Lyell, Deirdre J. MD1; Pullen, Kristin M. MD1; Mannan, Jana MD2; Chitkara, Usha MD1; Druzin, Maurice L. MD1; Caughey, Aaron B. MD, PhD3; El-Sayed, Yasser Y. MD1
Maintenance tocolysis is continued tocolysis after arrested preterm labor, with the goals of prolonging gestation and improving neonatal outcome. There are several reasons to consider maintenance tocolysis. After an episode of preterm labor, the stimulus for preterm labor may remain, the patient is at increased risk for preterm delivery, and prostaglandins, increased with contractions, can up-regulate oxytocin receptors,1 potentially increasing the risk for preterm delivery.
Nifedipine acts as a smooth muscle relaxant. Nifedipine reduces the influx of calcium into smooth muscle cells by inhibiting voltage-activated calcium channels,2 and it blocks the release of calcium from organelles.3 Both actions result in reduced intracellular free calcium, thus inhibiting calcium-dependent myosin light-chain kinase phosphorylation, and resulting in myometrial relaxation. There are limited data regarding nifedipine as a maintenance tocolytic, and no placebo-controlled trials. The two randomized studies in the literature, which compared nifedipine to no treatment, were not blinded and yielded conflicting results.4,5 Our objective was to estimate whether maintenance nifedipine tocolysis after arrested preterm labor prolongs pregnancy and improves neonatal outcomes.
We conducted a prospective, randomized double-blind trial at the Lucile Packard Children’s Hospital at Stanford University and Santa Clara Valley Medical Center. Patients were offered study participation if they were between 24 weeks and 34 weeks of gestational age, had been in active preterm labor as defined by contractions with cervical change, and the preterm labor had successfully arrested with intravenous magnesium sulfate or oral nifedipine. Other inclusion criteria were six or fewer contractions per hour, intact membranes, cervical dilation less than 4 cm by digital examination, and a maternal age of at least 18 years.
We excluded patients who had signs of placental abruption, placenta previa, a fetal anomaly incompatible with life, triplet or higher-order multiple pregnancies, documented intrauterine infection, or a maternal medical contraindication to ongoing tocolysis. Before study entry, all patients had received two doses of betamethasone, 12 mg intramuscularly 24 hours apart, and antibiotic prophylaxis against group B streptococci.
Randomization was generated by a random numbers table. The trial was double-blinded, and the pharmacies at both institutions maintained blinding and dispensed all drugs. Patients received coated tablets of either 10 mg nifedipine or an identical placebo, and were instructed to take two tablets orally every 6 hours. Treatment was continued until 37 weeks of gestation and was then stopped. If patients were discharged home they continued their study drug on an outpatient basis. Their treating physicians could change the dosing interval of the study drug to every 4 hours based on patient symptoms. Patients who experienced recurrent preterm labor before 34 weeks underwent tocolysis with magnesium sulfate if their membranes were intact and they lacked maternal or fetal contraindications to tocolysis. If recurrent preterm labor was arrested, the patient was restarted on the originally randomized drug regimen. Compliance was assessed based on physician query of patients and pharmacy prescription refills. All patients were enrolled between November 2001 and February 2007.
Our primary outcome was achievement of 37 weeks of gestational age. Secondary outcomes included mean gestational age at delivery, mean delay of delivery, delay of delivery more than 48 hours, 1, 2, 3, and 4 weeks, birth weight, and neonatal morbidity. A composite of neonatal morbidity included respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and death.
Based on our literature review of delay of delivery after an episode of arrested preterm labor among singletons and twins, we estimated a 75% rate of delivery by 37 weeks for the placebo group.4,5 We assumed a 50% reduction in preterm delivery with nifedipine. With a two-tailed alpha of 0.05 and power of 0.8, 33 patients per arm for a total of 66 patients were required.
All data were entered into a Stata 7.0 (Stata Corp., College Station, TX) database. Univariate statistical tests were considered significant with P<.05. Data were analyzed by intent to treat, Fisher exact tests, Student t tests, Mann-Whitney U tests, Kaplan-Meier survival analysis, and multivariable logistic regression to control for potential confounding variables.
We received approval for this study from the Human Subjects Committees at the Lucile Packard Children’s Hospital at Stanford University and Santa Clara Valley Medical Center. All subjects gave informed consent before study participation.
Seventy-one patients were randomly assigned. Two patients were excluded after randomization for being incorrectly enrolled as minors, and one patient was lost to follow-up. (Fig. 1) 68 patients were analyzed: 33 received nifedipine and 35 received placebo.
The two groups were similar with regard to prior preterm birth and gestational age at study entry (Table 1). It is of note that the placebo group had significantly greater cervical dilation and shorter cervical length by digital examination at study entry compared with the nifedipine group (Table 1). There were more twins in the nifedipine group, although this difference did not achieve statistical significance (45% nifedipine compared with 22% placebo, P=.07).
There was no difference in the proportion of patients that achieved 37 weeks: 39% among the nifedipine group and 37% among the placebo group (Table 2). Use of maintenance nifedipine did not prolong gestation, as measured by days from initiation of maintenance nifedipine until delivery. The Kaplan-Meier survival analysis appears similar between groups (Fig. 2) and was not statistically significantly different. There were no differences in delay of delivery for greater than 48 hours or 1, 2, 3, or 4 weeks. When singletons and twins were analyzed as separate groups, there were no differences in delay of delivery (singletons had a mean delay of delivery 31 days with nifedipine and 35 days with placebo, P=.88; twins had a mean delay of delivery 31 days with nifedipine and 27 days with placebo, P=.61). Mean gestational age at delivery was also similar between groups. Episodes of recurrent preterm labor were not different when patients received nifedipine. Outcomes were similar among patients enrolled before 32 weeks and after 32 weeks, including achievement of 37 weeks, gestational age at delivery, and delay of delivery (Table 2).
Outcomes were not altered by the cervical length at study entry, as assessed by digital examination. The 34 patients with a cervical length less than 2 cm attained 37 weeks of gestation equally, whether they received nifedipine or placebo (30.7% nifedipine compared with 23.8% placebo, P=.70); the same was true among the 34 patients with a cervical length 2 cm or more (45% nifedipine compared with 57% placebo, P=.73). Likewise, cervical dilation at study entry did not predict the attainment of 37 weeks of gestation when we controlled for group assignment (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.56–1.62). When we controlled for potential confounders, including the cervical examination at study entry and twin gestation, there was no difference in the likelihood of reaching 37 weeks of gestation (adjusted OR 1.08, 95% CI 0.33–3.48). When we controlled for these potential confounders independently, there were no differences in the likelihood of reaching 37 weeks of gestation; the adjusted OR was 0.73 (95% CI 0.25–2.15) when controlling for cervical examination at study entry, and 1.60 (95% CI 0.55–4.68) when controlling for twin gestation. Linear regression of days delayed was 0.48 (95% CI –10.9 to 9.9).
There were no differences between the two study centers with regard to randomization to nifedipine or placebo, or the proportion of patients that achieved 37 weeks when we controlled for potential confounding variables including cervical examination, twin gestation and randomization assignment.
Twelve patients were induced before 37 weeks, five of whom received placebo and seven of whom received nifedipine. It is standard practice in our institutions to induce patients for preterm premature rupture of membranes (PROM) when they achieve 34 weeks or if there are signs of chorioamnionitis or nonreassuring maternal or fetal status. We do not repeat tocolysis in the setting of preterm PROM.
Patients were induced for the following reasons: preterm PROM at or beyond 34 weeks (four patients: one taking nifedipine, three taking placebo), nonreassuring fetal status with intact membranes (five patients: one placebo, four nifedipine), bleeding (one patient: placebo), and preeclampsia (two patients: nifedipine). We did not detect a significant difference in induction before 34 weeks between the nifedipine and placebo groups. Maintenance nifedipine did not alter neonatal outcomes, including birth weight, incidence of low birth weight, composite and individual neonatal morbidities, and days spent in the neonatal intensive care unit (Table 3).
No patients in the study discontinued medications due to adverse effects or medication intolerance. However, one patient with a twin gestation developed pulmonary edema the same day acute tocolysis was discontinued and the maintenance study drug started. The study drug was unblinded by the Study Pharmacist and found to be placebo. The pulmonary edema was determined to be secondary to the earlier magnesium sulfate acute tocolysis. The patient received no further tocolytics and was eventually delivered for preeclampsia and preterm PROM. Her data were analyzed by intent to treat.
When compared with placebo, maintenance nifedipine tocolysis did not confer a large reduction in preterm birth or episodes of recurrent preterm labor, nor did it delay delivery, improve gestational age at delivery, or improve neonatal outcomes. When those entering the study at less than 32 weeks were examined, the results were unchanged. Given the study sample size, a smaller effect of nifedipine may not have been detected.
We searched the PubMed English-language literature from January 1950 to May 2008 using the key words maintenance nifedipine and placebo and found this to be the only placebo-controlled study of maintenance nifedipine after preterm labor. Two previous nonblinded studies of maintenance nifedipine have been conducted and yielded conflicting results. Carr et al4 randomly assigned 74 patients to nifedipine or no treatment and, similar to our conclusions, found no significant difference in latency. The randomization technique and tocolytic doses were similar to our own. Recurrent preterm labor was treated with intravenous magnesium sulfate or subcutaneous terbutaline; the latter treatment was not used in our study. On the other hand, Sayin et al5 randomly assigned 73 patients to maintenance nifedipine or no treatment once uterine quiescence was achieved after acute tocolysis with intravenous ritodrine and verapamil and found prolonged latency and greater gestational age at delivery with maintenance nifedipine. Neonatal morbidities were not different between groups. The randomization technique was not described, a 2-hour overlap between acute and maintenance tocolytics was used, and nifedipine was given at a dose of 20 mg every 6 hours. The authors postulate that improvement in uterine and placental perfusion from nifedipine may explain the benefits seen, but no data were given regarding the frequency of delivery for problems related to uterine and placental perfusion. Like our own, both studies are limited by relatively small numbers. A Cochrane review of calcium channel blockers for maintenance tocolysis,6 which included only the study by Carr et al,4 concluded that their role in preventing preterm birth is unclear and that well-designed randomized trials of sufficient size and appropriate outcomes are needed.
Most placebo-controlled trials of maintenance tocolysis have examined β-mimetics,7–12 with mixed results. Some have suggested pregnancy prolongation,7 pregnancy prolongation shown in subgroup analysis when terbutaline was initiated before 32 weeks,8 or decreased recurrence of preterm labor,9,10 whereas others have shown no benefit to pregnancy prolongation.11,12 A Cochrane meta-analysis concluded that maintenance terbutaline does not prevent preterm birth, reduce neonatal intensive care unit admission, or improve birth weight, perinatal mortality, or perinatal morbidity.13 Others have concluded that data do not support the routine use of maintenance tocolysis due to a lack of improvement in perinatal outcome.14,15 Adverse effects from β-mimetics are frequent, and may affect maternal compliance.
Although maternal adverse effects occur less frequently with nifedipine tocolysis when compared with β-mimetics,16,17 adverse effects are common and can be significant. Among 100 women who received nifedipine for acute tocolysis, 34% experienced adverse effects, 10% of which were considered severe.18 Adverse effects included headache (24%), shortness of breath (5%), pulmonary edema (5%), and hypotension (5%). Asymptomatic hypotension (blood pressure of 73/30 mm Hg) followed by fetal bradycardia and death of a 26-week potentially compromised fetus was reported after chewed 10-mg loading nifedipine tablets.19 Others have reported clinically significant hypotension after sublingual20 and oral nifedipine (Johnson KA, Mason GC. Severe hypotension and fetal death due to tocolysis with nifedipine. [letter-reply]. BJOG;112:1583). Twenty minutes after oral dosing with nifedipine, diastolic blood pressure decreases by a mean of 11%, and reflex tachycardia is seen.21 Nifedipine’s half-life is 1.35 hours.21 We did not observe clinically significant hypotension or significant morbidities when 20 mg of oral nifedipine was given after arrested preterm labor, but our study was unlikely large enough to identify such risk. Nifedipine should be used with caution during pregnancy.
Maintenance nifedipine tocolysis is a common practice in the United States. In a survey to which 46% of Society for Maternal–Fetal Medicine members responded, 29% reported that they would recommend maintenance tocolysis, of whom 79% reported that nifedipine is their first-line maintenance tocolytic.22 Nifedipine was the second most commonly used tocolytic for acute preterm labor, after magnesium sulfate,22 although delay of delivery, gestational age at delivery, and neonatal outcomes were shown to be similar between the two, with significantly more maternal adverse effects seen with magnesium sulfate.18
Our study has several limitations. Our numbers were relatively small. We were adequately powered to detect a large difference; if a small benefit to maintenance nifedipine exists, we may have missed this. We did not identify any differences between groups based on study entry less than 32 weeks as other studies have suggested, but the number of patients who achieved the primary outcome in both groups was small. Our placebo group had more advanced cervical dilation and effacement at study entry, which could have been a limitation of this study. However, given the fact that this was a negative study, and the placebo group was at higher risk, the more advanced cervical examinations seen in the placebo group only underscores our negative study findings. There were a large number of twins in our study, with a trend toward more twins in the nifedipine group. However, when we controlled for differences in twin gestation, as well as cervical exams, our findings held.
With a preterm birth rate of approximately 12.7% in the United States,23 effective prevention is needed today. However, the American College of Obstetricians and Gynecologists has concluded that “prolonged oral, subcutaneous, or intravenous tocolytic treatment is not effective.”24 Our study of maintenance nifedipine tocolysis did not refute this conclusion.
1. Soloff MS, Jeng YJ, Copland JA, Strakova Z, Hoare S. Signal pathways mediating oxytocin stimulation of prostaglandin synthesis in select target cells. Exp Physiol 2000;85 Spec No:51S–58S.
2. Nayler WG, Poole-Wilson P. Calcium antagonists: definition and mode of action. Basic Res Cardiol 1981;76:1–15.
3. Papatsonis DN, Lok CA, Bos JM, Geijn HP, Dekker GA. Calcium channel blockers in the management of preterm labour and hypertension in pregnancy. Eur J Obstet Gynecol Reprod Biol 2001;97:122–40.
4. Carr DB, Clark AL, Kernek K, Spinnato JA. Maintenance oral nifedipine for preterm labor: a randomized clinical trial. Am J Obstet Gynecol 1999;181:822–7.
5. Sayin NC, Varol FG, Balkanli-Kaplan P, Sayin M. Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor. J Perinat Med 2004;32:220–4.
6. Gaunekar NN, Crowther CA. Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour. The Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD004071. DOI: 10.1002/14651858.CD004071.
7. Brown SM, Tejani NA. Terbulatine sulfate in the prevention of recurrence of premature labor. Obstet Gynecol 1981;57:22–5.
8. Lewis R, Mercer BM, Salama M, Walsh MA, Sibai BM. Oral terbutaline after parenteral tocolysis: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 1996;175:834–7.
9. Creasy RK, Golbus MS, Laros RK Jr, Parer JT, Roberts JM. Oral ritodrine maintenance in the treatment of preterm labor. Am J Obstet Gynecol 1980;137:212–9.
10. Holleboom CA, Merkus JM, van Elferen LW, Keirse MJ. Double-blind evaluation of ritodrine sustained release for oral maintenance of tocolysis after active preterm labour. Br J Obstet Gynaecol 1996;103:702–5.
11. Guinn DA, Goepfert AR, Owen J, Wenstrom KD, Hauth JC. Terbutaline pump maintenance therapy for prevention of preterm delivery: a double-blind trial. Am J Obstet Gynecol 1998;179:874–8.
12. Rust OA, Bofill JA, Arriola RM, Andrew ME, Morrison JC. The clinical efficacy of oral tocolytic therapy. Am J Obstet Gynecol 1996;175:838–42.
13. Dodd JM, Crowther CA, Dare MR, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. The Cochrane Database of Systematic Reviews 2006, Issue 1. Art No.: CD003927. DOI: 10.1002/14651858.CD003927.
14. Sanchez-Ramos L, Kaunitz AM, Gaudier FL, Delke I. Efficacy of maintenance therapy after acute tocolysis: a meta-analysis. Am J Obstet Gynecol 1999;181:484–90.
15. Sanchez-Ramos L, Huddleston JF. The therapeutic value of maintenance tocolysis: an overview of the evidence. Clin Perinatol 2003;30:841–54.
16. 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.
17. Ferguson JE 2nd, 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.
18. Lyell DJ, Pullen KP, Campbell L, Ching S, Druzin ML, Chitkara U, et al. Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial. Obstet Gynecol 2007;110:61–7.
19. van Veen AJ, Pelinck MJ, van Pampus MG, Erwich JJ. Severe hypotension and fetal death due to tocolysis with nifedipine. BJOG: 2005;112:509–10.
20. Impey L. Severe hypotension and fetal distress following sublingual administration of nifedipine to a patient with severe pregnancy induced hypertension at 33 weeks. Br J Obstet Gynaecol 1993;100:959–61.
21. Ferguson JE 2nd, Schutz T, Pershe R, Stevenson DK, Blaschke T. Nifedipine pharmacokinetics during preterm labor tocolysis. Am J Obstet Gynecol 1989;161:1485–90.
22. Fox NS, Gelber SE, Kalish RB, Chasen ST. Contemporary practice patterns and beliefs regarding tocolysis among U.S. Maternal-fetal medicine specialists. Obstet Gynecol 2008;112:42–7.
24. ACOG Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin. Management of preterm labor. Number 43, May 2003. Int J Gynaecol Obstet 2003;82:127–35.