhD February 2015

2. Thalidomide – a lesson in medicine

3. Thalidomide Developed in Germany in 1954 Promoted as a tranquiliser and anti emetic Taken by thousands of pregnant women Resulted in >10,000 children with birth deformities McBride in Australia and Lenz in Germany raised the alarm Withdrawn in 1961 Has found new uses as an immune modulator & for multiple myeloma

4. Teratogenic action of Thalidomide Inserts itself into DNA of embryonic promotor zones for ears, limbs and eyes 15+ possible mechanisms of action Inhibits the angiogenic network Will have different teratogenic effects when taken at different stages of pregnancy

5. Lessons from Thalidomide The placental barrier is not effective against most orally administered drugs Animal teratogenic testing can be misleading Drug companies have a powerful commercial agenda But are not the sole culprits in a tragedy such as this

6. When considering drugs in pregnancy there are 4 different scenarios A pregnant woman who has ingested a drug and is seeking information about its possible consequences A pregnant woman with a medical condition for which a drug is usually prescribed - what is the safest and most effective drug to use? A woman planning pregnancy who requires long term medication seeks your advice about the teratogenicity of that medication Safe drugs to use in a woman of childbearing age

7. We need to remember that: We are in the post-thalidomide era Drug metabolism is altered by pregnancy Most drugs cross the placenta freely But Only a handful have been shown to be teratogenic And Some of the defects are relatively minor

8. Effects on the fetus: Can be irreversible teratogenesis e.g. Thalidomide Can be reversible side effects of the drugs e.g. anti depressant medication

9. Principles of safe prescribing: Is there a non pharmacological alternative? Do the benefits outweigh the risks? Extra caution in the first trimester Use drugs tested by TIME in WOMEN Choose the least harmful drug for the minimum time possible

10. Drug categorisation for Pregnancy Different in different countries Australian Drugs in Pregnancy – see website – A Okay to use B1 – no known effects in women or animals but more data required B2 – no known effects in women or animals but more testing required B3 – no known effects in women but teratogenic in some animals – C Harmful effects - not teratogenic – D Suspected of causing irreversibe damage – X High risk of permanent damage.

11. Known Teratogenic Drugs Systemic retinoids e.g Isotretinoin. Category X Drug – CNS abnormalities – Congenital heart defects – Facial dysmorphism – Risk approx. 40% Stilboestrol – Vaginal adenocarcinoma – Male & female genital tract abnormalities – Risk varies 22 – 58% Folic acid antagonists e.g. Methotrexate – Neural tube defects – Craniofacial abnormalities & Limb defects – Risk approx. 30%

12. Why is a drug not always teratogenic?

13. Known Teratogenic Drugs (2) Thalidomide – Phocomelia – Congenital heart defects, GIT & renal malformations – Risk approx. 20% Cytotoxic drugs e.g. Cyclophosamide – Various effects including fetal death & IUGR – Risk approx. 20% Anticonvulsants e.g. Phenytoin, Valproic acid, Carbamazepine – Risk 3 – 9% Warfarin – Dysmorphic face, congenital heart disease, genital defects, Brain effects – Risk 4 – 8%

14. Known Teratogenic Drugs (3) Tetracyclines e.g. Doxycycline – Dental staining – Non dysforming skeletal effects – Risk rate unknown Misoprostol – Moebius sequence i.e. Paralysis 6 th & 7 th cranial nerves – Risk may be as high as 50% Paroxetine – Congenital heart defects – Risk rate unknown

15. Known Teratogenic Drugs (4) Alcohol (Ethanol) – Fetal alcohol syndrome – characteristic face – Mental retardation, neurobehavioural abnormalities – Risk is dose dependent (no safe level?) Cocaine – Renal tract malformations – Risk rate unknown Heroin, Marijuana and Amphetamines – Are not teratogenic

16. Antibiotics in Pregnancy Penicillins Erythromycin Cephalosporins Nitrofurantoin Metronidazole Trimethoprim Sulpha drugs Chloramphenicol Tetracycline Gentamicin A A A A B2 B3 C A D D

17. Anti-malarial drugs for Pregnancy Chloroquine Quinine Paludrine (Proguanil) Maloprim, Daroprim Larium Fansidar Doxycycline A D B2 B3 D D

18. HAART drugs for Pregnancy AZT Lamivudine Nevirapine 3TC Abacavir B3

19. Anti-emetics for Pregnancy Pyridoxine Diphenhydramine Metoclopromide Hyoscine Ondansetron Promethazine Prochlorperazine A A A B2 B1 C C

20. Antihypertensive drugs in Pregnancy Aldomet Hydralazine Beta blockers Ca channel blockers Thiazides ACE Inhibitors A C C C C D ↑risk of CNS & CHD defects 3- fold in 1 st trimester, ?cause fetal death in 3 rd trimester

21. Analgesic Drugs for Pregnancy Paracetamol Codeine Aspirin Narcotics NSAIDs A A C C C Have the potential to cause in utero closure of the ductus arteriosus >34w

22. Anticonvulsant Drugs for Pregnancy All anticonvulsants are teratogenic But there is a genetic component because epileptics on no drugs have ↑rate defects Offspring of epileptic men have ↑rate defects Maternal and fetal risk of fits is greate r than the teratogenic risk Some defects can be detected by prenatal testing Spina bifida with sodium valproate Others are deemed acceptable risks 1% risk of isolated oral clefts with Lamatrogine Dilantin is best avoided Carbamazepine & Na valproate reasonable alternatives

23. Psychiatric Drugs for Pregnancy Most anti-depressants are Category C Except for Moclobemide & MAO Inhibitors (B3) Tricyclics slightly safer than SSRI’s Fluoexetine is the SSRI with the lowest known risk Paroxetine is teratogenic (D) Benzodiazepines and Barbiturates are (C) Benzo’s particularly bad because they accumulate in the fetus And the neonate metabolises them slowly But barbiturates actually hasten the resolution of neonatal jaundice

24. Drugs and Lactation: Most drugs which circulate in the blood will appear in breast milk But The dose which reaches the infant is small And In general it is inappropriate to deny the BABY and the MOTHER the benefits of breastfeeding

25. X Rays and Pregnancy: The first 4 weeks of amenorrhoea is not a critical period of radiosensitivity in humans Risk of microcephaly is linear from 8 - 15w And ? no threshold Thereafter threshold is 50-150 rads – Chest Xray is <1 rad – IVP is about 15 rads – CT may involve 15 rads

26. If a pregnant woman is exposed to radiation: Carefully calculate the dose involved Consult the best available authority Counsel along the same lines as for a woman inadvertently exposed to a drug