Chapter 32: Pregnancy and Lactation: Therapeutic Considerations

INTRODUCTION

• Resources on the use of drugs in pregnancy and lactation include the Food and Drug Administration (FDA) categorization system (A, B, C, D, and X), the primary literature, tertiary compendia, textbooks, and computerized databases (eg, www.motherisk.org and www.toxnet.nlm.nih.gov).

PHYSIOLOGIC AND PHARMACOKINETIC FACTORS

• The duration of pregnancy is approximately 280 days (measured from the first day of the last menstrual period to birth). Pregnancy is divided into three periods of three calendar months (ie, trimesters).

• Drug absorption during pregnancy may be altered by delayed gastric emptying and vomiting. An increased gastric pH may affect absorption of weak acids and bases. Hepatic perfusion increases. Higher estrogen and progesterone levels may alter liver enzyme activity and increase elimination of some drugs but cause accumulation of others.

• Maternal plasma volume, cardiac output, and glomerular filtration increase by 30% to 50% or higher during pregnancy, possibly lowering the plasma concentration of renally cleared drugs. Body fat increases; thus, volume of distribution of fat-soluble drugs may increase. Plasma albumin concentrations decrease; thus volume of distribution of highly protein bound drugs may increase. However, there may be little change in serum concentration, as these unbound drugs are more rapidly cleared by the liver and kidneys.

• The placenta is the organ of exchange between the mother and fetus for drugs. Drugs with molecular weights less than 500 Da transfer readily, drugs with molecular weights from 600 to 1000 Da cross more slowly, and drugs with molecular weights greater than 1000 Da (eg, insulin and heparin) do not cross in significant amounts.

• Lipophilic drugs (eg, opiates and antibiotics) cross more easily than do water-soluble drugs. Certain protein-bound drugs may achieve higher plasma concentrations in the fetus than in the mother.

DRUG SELECTION DURING PREGNANCY

• The incidence of congenital malformation is approximately 3% to 6%, and it is estimated that less than 1% of all birth defects are caused by medication exposure.

• Adverse effects on the fetus depend on drug dosage, route of administration, and stage of pregnancy when the exposure occurred.

• Fetal exposure to a teratogen in the first 2 weeks after conception may have an “all or nothing” effect (ie, could destroy the embryo or have no ill effect). Exposure during organogenesis (18–60 days postconception) may cause structural anomalies (eg, methotrexate, cyclophosphamide, diethylstilbestrol, lithium, retinoids, thalidomide, some antiepileptic drugs [AEDs], and coumarin derivatives).

• Exposure after this point may result in growth retardation, central nervous system (CNS) or other abnormalities, or death. Nonsteroidal anti-inflammatory drugs (NSAIDs) and tetracycline derivatives are more likely to exhibit effects in the second or third trimester.

• Principles for drug use during pregnancy include (1) selecting drugs that have been used safely for a long time; (2) prescribing doses at the lower end of the dosing range; (3) eliminating nonessential medication and discouraging self-medication; and (4) avoiding medications known to be harmful.

  ...