Nonsteroidal anti-inflammatory drugs.(Drugs, Pregnancy, And Lactation)

Nonsteroidal anti-inflammatory drugs epitomize the well-known characterization of drugs as double edged swords, as they have both beneficial and harmful edges. During pregnancy, the harmful edge primarily relates to embryonic/fetal toxicities such as premature closure of the ductus arteriosus, renal toxicity, and spontaneous abortion.

There are 21 different NSAIDs or the market (including the prototypical aspirin), which are marketed under more than 30 different brand names and as numerous generic brands. Three NSAIDs, excluding aspirin, are available as over-the-counter products. Indications for NSAIDs encompass analgesia, inflammation, fever, prevention of cardiac disease, dysmenorrhea, tocolysis, and pharmacologic closure of patent ductus arteriosus in premature infants.

The therapeutic effects of NSAIDs are mediated through the inhibition of the cyclooxygenase-2 (COX-2) enzyme, which is irreversible with aspirin but reversible with other NSAIDs. The newer COX-2 inhibitors--celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra)--are promoted as having fewer adverse effects, such as GI toxicity and a reduced antiplatelet effect.

NSAIDs do not appear to be human teratogens. In some animal species, aspirin has been associated with a slight increase in malformations, including ventricular septal defect, midline defects (such as gastroschisis), and diaphragmatic hernia. Other NSAIDs have also been associated with anomalies, such as oral clefts, vertebral abnormalities, and other skeletal defects in animals.

But because of the omnipresence of aspirin and other NSAIDs, combined with the fact that most birth defects have no known cause, a low-level association with congenital malformations cannot be excluded.

The use of NSAIDs during pregnancy may be related to significant embryonic/fetal toxicity. Until recently, the major toxicity associated with exposure to NSAIDs during pregnancy was thought to be premature closure of the ductus arteriosus in utero. This effect is related to the dosage and duration of NSAID use and gestational age. For example, this risk is associated with NSAID use during the third trimester, beginning as early as 27 weeks and increasing markedly at 27-32 weeks.

The consequences of premature constriction of the ductus arteriosus may be persistent pulmonary hypertension of the newborn (PPHN), a severe effect that can be fatal. A 1996 case-control study of 103 ...