Tocolysis for Acute Preterm Labor: Where Have We Been, Where Are We Now, and Where are We Going? 

Preterm birth (PTB) is defined as delivery between 20 0/7 and 366/7 weeks of gestation. It is estimated to occur in 11.3% of all pregnancies in the United States.1 It is responsible for 75 to 80% of all neonatal deaths and considerable neonatal morbidity.2 Spontaneous preterm labor precedes $50% of preterm deliveries. The diagnosis of preterm labor has historically been based on clinical criteria of regular uterine contractions (typically, >8/hour) accompanied by cervical change.3 For patients with true preterm labor, tocolytic therapy has been used to try to abolish contractions tempo- rarily, but it does not remove the underlying stimulus that initiated the process of parturition or reverse parturitional changes in the uterus and cervix.

Tocolysis is mainly used to delay delivery to enable the administration of antenatal corticosteroids and magnesium sulfate for neuroprotection, as well as permit maternal trans- port, if indicated, to a tertiary facility. The most beneficial intervention to improve neonatal outcomes among prema- ture infants is the administration of antenatal corticoste- roids.4 A Cochrane meta-analysis examined the effect of this therapy and concluded that a single course of antenatal corticosteroids should be administered to all women at high risk for imminent PTB, regardless of fetal membrane status.5

The American College of Obstetricians and Gynecologists states that “interventions to reduce the likelihood of delivery should be reserved for women with preterm labor at a 

gestational age at which a delay in delivery will provide benefit to the newborn. Because tocolytic therapy generally is effective for up to 48 hours, only women with fetuses that would benefit from a 48-hour delay in delivery should receive tocolytic treatment.”6

In current practice, acute tocolysis is generally initiated in response to the diagnosis of true preterm labor between 23 and 336/7 weeks of gestation.

Brief Physiology of Preterm Labor

The exact hormonal mechanisms regulating the onset and maintenance of human labor at term are not understood, and those circumstances surrounding preterm labor are even less so. The majority of data regarding hormonal mechanisms are extrapolated from animal studies. Clinical observations suggest that the mechanism of onset of term and preterm labor involves the removal of one or more of the complex multiple systems involved in maintaining uterine quiescence and preservation of pregnancy.7 Nevertheless, alteration in intracellular ionic calcium is likely the final modulator of myometrial activity. It is also the final mechanism by which all modalities of arresting preterm labor ultimately work, either directly or indirectly.8

Tocolysis: Where Have We Been

Tocolytic drugs have been around for over 60 years. Several have been proposed, yet most have either been insufficiently studied or have not been shown to be efficacious at prevent- ing PTB. Ethanol, betamimetics, and magnesium sulfate are examples of some of the first tocolytics studied and used, but with newer agents and better literature available on efficacy, they are rarely used clinically.

Ethanol

The use of ethanol for inhibiting preterm labor in humans stems partially from studies in pregnant rabbits at term, demonstrating that the release of oxytocin during parturition could be effectively inhibited by ethanol in this species. The observation was then applied to the treatment of human preterm labor.9 In the 1960s, the efficacy of ethanol in treating preterm labor was explored by several investigators. In two uncontrolled studies of 52 and 50 women with preterm labor with intact membranes, success rates of 67 and 68%, respectively, were reported9,10 but in a similar uncontrolled study of 15 patients, Graff obtained only 7% success in postponing delivery by 3 or more days.11 Similarly, in controlled studies, results using ethanol as a tocolytic were inconsistent when compared with placebo.12 The difference in success rates stem largely from differences in criteria for the diagnosis of preterm labor. This underscores the difficulty in diagnosing true from false preterm labor.13

Additionally, maternal and fetal side effects from ethanol can be significant. In published studies, maternal intoxication was common, with induced coma at higher levels. Ethanol quickly enters fetal circulation and can worsen fetal respiratory distress and increase the risk of central nervous system depression. 

Betamimetics

Betamimetics work on the β-2 receptors, found in smooth muscle. They stimulate the receptor through cyclic adenosine monophosphate, leading to a decrease in free calcium, which is needed for myometrial contractions.14 Ritodrine and ter- butaline have been studied in several randomized placebo- controlled trials. A 2014 meta-analysis included 20 trials; 12 of these compared betamimetics with placebo. Preterm de- livery within 48 hours and within 7 days was less common among women administered betamimetics (►Table 1). How- ever, there was no evidence of a reduction in PTB less than 37 weeks. Additionally, betamimetics did not improve peri- natal morbidity or mortality.15 Maternal side effects are significant and include chest pain, dyspnea, tachycardia, palpitations and tremor, headaches, hyperglycemia, hypoka- lemia, nausea, and vomiting.16

Betamimetics were widely used for many years but have fallen out of favor because other classes of agents are equally efficacious with fewer side effects. Intravenous ritodrine, for example, is no longer marketed in the United States. In 2011, the U.S. Food and Drug Administration issued a warning regarding terbutaline use. Specifically, it stated that injectable terbutaline should not be used in pregnant women for prolonged treatment (48–72 hours) of preterm labor in either the hospital or outpatient setting because of potential for serious maternal heart problems and death.17

Magnesium Sulfate

The precise mechanism of action of magnesium is not complete- ly understood; however, it is thought to work as an intracellular calcium antagonist, thereby inhibiting myometrial contrac- tions.18 Compared with placebo, there is insufficient evidence to show if magnesium reduces the incidence of PTB or perinatal morbidity or mortality. In a 2014 systematic review, the inci- dence of PTB 48 hours after presentation and less than 37 weeks’ gestation was similar between magnesium treated and untreat- ed women (►Table 1).19 Higher doses have not shown beneficial outcomes and are associated with significant side effects com- pared with standard 2 g/hour dosing.20 Other meta-analyses have found magnesium sulfate to be as effective as other

Table 1 Effectiveness of various tocolytic therapies vs. placebo 

Abbreviation: N/A, not available, as not evaluated in randomized con- trolled trials.
aOne trial showed benefit, while another did not, with data not feasible for meta-analysis. 

tocolytic agents in delaying birth, but these meta-analyses are hampered by the lack of available placebo-controlled trials.21,22 Additionally, there are risks for significant maternal side effects with magnesium sulfate use, including pulmonary edema and cardiac arrest, neonatal lethargy, and respiratory distress. Given these concerns, there is no convincing evidence for recommend- ing magnesium for tocolysis.19,23 Magnesium sulfate continues to be used for gestations less than 32 weeks for fetal neuroprotection.24 

Where We Are Now

Evaluation of Preterm Labor

Early diagnosis is the key to successful arrest of true preterm labor. However, early diagnosis is often difficult before pro- gressive cervical dilatation has occurred.14 Consequently, patients may experience a delay in treatment until well after preterm labor has become established, possibly when labor has progressed significantly and PTB is imminent. On the other hand, many women without true preterm labor may receive potent tocolytic agents and are, therefore, unneces- sarily exposed to their side effects.

Historically, evaluation of preterm labor is based on history and cervical exam, and it is defined by cervical change; however, interexaminer differences in digital examination add to the challenge of the preterm labor diagnosis. We prefer a diagnosis based on more objective criteria for cervical change, using transvaginal ultrasound of cervical length (transvaginal CL) as the main tool for evaluation of preterm labor, with the use of fetal fibronectin (fFN) for intermediate cases (►Fig. 1). Using this criterion, true preterm labor can be defined as uterine contrac- tions with transvaginal CL < 20 mm, or 20 to 29 mm with a positive fetal fFN.3 Women diagnosed with true preterm labor should be admitted for tocolysis and corticosteroid administra- tion. Threatened preterm labor is instead the condition when a woman has symptoms of preterm labor, such as contractions or cramping, but no cervical change, for example, a transvaginal CL !30 mm. There is no need for therapy in these women, including tocolysis, despite symptoms of threatened preterm labor.25

Compared with no knowledge, knowledge of transvaginal CL results is associated with a nonsignificant decrease in PTB < 37 weeks. Additionally, the benefit of knowledge of fFN as an adjunct to transvaginal CL was demonstrated by a randomized controlled trial (RCT).26 Many new algorithms 

Fig. 1 Suggested algorithm for the evaluation and management of threatened preterm labor. ( ) negative; (þ) positive; CL, cervical length; fFN, fetal fibronectin; PTB, preterm birth. 

suggest using a combination of transvaginal CL and fFN to help determine the need for tocolysis. This is based on the principle that women with preterm contractions but negative fFN and transvaginal CL ! 30 mm have <2% chance on delivering within 1 week, and a >95% chance of delivering at >35 weeks without treatment; therefore, they should not receive any treatment.27

Principles of Tocolytic Therapy

Tocolytic drugs have been used for stopping uterine contrac- tions in different clinical scenarios. The two most common are “primary” tocolytics and “maintenance” tocolytics. Primary tocolytics are intended for use as soon as the initial diagnosis of true preterm labor is made. There are dozens of RCTs on the safety and effectiveness of primary tocolysis. In a systematic review and network meta-analysis of 95 randomized trials of tocolytic therapy for preterm labor, all of the commonly used tocolytic agents (cyclooxygenase [COX] inhibitors, calcium channel blockers, betamimetics, magnesium sulfate, and oxytocin receptor antagonists) were statistically more effec- tive than placebo for delaying delivery for 48 hours.21,28

Maintenance tocolysis is defined as tocolysis used on a woman with a resolved episode of preterm labor, also called “arrested” preterm labor, when contractions have resolved because of primary tocolysis. Because some risk of PTB remains, maintenance tocolysis is mainly aimed at preventing recurrent preterm labor. Historically, prolonged oral or subcutaneous medications such as terbutaline, ritodrine, and nifedipine were administered as long as 34 to 36 weeks’ gestation. However, data now suggest that maintenance therapy may be ineffective and, in some cases, harmful. Magnesium sulfate, nifedipine, and betamimetics have all been shown to be ineffective in prolonging gestation, pre- venting PTB, and improving neonatal outcomes.29–31

Cyclooxygenase Inhibitors

COX, or prostaglandin synthase, is the enzyme responsible for conversion of arachidonic acid to prostaglandins, which are important in parturition. COX inhibitors, therefore, inhibit prostaglandin synthesis, thereby inhibiting myometrial con- tractions. This class of tocolytic agents includes indometha- cin, a nonselective COX-1 and COX-2 inhibitor, and the most commonly used tocolytic of this class. Selective COX-2 inhibitors (sulindac) are less well studied, and now carry a boxed warning because of significant adverse cardiovascular outcomes.

In a 2015 meta-analysis of 20 studies involving COX inhibitors, indomethacin was used in 15 studies.32 Only three studies compared COX inhibitors to placebo; one of these demonstrated a reduction in PTB < 37 weeks.33 No differ- ences in measures of neonatal morbidity or neonatal mortal- ity were observed with COX inhibitors versus placebo. Compared with betamimetics, COX inhibitors resulted in a reduction in birth less than 48 hours after trial entry and PTB < 37 weeks, although no benefit was shown in terms of neonatal morbidity or mortality (►Table 1). COX inhibition was also associated with fewer maternal adverse effects compared with betamimetics. No differences were shown

when comparing COX inhibitors with magnesium sulfate or calcium channel blockers.32 Use for >48 hours and !32 weeks is associated with significant fetal effects such as constriction of the ductus arteriosus. COX inhibitors are also associated with fetal renal insufficiency, particularly if administered for >48 hours. Additionally, a recent meta-analysis of 27 obser- vational studies revealed that antenatal exposure to indo- methacin was associated with an increased risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia.34

Calcium Channel Blockers

Calcium channel blockers impair calcium channels, thereby inhibiting the influx of calcium into the cell. They also act by preventing calcium release from the sarcoplasmic reticulum. The result is a decrease in available intracellular calcium, which leads to a decrease in actin–myosin interactions, and inhibits myometrial contractions. A total of 38 trials using calcium channel blockers were recently reviewed in a meta- analysis. Comparing calcium channel blockers (mainly nifed- ipine) with other tocolytics (betamimetics, nonsteroidal anti- inflammatories, and oxytocin receptor antagonists), there was no significant reduction in delivery within 48 hours of treatment or perinatal mortality.35 Due to substantial het- erogeneity, outcome data for PTB < 37 weeks were not combined; one placebo-controlled trial showed no differ- ence,36 while the other (non–placebo-controlled trial) reported a reduction in PTB < 37 weeks (►Table 1).37 Calci- um channel blockers have a favorable side-effect profile when compared with the betamimetics, with the most common side effect being hypotension-related.

Combination Tocolysis

It is unclear whether a combination of tocolytic drugs for preterm labor is superior to single-agent tocolysis due to a lack of large, well-designed trials. There are no trials of combination regimens using widely used tocolytic agents, such as COX inhibitors, calcium channel blockers, and/or oxytocin receptor antagonists. Further trials are needed before recommendations can be made on the use of combi- nation tocolytic therapy.38

Recommendations for Tocolysis

Tocolysis is important for 48-hour delay of delivery and administration of corticosteroids for fetal maturity. Based on the above data, the following guideline is suggested for determining appropriate tocolytic agent. COX inhibitors are the only class of primary tocolytics shown to decrease PTB < 37 weeks compared with placebo. Given the significant fetal side effects after 32 weeks, they should only be consid- ered as the first line for <32 weeks’ gestational age, and for up to 48 hours maximum. Following COX inhibitors, calcium channel blockers should be considered as the second (or first) line for <32 weeks’ gestational age, and as the first line for 32 weeks of gestation and beyond. The evidence on calcium channel blockers for PTB < 37 weeks is mixed; further stud- ies are needed. Betamimetics can be considered when there are contraindications to use of COX inhibitors and calcium channel blockers. Magnesium sulfate is not recommended for tocolysis.39

Tocolytics: Where Are We Going?

The future for tocolysis includes a better diagnosis of preterm labor, expanding the gestational age at which tocolysis can be considered to 22 as well as 34 to 36 weeks, and new classes of tocolytics, such as oxytocin receptor antagonists, nitric oxide donors, and progesterone.

A Better Diagnosis

Diagnosis of true preterm labor has come a long way: from regular uterine contractions and cervical change to assess- ment with transvaginal CL. This paradigm shift has worked to create more objective criteria for diagnosing true preterm labor. Additionally, we know that knowledge of transvaginal CL has led to delivery at a later gestational age.40 We expect improvements can continue to be made to the current evaluation and management algorithm (►Fig. 1). For exam- ple, as we study the clinical utility of cervicovaginal markers, we can further risk stratify patients by taking into account pathways to PTB that do not include early cervical change.

Expanding the Limits of Gestational Age for Tocolysis

Tocolytics are generally not indicated prior to viability since these drugs do not delay delivery for more than a few days. However, the lowest gestational age for which inhibition of preterm labor should be considered is contro- versial, and there are no definitive data from randomized trials on which to base a recommendation. As neonatal care improves, the threshold of viability continues to be chal- lenged, and neonatal resuscitation and antenatal cortico- steroids may be efficacious outside of the 230/7 to 336/7 weeks’ gestation-age window. One workshop panel com- posed of obstetrical and pediatric experts suggested 220/7 weeks of gestation as the lower limit for consideration of tocolysis if antenatal steroids were concurrently adminis- tered.41 However, on the international level, this gestation- al age limit remains controversial.42

Presently, there is greater consensus regarding the upper gestational age limit for treatment of preterm labor. A total of 34 weeks of gestation have for some time been defined as the threshold at which perinatal morbidity and mortality are felt to be too low to justify the potential maternal and fetal complications and costs associated with inhibition of labor and short-term delay of delivery.43,44 One decision analysis of preterm labor management strategies by gestational age concluded that, at 32 weeks, tocolysis was preferable to no tocolysis, based on fetal lung maturity assessment. Further- more, at 36 weeks, no tocolysis was the preferred approach, but neither strategy was clearly preferable at 34 weeks.45 Current studies are underway to examine whether antenatal corticosteroids improve neonatal outcomes when adminis- tered to mothers at risk for delivery between 34 and 37 weeks’ gestation. If benefit can be demonstrated in this late preterm cohort, consideration may be given to use of tocolysis to delay delivery to permit administration of antenatal corticosteroids through 36 weeks’ gestation, although tocolysis itself has been understudied at these late gestational ages.

Oxytocin Receptor Antagonists

Oxytocin receptor antagonists competitive inhibit oxytocin by blocking the oxytocin receptor. Atosiban is the most well- known agent of this class. In the latest update of the Cochrane reviews, a total of 14 studies were reviewed. When compared with placebo, there was no difference in birth <48 hours after trial entry, no difference in PTB < 37 weeks’ gestation, and no difference in perinatal morbidity and mortality (►Table 1).46 Trials comparing oxytocin receptor antagonists to other tocolytic classes were small and several were not blinded; however, overall, oxytocin receptor antagonists did not show improved outcomes compared with betamimetics and calci- um channel blockers. In one study, atosiban resulted in an increase in extremely preterm birth and infant death, but this may have been confounded by the randomization results.47 Because of possible neonatal harm which has not been substantiated, oxytocin receptor antagonists have not been approved in the United States, although they continue to be used in other countries for tocolysis. They do have a favorable side-effect profile compared with betamimetics and calcium channel blockers, and warrant further study.

Nitric Oxide Donors

Nitroglycerin converts into the free radical nitrous oxide, which works directly to relax the uterine muscle. In a 2013 meta-analysis of RCTs, 13 studies were reviewed comparing transdermal nitroglycerin versus placebo. No difference was found for delayed delivery within 48 hours, or for PTB less than 28, 34, and 37 weeks of gestation. There were no differences in neonatal outcomes (►Table 1).48 Compared with betamimetics, nitric oxide donors are associated with a decrease in PTB less than 34 and 37 weeks. Nitric oxide donors have not been shown to have increased benefit when compared with calcium channel blockers or magne- sium sulfate. Currently, there is insufficient evidence to support the use of nitric oxide donors for prevention of PTB in women presenting with true preterm labor.49

Progesterone

Currently, there are insufficient data examining the efficacy of any progesterone formulations for acute tocolysis. How- ever, there are some limited data to suggest a role for various progesterone formulations for longer term or ‘maintenance’ tocolysis. A recent meta-analysis of five randomized trials showed that women who received vagi- nal progesterone for maintenance tocolysis after arrested preterm labor had significantly lower rates of recurrent preterm labor, longer latency, and later gestational age at delivery. Additionally, these women had a significantly lower rate of PTB < 37 weeks.50 A meta-analysis examining the role of 17-α-hydroxyprogesterone caproate (17P) for maintenance tocolysis demonstrated a significantly later gestational age at delivery and longer latency with 17P. However, there were no significant differences in overall rates of PTB < 34 and < 37 weeks.51 

Our previous studies have suggested that there is not a role for maintenance tocolysis with our current primary tocolytic agents. This evidence suggests that while progesterone may not be recommended for primary tocolysis, further studies should be conducted for maintenance tocolysis.

Modern Tocolysis

Current tocolysis, as the name implies, is aimed at stopping, or at least decreasing, contractions, with the ultimate goal of subsequently arresting the process of cervical change, and delaying delivery, with the end result of improving neonatal outcomes. Attenuation of uterine contractions is primarily achieved through uterine muscle relaxation, or through direct competition with contractility mediators. However, elucidation of the complex pathway ultimately leading to preterm labor can provide other targeted strategies to treat preterm labor. A better understanding of the pathophysiology of preterm labor will bring new pharmacologic approaches to preventing preterm labor and PTB, by focusing not only on uterine contractions, but also on what originally causes the contractions to begin with.

Conclusion

Acute tocolysis therapy in response to preterm labor is associated with the short-term prolongation of pregnancy. This delay in delivery can allow for a course of antenatal corticosteroids to be administered, magnesium sulfate to be infused for fetal neuroprotection, and, if needed, it can allow for transfer to a tertiary care facility. These efforts have been shown to improve neonatal outcomes.

We must keep in mind that while tocolysis is an important tool in the battle against PTB, it is not the only answer. As we better understand the pathophysiology of preterm labor and work on better evaluation and management strategies, we will hopefully develop better detection and management strategies. Eventually, we should seek to develop additional preventative strategies rather than reactionary treatments such as tocolysis. Thus, we should continue to ask the question: how can we use our knowledge to prevent PTB?

Conflicts of Interest
None.

Funding
None. 

References

1. Hamilton B, Martin J, Osterman M, Curtin S. Division of vital statistics births: Preliminary data for 2014. National Vital Statistics Reports. http://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_06. pdf. [Accessed 2015]

2. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371(9606):75–84

3. Berghella V. Obstetric evidence-based guidelines. London: CRC Press; 2012

4. Hayes EJ, Paul DA, Stahl GE, et al. Effect of antenatal corticosteroids on survival for neonates born at 23 weeks of gestation. Obstet Gynecol 2008;111(4):921–926

5. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. [Review] Cochrane Database Syst Rev 2006;19(3):CD004454

6. American College of Obstetricians and Gynecologists; Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin no. 127: management of preterm labor. Obstet Gynecol 2012;119(6): 1308–1317

7. Smith R. Parturition. N Engl J Med 2007;356(3):271–283

8. López Bernal A. Mechanisms of labour—biochemical aspects. BJOG 2003;110(Suppl 20):39–45

9. Fuchs F, Fuchs AR, Poblete VF Jr, Risk A. Effect of alcohol on threatened premature labor. Am J Obstet Gynecol 1967;99(5):627–637

10. Mehra P, Raghavan KS, Devi PK, et al. Effect of intravenous alcohol on premature labour. Int J Gynaecol Obstet 1970;8:160

11. Graff G. Failure to prevent premature labor with ethanol. Am J Obstet Gynecol 1971;110(6):878–880

12. Watring WG, Benson WL, Wiebe RA, Vaughn DL. Intravenous alcohol—a single blind study in the prevention of premature delivery: a preliminary report. J Reprod Med 1976;16(1):35–38 

13. Keirse MJ. The history of tocolysis. BJOG 2003;110(Suppl 20):94–97

14. Gary CF, Gant N, Leveno K, Gilstrap L, Hauth J, Wenstrom KD.Williams Obstetrics. New York, NY: McGraw-Hill; 2005:823–829 

15. Neilson JP, West HM, Dowswell T. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2014;2:CD004352 

16. Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A. Tocolytics for preterm labor: a systematic review. Obstet Gynecol 1999;94(5, Pt 2):869–877

17. US Food and Drug Administration. FDA Drug Safety Communication: New Warnings Against Use of Terbutaline to Treat Preterm Labor. Silver Spring, MD: FDA; 2011

18. Mizuki J, Tasaka K, Masumoto N, Kasahara K, Miyake A, Tanizawa O. Magnesium sulfate inhibits oxytocin-induced calcium mobili- zation in human puerperal myometrial cells: possible involvement of intracellular free magnesium concentration. Am J Obstet Gynecol 1993;169(1):134–139

19. Crowther CA, Brown J, McKinlay CJ, Middleton P. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 2014;8:CD001060

20. Terrone DA, Rinehart BK, Kimmel ES, May WL, Larmon JE, Morri- son JC. A prospective, randomized, controlled trial of high and low maintenance doses of magnesium sulfate for acute tocolysis. Am J Obstet Gynecol 2000;182(6):1477–1482

21. Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ 2012;345:e6226

22. Conde-Agudelo A, Romero R, Kusanovic JP. Nifedipine in the management of preterm labor: a systematic review and meta- analysis. Am J Obstet Gynecol 2011;204(2):134.e1–134.e20

23. Mercer BM, Merlino AA; Society for Maternal-Fetal Medicine. Magnesium sulfate for preterm labor and preterm birth. Obstet Gynecol 2009;114(3):650–668

24. Doyle L, Crowther C, Middleton P, Marret S. Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Anesthes Dig 2010;30(2):94–95

25. Gomez R, Romero R, Medina L, et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sono- graphic cervical length in patients with preterm uterine con- tractions and intact membranes. Am J Obstet Gynecol 2005; 192(2):350–359

26. Ness A, Visintine J, Ricci E, Berghella V. Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? A randomized trial. Am J Obstet Gynecol 2007;197(4):426.e1–426.e7 

27. 27  Gomez R, Romero R, Medina L, et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. Am J Obstet Gynecol 2005;192(2):350–359

28. 28  Haas DM, Kirkpatrick P, McIntosh JJ, Caldwell DM. Assessing the quality of evidence for preterm labor tocolytic trials. J Matern Fetal Neonatal Med 2012;25(9):1646–1652

29. 29  Dodd JM, Crowther CA, Middleton P. Oral betamimetics for main- tenance therapy after threatened preterm labour. Cochrane Data- base Syst Rev 2012;12:CD003927

30. 30  Lyell DJ, Pullen KM, Mannan J, et al. Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial. Obstet Gynecol 2008;112(6):1221–1226

31. 31  Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2013;5:CD000940

32. 32  Reinebrant HE, Pileggi-Castro C, Romero CL, et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 2015;6:CD001992

33. 33  Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of premature labor by indomethacin. Part II double- blind study. J Perinat Med 1984;12(1):25–29

34. 34  Hammers AL, Sanchez-Ramos L, Kaunitz AM. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leuko- malacia: a systematic review with metaanalysis. Am J Obstet Gynecol 2015;212(4):505.e1–505.e13

35. 35  Flenady V, Wojcieszek AM, Papatsonis DN, et al. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Data- base Syst Rev 2014;6:CD002255

36. 36  Ara I, Banu H. A prospective randomised trial of nifedipine versus placebo in preterm labour. Bangladesh J Obstet Gynaecol 2008; 23(2):61–64

37. 37  Zhang X, Liu M. Clinical observations on the prevention and treatment of premature labor with nifedipine [in Chinese]. Hua Xi Yi Ke Da Xue Xue Bao 2002;33(2):288–290

38. 38  Vogel JP, Nardin JM, Dowswell T, West HM, Oladapo OT. Combina- tion of tocolytic agents for inhibiting preterm labour. Cochrane Database Syst Rev 2014;7:CD006169

39. 39  Grimes DA, Nanda K. Magnesium sulfate tocolysis: time to quit. Obstet Gynecol 2006;108(4):986–989

40. Berghella V, Baxter JK, Hendrix NW. Cervical assessment by ultrasound for preventing preterm delivery. Cochrane Database Syst Rev 2013;1:CD007235

41. Raju TN, Mercer BM, Burchfield DJ, Joseph GF Jr. Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Develop- ment, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecolo- gists. Obstet Gynecol 2014;123(5):1083–1096

42. Fanaroff JM, Hascoët JM, Hansen TWR, et al; International Perinatal Collegium (IPC). The ethics and practice of neonatal resuscitation at the limits of viability: an international perspective. Acta Pae- diatr 2014;103(7):701–708

43. Goldenberg RL. The management of preterm labor. Obstet Gynecol 2002;100(5, Pt 1):1020–1037  

44. Korenbrot CC, Aalto LH, Laros RK Jr. The cost effectiveness of stopping preterm labor with beta-adrenergic treatment. N Engl J Med 1984;310(11):691–696

45. Macones GA, Bader TJ, Asch DA. Optimising maternal-fetal out- comes in preterm labour: a decision analysis. Br J Obstet Gynaecol 1998;105(5):541–550

46. Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DN. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2014;6:CD004452

47. Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a ran- domized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000;182(5):1173–1183

48. Conde-Agudelo A, Romero R. Transdermal nitroglycerin for the treatment of preterm labor: a systematic review and metaanalysis. Am J Obstet Gynecol 2013;209(6):551.e1–551.e18

49. Duckitt K, Thornton S, O’Donovan OP, Dowswell T. Nitric oxide donors for treating preterm labour. Cochrane Database Syst Rev 2014;5:CD002860

50. Suhag A, Saccone G, Berghella V. Vaginal progesterone for mainte- nance tocolysis: a systematic review and metaanalysis of random- ized trials. Am J Obstet Gynecol 2015;213(4):479–487

51. Saccone G, Suhag A, Berghella V. 17-alpha-hydroxyprogesterone caproate for maintenance tocolysis: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol 2015; 213(1):16–22