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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 infants found a highly significant association between PPHN and the use of aspirin or other NSAIDs during pregnancy. Short-term courses (such as 48 hours) of NSAIDs for tocolysis have not been associated with PPHN.

Continuous exposure to NSAIDs over at least several days during the third trimester has been related to fetal renal toxicity, as evidenced by a decrease in amniotic fluid. Although the renal toxicity is usually reversible, exposure to NSAIDs near delivery may result in poor neonatal outcomes.

Two recent studies have found a significant relationship between the use of NSAIDs in early gestation and spontaneous abortions. In a 2001 Danish study, a significant association was found in 63 women between the use of NSAIDs early in gestation and spontaneous abortion. The odds ratio was highest when drug exposure occurred close to the miscarriage, and decreased as the interval from exposure to the adverse event increased.

The second report, a prospective study published in August, involved more than 1,000 women in Northern California who were enrolled after they had a positive pregnancy test, at a median gestational age of 40 days. The risk of miscarriage in 53 women who reported use of NSAIDs--excluding aspirin--around conception or during pregnancy was 80% higher than that of 980 women who did not use NSMDS or aspirin.

The strongest association was found when NSAIDs were used close to conception or when they were used for more than 1 week. Use of aspirin around conception by 22 women was also related to miscarriage, but the association was weaker because of the small number of women (BMJ 327[7411]:368, 2003).

Although more studies are needed to confirm the hypothesis that NSAIDs cause miscarriage, the available data suggest that clinicians should counsel women of reproductive age to avoid all NSAIDs (including aspirin) around the time when conception might occur through the end of the first trimester. Further, pregnant patients should he counseled to avoid NSAIDs during the last 4 months of gestation because of the proven risk of fetal toxicity.

GERALD G. BRIGGS is pharmacist clinical specialist, Women's Hospital, Long Beach Memorial Medical Center; clinical professor of pharmacy, University of California, San Francisco; and adjunct professor of pharmacy, University of Southern California, Los Angeles. He is also coauthor of the reference book "Drugs in Pregnancy and Lactation."