Background The use of indomethacin as a tocolytic agent in pregnantwomen appears to be accompanied by a low incidence of neonatalcomplications. However, the neonatal effects of indomethacinhave been studied primarily in infants born after 32 weeks'gestation. This study was designed to examine the incidenceof neonatal complications in very premature infants.
Methods We identified 57 infants delivered at or before 30 weeks'gestation whose mothers had been treated with indomethacin forpreterm labor and matched them with 57 infants whose mothershad not received indomethacin. The infants in the two groupswere matched for sex, gestational age at delivery (mean [±SD],27.6 ±2.0 weeks), exposure to betamethasone for 24 hoursor more before delivery, and rupture of membranes 24 hours ormore before delivery.
Results There were no significant differences between the twogroups in birth weight, Apgar scores, cord-blood gas values,frequency of multiple gestation, or incidence of respiratorydistress syndrome. The proportion of infants who required exogenoussurfactant was similar, as were ventilator settings at 24 hours,the incidence of chronic lung disease, and the incidence ofsepsis. The infants exposed to indomethacin had a lower urineoutput and higher serum creatinine concentrations during thefirst three days after delivery. More indomethacin-exposed infantshad necrotizing enterocolitis (29 percent vs. 8 percent, P =0.005), intracranial hemorrhage grade II to IV (28 percent vs.9 percent, P = 0.02), and patent ductus arteriosus (62 percentvs. 44 percent, P = 0.05). More indomethacin-exposed infantswith a patent ductus arteriosus required surgical ligation becauseof either a lack of initial response or a reopening of the ductafter postnatal indomethacin therapy (50 percent vs. 20 percentof the unexposed infants, P = 0.05).
Conclusions Antenatal indomethacin therapy for preterm laborappears to increase the risk of serious neonatal complicationsin infants born at or before 30 weeks' gestation.
Indomethacin, a potent inhibitor of prostaglandin synthesis,has been used as a tocolytic agent since the mid-1970s. It crossesthe placenta freely1 and can inhibit the synthesis of prostaglandinsin fetal tissues. The use of indomethacin during pregnancy cancause constriction of the fetal ductus arteriosus and oligohydramniosdue to decreased fetal urine output2,3,4,5.
Indomethacin has profound effects on platelet and neutrophilfunction,6 cerebral, mesenteric, and renal hemodynamics,7,8,9renal tubular function,9 and gastrointestinal oxygen consumptionin both animals and premature infants7. However, the neonatalcomplications most frequently associated with these effects-- sepsis, intracranial hemorrhage, renal dysfunction, and necrotizingenterocolitis2,10 -- have not occurred consistently in controlledtrials of antenatal indomethacin therapy, in which the meangestational age of the newborns was more than 32 weeks11,12,13,14,15.Because these complications occur most frequently among infantsdelivered at or before 30 weeks' gestation, we hypothesizedthat the rarity of neonatal complications after antenatal exposureto indomethacin was due to the advanced gestational age of theinfants studied. We therefore performed a matched retrospectivecohort study to determine the incidence of neonatal complicationsamong infants exposed to indomethacin in utero and deliveredat or before 30 weeks' gestation.
Methods
We identified 57 infants born from 24 through 30 weeks of gestationwhose mothers had been treated with indomethacin for pretermlabor between January 1986 and January 1991. These infants werechosen from a computerized data base containing informationon the mothers, from which we obtained no information aboutneonatal outcome. Each infant was matched with an infant notexposed to indomethacin, according to sex, gestational age atdelivery, exposure to betamethasone for 24 hours or more beforedelivery, premature rupture of membranes 24 hours or more beforedelivery, and year of delivery. Gestational age was determinedas the best obstetrical estimate based on early ultrasonographyor information supplied by the mother and was confirmed by examinationof the infants. Infants with serious congenital anomalies wereexcluded.
The mothers' records were reviewed to determine the total doseof indomethacin administered and the duration of treatment,the lengths of time from the first and last doses to delivery,the duration of any antenatal betamethasone treatment, and whetherthey received treatment with other tocolytic agents. Neonataldata, obtained from the medical records by a separate investigator,included birth weight, Apgar scores, umbilical-cord blood gasvalues, presence or absence of intrauterine growth retardation,incidence of fetal anomalies, use of neonatal surfactant therapy,ventilator settings 24 hours after delivery, and the incidenceof respiratory distress syndrome, chronic lung disease, or neonataldeath. Respiratory distress syndrome was defined as a typicalclinical presentation with characteristic x-ray findings anda need for inspired oxygen at a fraction of 0.25 or more formore than 24 hours. Chronic lung disease was defined as a needfor oxygen or ventilatory support at 28 days of age for reasonsother than apnea.
We specifically examined the infants' charts for neonatal complicationspotentially associated with indomethacin exposure: sepsis, necrotizingenterocolitis, intracranial hemorrhage, patent ductus arteriosus,and renal dysfunction. Sepsis was diagnosed only when the infanthad positive blood or cerebrospinal fluid cultures. The diagnosisof confirmed necrotizing enterocolitis required either bowelperforation or intramural intestinal air (pneumatosis intestinalis)on abdominal radiography. Suspected necrotizing enterocolitiswas defined as persistently abnormal radiographic findings (butwithout pneumatosis intestinalis or free air) with guaiac-positivestools or abdominal distention and symptoms that required thediscontinuation of oral feedings and treatment with antibioticsfor 10 days. All the infants underwent cranial ultrasonographywithin the first week after delivery and weekly thereafter until36 weeks' gestation (postconceptional age) to detect intracranialhemorrhage. The images were graded according to the criteriaof Papile et al16. Patent ductus arteriosus was diagnosed whenthe clinical suspicion of this condition was confirmed by echocardiography.Evaluation of renal function included measurements of serumcreatinine concentrations at 24, 48, and 72 hours of age andof urine output at these same times.
The results were analyzed with two-tailed Student's t-tests,chi-square tests, or McNemar's test, as appropriate. In addition,the categorical outcome variables (presence or absence of necrotizingenterocolitis, intracranial hemorrhage, and patent ductus arteriosus)were analyzed with use of hierarchical logistic regression,and the numerical outcomes (urine output and serum creatinineconcentration) by repeated-measures analysis of variance toexamine the possible effects and interactions with the othervariables, such as multiple gestation, sex, gestational age,birth weight, prolonged rupture of membranes, betamethasoneadministration, cesarean section, and administration of othertocolytic agents, specifically magnesium sulfate, ritodrine,and terbutaline17. The results are presented as means ±SD.P values below 0.05 were considered to indicate statisticalsignificance.
Results
All infants were delivered at or before 30 weeks' gestation.As intended, the groups were similar in weight and gestationalage at birth (according to the pediatric examination) (Table 1).They were also similar in the incidence of multiple gestation,delivery by cesarean section, and use of other tocolytic agents,specifically magnesium sulfate and beta-sympathomimetic drugs(terbutaline or ritodrine). The indication for indomethacintreatment was preterm labor that was unresponsive to these otheragents. Whether indomethacin was used in such cases dependedsolely on the discretion of the attending physician.
Table 1. Characteristics of Infants Delivered at or before 30 Weeks' Gestation According to Antenatal Indomethacin Exposure.
The mothers of the infants exposed to indomethacin received50 to 6000 mg of the drug (median, 425). The infants' mean gestationalage at the time of initial exposure was 25.7 ±1.8 weeks,and the median duration of therapy was 3 days (range, 1 to 79).Sixty-five percent of the mothers received indomethacin for4 days or less, 81 percent for 7 days or less, and 88 percentfor 10 days or less. Sixty-five percent of the mothers receivedtheir last dose of indomethacin within 24 hours of delivery,and 81 percent received their last dose within 48 hours.
All the indomethacin-exposed infants were delivered after spontaneouspreterm labor. In the control group, 3 infants were deliveredafter labor was induced because of maternal preeclampsia; theremaining 54 infants were delivered after spontaneous pretermlabor.
The characteristics of the infants after delivery are shownin Table 2. There were no significant differences in the frequencyof Apgar scores below 6 at five minutes, in the mean umbilical-cordblood pH, or in the incidence of intrauterine growth retardation,minor fetal anomalies, or use of surfactant therapy. The incidenceof respiratory distress syndrome, the ventilator settings at24 hours, and the frequency of the ultimate development of chroniclung disease were similar in the two groups. The rate of culture-provedsepsis was identical in the two groups (19 percent), and thelowest white-cell counts (9700 ±4700 per cubic milliliterin the indomethacin group vs. 8700 ±4800 per cubic milliliterin the unexposed group) and the lowest platelet counts (221,000±100,000 per cubic milliliter vs. 228,000 ±78,000per cubic milliliter) during the first seven days after deliverywere similar. There was a trend toward higher mortality in theindomethacin group (P = 0.15). In addition, the incidence ofdeath due to causes unrelated to necrotizing enterocolitis (fourin the unexposed group vs. six in the indomethacin group) wassimilar in the two groups.
Table 2. Neonatal Characteristics of Infants Exposed to Indomethacin Antenatally and of Unexposed Infants.
The infants exposed to indomethacin had a significantly higherincidence of necrotizing enterocolitis (P = 0.005) (Figure 1),primarily because of the increased incidence of confirmed necrotizingenterocolitis (19 percent in the indomethacin group vs. 2 percentin the unexposed group, P = 0.005). There was a significantindependent association of necrotizing enterocolitis with lowgestational age, low birth weight, and the absence of antenatalbetamethasone therapy (P = 0.025). However, there was no significantinteraction between these or other risk factors and the effectof antenatal indomethacin exposure on the frequency of necrotizingenterocolitis. The excess incidence of necrotizing enterocolitiswas not attributable to the postnatal use of indomethacin, becausethis was comparable in the two groups (47 percent of the indomethacin-exposedgroup received postnatal indomethacin, as compared with 36 percentof the unexposed group). In addition, there was no significantdifference in the incidence of necrotizing enterocolitis inthe group with antenatal indomethacin exposure between the infantswho received indomethacin postnatally (19 percent of whom hadnecrotizing enterocolitis) and those who did not (35 percenthad necrotizing enterocolitis). Among the infants exposed toindomethacin who required surgical exploration for confirmednecrotizing enterocolitis, four had typical intestinal necrosisand three had isolated perforation. The one infant in the controlgroup with confirmed necrotizing enterocolitis did not havea perforation or require surgery. Nine percent of the infantsexposed to indomethacin died of complications of necrotizingenterocolitis, as compared with 2 percent of the infants inthe unexposed group.
Figure 1. Incidence of Necrotizing Enterocolitis among Infants Delivered at or before 30 Weeks' Gestation Who Were Exposed to Indomethacin Antenatally and among Infants Who Were Not Exposed.
The infants who were exposed to indomethacin also had an increasedincidence of grade II to IV intracranial hemorrhage (P = 0.02)(Figure 2), primarily because of an increase in the incidenceof grade II intracranial hemorrhage (21 percent, vs. 6 percentamong the unexposed infants; P = 0.03). There was a significant(P = 0.025) independent interaction among early gestationalage, low birth weight, and intracranial hemorrhage. There wasno significant interaction, however, between these or otherrisk factors and the effect of antenatal indomethacin exposureon intracranial hemorrhage.
Figure 2. Incidence of Intracranial Hemorrhage among Infants Delivered at or before 30 Weeks' Gestation Who Were Exposed to Indomethacin Antenatally and among Infants Who Were Not Exposed.
Cranial ultrasound images were graded according to the criteria of Papile et al.,16 as follows: grade I, subependymal hemorrhage; grade II, intraventricular hemorrhage; grade III, intraventricular hemorrhage with subsequent increase in ventricular size; and grade IV, intraparenchymal hemorrhage. The difference in incidence between exposed and unexposed infants was significant (P = 0.02) for grade II through IV hemorrhage.
The infants exposed to indomethacin in utero had significantlymore renal dysfunction, as evidenced by elevated serum creatinineconcentrations and decreased urine output during the first threedays after birth (Figure 3). The mean serum creatinine concentrationwas significantly higher among the infants exposed to indomethacinon days 1, 2, and 3. Urine output was significantly lower amongthe indomethacin-exposed infants on days 1 and 2, but not day3. Fluid intake did not differ significantly between the twogroups. There was no significant interaction between the otherrisk factors and the effect of antenatal indomethacin exposureon the serum creatinine concentration or urine output.
Figure 3. Serum Creatinine Concentration, Fluid Intake, and Urine Output in Infants Delivered at or before 30 Weeks' Gestation Who Were Exposed to Indomethacin Antenatally and in Unexposed Infants.
The data points represent means ±SD. To convert serum creatinine values to micromoles per liter, multiply by 88.4. Fluid intake and urine output are expressed in milliliters per kilogram of body weight per unit of time.
The infants exposed antenatally to indomethacin had a significantlyhigher incidence of patent ductus arteriosus (62 percent, vs.44 percent among the unexposed infants; P = 0.05) (Table 3).Lower gestational age and lower birth weight were independentlyassociated with a higher incidence of patent ductus arteriosus.Both these risk factors also had a significant (but opposite)effect on the action of antenatal indomethacin on the ductusarteriosus -- that is, the more mature the infant, the morelikely antenatal indomethacin exposure was to be associatedwith patent ductus arteriosus. For example, among infants withbirth weights of 1000 g or less, 68 percent of the infants inthe unexposed group had a patent ductus arteriosus, as comparedwith 71 percent of the infants with antenatal indomethacin exposure.In contrast, among infants with birth weights above 1000 g,the incidence was 15 percent in the unexposed group and 52 percentin the group with antenatal indomethacin exposure (P = 0.03).
Table 3. Incidence of Patent Ductus Arteriosus According to Antenatal Indomethacin Exposure.
The response to neonatal treatment of patent ductus arteriosusalso differed in the two groups. One infant in each group hada patent ductus arteriosus that was not hemodynamically importantand did not require treatment. Seven infants in the indomethacingroup and three in the unexposed group had a patent ductus arteriosusthat was treated with surgical ligation; these infants werenever given indomethacin as neonates. The indication for directsurgical management was abnormal renal function, which was consideredto be a contraindication to indomethacin therapy. Indomethacinwas the most frequent initial form of therapy in the neonatalperiod for a patent ductus arteriosus (used in 76 percent ofthose with a patent ductus arteriosus who had antenatal indomethacinexposure and 83 percent of those without such exposure). Neonatalindomethacin therapy was significantly less successful, however,in closing the patent ductus arteriosus in infants deliveredafter exposure to indomethacin in utero; 50 percent of suchneonates treated with indomethacin after birth ultimately requiredsurgical ligation, as compared with 20 percent in the unexposedgroup (P = 0.05).
None of the complications in the indomethacin group were relatedto the length of time between the last dose of indomethacinand delivery or to the total dose of indomethacin given to themother.
Discussion
We found a significantly increased risk of necrotizing enterocolitis,patent ductus arteriosus, intracranial hemorrhage, and renaldysfunction in preterm infants after the administration of indomethacinto their mothers for treatment of preterm labor. This studywas retrospective and thus subject to unanticipated biases incase selection. The use or nonuse of indomethacin in the motherswas not randomly assigned but depended solely on the decisionof the attending physician to use another agent to treat persistentlabor in women in whom standard tocolytic therapy had failed.Careful review of all maternal charts did not reveal other indicationsfor the use of indomethacin. Under these conditions, 70 percentof the mothers who received indomethacin at our institutionnonetheless delivered at or before 30 weeks' gestation.
Obviously, tocolytic therapy was unsuccessful in both groups.The groups were closely matched in terms of factors known toinfluence neonatal outcome. The fact that we studied very prematureinfants, who are much more susceptible to neonatal complicationsthan infants born later, may explain why other investigatorshave not found similar results. In addition, 81 percent of theinfants in our study were delivered within 48 hours after theirexposure to indomethacin. Such recent exposure would not beexpected among infants delivered closer to term. We did notfind a significant relation between neonatal complications andthe length of time from the last dose of indomethacin to delivery.However, the majority of infants were delivered within a shortinterval after the last dose, making it difficult to examinethis relation. Similarly, the majority of infants were exposedto a narrow range of indomethacin doses, making it difficultto examine the relation of neonatal complications to the amountof indomethacin administered to the mother.
Gastrointestinal complications, including intestinal perforation,are known side effects of indomethacin therapy in adults andnewborn infants18,19. Indomethacin decreases mesenteric bloodflow,20,21,22 blocks autoregulation of oxygen consumption inthe terminal ileum,7 and increases the risk of bowel necrosisafter temporary ischemia23. Prenatal intestinal perforationhas not been reported after exposure to indomethacin. Germ-freerats are resistant to indomethacin-induced small-bowel perforations;thus, the sterile fetal intestine may explain the delayed appearance,after delivery, of gastrointestinal lesions in human neonatesexposed to indomethacin in utero10,24.
The increased incidence of patent ductus arteriosus in the indomethacin-exposedneonates may seem puzzling. Between 60 percent and 80 percentof fetuses exposed to indomethacin antenatally have constrictionof the ductus in utero, often with tricuspid regurgitation4,5.The frequency of this response to antenatal indomethacin exposureincreases with advancing gestational age. The constriction ofthe fetal ductus usually resolves within 24 hours after thediscontinuation of indomethacin5. However, after initial constriction,the ability of the ductus to contract actively in response tooxygen or indomethacin is limited25. This loss of responsivenessprobably reflects early ischemic damage to the inner musclewall. In infants who have had some degree of ductal constrictionin response to indomethacin exposure in utero, the ductus probablyhas an impaired ability to contract in response to the normalincrease in oxygen tension that occurs after birth. This phenomenonmay account for the higher incidence of patent ductus arteriosusamong the neonates in the indomethacin-exposed group. It mayalso explain why indomethacin was more likely to be associatedwith patent ductus arteriosus when it was given later in gestation.In addition, the loss of responsiveness of the ductus may explainwhy these infants had such a poor response to neonatal indomethacintherapy and required surgical ligation to treat the patent ductusarteriosus. The combination of betamethasone and indomethacingiven antenatally causes an even greater constriction of thefetal ductus arteriosus26. Eighty-nine percent of the infantsin this study were exposed antenatally to betamethasone, whichmay have contributed to the loss of ductal responsiveness andthe increased rate of patent ductus arteriosus.
The increase in intracranial hemorrhage among indomethacin-exposedinfants in our study contrasts with reports that indomethacinadministered neonatally reduces the risk of severe intracranialhemorrhage in very premature infants27,28. The postnatal administrationof indomethacin attenuates the cerebral hyperemic response thatnormally follows hypoxia and hypercapnia and in this way isthought to protect the fragile germinal matrix of the preterminfant29. On the other hand, indomethacin inhibits plateletaggregation, and previous studies have indicated an associationbetween intracranial hemorrhage and hemostatic disorders6,30.In addition, maternal ingestion of other nonsteroidal antiinflammatorydrugs has been associated with an increased incidence of intracranialhemorrhage in preterm infants31. Perhaps the extreme changesin fetal intracranial pressure that occur during preterm laborand delivery exacerbate this bleeding diathesis and cause intracranialhemorrhage.
Transient renal dysfunction has been reported as a complicationof the administration of indomethacin in adults, newborns, preterminfants, and fetuses3,8. Our results confirm these earlier findingsand demonstrate that when indomethacin is administered shortlybefore delivery, its renal effects can persist into the neonatalperiod. This alteration in renal function may result in metabolicand volume derangements.
Indomethacin is an effective tocolytic agent12,13,14. Nevertheless,it freely crosses the placenta, interferes with fetal prostaglandinproduction, and alters the normal fetal cardiovascular responseto stress1. In our study, indomethacin appeared to increasethe risk of several of the important complications associatedwith preterm birth. It is possible that a randomized, prospectivetrial of earlier use of indomethacin in the treatment of pretermlabor might demonstrate that its efficacy as a tocolytic agentoutweighs the risk of these complications. The dilemma thatfaces the obstetrician is that the fetuses most in need of effectivetocolysis are also those at highest risk for indomethacin-inducedneonatal complications when tocolysis fails to prevent pretermdelivery.
Supported in part by a grant (HL 46691) from the National Heart,Lung, and Blood Institute and by a gift from Perinatal AssociatesResearch Foundation.
We are indebted to Mr. Paul Sagan for his skillful editorialassistance.
Source Information
From the Cardiovascular Research Institute (R.I.C.) and the Departments of Pediatrics (J.M., R.I.C.) and Obstetrics, Gynecology and Reproductive Sciences (M.E.N., J.A.K.), University of California, San Francisco, and the California School of Professional Psychology, Alameda, Calif. (B.A.B.C.).
Address reprint requests to Dr. Clyman at Box 0544, Rm. 1403 HSE, University of California, San Francisco, CA 94143.
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