NSAIDs have gained popularity as a pediatric treatment for pain and fever. However, these drugs may still be associated with some important risks. In the March WMSHP newsletter, Renee Marana, Pharm.D., a Pharmacy Practice Resident at Bronson Methodist Hospital, writes of the use of NSAIDs in neonatal patients.

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NSAIDs in Neonates: Are They Safe?

Renee Marana, Pharm.D.

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Pain and fever are common symptoms in neonates for which effective treatments are necessary.¹ Neonates may experience pain after procedures or related to underlying conditions. Acetaminophen is often used first line to treat pain and fever, although physicians, nurses, and families often find the need for additional analgesics and/or antipyretics. This is usually when nonsteroidal agents are considered.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) has become routine for adults and children in the management of pain, and NSAIDs have gained popularity for the treatment of fever secondary to the association of Reye syndrome with aspirin.¹ NSAIDs are also commonly used in neonates for closure of patent ductus arteriosus. Although generally considered relatively safe agents, NSAIDs are not without their risks, especially when used during the neonatal period. Overall, there is a lack of data concerning the use of NSAIDs in the neonatal population for purposes other than closure of the ductus arteriosus.

NSAIDs inhibit the cyclooxygenase enzyme, which leads to decreased synthesis of prostaglandins. Prostaglandins are important for the healthy development of neonates. They are involved in the development of numerous organ and physiologic systems such as the sleep cycle, cerebral blood flow, renal hemodynamics, thermoregulation, hemostasis, and the pulmonary, central nervous, and cardiovascular systems.¹ There is evidence that the proper genesis of these systems may be adversely affected by NSAID exposure in utero and during the neonatal period.¹

Therefore, interfering with prostaglandin synthesis with the use of NSAIDs may expose the newborn child to unique developmental risks. There have been numerous reports of nephrotoxicity in neonates that were exposed to NSAIDs at an early age.³ Although indomethacin appears to have the most effect on renal blood flow, other NSAIDs, such as ibuprofen, are also associated with decreased renal function.⁴ When assessing the increased risk for bleeding, ketorolac has been associated with the most pronounced effect, although other NSAIDs also increase the risk of bleeding.²

The NSAIDs are also associated with adverse effects on the gastrointestinal (GI) system, such as abdominal pain and ulceration. In response to adverse GI effects came the development of the cyclooxyenase-2 (COX-2) inhibitors. Although they are relatively safe to use in adults, safety and efficacy have not been evaluated in neonates. The COX-2 enzyme is also involved in the development of many organ systems, and its inhibition may lead to a prothrombotic state.¹

NSAIDs should be used cautiously in infants with underlying hepatic dysfunction, impaired renal function, hypovolemia or hypotension, coagulation disorders, thrombocytopenia, or active bleeding from any cause.^2,3 It is important to be aware of the possible adverse reactions caused by NSAIDs so that proper monitoring can be performed and the agent can be discontinued, if needed.²

When the need for an analgesic or antipyretic arises in the neonatal population, many factors must be considered before choosing a non-steroidal agent. Intermittent doses of a non-steroidal may at times be needed and appropriate, although regular scheduled use of these agents is usually not indicated. It has been stated that NSAIDs should be used with extreme caution in infants. Other agents, such as acetaminophen, and narcotic agents should be used preferentially for fever and pain. Neonates that do receive NSAIDs should be monitored closely for adverse effects on the kidneys, platelets, hemostasis, and other organ systems.

References:

1. Morris JL, Rosen DA, Rosen KR. Nonsteroidal anti-inflammatory agents in neonates. Paediatr Drugs 2003;5:385-405.
2. Kokki H. Nonsteroidal anti-inflammatory drugs for postoperative pain: a focus on children. Paediatr Drugs 2003;5:103-23.
3. Cuzzolin L, Dal Cere M, Fanos V. NSAID-induced nephrotoxicity from the fetus to the child. Drug Saf 2001;24:9-18.
4. Pezzati M, Vangi V, Biagiotti R, et al. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. J Pediatr 1999;135:733-8.