Fox, Nathan S. MD; Gelber, Shari E. MD, PhD; Kalish, Robin B. MD; Chasen, Stephen T. MD
Preterm birth is a major cause of neonatal morbidity and mortality. Tocolytics are used to prevent preterm birth or to prolong gestation, yet there is limited evidence supporting their efficacy in improving neonatal outcomes.1–5 Currently, there is no clear first-line tocolytic for the management of preterm labor, and the choice is dependant on clinical circumstance and provider preference.6 Consequently, decisions regarding tocolysis are left to much debate. Recently, the use of magnesium sulfate has been called into question because of its ineffectiveness and possible associated harms.7 The effect of these studies and recommendations on U.S. obstetricians’ practice patterns has not been addressed in large studies. In a recent review of the practice preferences of 20 U.S. maternal–fetal medicine specialists, most used tocolytics in the setting of preterm labor, with magnesium being the most commonly preferred first-line agent.8 Another study of tocolytic use among Canadian obstetricians and gynecologists reported that, in 2004, 92% prescribed tocolytics for women with signs and symptoms of preterm labor; indomethacin was the most commonly prescribed first-line tocolytic (47.5% of respondents).9
Additionally, there are different settings in which tocolytics could be prescribed: acute preterm labor, maintenance tocolysis after arrested preterm labor, repeat acute preterm labor, and preterm premature rupture of membranes (PROM). It is possible that decisions regarding tocolytic use could vary based on the indication. Finally, there are no published reports documenting the association between decisions regarding tocolytic use and physician demographics such as age, location of practice, and type of practice.
The purpose of this study was to estimate tocolysis practice patterns among a large group of U.S. maternal–fetal medicine specialists. Our hypothesis was that practice patterns would vary greatly, would depend on the specific indication for tocolysis, and would vary based on physician demographics.
We conducted a mail-based survey of all Society for Maternal–Fetal Medicine (SMFM) members with U.S. addresses. An initial mailing was sent in June 2007, and a second mailing was sent to nonresponders 3 months later. The SMFM mailing list is available to SMFM members for an administrative fee and is updated regularly. Weill Cornell Medical College Institutional Review Board approval was obtained before mailing any surveys.
The survey consisted of multiple-choice style questions based on specific clinical scenarios. Respondents were asked about the use of tocolytics in five separate clinical scenarios: 1) acute preterm labor at 26 weeks; 2) maintenance tocolysis after arrested preterm labor at 26 weeks; 3) repeat acute preterm labor at 28 weeks; 4) preterm PROM without contractions at 26 weeks; and 5) preterm PROM with contractions at 26 weeks. The exact wording of each scenario is detailed in Table 1.
In our experience, decisions regarding tocolytics are sometimes made by the obstetrician and patient together. For example, an obstetrician may determine that there is not enough evidence to support a firm recommendation for tocolysis but that it would not be unreasonable to attempt it. In this setting, the obstetrician may discuss the possible risks and benefits and defer to the patient’s decision. Or, the obstetrician may believe tocolysis to be ineffective, but also relatively harmless, and would agree to tocolysis if the patient desired. Therefore, when designing the multiple-choice options regarding attitudes toward tocolysis in each scenario, we offered the following three options: 1) I would recommend it; 2) I would not recommend it, but if the patient desired it, I would prescribe a tocolytic; and 3) I would not recommend it, and if the patient desired it, I would not prescribe a tocolytic. Respondents who selected the first or second option were asked to identify their first-line tocolytic agent for three of the scenarios. Additionally, respondents were asked to select how much benefit (none, minimal, moderate, significant) and how much risk (none, minimal, moderate, severe) was associated with tocolysis for each of the five scenarios.
Respondents also were asked a number of demographic questions regarding year and location of training (U.S. state), practice style and location, age, gender, and local neonatal intensive care unit level. Geographic location was converted from U.S. state to region based on the U.S. Census Bureau definition of the four regions in the United States (Northeast, Midwest, South, and West).
Fisher exact test and χ2 were used for categorical variables, and Student’s t test was used for continuous variables. Multiple logistic regression was used to adjust for confounding variables (SPSS 12.0 for Windows, copyright 1989–2003, Chicago, IL). Multiple responses to the same question and responses left blank were censored.
A total of 1,874 SMFM members were identified and mailed questionnaires. Sixty-two questionnaires were undeliverable, leaving a total study population of 1,812. A total of 827 questionnaires were returned, for a response rate of 46%. Twelve respondents indicated they had retired or did not practice obstetrics. Our data, therefore, are from 815 SMFM members. The demographics of the respondents are shown in Table 2. Compared with the entire survey population, respondents had a similar gender breakdown (59% male, 41% female versus 61% male, 39% female) and geographic distribution (27% Northeast, 20% Midwest, 29% South, 24% West versus 27% Northeast, 20% Midwest, 31% South, 22% West).
Table 3 describes respondents’ recommendations for tocolysis. Ninety-six percent of respondents indicated they would recommend tocolysis in the setting of acute preterm labor at 26 weeks, whereas fewer would recommend tocolysis for the other indications. As we predicted, many respondents indicated they would not recommend a tocolytic but would prescribe one if the patient desired. This was true for 50%, 43%, and 42% of respondents who did not recommend tocolysis for acute preterm labor, repeat acute preterm labor and maintenance tocolysis, respectively. In the setting of preterm PROM, however, respondents appeared to be more firm with their recommendations. Only 25% and 21% of respondents who did not recommend tocolysis for preterm PROM without and with contractions, respectively, would agree to tocolysis if the patient desired.
In the setting of acute preterm labor and repeat acute preterm labor, the most common first-line tocolytic was magnesium, followed by nifedipine and indomethacin. For maintenance tocolysis, however, nifedipine was the most common tocolytic used, followed by terbutaline. Among those who recommended terbutaline for maintenance tocolysis (n=53), the route of administration was oral in 61%, subcutaneous pump in 29%, repeat subcutaneous injections in 4%, and a combination of the above in 6%.
A total of 80% of respondents indicated that there was moderate or significant benefit to tocolysis in the setting of acute preterm labor at 26 weeks. Fewer responded similarly for the other indications (42%, 29%, 28%, and 18% for preterm PROM with contractions, repeat acute preterm labor, preterm PROM without contractions, and maintenance tocolysis, respectively). In all five scenarios, the majority of respondents indicated there was minimal or no risk associated with tocolytics (82%, 81%, 79%, 61%, and 55% for acute preterm labor, maintenance tocolysis, repeat acute preterm labor, and preterm PROM without and with contractions, respectively).
In the setting of repeat acute preterm labor at 28 weeks, 21% indicated they would recommend another single course of corticosteroids, 25% indicated they would not recommend another course of corticosteroids but would administer them if the patient desired them, and 54% indicated they would not recommend another course of corticosteroids even if the patient desired them.
We evaluated demographic characteristics to identify those associated with the recommendation for tocolysis. We did not find any differences in the setting of acute preterm labor, but the number of respondents who did not recommend tocolysis was very small, making statistical significance unlikely. For the other four scenarios with more varied recommendations, respondents who were older, in practice longer, and who had a nonacademic practice were significantly more likely to recommend tocolysis (Table 4). Tocolytics were used more commonly in the Western region, but this had statistical significance only for maintenance tocolysis. Gender was not associated with the recommendation for tocolysis. To identify demographic characteristics independently associated with the recommendation for tocolysis, we performed a multiple logistic regression analysis. Controlling for age, gender, years since residency training, and practice type (academic, nonacademic), having a nonacademic practice was independently associated with the recommendation for tocolysis in the setting of repeat acute preterm labor (odds ratio [OR] 1.45, confidence interval [CI] 1.05–1.99, P=.02), maintenance tocolysis (OR 3.17, CI 2.27–4.42, P<.001), and preterm PROM without contractions (OR 1.42, CI 1.02–1.97, P=.04).
In this study, we found that tocolytics are prescribed commonly by U.S. maternal–fetal medicine specialists. As many as 96% recommend tocolysis in the setting of acute preterm labor at 26 weeks, and 80% indicated there was moderate or significant benefit associated with tocolysis in this setting. However, there are limited data supporting this recommendation and belief. It is possible that many respondents recommend tocolytics in the first 48 hours of preterm labor because the majority believe there is minimal or no harm to this recommendation (82% in our study), and corticosteroids have been shown to improve neonatal outcomes in the setting of spontaneous preterm birth.10 We did find that after the first 48 hours (when steroids administration typically would be completed), only 29% would continue tocolysis, suggesting an association between the recommendation for tocolysis and steroid administration. However, it appears that many respondents believe there are benefits to tocolysis aside from corticosteroid administration, as 56% indicated they would recommend tocolysis in the setting of repeat acute preterm labor, even though only 21% would recommend another course of corticosteroids.
We found that, for a patient with intact membranes, many respondents may not recommend tocolysis but would be comfortable with it if the patient desired. However, in the setting of preterm PROM, maternal–fetal medicine specialists are less flexible; either they do or do not recommend tocolysis and are less persuaded by patient request. This is likely because there is more perceived harm with the use of tocolytics in the setting of preterm PROM, as 45% and 39% of respondents believed there was moderate or severe risk associated with tocolysis in the setting preterm PROM with and without contractions, respectively.
We also found that having a nonacademic practice was independently associated with the recommendation for tocolysis. It is plausible that those practicing in an academic setting would be less likely to recommend an intervention with limited evidence. However, many academic maternal–fetal medicine specialists did recommend tocolysis in each of the scenarios, which illustrates how ingrained tocolysis has become in our management of preterm labor and preterm PROM.
It is possible that selection bias limits our study as slightly fewer than one half of SMFM members responded to our survey. However, we received completed surveys from a very large number of SMFM members from all regions of the United States, and our response rate of 46% was similar to other published surveys regarding practice patterns of SMFM members.11,12 Also, the gender and geographic distribution of respondents was similar to the SMFM membership as a whole. Therefore, we believe our sample is likely to represent U.S. maternal–fetal medicine specialists in general. A recent study showed improved neonatal outcomes with the use of transdermal nitroglycerin in the setting of preterm labor.13 It is possible that responses would have been different had we specifically included nitroglycerin as a tocolytic option. However, very few responded that they would use “other” tocolytics, and we suspect that transdermal nitroglycerin is not currently being used by many U.S. maternal–fetal medicine specialists, especially considering that this study was published only a few months before our survey was distributed. Finally, although 91% of respondents indicated that they take care of obstetric patients, it is possible that practice patterns could also vary based on the proportion of time the SMFM member spends taking care of laboring and hospitalized patients, as opposed to time spent in an outpatient setting. Our study did not address this.
There is a need for large, randomized trials evaluating the role of tocolysis in the setting of repeat acute preterm labor, maintenance tocolysis, and preterm PROM. Also, although large, randomized trials have been completed evaluating the role of tocolysis in the setting of acute preterm labor, there is a need for more contemporary studies because other factors that could improve neonatal outcome have changed, such as the prevalent use of corticosteroids and improved neonatal care.
1. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 2002;4:CD001060.
2. Nanda K, Cook LA, Gallo MF, Grimes DA. Terbutaline pump maintenance therapy after threatened preterm labor for preventing preterm birth. Cochrane Database Syst Rev 2002;4:CD003933.
3. Dodd JM, Crowther CA, Dare MR, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database Syst Rev 2006;1:CD003927.
4. Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2004;4:CD004352.
5. King JF, Flenady VJ, Papatsonis DN, Dekher GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003;1:CD002255.
6. Management of preterm labor. ACOG Practice Bulletin No. 43. American College of Obstetricians and Gynecologists. Obstet Gynecol 2003;101:1039–47.
7. Grimes DA, Nanda K. Magnesium sulfate tocolysis: time to quit. Obstet Gynecol 2006;108:986–9.
8. Klauser CK, Briery CM, Magann EF, Martin RW, Chauhan SP, Morrison JC. Tocolytic preference for treatment of preterm labor. J Miss State Med Assoc 2007;48:35–8.
9. Hui D, Liu G, Kavuma E, Hewson SA, McKay D, Hannah ME. Preterm labour and birth: a survey of clinical practice regarding use of tocolytics, antenatal corticosteroids, and progesterone. J Obstet Gynaecol Can 2007;29:117–30.
10. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006 19;3:CD004454.
11. Ramsey PS, Nuthalapaty FS, Lu G, Ramin S, Nuthalapaty ES, Ramin KD. Contemporary management of preterm premature rupture of membranes (PPROM): a survey of maternal-fetal medicine providers. Am J Obstet Gynecol 2004;191:1497–502.
12. Nuthalapaty F, Lu G, Ramin S, Nuthalapaty E, Ramin KD, Ramsey PS. Is there a preferred gestational age threshold of viability?: a survey of maternal-fetal medicine providers. Matern Fetal Neonatal Med 2007;20:293–7.
13. Smith GN, Walker MC, Ohlsson A, O’Brien K, Windrim R. Canadian Preterm Labour Nitroglycerin Trial Group. Randomized double-blind placebo-controlled trial of transdermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2007;196:37.e1–8.