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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology and Epidemiology and Biostatistics, Free University Hospital Amsterdam, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands; and Departments of Obstetrics and Gynecology and Pediatrics, North Western Adelaide Health Service, The University of Adelaide, Adelaide, South Australia.
Address reprint requests to: D. N. M. Papatsonis, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Free University Hospital, De Boelelaan, 1117, 1081 HV, Amsterdam, The Netherlands
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Abstract |
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Methods: We conducted an open randomized multicenter study of neonatal outcome in 185 women who received either oral nifedipine (n = 95) or intravenous (IV) ritodrine (n = 90) for treatment of preterm labor. Secondary outcome measures included neonatal mortality and morbidity, especially neonatal intensive care unit (NICU) admission, respiratory distress syndrome (RDS), and intracranial bleeding.
Results: There were no significant differences in umbilical artery pH values and Apgar scores between groups. Nifedipine was associated with lower admission rates to the NICU (49% versus 66%; odds ratio 0.51, confidence interval 0.28, 0.93) compared with ritodrine, and lower incidences of RDS (21% versus 37%; 0.46, 0.24, 0.89), intracranial bleeding (18% versus 31%; 0.48, 0.24, 0.96), and neonatal jaundice (52% versus 67%; 0.53, 0.29, 0.97). Logistic regression analysis showed that even after correction for gestational age at birth, newborn risk of RDS, intracranial bleeding, or neonatal jaundice was significantly lower in the nifedipine group than the ritodrine group.
Conclusion: Nifedipine for treatment of preterm labor was associated with a lower incidence of neonatal morbidity than ritodrine. That difference appeared to be partly because of the higher tocolytic efficacy of nifedipine and partly because of an intrinsic beneficial effect of nifedipine, or the lack of harmful effects when compared with ritodrine.
We previously reported that nifedipine, a dihydropyridine calcium entry blocker, was more effective in postponing delivery in preterm labor than ritodrine.1 In this study we did a detailed analysis of neonatal morbidity after tocolysis with nifedipine versus ritodrine in preterm labor.
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Materials and Methods |
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Preterm labor was diagnosed as regular objective uterine contractions, ie, at least one every 10 minutes for at least an hour or rupture of membranes. Changes in cervical status (dilatation or effacement) were not obligatory for inclusion. Vaginal examinations were done only in women with intact membranes.
Exclusion criteria included multiple pregnancy, documented intrauterine infection, fetal congenital anomalies, clinical diagnosis of (partial) abruptio placentae, severe fetal growth restriction, and any maternal contraindication to ß-adrenergic drugs, such as diabetes mellitus, cardiovascular disease, hyperthyroidism, or severe preeclampsia.
After stratification for gestational age and state of membranes (intact or ruptured), subjects were assigned randomly to either oral nifedipine or intravenous (IV) ritodrine. Randomization was done separately in each hospital by that hospital’s pharmacist, using sealed opaque envelopes. Envelopes were stratified for gestational age at entry and for intact or ruptured membranes. There were equal numbers of envelopes for ritodrine or nifedipine in each stratum. Envelope numbering within each stratum was generated randomly by computer. The study protocol did not allow therapeutic crossover.
An intent-to-treat analysis was done to compare neonatal outcomes of both drugs. Ritodrine was administered IV according to the protocol of Holleboom et al.2 After stopping IV ritodrine, two of the three hospitals continued treatment with oral slow-release ritodrine (ritodrine retard) 40 mg three times daily until 34 weeks, and one hospital did not. In cases of recurrent preterm contractions, IV ritodrine was administered again. Intravenous or oral ritodrine was continued until 34 weeks’ gestation.
Tocolysis with nifedipine was initiated with an oral loading dose of 10–40 mg in the first hour and a maintenance dose of 60–160 mg of slow-release nifedipine daily until 34 weeks’ gestation. Indomethacin was used in both groups as a second-line tocolytic when contractions did not cease after the maximum dose of nifedipine or ritodrine was reached. The maximum dose of indomethacin was 300 mg a day for 3 consecutive days. Women between 26 and 32 weeks’ gestation received steroids to promote fetal lung maturation unless there was suspicion of intrauterine infection.
Intracranial bleeding was classified as proposed by Volpe.3 Periventricular leukomalacia was classified according to De Vries et al.4 Bronchopulmonary dysplasia was defined as oxygen need on day 28 after a period of mechanical ventilation and a chest x-ray consistent with that diagnosis. Respiratory distress syndrome (RDS) was defined as tachypnea, chest-wall retractions, and oxygen requirement in the presence of a chest x-ray classified as RDS.5 Infants with transient tachypnea, pulmonary edema, and pneumonia were excluded from the RDS category. Patent ductus arteriosus was diagnosed when clinical symptoms were confirmed by cardiac ultrasound. Necrotizing enterocolitis was diagnosed by pneumatosis on abdominal radiograph or by findings during surgery. Neonatal intensive care unit (NICU) treatment was defined as intensive care treatment for newborns less than 30 weeks’ gestation at birth, less than 1 kg at birth, or newborns 
30 weeks or 1 kg at birth who needed assisted mechanical ventilation. Newborns with high-care treatment were excluded from this definition. Phototherapy was given according to clinical guidelines.
The research hypothesis was that nifedipine was more successful than ritodrine in delaying delivery until the end of the first week after tocolytic therapy had started. Based on a 25% difference, we needed a sample of 85 in each group to have a power of 90% with an 
of .05.
Student t test was used to compare gestational ages in both groups, at starting tocolysis and at delivery. Analysis of covariance was done to assess differences in neonatal outcomes between the tocolytic agents, with gestational age at birth as a covariate. Stepwise logistic regression analysis was used to analyze the risk factors for RDS, intracranial bleeding, and neonatal jaundice. Possible risk factors were the tocolytic agent used, steroid use, state of membranes, antepartum blood loss, abdominal complaints, birth weight, and gender. Gestational age was included in all models as a covariate. P < .05 was considered statistically significant.
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Results |
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). The groups were similar with respect to maternal age, gestational age, parity, state of membranes, and dilatation of cervix (in those with intact membranes) (Table 1).
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Ritodrine administration was stopped in 12 of 90 women because of severe maternal side effects (nausea, vomiting, tachycardia, anxiety, and headache). Nifedipine was not stopped in any women. The women in whom ritodrine failed (13.3%) were subsequently treated with nifedipine. Because of the intent-to-treat analysis, the perinatal outcome of those women has been included in the statistical analysis. Among the 12 women in whom ritodrine medication was discontinued, eight of their infants were admitted to the NICU. There were no perinatal deaths among them, three infants developed RDS, one had intracranial bleeding (grade 1), seven had neonatal jaundice, and none had bronchopulmonary dysplasia. Twenty women (22.2%) in the ritodrine group and 26 (27.4%) in the nifedipine group received indomethacin (P = .50).
Table 2 shows the conditions of newborns at birth. Nifedipine was associated with a significantly higher mean gestational age at birth and a higher mean birth weight compared with ritodrine. Table 3 shows neonatal morbidity. Respiratory distress syndrome and intracranial bleeding (all grades) were significantly lower in the nifedipine group than in the ritodrine group. That difference cannot be explained by differences in the use of surfactant in neonates. The mean (± standard deviation) gestational age of newborns treated with surfactant was 27.1 ± 1.2 weeks in the nifedipine group and 28.0 ± 1.9 weeks in the ritodrine group (P = .26). Logistic regression analysis in Table 4 shows that, even after correction for gestational age at birth, nifedipine was associated with significantly lower incidence of RDS than ritodrine. That apparent protective effect of nifedipine was also found for the risk of developing intracranial bleeding or neonatal jaundice.
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Discussion |
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Respiratory distress syndrome is the major cause of neonatal death or severe neonatal morbidity.21 In this study we found that the incidence of RDS was significantly lower in the nifedipine group, despite similar use of corticosteroids antenatally and surfactant postnatally, even after correction for gestational age at birth.
The relationship between intracranial bleeding and obstetric and neonatal factors has been studied by many investigators. Very early preterm birth is an independent risk factor for intracranial bleeding. The lower the gestational age at birth, the higher the incidence and severity of intracranial bleeding.21 Infants born with respiratory complications have an independent association with an increased risk of intracranial bleeding.22,23
Beta-sympathomimetic tocolytic agents increase fetal aortic blood flow and fetal cardiac output, which might be limited to the left ventricle, suggesting redistribution of flow to the upper body and increase in systolic blood pressure.24,25 That rise in blood pressure might increase fetal cerebral blood flow, which can lead to increased incidence of intracranial bleeding in immature fetal brains because of limited cerebrovascular autoregulation.24,25 We found that the overall incidence of intracranial bleeding was significantly lower in the nifedipine group, even after correction for gestational age at birth, which supports other studies that found a significant increase in incidence of intracranial bleeding with ß-mimetic agents.25,26 Not all studies found such significant association between ß-mimetic agents and the incidence of intracranial bleeding.22,27 Our study supports the use of nifedipine as a safe and effective tocolytic agent in the treatment of preterm labor.
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Footnotes |
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Received June 29, 1999. Received in revised form October 12, 1999. Accepted October 15, 1999.
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References |
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2. Holleboom CAG, Merkus JMWM, van Elferen LWM. A loading–dose infusion scheme for intravenous tocolysis with ritodrine: A pilot study. Eur J Obstet Gynecol Reprod Biol 1987;26:119–26.[Medline]
3. Volpe JJ. Intracranial hemorrhage. In: Volpe JJ, ed. Neurology of the newborn. 3rd ed. Philadelphia: WB Saunders Company, 1995: 403–66.
4. De Vries LS, Eken P, Dubowitz LMS. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 1992;49:1–6.
5. Giedion A, Haefliger H, Dangel P. Acute pulmonary x–ray changes in hyaline membrane disease treated with artificial ventilation and positive end–expiratory pressure (PEP). Pediatr Radiol 1973;1:145–52.[Medline]
6. Ferguson JE II, Dyson DC, Schutz T, Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine. Analysis of efficacy and maternal, fetal, and neonatal outcome. Am J Obstet Gynecol 1990;163:105–11.[Medline]
7. Meyer WR, Randall HW, Graves WL. Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med 1990;35:649–53.[Medline]
8. Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br J Obstet Gynaecol 1986;93:933–7.[Medline]
9. Kupferminc M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for supression of preterm labour. Br J Obstet Gynaecol 1993;100:1090–4.[Medline]
10. Bracero LA, Leikin E, Kirshenbaum N, Tejani N. Comparison of nifedipine and ritodrine for the treatment of preterm labor. Am J Perinatol 1991;8:365–9.[Medline]
11. Keirse MJNC. Betamimetic tocolytics in preterm labour. In: Enkin M, Keirse MJNC, Renfrew MJ, Neilson JP, eds. Pregnancy and childbirth module of the cochrane database of systematic reviews, (updated February 1995). London: BMJ Publishing Group, 1995.
12. Harake B, Gilbert RD, Ashwal S, Power GG. Nifedipine: Effects on fetal and maternal hemodynamics in pregnant sheep. Am J Obstet Gynecol 1987;157:1003–8.[Medline]
13. Ducsay CA, Thompson JS, Wu AT, Novy MJ. Effects of calcium entry blocker (nicardipine) tocolysis in rhesus macaques: Fetal plasma concentrations and cardiorespiratory changes. Am J Obstet Gynecol 1987;157:1482–6.[Medline]
14. Furberg CD, Psaty BM, Meyer JV. Nifedipine dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326–31.
15. Pahor M, Guralnik JM, Salive ME, Corti MC, Carbonin P, Havlik RJ. Do calcium channel blockers increase the risk of cancer? Am J Hypertens 1996;9:695–9.[Medline]
16. Pahor M, Guralnik JM, Furberg CD, Carbonin PU, Havlik RJ. Risk of gastrointestinal hemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996;347:1061–5.[Medline]
17. Braun S, Boyko V, Behar S, Reicher–Reiss H, Shotan A, Schlesinger Z, et al. Calcium antagonist and mortality in patients with coronary artery disease. J Am Coll Cardiol 1996;28:7–11.[Abstract]
18. Jick H, Jick S, Derby LE, Vasilakis C, Myers MW, Meier CR. Calcium-channel blockers and risk of cancer. Lancet 1997;349: 525–8.[Medline]
19. Olson JH, Toft Sorensen H, Friis S, McLaughlin JK, Steffensen FH, Nielsen GL, et al. Cancer risk in users of calcium channel blockers. Hypertension 1997;29:1091–4.
20. Ahr HJ, Bomhard E, Mager E, Schlüter G. Calcium channel blockers and cancer: Is there preclinical evidence for an association? Cardiology 1997;88 (Suppl 3):68–72.
21. Robertson PA, Sniderman SH, Laros RK Jr, Cowan R, Heilbron D, Goldenberg RL, et al. Neonatal morbidity according to gestational age and birth weight from five tertiary care centers in the United States, 1983 through 1986. Am J Obstet Gynecol 1992;166:1629–45.[Medline]
22. Levene MI, Fawer CL, Lamont RF. Risk factors in the development of intraventricular haemorrhage in the preterm neonate. Arch Dis Child 1982;57:410–7.[Abstract]
23. Low JA, Galbraith RS, Sauerbrei EE, Muir DW, Killen HL, Pater EA, et al. Maternal, fetal and newborn complications associated with newborn intracranial hemorrhage. Am J Obstet Gynecol 1986;154:345–51.[Medline]
24. Lou HC, Lassen NA, Friis–Hansen B. Impaired autoregulation of cerebral blood flow in the distressed newborn infant. J Pediatr 1979;94:118–21.[Medline]
25. Groome LJ, Goldenberg RL, Cliver SP, Davis RO, Copper RL. Neonatal periventricular–intraventricular hemorrhage after maternal ß–sympathomimetic tocolysis. The March of Dimes Multi-center Study Group. Am J Obstet Gynecol 1992;167:873–9.[Medline]
26. Dolfin T, Skidmore MB, Fong KW, Hoskin EM, Milligan JE, Moore DC, et al. Perinatal factors that influence the incidence of sub-ependymal and intraventricular hemorrhage in low birthweight infants. Am J Perinatol 1984;1:107–13.[Medline]
27. Laros RK, Jr, Kitterman JA, Heilbron DC, Cowan RM, Tooley WH. Outcome of very-low-birth-weight infants exposed to ß-sympathomimetics in utero. Am J Obstet Gynecol 1991;164:1657–65.[Medline]
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