Incidence
• Of women 20–25% report using medications on a regular basis throughout pregnancy.
• Major congenital anomalies occur in 3–4% of live births and 70% of such anomalies have no known cause. It is estimated that 2–3% are due to medications and 1% to environmental toxins.
Drug trials in Pregnancy
• Drug trials are difficult to carry out in pregnancy because of concern over the fetus. As such, many drugs have not been validated for use or safety in human pregnancy.
• Recommendations often rely on data from animal models. The occurrence of thalidomide-associated embryopathy has led to the belief that human teratogenicity cannot be predicted by animal studies.
However, every drug that has since been found to be teratogenic in humans has caused similar effects in animals.
Pharmacokinetics during pregnancy
• Pharmacokinetics is the study of how a drug moves through the body.
• Drug absorption is altered in pregnancy. Gastric emptying and gastric acid secretion are reduced. Intestinal motility is decreased. Pulmonary tidal volume is increased which may affect the absorption of inhaled drugs.
• The volume of distribution changes in pregnancy. Plasma volume rises by 40%, total body water increases 7–8 L, and body fat increases 20–40%. Despite these changes (which would be expected to decrease drug levels), albumin concentrations decline, and free fatty acid and lipoprotein values rise. As a result, protein binding of many drugs is lower in pregnancy, leading to an increase in circulating free (biologically active) drug levels.
• Metabolism and elimination are also altered in pregnancy. High steroid hormone levels affect hepatic metabolism and prolong the half-life of some drugs. Glomerular filtration rate rises 50–60%, thereby increasing the renal clearance of other drugs.
Teratogenicity
• Teratogenicity is the study of abnormal fetal development, and refers to both structural and functional abnormalities.
• With the exception of large molecules (such as heparin), all drugs given to the mother cross the placenta to some degree.
• The effect of a given drug on a fetus depends on dose, time, and duration of exposure, and as yet poorly defined genetic and environmental factors that interact to determine the susceptibility of any individual fetus for structural injury. A fetus is at highest risk for injury during embryogenesis (days 17–54 post-conception).
• Paternal exposure has never been shown to be teratogenic.
Risk categories for drugs in pregnancy
The Food and Drug Administration (FDA) in the USA has defined five risk categories for drug use in pregnancy: A, B, C, D, X.
Category A :
Controlled studies in women fail to demonstrate a risk to the fetus and the
possibility of fetal harm appears remote
Examples: – Vitamin C, folate, L-thyroxine
Category B :
Either animal studies have not demonstrated a fetal risk but there are no controlled
studies in pregnant women, or animal studies have shown an adverse effect that was
not confirmed in controlled studies in women
Examples: – Hydrochlorothiazide, alpha-methyldopa,ampicillin
Category C :
Either studies in animals have revealed adverse effects on the fetus and there are no
controlled studies in women, or there are no controlled studies in animals or women. Only use if potential benefit justifies risk to fetus
Examples:– Theophylline, nifedipine, digoxin, beta-blockers, verapamil, zidovudine (AZT), acyclovir
Category D :
Positive evidence of human fetal risk, but the benefits from use in pregnant women
may be acceptable despite the risk
Examples: – Cytoxan, spironolactone, ACE inhibitors,
methotrexate, phenytoin
Category X :
Positive evidence of animal or human fetal abnormalities, or the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. Contraindicated in women who are or may become pregnant
Examples– Aminopterin, isotretinoin (vitamin A),
radioisotopes, oral contraceptives
Principles of drug use in pregnancy
• Use medications only if absolutely indicated.
• If possible, avoid initiating therapy during the first trimester.
• Select a safe medication (preferably an older drug with a proven
track record in pregnancy).
• Use the lowest effective dose.
• Single-agent therapy is preferable.
• Discourage the use of over-the-counter drugs.
DRUGS NOT CONSIDERED TERATOGENS (safe for fetus)
• Acetaminophen
• Aciclovir
• Antiemetics (e.g. phenothiazines)
• Antihistamines (e.g. doxylamine)
• Aspirin
• Caffeine
• Hairspray
• Metronidazole
• Minor tranquilizers (e.g. fluoxetine)
• Occupational chemical agents
• Oral contraceptives
• Pesticides
• Trimethoprim/sulfamethoxazole
• Vaginal spermicides
• Zidovudine (AZT)
DRUGS WITH PROVEN BENEFIT IN PREGNANCY
• Folic acid (folate)–4 mg/day (10 x RDA) begun 4 weeks prior to conception will
reduce the incidence of neural tube defects by 70–80%
• Zidovudine (AZT)–decreases vertical transmission of HIV
from 25% to 8%
• Acyclovir–200 mg p.o. t.i.d. after 36 weeks’ gestation to women with frequent
recurrent genital herpes infection or first episode primary herpes infection in
pregnancy will reduce the need for cesarean delivery for active herpes in labor
• Iron supplementation–prevents anemia
• Anesthetic agents–pain relief in labor
DRUGS WITH PROVEN TERATOGENIC EFFECTS IN HUMANS (harmful to fetus)
• Androgens
• Angiotensin-converting enzyme (ACE) inhibitors
• Anticholinergic drugs
• Antithyroid drugs
• Coumarin derivatives (e.g. warfarin)
• Carbamazepine (tegretol)
• Cyclophosphamide
• Folic acid antagonists (aminopterin, methotrexate)
• Diethylstilbestrol (DES)
• Lithium
• Phenytoin
• Streptomycin and kanamycin
• Tetracycline
• Thalidomide
• Trimethadione and paramethadione
• Valproic acid
•Vitamin A and its derivatives (e.g. isotretinoin and retinoids)
Illicit and social drug use
Cocaine
• Cocaine is associated with intrauterine fetal growth restriction (IUGR), cerebral infarction, and placental abruption. Reported congenital anomalies (limb reduction defects, porencephalic cysts,
microcephaly, bowel atresias, necrotizing enterocolitis, and longterm behavioral effects) may be secondary to cocaine-induced vasospasm.
• Maternal complications include uterine rupture, hypertension, seizures, and death.
Alcohol
• Fetal alcohol syndrome is characterized by facial abnormalities (midfacial hypoplasia), central nervous system dysfunction (microcephaly, learning disability), and IUGR. Renal and cardiac defects may also occur.
• The risk of anomalies is related to the extent of alcohol use: 10% with rare use, 15% with moderate use, and 30–40% with heavy use (more than six drinks per day). There is no absolute safe level of alcohol use in pregnancy.
Marijuana
• No known teratogenic effect.
• Weak association with preterm birth, IUGR, and subsequent neurodevelopmental delay.
• Cigarette smoke (nicotine and thiocyanate)
• Of pregnant women, 20–30% continue to smoke during pregnancy.
• Adverse effects include decreased fertility as well as increased spontaneous abortion, preterm birth, perinatal mortality, and lowbirthweight infants (200 g decrease in birth weight for every 10 cigarettes smoked per day).
• Neonatal exposure is associated with sudden infant death syndrome, asthma, respiratory infections, and attention deficit disorder.
Caffeine
• No known teratogenic effect.
• Weak association with spontaneous abortion.
Environmental toxins
Radiation
• Associated with spontaneous abortion, learning disability, microcephaly,
and (possibly) malignancy in later life.
• Fetal exposure of >5–10 rad is required for any adverse effect (estimated
fetal exposure from common radiological procedures is
1–3 mrad).
Heat
• Weak association with spontaneous abortion and neural tube defects.
Electromagnetic field
• No known teratogenic effect.