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ORIGINAL RESEARCH |
From the Section of Maternal-Fetal Medicine and the Department of Obstetrics and Gynecology, Northwestern Memorial Hospital and Evanston Hospital, Northwestern University Medical School, Chicago, Illinois.
Address reprint requests to: William A. Grobman, MD, MBA Northwestern Memorial Hospital 333 East Superior Street, Suite 410 Chicago, IL 60611 E-mail: w-grobman{at}northwestern.edu
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Abstract |
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Methods: Fifty-six preterm neonates with intraventricular hemorrhage were matched by gestational age with neonates (n = 224) without this morbidity. Maternal and neonatal charts were reviewed to ascertain the type of tocolytic exposure experienced by the neonate. Other maternal and neonatal demographic and outcome data were also abstracted. Results were analyzed using the Student t test, 
2 analysis, and multivariable logistic regression. The number of studied subjects provided 80% power to determine if antenatal exposure to indomethacin was twice as likely among infants with intraventricular hemorrhage.
Results: Univariate analysis revealed that there were no significant differences between the study and control groups with respect to maternal age, parity, or betamethasone exposure. Infants with intraventricular hemorrhage were significantly more likely to be born at an earlier gestational age, a lower birth weight, after maternal chorioamnionitis, after vaginal delivery, and after exposure to either indomethacin alone or a combination of indomethacin and magnesium. Additionally, their neonatal course was significantly more likely to be complicated by sepsis and respiratory distress syndrome. In a multivariable logistic model, only gestational age, chorioamnionitis, vaginal delivery, and respiratory distress syndrome continued to be significantly associated with intraventricular hemorrhage. Indomethacin exposure, either as single-agent (adjusted odds ratio 1.3, 95% confidence interval 0.5, 3.3) or combination tocolytic therapy (adjusted odds ratio 2.0, 95% confidence interval 0.8, 4.8), was not significantly associated with intraventricular hemorrhage.
Conclusion: Indomethacin tocolysis is not associated with an increased risk of intraventricular hemorrhage.
Prostaglandins have an important role in the physiology of uterine contractions.1 Consequently, prostaglandin synthetase inhibitors have been one class of pharmacologic agents used for the treatment of preterm labor. The tocolytic effect of indomethacin, a type of prostaglandin synthetase inhibitor, has been widely studied and found to be clinically equivalent to alternative tocolytic regimens.2,3 In marked contrast to other tocolytic agents, such as magnesium sulfate and ritodrine, the favorable maternal side effect profile of indomethacin further supports its use as a first-line tocolytic agent.4,5
Studies by Ianucci et al6 and Norton et al,7 however, have suggested that the use of indomethacin for the treatment of preterm labor increases the subsequent risk of neonatal intraventricular hemorrhage. These authors base their conclusion on studies in which indomethacin was predominantly administered as part of a multiple tocolytic regimen. It has been shown that multiple tocolytic regimens are used more commonly in women with recalcitrant preterm labor and subclinical chorioamnionitis.8 Because intra-amniotic infection itself is associated with an increased risk of intraventricular hemorrhage,9 the independent association of indomethacin with intraventricular hemorrhage remains uncertain.
Because indomethacin is the preferred tocolytic agent at our institution, our ability to study indomethacin as a single agent and control for combined therapy offers an advantage over prior studies. Thus, we performed a case control study to evaluate the independent association between indomethacin tocolysis and neonatal intraventricular hemorrhage.
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Materials and Methods |
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All neonates who developed intraventricular hemorrhage during the 2 years after the introduction of indomethacin as the first-line tocolytic agent were identified through review of a perinatal database. All infants born at 32 weeks’ gestation or less receive a routine cranial ultrasonography during day 7–10 of life. Neonates delivered at greater gestational ages receive cranial ultrasonography if physical findings, neurologic signs, or laboratory abnormalities appear that are consistent with the occurrence of intraventricular hemorrhage. Diagnosis of intraventricular hemorrhage was confirmed by inspection of the neonatal charts and required ultrasonographic findings as outlined by Papile et al.10 These neonates were matched on a 1:4 basis with control neonates who did not develop intraventricular hemorrhage. Control neonates were chosen by random computer selection from among the population of neonates admitted to the special care nursery without intraventricular hemorrhage who were born during the same time period and within the same gestational age range (24–33 weeks) as the cases.
Maternal charts were reviewed to obtain demographic data such as maternal age, parity, and gestational age at delivery. Antepartum and intrapartum events such as premature rupture of membranes, chorioamnionitis, use of tocolytics, betamethasone exposure, and route of delivery were also ascertained. The only tocolytic regimens used were indomethacin alone, magnesium sulfate alone, or a combination of the two. Combination tocolysis was defined as those cases where magnesium was administered concurrently with indomethacin or sequentially to indomethacin when no further indomethacin could be administered according to protocol. The diagnosis of chorioamnionitis was based on clinical parameters that required two of the following three criteria: fetal tachycardia, maternal temperature of 100.4 F or greater, and uterine tenderness without another identifiable source of infection.
Neonatal information obtained for both groups included birth weight, umbilical cord blood gas values, morbidity (necrotizing enterocolitis, respiratory distress syndrome [RDS], sepsis), and mortality. Neonatal sepsis was defined by the presence of positive blood cultures or by the diagnosis of an attending neonatologist based on a combination of clinical signs and laboratory findings that resulted in antibiotic therapy for at least 10 days. The diagnosis of RDS was made when neonates required at least 24 hours of ventilatory oxygen support in the presence of characteristic clinical and radiographic findings. Necrotizing enterocolitis was diagnosed in those neonates who demonstrated abdominal distention and guaiac positive stools along with radiographic evidence of bowel perforation or intestinal pneumatosis.
An ante hoc power calculation ensured that we would be able to discern at least a two-fold increased risk of exposure to indomethacin in those neonates with intraventricular hemorrhage. Using an 
= .05 and assuming that 20% of controls were exposed to indomethacin, 54 neonates matched with 216 controls were required to achieve a power of 80%. Results were analyzed using the unpaired Student t test, 2 analysis, and Fisher exact test as appropriate. After univariate analysis elucidated the variables that were most strongly associated with the presence of intraventricular hemorrhage (P < .1), multivariable logistic regression was used to determine which of these variables were independently associated with intraventricular hemorrhage. In this final multivariable regression, significance was defined at a P value < .05. All statistics were calculated with Minitab Release 13 (Minitab, Inc., State College, PA).
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Results |
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. There were no differences observed in maternal age, parity, betamethasone exposure, or gender. Infants with intraventricular hemorrhage were more likely to have been born vaginally, at an earlier gestational age, and with a lower birth weight. These pregnancies were also more likely to have been complicated by chorioamnionitis. Neonatal morbidity and mortality data, displayed in Table 2, reveal a greater incidence of sepsis, RDS, and death in those infants with intraventricular hemorrhage.
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, reveals that exposure to indomethacin either alone or in combination with magnesium sulfate was associated with an increased risk of intraventricular hemorrhage. In contrast, multivariable logistic regression, after controlling for the factors most strongly associated with intraventricular hemorrhage in univariate analysis, revealed that exposure to indomethacin tocolysis, either alone or in combination with magnesium sulfate, was not independently associated with intraventricular hemorrhage (Table 4). Variables that continued to be associated with intraventricular hemorrhage were an earlier gestational age at delivery and the presence of chorioamnionitis, vaginal delivery, and RDS.
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Discussion |
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Those pregnancies in which two tocolytic agents are used are more likely to have other characteristics that predispose to the occurrence of intraventricular hemorrhage. For example, it is well established that the risk of intraventricular hemorrhage increases with earlier gestational age at delivery. Pregnancies that are at risk for extreme prematurity are also more likely to receive multiple tocolytic agents. If indomethacin is being used as a second-line agent, it is not the exposure to the indomethacin, but the population that is preferentially being exposed, which leads to an apparent association between indomethacin and intraventricular hemorrhage. The present study demonstrates this confounding effect. When gestational age is in the multivariable model, there is no significant association between indomethacin and intraventricular hemorrhage. However, when gestational age is removed from the model, combination tocolytic therapy becomes significantly associated with intraventricular hemorrhage (adjusted odds ratio 2.4, 95% confidence interval 1.1, 5.7).
Similarly, women with preterm labor that is recalcitrant to tocolysis with one agent are more likely to receive additional tocolytic agents. Subclinical chorioamnionitis has been identified in a significant number of women who develop preterm labor.11 The risk of having subclinical chorioamnionitis is particularly high in the presence of recalcitrant preterm labor.12 Yet, chorioamnionitis is itself associated with an increased risk of intraventricular hemorrhage,9,13,14 and studies by Yoon et al15 and Gomez et al16 suggest a pathogenic mechanism for this association. In the present analysis, chorioamnionitis is again demonstrated to be significantly associated with intraventricular hemorrhage, and indomethacin exposure is not significantly associated with intraventricular hemorrhage after controlling for chorioamnionitis.
Although vaginal delivery was associated with intraventricular hemorrhage, we do not believe this relationship is causal. Other authors have argued that it is not the passage through the birth canal but the underlying processes that culminate in preterm labor that are responsible for this increased risk they have observed. For example, the univariate association between vaginal delivery and intraventricular hemorrhage demonstrated by Hansen and Leviton was no longer evident after adjustment for the presence of fetal vasculitis on pathology specimens.17 Other studies have demonstrated that labor progression into the active phase during a preterm delivery, and not the mode of delivery itself, is most predictive of development of intraventricular hemorrhage.18,19
Results from animal studies and other clinical trials cast doubt on the association between indomethacin and intraventricular hemorrhage. For example, studies of the effect of in utero exposure to indomethacin on the germinal matrix of fetal pigs and beagle pups have shown that indomethacin helps to modulate cerebral blood flow changes in response to hypercarbic insult and encourages germinal matrix maturation.20,21 This action should serve to protect neonates from intraventricular hemorrhage. In fact, substantial clinical evidence supports the protective effect of indomethacin in the preterm neonate. Ment et al22 have shown a significant decrease in the incidence and severity of intraventricular hemorrhage with the use of indomethacin in very low birth weight infants. Ment et al23 have also provided evidence that neonatal treatment with indomethacin is not associated with the extension of a preexisting intraventricular hemorrhage.
This study cannot entirely reject the hypothesis that indomethacin tocolysis is associated with any increased risk of intraventricular hemorrhage. For example, power analysis ensures that a two-fold increase in risk does not exist, but the possibility of a smaller increase remains possible. Also, grades 3 and 4 intraventricular hemorrhage are most significantly related to long-term disability. Because the present study was conducted to explore the relationship between indomethacin and any intraventricular hemorrhage (including grades 1 and 2), a conclusive statement of the association between indomethacin tocolysis and the more severe grades of intraventricular hemorrhage cannot be made.
This study does demonstrate that the association of indomethacin with intraventricular hemorrhage reported in previous studies is likely related to confounding factors and not independently significant. Because indomethacin is as effective as other tocolytic agents, and is also better tolerated, easier to administer, and less expensive than these agents, the present findings support the use of indomethacin as a first-line tocolytic agent. Further evidence in the form of prospective randomized controlled trials is necessary to fully evaluate its safety.
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Footnotes |
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Received October 16, 2000. Received in revised form January 8, 2001. Accepted January 31, 2001.
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2. Zuckerman H, Reiss U, Rubinstein I. Inhibition of human premature labor by indomethacin. Obstet Gynecol 1974;44:787–92.
3. Neibyl JR, Blake DA, White RD, Kumor KM, Dubin NH, Robinson JC, et al. The inhibition of premature labor with indomethacin. Am J Obstet Gynecol 1980;135:1014–9.
4. Morales WJ, Smith SG, Angel JL, O’Brien WF, Knuppel RA. Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor: A randomized study. Obstet Gynecol 1989;74:567–72.
5. Morales WJ, Madhav H. Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: A randomized study. Am J Obstet Gynecol 1993;169:97–102.[Medline]
6. Ianucci TA, Besinger RE, Fisher SG, Gianopolous JG, Tomich PG. Effect of dual tocolysis on the incidence of severe intraventricular hemorrhage among extremely low-birth-weight infants. Am J Obstet Gynecol 1996;175:1043–6.[Medline]
7. Norton ME, Merrill J, Cooper BA, Kuller JA, Clyman RI. Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 1993;329:1602–7.
8. Gardner MO, Owen J, Skelly S, Hauth JC. Preterm delivery after indomethacin: A risk factor for complications? J Reprod Med 1996;41:903–6.[Medline]
9. Salafia CM, Minior VK, Rosenkratz TS, Pezzullo JC, Popek EJ, Cusick W, et al. Maternal, placental, and neonatal associations with early germinal matrix intraventricular hemorrhage in infants born before 32 weeks gestation. Am J Perinatol 1995;12:429–36.[Medline]
10. Papile LA, Munsick-Bruno G, Schaefer A. The relationship between cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr 1983;103:273–7.[Medline]
11. Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992;166:1515–25.[Medline]
12. Gomez R, Ghezzi F, Munoz H, Tolosa JE, Rojas I. Premature labor and intra-amniotic infection: Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol 1995; 22:281–342.[Medline]
13. Alexander JM, Gilstrap LC, Cox SM, McIntire DM, Leveno KJ. Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 1998;5:725–9.
14. Verma U, Tejani R, Klein S, Reale MR, Beneck D, Figueroa R, et al.Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low birth weight neonate. Am J Obstet Gynecol 1997;176:275–81.[Medline]
15. Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, et al. Amniotic fluid interleukin-6: A sensitive test for antenatal diagnosis of acute inflammatory lesion of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995;172:960–70.[Medline]
16. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194–202.[Medline]
17. Hansen A, Leviton MD. Labor and delivery characteristics and risks of cranial ultrasonographic abnormalities among very-low-birth-weight infants. Am J Obstet Gynecol 1999;181:997–1006.[Medline]
18. Anderson GD, Bada HS, Shaver DC, Harvey CJ, Korones SB, Wong SP, et al. The effect of cesarean section on intraventricular hemorrhage in the preterm infant. Am J Obstet Gynecol 1992;166:1091–101.[Medline]
19. Anderson GD, Bada HS, Sibai BM, Harvey C, Korones SB, Magill HL, et al. The relationship between labor and route of delivery in the preterm infant. Am J Obstet Gynecol 1992;158:1382–9.
20. Leffler CW, Busija DW, Fletcher AM, Beasley DG, Hessler JR, Green RS. Effects of indomethacin upon cerebral hemodynamics of newborn pigs. Pediatr Res 1985;19:1160–74.[Medline]
21. Ment LR, Stewart WB, Ardito TA, Huang E, Madr JA. Indomethacin promotes germinal matrix microvessel maturation in the newborn beagle pup. Stroke 1992;23:1132–7.
22. Ment LR, Oh W, Ehrenkranz RA, Philip AG, Vohr B, Allan W, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: A multicenter randomized trial. Pediatrics 1994;93:543–50.
23. Ment LR, Oh W, Ehrenkranz RA, Philip AG, Vohr B, Allan W, et al.Low dose indomethacin and extension of intraventricular hemorrhage. J Pediatr 1994;124:951–5.[Medline]
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