Drug Safety In Pregnancy

13.3.06

Primum non nocere ("First, do no harm").
• Mother.
• Child.

Adverse drug reactions
• Appreciably HARMFUL of UNPLEASANT reaction, resulting from intervention related to USE of medicinal product, which predicts hazard from future administration and warrants prevention or specific TREATMENT, or ALTERATION of dosage regimen, or WITHDRAWAL of product.
• Common.
• 6.2% of all hospital admissions.
• Occupy seven 800-bed hospitals in UK.

Drug safety in pregnancy
• Pre-existing disorders eg. epilepsy.
• Infections eg. urinary tract infections.
• Disorders of pregnancy.
• Treatment of foetus.

Physiological changes in pregnancy
Absorption…
• Decrease in intestinal motility.
• Decreased gastric emptying.
• Emesis/reflux - decreased absorption.

Distribution…
• Increased plasma volume by 45% (32 weeks).
• Total body fat increased.
• Protein concentration decreased.
• Uterine blood flow increased (<1% to 16-25%).

Excretion…
• 50% increase in glomerular filtration rate by mid-pregnancy.
• Increased excretion of drugs, increased dose requirements.

Bacteriuria in pregnancy…
• 6% of normal pregnant women have asymptomatic bacteriuria.
• 23-40% of these will develop acute pyelonephritis.
• Screening at initial test.
• For E. coli, commonly.

Treatment…
• Asymptomatic.
-Trial of single-dose therapy.
-If fails, 7-day course.
• Safe: penicillins and nitrofurantoin.
• Contraindicated: quinolones, tetracycline and trimethoprim.
• Symptomatic UTI: 1-2% pregnant women.
• Prevent complication to mother and foetus.
• Prevent recurrence.
• Ampicillin 10-14 day course.

Adverse effects of penicillins
• Nausea.
-Pregnancy can cause nausea.
-UTI may cause nausea.
-Drug can cause nausea.
• Diarrhoea.
-Vary in severity.
-Mild to fulminant colitis.
• Rash.

Causality
• Pregnancy-related?
• Disease-related?
• Drug-related?
• Temporal relationship.
• Rechallenge.
• Exclusion of other causes.
• Previous reports.
• ALWAYS CONSIDER DRUGS IN DIFFERENTIAL DIAGNOSIS OF NEW SYMPTOMS.

Placental circulation

Placental transfer
• Molecular weight of drug <500 daltons.
• Lipid solubility.
• Degree of ionisation of drug.
• Extent of plasma protein binding.
• Type I (intermediate).
-Equal concentrations.
-Complete transfer profile.
• Type II (most unsafe for foetus).
-Higher foetal than maternal plasma concentrations.
• Type III (safest for foetus).
-Higher maternal concentrations.
-Incomplete transfer profile.

Teratogenicity
• Regard every drug as being potentially teratogenic.
• 1-5% all congenital anomalies caused by drugs.
• Thalidomide disaster.
• Yellow card adverse drug reaction reporting scheme.

Yellow cards
• Introduced in 1964.
• 500,000 reports.
• ≈20,000 reports per year.

Screening for teratogenicity…
• Animals used as models for man.
• 2 species (rat/mouse + rabbit).
• 3 dose levels.
• Period of organogenesis.
• Males tested for effect on fertility.
• Females administered drug in third trimester to assess effects on foetal growth.

Stage of pregnancy…
• Period of organogenesis.
• Late stages may lead to foetal growth retardation and/or mental retardation.

Most teratogenic drugs during pregnancy:
• Alcohol.
• Anticonvulsants.
• Thalidomide.
• Corticosteroids.
• Vitamin A and derivatives.

Sources of information
• BNF.
• Drug information centres.
• National Teratology Information Centre, Newcastle.

Prescribing in pregnancy
• Disease pre-pregnancy.
-Does drug therapy need to be continued?
-Does it need to be altered?
• Try non-drug treatment first.
• Avoid multiple drugs.
• Select safest and most efficacious drug.
• Dose changes may be necessary.

Adverse drug reactions in pregnancy
• Consider stopping drug.
• Treat mother.
• If harm to foetus suspected, get specialist advice.
• Communication with mother.
• Report adverse reaction.