Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin

Heijden, Bert J. van der; Carlus, C.; Narcy, F.; Bavoux, F; Delezoide, Anne‐Lise; Gubler, Marie–Claire

doi:10.1016/0002-9378(94)90073-6

Cited by 94 publications

(43 citation statements)

References 12 publications

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“…Prolonged in utero exposure of human fetuses to high dose NSAIDs was reported by Kaplan et al (23) and van der Heijden et al (24); the newborns all had various degrees of oliguria-anuria with severe renal insufficiency and a high mortality rate. The histological picture of the kidneys described by these two groups of investigators was rather similar with small glomeruli and tubular damage, including glomerular and cortical (micro)cysts and ischemic changes in the deep cortex.…”

Section: Fetal Renal Functionmentioning

confidence: 86%

The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

Drukker

2002

Paediatrics &Amp; Child Health

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OBJECTIVES:To summarize experimental animal data and to provide a limited literature review on the adverse renal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the developing fetus and the maturing newborn. DATA: The experimental data were obtained from anesthetized, ventilated, six-to eight-day-old rabbits that received an intravenous bolus of either acetylsalicylic acid (ASA), ibuprofen (IBU) or indomethacin (INDO). In one set of experiments, ASA was also tested in 12-week-old (young adult) rabbits. Renal function was monitored with inulin and para-aminohippuric acid clearances measuring glomerular filtration rate (GFR) and renal blood flow. The renal vascular resistance was calculated. All three nonspecific cyclo-oxygenase-1 or -2 (COX-1/2) inhibitors caused remarkably similar reversible, oliguric, acute renal failure (ARF). In young adult animals, the side effects were attenuated. The underlying pathophysiology is related to the carefully maintained low GFR of the fetus and the newborn, dependent on a delicate interplay between vasoconstriction (angiotensin II) and vasodilation (prostaglandins [PGs]). When PG-synthesis is inhibited, the vasoconstriction is relatively unopposed, causing ARF. LITERATURE REVIEW: The renal effects of fetal exposure to NSAIDs are discussed, as are new insights into the role of COX-1/2 for a normal nephrogenesis. COX-nil or COX-inhibited animals have long lasting renal structural injury. Fetuses exposed in utero to significant amounts of NSAIDs have at birth various degrees of renal insufficiency and structural renal defects with a very high mortality. CONCLUSIONS: All NSAIDs, both specific and nonspecific COX inhibitors, have renal side effects in the immediate postnatal period and should, therefore, be given with the utmost caution. NSAIDs given during pregnancy for the prevention of toxemia, polyhydramnios and premature labour may affect fetal renal function and structure. In animal experiments, IBU was not less nephrotoxic than INDO, as suggested recently by human premature neonates.

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Section: Fetal Renal Functionmentioning

confidence: 86%

The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

Drukker

2002

Paediatrics &Amp; Child Health

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“…In 1978, Novy (5) documented the occurrence of irreversible renal failure in indomethacin-exposed rhesus monkey fetuses. Since then, reports of the use of nonselective NSAIDs in experimental animals and humans have showed an increased incidence of oligohydramnios as a result of a decrease of fetal renal function (9,11,53,54). In addition to the hemodynamic side effects, renal dysgenesis was reported (9,54).…”

Section: Nimesulide and The Newborn Kidneymentioning

confidence: 99%

“…Since then, reports of the use of nonselective NSAIDs in experimental animals and humans have showed an increased incidence of oligohydramnios as a result of a decrease of fetal renal function (9,11,53,54). In addition to the hemodynamic side effects, renal dysgenesis was reported (9,54). In the embryonic kidney, both isoforms COX1 and COX2 are constitutively expressed, notably in cells undergoing induction and/or morphogenesis (52).…”

Section: Nimesulide and The Newborn Kidneymentioning

confidence: 99%

“…Meanwhile, the use of NSAIDs during pregnancy to treat toxemia, polyhydramnios, or preterm labor and in the immediate postnatal period to induce closure of a symptomatic patent ductus arteriosus is increasing (1)(2)(3)(4). However, side effects that affect mainly the cerebral, mesenteric, and renal microcirculations have been reported in fetuses and neonates (5)(6)(7)(8)(9)(10), and NSAID-associated pulmonary hypoperfusion and persistence of fetal circulation may also compromise the newborn renal function (4,11).…”

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confidence: 99%

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Nimesulide, a Cyclooxygenase-2 Preferential Inhibitor, Impairs Renal Function in the Newborn Rabbit

et al. 2004

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Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 g/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 g · kg Ϫ1 · min Ϫ1 infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (Ϫ5, Ϫ23, and Ϫ44%), GFR (Ϫ12, Ϫ23, and Ϫ47%), and renal blood flow (Ϫ23, Ϫ23, and Ϫ48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period. Because of the role of prostaglandins (PGs) in the genesis of labor (term or preterm), nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been used as tocolytic drugs for several decades. Meanwhile, the use of NSAIDs during pregnancy to treat toxemia, polyhydramnios, or preterm labor and in the immediate postnatal period to induce closure of a symptomatic patent ductus arteriosus is increasing (1-4). However, side effects that affect mainly the cerebral, mesenteric, and renal microcirculations have been reported in fetuses and neonates (5-10), and NSAID-associated pulmonary hypoperfusion and persistence of fetal circulation may also compromise the newborn renal function (4, 11).It has been claimed that selective cyclooxygenase-2 (COX2) inhibitors could have the same curative effects as nonselective NSAIDs without the deleterious side effects attributed to COX1 inhibition. Therefore, the use of the COX2-preferential NSAID nimesulide (12, 13) has been proposed for tocolysis in humans (14). In a case report, Sawdy et al. (14) found no effect of nimesulide administered from the 16th to the 34th week of gestation on the renal and ductal functions of the fetus. Doppler flow indices for the ductus arteriosus and amniotic fluid index remained normal, and the infant was born with no congenital abnormalities and an uncomplicated neonatal course (14). However, recent data reporting severe oligohydramnios (15)

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“…In mice with a null mutation of the gene for PGHS-2, there is a severe reduction in the number of functional nephrons developed in the fetal kidney (9). Administration of indomethacin, an inhibitor of prostaglandin synthesis, to women in threatened preterm labor also results in abnormalities in glomerular and tubular morphology in the fetal kidney and a loss of fetal and neonatal urine production (10,11). Similarly, chronic suppression of prostaglandin synthesis in the pregnant Rhesus monkey during late gestation resulted in fetal renal dysgenesis (13).…”

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confidence: 99%

Placental Restriction Increases the Expression of Prostaglandin Endoperoxide G/H Synthase-2 and EP2 mRNA in the Fetal Sheep Kidney during Late Gestation

et al. 2002

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Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin

Cited by 94 publications

References 12 publications

The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

Nimesulide, a Cyclooxygenase-2 Preferential Inhibitor, Impairs Renal Function in the Newborn Rabbit

Placental Restriction Increases the Expression of Prostaglandin Endoperoxide G/H Synthase-2 and EP2 mRNA in the Fetal Sheep Kidney during Late Gestation

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