DRUG USED IN PREGNANCY

We Are In Era Of E. B. M. Absence of Evidence is

NOT An Evidence of Absence

Pregnancy - Whether planned or unplanned , a pleasant or an unpleasant surprise always brings concerns about prescription and over the counter drugs.

History
Thalidomide: probably the most notorious human teratogen Marketed as a sedative in late 1950s
Associated with up to 12,000 birth defects,

primarily phocomelias

Other effects included:

facial hemangiomata, oesophageal & duodenal atresia, teratology of Fallot, renal agenesis & anomalies of the external ear

Thalidomide
No malformations if taken before the 34th day after last menstruation &
Usually no malformations if taken after the 50th day

Sensitive time period: day 35 to day 49

Day Day Day Day 35 39 43 46 37: 41: 44: 48: absence of ears & deafness absence of arms phocomelia with three fingers thumbs with three joints

If taken throughout the sensitive period: severe defects of the ears, arms & legs & internal malformations often leading to early death (40% died before their 1st birthday)
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Association between thalidomide and human teratogenicity suspected by Lenz (Germany) in November 1961 & endorsed By a letter by McBride to the Lancet in November 1961. Withdrawn in Germany at the end of Nov 1961

end of malformation epidemic seen in July 1962 (as predicted)

Thalidomide continued to be sold for several Months in some countries e.g. Belgium, Brazil, Canada, Italy & Japan. Finally withdrawn in Japan in Sept 1962
Peak in epidemic occurred in Japan at a time when epidemic had ended in Germany
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20% of pregnancies exposed during this period resulted in anomalies Administration to female rabbits did not show any adverse effects on fertility
There was an increase in early pregnancy loss (equivalent to miscarriage)

There were no thalidomide-associated malformations in surviving foetuses

Overview
All drugs should be avoided in pregnancy unless they are essential In practice, it may not be easy to know what treatment is really necessary or whether a particular medicine is an appropriate choice Requires a balanced approach:
Being over-cautious may deny a beneficial therapy Lack of due caution might harm babies as a consequence of drug exposure

Benefits of treatment need to be weighed against the risks of giving no medication

Note: while the benefits of Tx may be clear, the risks may be largely unknown or unquantifiable For minor conditions, the risks almost always outweigh the (often trivial) benefits

The problem
80% of women use prescribed or OTC drugs during pregnancy
3 8 different drugs (partly prescribed and partly self-medication)

The risks of drug use in pregnancy has lagged far behind advances in other areas of pharmacotherapy Main reasons: epidemiological difficulties in establishing causality and ethical barriers to prospective RCTs

INTRODUCTION Since antiquity, women have been advised to avoid drug usage in pregnancy because of possible harm to the fetus. - Though the uterine environment is priviledged, it is not totally immune to exposure from exogenous substances.

- The overriding concern is the potential effects of medication fetus, on the developing TERATOGENESIS - A Teratogen is defined as a drug or other agent that causes abnormal development: (Rubella virus, Radiation
Drugs)

so-called

Tetratogenesis (Greekword) is the origin or mode of production of a monster or a disturbed growth process involved in the production of a monster (Teras: meaning monster Genesis: meaning origin.

Teratogenesis may be classified as

Morphologic classical teratogenesis

Functional teratogenesis Behavioural teratogenesis * In human being the classic teratogenesis is from approximately day 17 to day 54 post conception.

Factors to consider in Drug prescription in Pregnancy 1. Most drugs, with molecular weight >1000 cross the placenta and are excreted in breast milk. 2. The timing of exposure to a teratogen determines the nature and extent of adverse effects. (a) Pre-embryonic phase (days 0-14 after conception) - Tends to be an all or nothing effect, i.e damage to all or most cells leads to death.

If small no of undifferentiated cells are involved, normal development is likely.

(b) Embryonic phase (3-8weeks) - Most crucial period of organogenesis and therefore the time of greatest theoretical risk of congenital malformation. (c) Fetal phase (9th week to birth) - Fetal growth and development can be impaired by drugs taken during this phase.

Drugs which cross the placenta may have direct actions on the fetus e.g. warfarin may cause Haemorrhage some drugs given close to term may affect the neonate e.g. diazepam or pethidine.

3. Even non prescription drugs such as cough medianes conaining lodides can be harmful

1.

2. 3. 4.

PRINCIPLES FOR PRESCRIBING DURING PREGNANCY AND LACTATION. Drugs to be given only when he indications are clear and specific and the expected benefit to the mother is greater than the risk to the fetus If at all possible, avoid all drugs in the first trimester. Prescribe drugs which have been well tried in pregnancy in preference to newer preparations. Use the smallest effective dose for the

CATEGORISATION OF DRUGS IN PREGNANCY: (According to US, food and Drug Administration) 1. CATEGORY A - Essentially safe, based on controlled studies in pregnancy e.g. L-Thyroxine 2. CATEGORY B - Safe in animals but not confirmed in human studies e.g. Hydrolorothiazide

3. CATEGORY C - Animal studies reveal adverse effects on the fetus (embryocidal, teratogenic) No controlled studies in women or studies in women not available. Use only if potential benefits justifies risk to fetus e.g. Theophylline Nifedipin.

4. CATEGORY D - Positive evidence of human fetal risk - Benefit may be acceptable, e.g. Cytoxan despite risk - Drug may be necessary in life threatening situations. 5. CATEGORY E - Contraindicated in women who are or may become pregnant e.g. Aminopterin oral contraceptive

POTENTIAL FETAL EFFECTS OF SOME DRUGS I.

-

Drugs with human Teratogenic potential

Thalidomide, warfarin, methotrexate, aminopterine, phenytoin, carbamazepine, lithium, ACE inhibitors, Angiotesin receptor blockers, Alcohol.

II. Other Drugs to Avoid drug pregnancy (a) Methimazole - Aplasia cutis, fetal goiter (b) Tetracycline Bone and tooth enamel effects in 2nd trimester. (c) Aminoglycosides affect fetal vestibular and auditory systems. (d) Quinolone antibiotics skeletal abnormalities in rat (e) Immunosuppressives Fetal toxicity

III. Drugs without Conclusive Adverse Effects

Acetaminophen, Penicillin derivatives, cephalosporins, macrolydes (erythromycin) metronidazole, Hydrochlorothiazide calcium channel blockers, Beta blockers Acyclovir, zidovudine.

Drug Usage in Pregnancy can be (1)Prophylactic (2)Therapeutic Prophylactic

To prevent certain adverse consequences during pregnancy. - May require pre-conceptional counselling and informed choice for patients to know the risk to her unborn child if some medications are not taken

e.g. Folic Acid

- Necessary component for proper hematopoiesis. - Deficiency leads to ed risk of neural tube defects Fe. - Vitamin supplement:
Excesses of these vitamins may be bad in pregnancy. e.g Excess B6 causing Neurotoxicity at doses exceeding 200mg/day or Vitamin A may be teratogenic at doses exceeding 8000g/day

Therapeutic Medications Advances in Medicine and technology have led many patients with chronic medical illness to get pregnant and carry their pregnancy successfully to viability and the need to continue their medication in pregnancy is imperative.

Some of the Medications in use include:

(a) Anticoagulants particularly in patient with thromboembolic disease or who are at high risk for thromboembolic disease. Heparin: - parenterally administered anticoagulant - Has a high molecular weight and charge
Does not cross placenta and is not teratogenic No fetal risks Maternal risks -osteopenia or osteoporosis

Warfarin (Coumadin)
- Teratogenic (Warfarin embryopathy) causing nasal hypoplasia, optic atrophy, scoliosis, epiphyseal stippling, mental retardation and microcephaly.

- Contraindicated in first trimesters - Heparin is the preferred anticoagulant in 1st trimester and some few weeks towards delivery.

B. Anticonvulsants Phenytoin (Epanutin): given to control epilepsy is a folic acid antagonist and if used in pregnancy, additional folic acid must also be given. C Sedatives and Analgesics - Morphine and pethidine given within 2-3hrs of delivery will depress the fetal respiratory center.

- Aspirin and other non steroidal antiinflammatory drugs e.g. Indomethacin may inhibit prostaglandin synthesis and produce premature closure of the fetal ductus arteriosus. They may postpone onset of labour. Diazepam - Before delivery will depress the fetal medullary centers and cause loss of the normal baseline variation of he heart rate, and there is hypotonia after delivery.

D. Antihypertensives: Alphamethydopa is a category B drug while others such as bethanidine, guanethidine and hydralazine are category C drugs but seem to have no harmful effect on the fetus.

E. Antibiotics Sulfonamides compete with billirubin for binding sites or serum Albumin and risk of kernicterus. Streptomycin - damages 8th cranial nerve congenital deafness. Penicillin safe in pregnancy

F. Antithyroid drugs cause fetal goitre or hypothyroidism e.g. Thiouracil. G. Cytotoxic and Alkylating Agents may harm the fetus - should not be used in pregnancy H. Alcohol During Preg. When mothers are addicted babies of low birth weight are delivered with chance of neonatal and infant mortality.

- a few will have fetal Alcohol syndrome with characteristic facial appearance with a broad base to the nose, epicanthic folds, a long upper lip and a small lower jaw with mental retardation. I Smoking
harmful to the fetus and gives rise to LBW. CO interferes with 02 transport Nicotine causes vasoconstrive effect of placental bed.

J. *Marijuana * Heroine * Cocaine K. Antiretroviral Therapy

Has become more common place during pregnancy to prevent MTCT. A lot of them are being used in various combination. Long term study is necessary to determine their full effects on the fetus. They all reduce: vertical transmission of HIV. viral load Benefits of its use outweighs their risk.

CONCLUSION Medication use in pregnancy creates a challenge for the health care provider as well as the patient. Judging benefits and risks can be objective but in many instances is largely subjective. Excellent communication between health care providers and recipients is essential to optimize pregnancy outcome. The contribution of effective preconception counselling to improving pregnancy outcome can not be emphasized.