Which drugs would the nurse anticipate administering for tocolysis during preterm labor?

Background

Preterm birth is defined as birth between 20 0/7 weeks of gestation and 36 6/7 weeks of gestation. The diagnosis of preterm labor generally is based on clinical criteria of regular uterine contractions accompanied by a change in cervical dilation, effacement, or both, or initial presentation with regular contractions and cervical dilation of at least 2 cm. Less than 10% of women with the clinical diagnosis of preterm labor actually give birth within 7 days of presentation (11). It is important to recognize that preterm labor with intact membranes is not the only cause of preterm birth; numerous preterm births are preceded by either rupture of membranes or other medical problems necessitating delivery (2, 6, 12).

Historically, nonpharmacologic treatments to prevent preterm births in women with preterm labor have included bed rest, abstention from intercourse and orgasm, and hydration. Evidence for the effectiveness of these interventions is lacking, and adverse effects have been reported (13–16). Proposed pharmacologic interventions to prolong pregnancy have included the use of tocolytic drugs to inhibit uterine contractions as well as antibiotics to treat intrauterine bacterial infection. The therapeutic agents currently thought to be clearly associated with improved neonatal outcomes include antenatal corticosteroids for maturation of fetal lungs and other developing organ systems, and the targeted use of magnesium sulfate for fetal neuroprotection.

Clinical Considerations and Recommendations

• Which tests can be used to stratify risk for preterm delivery in patients who present with preterm contractions?

Because the presence of fetal fibronectin or a short cervix has been associated with preterm birth (17–19), the utility of fetal fibronectin testing and the cervical length measurement, alone or in combination, to improve upon the clinical ability to diagnose preterm labor and predict preterm birth in symptomatic women were examined. Although the results of observational studies have suggested that knowledge of fetal fibronectin status or cervical length may help health care providers reduce use of unnecessary resources (20, 21), these findings have not been confirmed by randomized trials (22–24). Further, the positive predictive value of a positive fetal fibronectin test result or a short cervix alone is poor and should not be used exclusively to direct management in the setting of acute symptoms (25).

• Which patients with preterm labor are appropriate candidates for intervention?

Identifying women with preterm labor who ultimately will give birth preterm is difficult. Approximately 30% of preterm labor spontaneously resolves (26) and 50% of patients hospitalized for preterm labor actually give birth at term (27–29). 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 (30), only women with fetuses that would benefit from a 48-hour delay in delivery should receive tocolytic treatment.

In general, tocolytics are not indicated for use before neonatal viability. Regardless of interventions, perinatal morbidity and mortality at that time are too high to justify the maternal risks associated with tocolytic therapy. Similarly, no data exist regarding the efficacy of corticosteroid use before viability. However, there may be times when it is appropriate to administer tocolytics before viability. For example, inhibiting contractions in a patient after an event known to cause preterm labor, such as intra-abdominal surgery, may be reasonable even at previable gestational ages, although the efficacy of such an intervention remains unproved (31, 32). The upper limit for the use of tocolytic agents to prevent preterm birth generally has been 34 weeks of gestation. Because of the possible risks associated with tocolytic and steroid therapies, the use of these drugs should be limited to women with preterm labor at high risk of spontaneous preterm birth. Tocolysis is contraindicated when the maternal and fetal risks of prolonging pregnancy or the risks associated with these drugs are greater than the risks associated with preterm birth (see Box 1).

• Should women with preterm contractions but without cervical change be treated?

Regular preterm contractions are common; however, these contractions do not reliably predict which women will have subsequent progressive cervical change (33). In a study of 763 women who had unscheduled triage visits for symptoms of preterm labor, only 18% gave birth before 37 weeks of gestation and only 3% gave birth within 2 weeks of presenting with symptoms (17). No evidence exists to support the use of prophylactic tocolytic therapy (34), home uterine activity monitoring, cerclage, or narcotics to prevent preterm delivery in women with contractions but no cervical change. Therefore, women with preterm contractions without cervical change, especially those with a cervical dilation of less than 2 cm, generally should not be treated with tocolytics.

• Does the administration of antenatal corticosteroids improve neonatal outcomes?

The most beneficial intervention for improvement of neonatal outcomes among patients who give birth preterm is the administration of antenatal corticosteroids. A single course of corticosteroids is recommended for pregnant women between 24 weeks and 34 weeks of gestation who are at risk of delivery within 7 days. For women with ruptured membranes or multiple gestations who are at risk of delivery within 7 days, a single course of corticosteroids is recommended between 24 weeks and 34 weeks of gestation. A single course of corticoster- oids may be considered starting at 23 weeks of gestation for pregnant women who are at risk of preterm delivery within 7 days, irrespective of membrane status (35–37). Recent data indicate that betamethasone decreases newborn respiratory morbidity when given to women in the late preterm period between 34 0/7 weeks and 36 6/7 weeks who are at risk of preterm delivery within 7 days and who have not previously received corticosteroids (38). Administration of corticosteroids for pregnant women during the periviable period who are at risk of preterm delivery within 7 days is linked to a family’s decision regarding resuscitation and should be considered in that context.

A Cochrane meta-analysis of corticosteroids therapy before 34 weeks of gestation reinforces the beneficial effect of this therapy regardless of membrane status and concludes that a single course of antenatal corticosteroids should be considered routine for all preterm deliveries (39). The administration of antenatal corticosteroids to the woman who is at risk of imminent preterm birth is strongly associated with decreased neonatal morbidity and mortality (39–41). Neonates whose mothers receive antenatal corticosteroids have significantly lower severity, frequency, or both of respiratory distress syndrome (relative risk [RR], 0.66; 95% confidence interval [CI], 0.59–0.73), intracranial hemorrhage (RR, 0.54; 95% CI, 0.43–0.69), necrotizing enterocolitis (RR, 0.46; 95% CI, 0.29–0.74), and death (RR, 0.69; 95% CI, 0.58–0.81), compared with neonates whose mothers did not receive antenatal corticosteroids (39).

One randomized trial demonstrated that additional neonatal benefit could be derived from a single rescue course of corticosteroids (42). The investigators reserved this intervention for patients with intact membranes, if the antecedent treatment had been given at least 2 weeks before the rescue course, the gestational age was less than 33 weeks, and the women were judged by the clinician to be likely to give birth within the next week. A single repeat course of antenatal corticosteroids should, therefore, be considered in women who are less than 34 weeks of gestation, who are at risk of preterm delivery within the next 7 days, and whose prior course of antenatal corticosteroids was administered more than 14 days previously. Rescue course corticosteroids could be provided as early as 7 days from the prior dose, if indicated by the clinical scenario (38, 43). In the study of betamethasone in the late preterm period, patients who had received corticosteroids earlier in pregnancy were excluded, and it is unclear whether there is benefit to a repeat course of betamethasone in those women (38). Whether to administer a repeat or rescue course of corticosteroids with preterm premature rupture of membranes is controversial, and there is insufficient evidence to make a recommendation for or against.

Betamethasone and dexamethasone are the most widely studied corticosteroids and have been the preferred antenatal treatments to accelerate fetal organ maturation. The administration of betamethasone or dexamethasone has been shown to decrease neonatal mortality (44, 45). Treatment, for either a primary or a rescue course, should consist of either two 12-mg doses of betamethasone given intramuscularly 24 hours apart or four 6-mg doses of dexamethasone every 12 hours administered intramuscularly (45). Because treatment with corticosteroids for less than 24 hours is still associated with significant reductions in neonatal morbidity and mortality, a first dose of antenatal corticosteroids should be administered even if the ability to give the second dose is unlikely, based on the clinical scenario (36). However, no additional benefit has been demonstrated for courses of antenatal steroids with dosage intervals shorter than those outlined previously, often referred to as accelerated dosing, even when delivery appears imminent.

• What is the role for magnesium sulfate for fetal neuroprotection?

Early observational studies suggested an association between prenatal exposure to magnesium sulfate and the less frequent occurrence of subsequent neurologic morbidities (46–48). Subsequently, several large clinical studies have evaluated the evidence regarding magnesium sulfate, neuroprotection, and preterm births (49–53). A 2009 meta-analysis synthesized the results of the clinical trials of magnesium sulfate for neuroprotection (54). Pooling the results of the available clinical trials of magnesium sulfate for neuroprotection suggests that predelivery administration of magnesium sulfate reduces the occurrence of cerebral palsy when given with neuroprotective intent (RR, 0.71; 95% CI, 0.55–0.91) (55). Two subsequent meta-analyses of similar design have confirmed these results (56, 57).

None of the trials demonstrated significant pregnancy prolongation when magnesium sulfate was given for neuroprotection. Although minor maternal complications were more common with magnesium sulfate in the three major trials, serious maternal complications (eg, cardiac arrest, respiratory failure, and death) were not seen more frequently in these studies or in the larger meta-analyses (51–54).

Although the goal of each of the three major randomized clinical trials was to evaluate the effect of magnesium sulfate treatment on neurodevelopmental outcomes and death, comparison between the trials is made difficult by differences in inclusion and exclusion criteria, populations studied, magnesium sulfate regimens, gestational age at treatment, and outcome variables evaluated. However, accumulated available evidence suggests that magnesium sulfate reduces the severity and risk of cerebral palsy in surviving infants if adminis- tered when birth is anticipated before 32 weeks of gestation. Hospitals that elect to use magnesium sulfate for fetal neuroprotection should develop uniform and specific guidelines for their departments regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials (6, 51–53).

• Does tocolytic therapy improve neonatal outcomes?

Tocolytic therapy may provide short-term prolongation of pregnancy, enabling the administration of antenatal corticosteroids and magnesium sulfate for neuroprotection, as well as transport, if indicated, to a tertiary facility. However, no evidence exists that tocolytic therapy has any direct favorable effect on neonatal outcomes or that any prolongation of pregnancy afforded by tocolytics actually translates into statistically significant neonatal benefit.

Contractions are the most commonly recognized antecedent of preterm birth. For this reason, cessation of uterine contractions has been the primary focus of therapeutic intervention. Many agents have been used to inhibit myometrial contractions, including magnesium sulfate, calcium channel blockers, oxytocin antagonists, nonsteroidal antiinflammatory drugs (NSAIDs), and beta-adrenergic receptor agonists (Table 1). Overall, the evidence supports the use of first-line tocolytic treatment with beta-adrenergic receptor agonists, calcium channel blockers, or NSAIDs for short-term prolongation of pregnancy (up to 48 hours) to allow for the administration of antenatal steroids (see Table 1) (30, 58, 59). One randomized trial suggested the potential role of transdermal nitroglycerine in short-term pregnancy prolongation, particularly those pregnancies at less than 28 weeks of gestation. However, its use was associated with significant maternal side effects (60). Recommendations for its use would require additional data that demonstrate its efficacy and safety.

Table 1.:

Common Tocolytic Agents

The use of magnesium sulfate to inhibit acute preterm labor has similar limitations when used for pregnancy prolongation (34, 61). However, if magnesium sulfate is being used in the context of preterm labor for fetal neuroprotection and the patient still is experiencing preterm labor, a different agent could be considered for short-term tocolysis. However, because of potential serious maternal complications, beta-adrenergic receptor agonists and calcium-channel blockers should be used with caution in combination with magnesium sulfate for this indication. Before 32 weeks of gestation, indometh-acin is a potential option for use in conjunction with magnesium sulfate. Several retrospective case–control studies and cohort studies evaluated neonatal outcomes, including necrotizing enterocolitis, after short-term antenatal indomethacin therapy (62–66). They have shown conflicting results regarding duration of therapy, gestational age at exposure, and the interval between exposure and delivery. As with all other tocolytics, indomethacin for short-term treatment of preterm labor should be used after carefully weighing the potential benefits and risks.

In 2011, the U.S. Food and Drug Administration (FDA) issued a warning regarding the use of terbutaline to treat preterm labor because of reports of serious maternal side effects (67). Another review reported possible deleterious behavioral effects in offspring after in utero exposure to beta-adrenergic receptor agonists (68). These data suggest that the use of terbutaline should be limited to short-term inpatient use as a tocolytic or for the acute antepartum therapy of uterine tachysystole.

• Should tocolytics be used after acute therapy?

Maintenance therapy with tocolytics is ineffective for preventing preterm birth and improving neonatal outcomes and is not recommended for this purpose. A meta-analysis has not shown any differences between magnesium sulfate maintenance therapy and either placebo or beta-adrenergic receptor agonists in preventing preterm birth after an initial treated episode of threatened preterm labor (69). Likewise, maintenance beta-agonist therapy has not been demonstrated to prolong pregnancy or prevent preterm birth and should not be used for this purpose (70). The FDA posted warnings specifically cautioning against the use of maintenance oral terbutaline during pregnancy (67). Because of the lack of efficacy and potential maternal risk, the FDA states that oral terbutaline should not be used at all to treat preterm labor. Injectable terbutaline may be used only in an inpatient, monitored setting but should not be used for longer than 48–72 hours (67). When compared with placebo, maintenance tocolysis with nifedipine does not appear to confer a reduction in preterm birth or improvement in neonatal outcomes (71). Atosiban is the only tocolytic that has demonstrated superiority as maintenance therapy over placebo in prolonging pregnancy, but atosiban is not available in the United States (72).

• Is there a role for antibiotics in preterm labor?

Intrauterine bacterial infection is an important cause of preterm labor, particularly at gestational ages less than 32 weeks (73, 74). It has been theorized that infection or inflammation is associated with contractions. Based on this concept, the utility of antibiotics to prolong pregnancy and reduce neonatal morbidity in women with preterm labor and intact membranes has been evaluated in numerous randomized clinical trials. However, most have failed to demonstrate antibiotic benefit; a meta-analysis of eight randomized controlled trials that compared antibiotic treatment with placebo for patients with documented preterm labor found no difference between the antibiotic treatment and placebo for prolonging pregnancy or preventing preterm delivery, respiratory distress syndrome, or neonatal sepsis (58). In fact, antibiotic use may be associated with long-term harm (75). Thus, antibiotics should not be used to prolong gestation or improve neonatal outcomes in women with preterm labor and intact membranes. This recommendation is distinct from recommendations for antibiotic use for pre-term premature rupture of membranes (76) and group B streptococci carrier status (77, 78).

• Is there a role for nonpharmacologic management of women with preterm contractions or preterm labor?

The assessment of preterm delivery risk based on symp-toms and physical examination alone is inaccurate (17, 79, 80). Previously, when symptoms of possible preterm labor were present, clinicians recommended reduced maternal activity and hydration with or without sedatives, with the aim of reducing uterine activity. Most experts advocated awaiting cervical dilation or effacement before administering tocolytic drugs. However, prophylactic therapy (tocolytic drugs, bed rest, hydration, and sedation) in asymptomatic women at increased risk of preterm delivery has not been demonstrated to be effective (41, 81). Although bed rest and hydration have been recommended to women with symptoms of preterm labor to prevent preterm delivery, these measures have not been shown to be effective for the prevention of preterm birth and should not be routinely recommended. Furthermore, the potential harm, including venous thromboembolism, bone demineralization, and deconditioning, and the negative effects, such as loss of employment, should not be underestimated (13–16, 82, 83).

• Is preterm labor managed differently in women with multiple gestations?

The use of tocolytics to inhibit preterm labor in multiple gestations has been associated with a greater risk of maternal complications, such as pulmonary edema (84, 85). In addition, prophylactic tocolytics have not been shown to reduce the risk of preterm birth or improve neonatal outcomes in women with multiple gestations (86–89). Adequate data do not exist to specifically demonstrate benefit from the use of antenatal corticosteroids in multiple gestations. However, because of the clear benefit attributable to the use of antenatal corticosteroids in singleton gestations, most experts recommend their use in preterm multiple gestations. Similar extrapolation could also apply to the use of magnesium sulfate for fetal neuroprotection in multiple gestations.

Summary of Recommendations

The following recommendations and conclusions are based on good and consistent scientific evidence (Level A):

• A single course of corticosteroids is recommended for pregnant women between 24 weeks and 34 weeks of gestation who are at risk of delivery within 7 days.
• Accumulated available evidence suggests that magnesium sulfate reduces the severity and risk of cerebral palsy in surviving infants if administered when birth is anticipated before 32 weeks of gestation. Hospitals that elect to use magnesium sulfate for fetal neuroprotection should develop uniform and specific guidelines for their departments regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.
• The evidence supports the use of first-line tocolytic treatment with beta-adrenergic agonist therapy, calcium channel blockers, or NSAIDs for short-term prolongation of pregnancy (up to 48 hours) to allow for the administration of antenatal steroids.
• Maintenance therapy with tocolytics is ineffective for preventing preterm birth and improving neonatal outcomes and is not recommended for this purpose.
• Antibiotics should not be used to prolong gestation or improve neonatal outcomes in women with preterm labor and intact membranes.

The following recommendations and conclusions are based on limited and inconsistent scientific evidence (Level B):

• For women with ruptured membranes or multiple gestations who are at risk of delivery within 7 days, a single course of corticosteroids is recommended between 24 weeks and 34 weeks of gestation.
• A single course of corticosteroids may be considered starting at 23 weeks of gestation for pregnant women who are at risk of preterm delivery within 7 days, irrespective of membrane status.
• A single repeat course of antenatal corticosteroids should, therefore, be considered in women who are less than 34 weeks of gestation, who are at risk of preterm delivery within the next 7 days, and whose prior course of antenatal corticosteroids was administered more than 14 days previously. Rescue course corticosteroids could be provided as early as 7 days from the prior dose, if indicated by the clinical scenario.
• Bed rest and hydration have not been shown to be effective for the prevention of preterm birth and should not be routinely recommended.
• The positive predictive value of a positive fetal fibronectin test result or a short cervix alone is poor and should not be used exclusively to direct management in the setting of acute symptoms.

Proposed Performance Measure

The proportion of women with preterm labor at less than 34 weeks of gestation who receive corticosteroid therapy

References

1. Tucker JM, Goldenberg RL, Davis RO, Copper RL, Winkler CL, Hauth JC. Etiologies of preterm birth in an indigent population: is prevention a logical expectation? Obstet Gynecol 1991;77:343–7. (Level II-3)

2. Savitz DA, Blackmore CA, Thorp JM. Epidemiologic characteristics of preterm delivery: etiologic heterogeneity. Am J Obstet Gynecol 1991;164:467–71. (Level III)

3. Kramer MS. Preventing preterm birth: are we making any progress? Yale J Biol Med 1997;70:227–32. (Level III)

4. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Mathews TJ, Osterman MJ. Births: final data for 2008. Natl Vital Stat Rep 2010;59(1):1–72. Available at http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_01.pdf. Retrieved June 28, 2011. (Level II-3)

5. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for 2009. Natl Vital Stat Rep 2010;59(3):1–19. Available at http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_03.pdf. Retrieved June 28, 2011. (Level II-3)

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

7. Volpe JJ. Overview: perinatal and neonatal brain injury. Ment Retard Dev Disabil Res Rev 1997;3:1–2. (Level III)

8. Mathews TJ, MacDorman MF. Infant mortality statistics from the 2006 period linked birth/infant death data set. Natl Vital Stat Rep 2010;58(17):1–31. (Level II-3)

9. MacDorman MF, Callaghan WM, Mathews TJ, Hoyert DL, Kochanek KD. Trends in preterm-related infant mortality by race and ethnicity: United States, 1999–2004. NCHS Health E-Stat. Hyattsville (MD): National Center for Health Statistics; 2007. Available at: http://www.cdc.gov/nchs/data/hestat/infantmort99-04/infantmort99-04.htm. Retrieved July 25, 2011. (Level II-3)

10. Institute of Medicine. Preterm birth: causes, consequences, and prevention. Washington, DC: National Academies Press; 2007. (Level III)

11. Fuchs IB, Henrich W, Osthues K, Dudenhausen JW. Sonographic cervical length in singleton pregnancies with intact membranes presenting with threatened preterm labor. Ultrasound Obstet Gynecol 2004;24:554–7. (Level II-3)

12. Berkowitz GS, Blackmore-Prince C, Lapinski RH, Savitz DA. Risk factors for preterm birth subtypes. Epidemiology 1998;9:279–85. (Level II-3)

13. Kovacevich GJ, Gaich SA, Lavin JP, Hopkins MP, Crane SS, Stewart J, et al. The prevalence of thromboembolic events among women with extended bed rest prescribed as part of the treatment for premature labor or preterm premature rupture of membranes. Am J Obstet Gynecol 2000; 182:1089–92. (Level III)

14. Sosa C, Althabe F, Belizan JM, Bergel E. Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003581. DOI: 10.1002/14651858.CD003581.pub2. (Level III)

15. Kaji T, Yasui T, Suto M, Mitani R, Morine M, Uemura H, et al. Effect of bed rest during pregnancy on bone turnover markers in pregnant and postpartum women. Bone 2007;40:1088–94. (Level II-3)

16. Maloni JA. Antepartum bed rest for pregnancy complications: efficacy and safety for preventing preterm birth. Biol Res Nurs 2010;12:106–24. (Level III)

17. Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A, Iams JD, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol 1997;177:13–8. (Level II-2)

18. Swamy GK, Simhan HN, Gammill HS, Heine RP. Clinical utility of fetal fibronectin for predicting preterm birth. J Reprod Med 2005;50:851–6. (Level II-2)

19. Skoll A, St Louis P, Amiri N, Delisle MF, Lalji S. The evaluation of the fetal fibronectin test for prediction of preterm delivery in symptomatic patients. J Obstet Gynaecol Can 2006;28:206–13. (Level II-3)

20. Giles W, Bisits A, Knox M, Madsen G, Smith R. The effect of fetal fibronectin testing on admissions to a tertiary maternal–fetal medicine unit and cost savings. Am J Obstet Gynecol 2000;182:439–42. (Cost–benefit analysis)

21. Joffe GM, Jacques D, Bemis-Heys R, Burton R, Skram B, Shelburne P. Impact of the fetal fibronectin assay on admissions for preterm labor. Am J Obstet Gynecol 1999; 180:581–6. (Level II-2)

22. Plaut MM, Smith W, Kennedy K. Fetal fibronectin: the impact of a rapid test on the treatment of women with preterm labor symptoms. Am J Obstet Gynecol 2003; 188:1588–93; discussion 1593–5. (Level I)

23. Grobman WA, Welshman EE, Calhoun EA. Does fetal fibronectin use in the diagnosis of preterm labor affect physician behavior and health care costs? A randomized trial. Am J Obstet Gynecol 2004;191:235–40. (Level I)

24. 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;197:426.e1–7. (Level II)

25. Berghella V, Hayes E, Visintine J, Baxter JK. Fetal fibro- nectin testing for reducing the risk of preterm birth.Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD006843. DOI: 10.1002/14651858.CD006843.pub2. (Systematic review)

26. Lewit EM, Baker LS, Corman H, Shiono PH. The direct cost of low birth weight. Future Child 1995;5:35–56. (Level III)

27. Ferguson JE 2nd, Dyson DC, Holbrook RH Jr, Schutz T, Stevenson DK. Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis. Am J Obstet Gynecol 1989;161:788–95. (Level I)

28. 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. (Level I) [PubMed]

29. Bracero LA, Leikin E, Kirshenbaum N, Tejani N. Com-parison of nifedipine and ritodrine for the treatment of preterm labor. Am J Perinatol 1991;8:365–9. (Level I)

30. Anotayanonth S, Subhedar NV, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004352. DOI: 10.1002/14651858.CD004352.pub2. (Level III)

31. Allen JR, Helling TS, Langenfeld M. Intraabdominal surgery during pregnancy. Am J Surg 1989;158:567–9. (Level III)

32. Hunt MG, Martin JN Jr, Martin RW, Meeks GR, Wiser WL, Morrison JC. Perinatal aspects of abdominal surgery for nonobstetric disease. Am J Perinatol 1989;6:412–7. (Level III)

33. Iams JD, Romero R. Preterm birth. In: Gabbe SG, Niebyl JR, Simpson JL, editors. Obstetrics: normal and problem pregnancies. 5th ed. Philadelphia (PA): Churchill Living-stone Elsevier; 2007. p. 668–712. (Level III)

34. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour.Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD001060. DOI: 10.1002/14651858.CD001060. (Level III)

35. Periviable Birth. Obstetric Care Consensus No. 3. American College of Obstetricians and Gynecologists. Obstet Gynecol 2015;126:e82–94. (Level III)

36. Antenatal corticosteroids revisited: repeat courses. NIH Consens Statement 2000;17(2):1–18. (Level III)

37. Antenatal Corticosteroid Therapy for Fetal Maturation. Committee Opinion No. 677. American College of Obstetricians and Gynecologists. Obstet Gynecol 2016; 128:e187–94.

3 8. Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, et al. Antenatal betamethasone for women at risk for late preterm delivery. NICHD Maternal–Fetal Medicine Units Network. N Engl J Med 2016;374:1311–20. (Level I) [PubMed] [Full Text]

39. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004454. DOI: 10.1002/14651858.CD004454.pub2. (Meta-analysis)

40. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consens Statement 1994;12(2):1–24. (Level III)

41. Berkman ND, Thorp JM Jr, Hartmann KE, Lohr KN, Idicula AE, McPheeters M, et al. Management of preterm labor. Evidence Report/Technology Assessment No. 18 (Prepared by Research Triangle Institute under Contract No. 290-97-0011). AHRQ Publication No. 01-E021. Rockville (MD): Agency for Healthcare Research and Quality; 2000. (Level III)

42. Garite TJ, Kurtzman J, Maurel K, Clark R. Impact of a ‘rescue course’ of antenatal corticosteroids: a multi-center randomized placebo-controlled trial. Obstetrix Collaborative Research Network [published erratum appears in Am J Obstet Gynecol 2009;201:428]. Am J Obstet Gynecol 2009;200:248.e1–9. (Level I)

43. Crowther CA, McKinlay CJ, Middleton P, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD003935. DOI: 10.1002/14651858.CD003935.pub4. (Meta-analysis)

44. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995;173:254–62. (Level III)

45. Antenatal corticosteroid therapy for fetal maturation. Com-mittee Opinion No. 475. American College of Obstetri-cians and Gynecologists. Obstet Gynecol 2011;117:422–4. (Level III)

46. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95:263–9. (Level II-3)

47. Schendel DE, Berg CJ, Yeargin-Allsopp M, Boyle CA, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996;276:1805–10. (Level II-2)

48. Paneth N, Jetton J, Pinto-Martin J, Susser M. Magnesium sulfate in labor and risk of neonatal brain lesions and cerebral palsy in low birth weight infants. The Neonatal Brain Hemorrhage Study Analysis Group. Pediatrics 1997;99:E1. (Level II-2)

49. Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet 1997; 350:1517–8. (Level III)

50. Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG, Besinger RE, et al. Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. Am J Obstet Gynecol 2002; 186:1111–8. (Level I)

51. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. JAMA 2003;290:2669–76. (Level I)

52. Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Leveque C, Hellot MF, et al. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomised controlled PREMAG trial. PREMAG trial group. BJOG 2007;114:310–8. (Level I)

53. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. Eunice Kennedy Shriver NICHD Maternal–Fetal Medicine Units Network. N Engl J Med 2008;359:895–905. (Level I)

54. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD004661. DOI: 10.1002/14651858.CD004661.pub3. (Meta-analysis)

55. Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and metaanalysis. Am J Obstet Gynecol 2009;200:595–609. (Meta-analysis)

56. Costantine MM, Weiner SJ. Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis. Eunice Kennedy Shriver National Institute of Child Health and Human Develop-ment Maternal–Fetal Medicine Units Network. Obstet Gynecol 2009;114:354–64. (Meta-analysis)

57. Magnesium sulfate before anticipated preterm birth for neuroprotection. Committee Opinion No. 455. American College of Obstetricians and Gynecologists and Society for Maternal–Fetal Medicine. Obstet Gynecol 2010;115: 669–71. (Level III)

58. King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002255. DOI: 10.1002/14651858.CD002255; 10.1002/14651858.CD002255. (Meta-analysis)

59. King JF, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD001992. DOI: 10.1002/14651858.CD001992.pub2. (Level III)

60. Smith GN, Walker MC, Ohlsson A, O’Brien K, Windrim R. Randomized double-blind placebo-controlled trial of transdermal nitroglycerin for preterm labor. Canadian Preterm Labour Nitroglycerin Trial Group. Am J Obstet Gynecol 2007;196:37.e1–8. (Level I)

61. Mercer BM, Merlino AA. Magnesium sulfate for preterm labor and preterm birth. Society for Maternal–Fetal Medi-cine. Obstet Gynecol 2009;114:650–68. (Meta-analysis)

62. Sood BG, Lulic-Botica M, Holzhausen KA, Pruder S, Kellogg H, Salari V, et al. The risk of necrotizing enter- ocolitis after indomethacin tocolysis. Pediatrics 2011;128: e54–62. (Level II-2)

63. Abbasi S, Gerdes JS, Sehdev HM, Samimi SS, Ludmir J. Neonatal outcome after exposure to indomethacin in utero: a retrospective case cohort study. Am J Obstet Gynecol 2003;189:782–5. (Level II-2)

64. Parilla BV, Grobman WA, Holtzman RB, Thomas HA, Dooley SL. Indomethacin tocolysis and risk of necrotizing enterocolitis. Obstet Gynecol 2000;96:120–3. (Level II-2)

65. 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 (Level II-2)

66. Soraisham AS, Dalgleish S, Singhal N. Antenatal indomethacin tocolysis is associated with an increased need for surgical ligation of patent ductus arteriosus in pre- term infants. J Obstet Gynaecol Can 2010;32:435–42. (Level II-2)

67. U.SFood and Drug Administration. FDA drug safety communication: new warnings against use of terbutaline to treat preterm labor. Silver Spring (MD): FDA; 2011. Available at: http://www.fda.gov/drugs/drugsafety/ucm243539.htm. Retrieved March 20, 2012. (Level III)

68. Witter FR, Zimmerman AW, Reichmann JP, Connors SL. In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes. Am J Obstet Gynecol 2009;201:553–9 (Level III)

69. Han S, Crowther CA, Moore V. Magnesium mainte- nance therapy for preventing preterm birth after threat-ened preterm labour. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD000940. DOI: 10.1002/ 14651858.CD000940.pub2. (Level III)

70. Dodd JM, Crowther CA, Dare MR, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD003927. DOI: 10.1002/ 14651858.CD003927.pub2. (Level III)

71. Lyell DJ, Pullen KM, Mannan J, Chitkara U, Druzin ML, Caughey AB, et al. Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial. Obstet Gynecol 2008;112:1221–6. (Level I)

72. Valenzuela GJ, Sanchez-Ramos L, Romero R, Silver HM, Koltun WD, Millar L, et al. Maintenance treatment of preterm labor with the oxytocin antagonist atosiban. The Atosiban PTL-098 Study Group. Am J Obstet Gynecol 2000;182:1184–90. (Level I)

73. Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319:972–8. (Level II-2)

74. Hillier SL, Witkin SS, Krohn MA, Watts DH, Kiviat NB, Eschenbach DA. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection. Obstet Gynecol 1993;81:941–8. (Level III)

75. King JF, Flenady V, Murray L. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD000246. DOI: 10.1002/14651858.CD000246. (Meta-analysis)

76. Premature rupture of membranes. ACOG Practice Bulle-tin No. 80. American College of Obstetricians and Gyne-cologists. Obstet Gynecol 2007;109:1007–19. (Level III)

77. Prevention of perinatal group B streptococcal disease — revised guidelines from CDC, 2010. Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases. MMWR Recomm Rep 2010;59 (RR-10):1–36. (Level III)

78. Prevention of early-onset group B streptococcal disease in newborns. Committee Opinion No. 485. American College of Obstetricians and Gynecologists. Obstet Gynecol 2011;117:1019–27. (Level III)

79. Main DM, Gabbe SG, Richardson D, Strong S. Can preterm deliveries be prevented? Am J Obstet Gynecol 1985; 151:892–8. (Level I)

80. Dyson DC, Crites YM, Ray DA, Armstrong MA. Prevention of preterm birth in high-risk patients: the role of education and provider contact versus home uterine monitoring. Am J Obstet Gynecol 1991;164:756–62. (Level II-1)

81. Goldenberg RL. The management of preterm labor. Obstet Gynecol 2002;100:1020–37. (Level III)

82. Luke B, Mamelle N, Keith L, Munoz F, Minogue J, Papiernik E, et al. The association between occupational factors and preterm birth: a United States nurses’ study. Research Committee of the Association of Women’s Health, Obstetric, and Neonatal Nurses. Am J Obstet Gynecol 1995;173:849–62. (Level II-3)

83. Stan CM, Boulvain M, Pfister R, Hirsbrunner-Almagbaly P. Hydration for treatment of preterm labour. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD003096. DOI: 10.1002/14651858.CD003096. (Meta-analysis)

84. Wilkins IA, Lynch L, Mehalek KE, Berkowitz GS, Berkowitz RL. Efficacy and side effects of magnesium sulfate and ritodrine as tocolytic agents. Am J Obstet Gynecol 1988;159:685–9. (Level I)

85. Samol JM, Lambers DS. Magnesium sulfate tocolysis and pulmonary edema: the drug or the vehicle? Am J Obstet Gynecol 2005;192:1430–2. (Level II-3)

86. Cetrulo CL, Freeman RK. Ritodrine HCL for the prevention of premature labor in twin pregnancies. Acta Genet Med Gemellol 1976;25:321–4. (Level III)

87. O’Leary JA. Prophylactic tocolysis of twins. Am J Obstet Gynecol 1986;154:904–5. (Level II-2)

88. Ashworth MF, Spooner SF, Verkuyl DA, Waterman R, Ashurst HM. Failure to prevent preterm labour and deliv- ery in twin pregnancy using prophylactic oral salbutamol. Br J Obstet Gynaecol 1990;97:878–82. (Level I)

89. Yamasmit W, Chaithongwongwatthana S, Tolosa JE, Limpongsanurak S, Pereira L, Lumbiganon P. Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD004733. DOI: 10.1002/ 14651858.CD004733.pub2. (Meta-analysis)