Transcript Drugs in Pregnancy - Max Brinsmead MB BS PhD

Drugs in Pregnancy and
Lactation
Max Brinsmead MB BS PhD
February 2015
Thalidomide – a lesson in medicine
Thalidomide
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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• Withdrawn in 1961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
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
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
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
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
Effects on the fetus:
• Can be irreversible teratogenesis
e.g. Thalidomide
• Can be reversible side effects of the drugs
e.g. anti depressant medication
Principles of safe prescribing:
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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
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.
Known Teratogenic Drugs
• Systemic retinoids e.g Isotretinoin. Category X Drug
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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%
Why is a drug not always
teratogenic?
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%
Known Teratogenic Drugs (3)
• Tetracyclines e.g. Doxycycline
– Dental staining
– Non dysforming skeletal effects
– Risk rate unknown
• Misoprostol
– Moebius sequence i.e. Paralysis 6th & 7th cranial nerves
– Risk may be as high as 50%
• Paroxetine
– Congenital heart defects
– Risk rate unknown
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
Antibiotics in Pregnancy
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Penicillins
Erythromycin
Cephalosporins
Nitrofurantoin
Metronidazole
Trimethoprim
Sulpha drugs
Chloramphenicol
Tetracycline
Gentamicin
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B2
B3
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Anti-malarial drugs for Pregnancy
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Chloroquine
Quinine
Paludrine (Proguanil)
Maloprim, Daroprim
Larium
Fansidar
Doxycycline
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B2
B3
B3
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HAART drugs for Pregnancy
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AZT
Lamivudine
Nevirapine
3TC
Abacavir
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B3
B3
B3
B3
B3
Anti-emetics for Pregnancy
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Pyridoxine
Diphenhydramine
Metoclopromide
Hyoscine
Ondansetron
Promethazine
Prochlorperazine
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B2
B1
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Antihypertensive drugs in
Pregnancy
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Aldomet
Hydralazine
Beta blockers
Ca channel blockers
Thiazides
ACE Inhibitors
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• ↑risk of CNS & CHD defects 3fold in 1st trimester, ?cause
fetal death in 3rd trimester
Analgesic Drugs for Pregnancy
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Paracetamol
Codeine
Aspirin
Narcotics
NSAIDs
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• Have the potential to cause
in utero closure of the
ductus arteriosus >34w
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 greater 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
Psychiatric Drugs for Pregnancy
• Most anti-depressants are Category C
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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
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
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
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
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Comments?
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