Adverse and beneficial effects of tocolytic therapy

Adverse and Beneficial Effects of Tocolytic Therapy Peter G. Pryde, Richard E. Besinger, John G. Gianopoulos, and Robert Mittendorf

In addition to questions raised about the efficacy of many tocolytics, appropriate c o n c e r n has b e e n voiced about the safety of these potent drugs. Although s o m e degree of risk for adverse effects with drugs promising a strong therapeutic effect can be accepted, caution n e e d s to be exercised when benefits are marginal or unproven. Unfortunately, s o m e o f the tocolytics, m o s t notably the betamitactics and maomaesium sulfate, have been f o u n d to have considerable potential for adverse maternal cardiovascular and respiratory effects. Although less dearly established, the use of indomethacin appears to be associated with increased fetal and neonatal risks. Concerning magnesium sulfate, in addition to the well-known maternal effects, the accum~ating evidence showing an increased frequency o f adverse o u t c o m e s in the fetus and n e o n a t e has led to the r e c o m m e n d a t i o n s to a b a n d o n its use entirely as a tocolytic. Given the limitations o f our current state of knowledge, nifedipine w o u l d appear to be a m o n g the m o r e efficacious and safer tocolytics available to use w h e n properly indicated. Co~'ght

9 2001 by W.B. Saunders Company

p

reterm birth is the leading cause of neonatal mortality and morbidity in developed countries-. 1 Although some instances of preterm birth are iatrogenic (deliberately effected preterm deliveries for maternal or fetal indications), the majority is caused by spontaneous preterm labor with or without prior rupture of membranes. 2 In view of the enormity of the social, economic, and emotional costs of premature birth, there has been an intensive effort, by scientists and clinicians Mike, to understand its pathophysiology, and to develop treatment strategies. Despite this effort, highlighted by the hopeful introduction of numerous "tocolytic" agents, there has been no decline in the rate of preterm birth in the past 40 years, a,4 Tocolytic medications, drugs that are given with the intention of inhibiting uterine contractions to prolong pregnancy, are extensively emFrom the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI; and the Divisions of Maternal-Fetal Medicine and General Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Loyola University Medical Center, Maywood, IL. Address reprint requests to Robert Mittendorf MD, Department of Obstetrics and Gynecology, Loyola UniversityMedical Center, 2160 South First Ave, Maywood, IL 60153; e-mail: [email protected]. Copyright 9 2001 by W.B. Saunders Company 0146-0005/01/2505-0006535.00/0 doi:l O.l O53/sper.2001.2754 7

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ployed in the m o d e r n m a n a g e m e n t of preterm labor. 5 However, several recent reviews and meta-analyses have questioned the evidence basis of such practice. 6-8 Unfortunately, tocolytic utility (that we define as the ability not only to prolong pregnancy, but also to measurably improve perinatal outcomes, and to do so safely) has been difficult to show with currently available agents. In fact, there are remarkably few data demonstrating measurable improvement in perinatal outcomes using any of the currently available tocolytics.4,6,7 More worrisome, in this light, are emerging data that bring the maternal and fetal safety of most currently employed tocolytics into question. With many medical interventions, clinicians make choices among treatment options after careful consideration of therapeutic risks and benefits. In the best circumstances, medical science provides firm data to allow an evidence basis for such analyses. If a therapy is available that has considerable potential benefit, then, depending on clinical circumstances and patient preferences, varying levels of risk are considered acceptable. However, if the proposed therapy is of marginal, or unsure benefit, then far less therapy-related risk can be tolerated. Unfortunately, there remain medical problems for which available data are not yet sufficient to allow optimal evidence-based decision-making.

Seminars in Perinatology, Vol 25, No 5 (October), 2001: pp 316-340

Tocolytic Therapy

Preterm labor is one of these situations and, as such, clinical decisions need to be made based on data of less than optimal strength. 4 Herein we review modern tocolytic therapies with an emphasis on current data that are available relating to the benefits and risks of such therapy. Hopefully, this summary can assist clinicians making treatment decisions in women with suspected preterm labor. Finally, we briefly discuss future research directions that may clarify this still highly controversial area.

Magnesium Sulfate Intravenous magnesium sulfate has been used in the United States as treatment for eclamptic convulsions, and for seizure prophylaxis in the setting of suspected preeclampsia, since 1906. 9 This practice, although previously controversial, has recently gained wide international acceptance due to convincing evidence from randomized clinical trials demonstrating both efficacy and superiority over alternative preeclampsia seizure-prophylactic therapies. 1~ In contrast, the employment of magnesium sulfate as a tocolyric, although recently identified as the first line agent for that indication in North America, 5 has met with cautious criticism and avoidance in m u c h of Europe, Australia, and the United Kingdom. 12 The basis for such criticism is the absence of clear evidence showing tocolytic efficacy, despite reports indicating potential maternal, and possibly even fetal, toxicity when delivered in the high dosages sometimes used for tocolysis.

Tocolytic Efficacy The earliest reported use of magnesium sulfate as a tocolytic, in the late 1960s, was based not on controlled clinical trials, but rather on the promise of compelling laboratory experiments. These experiments showed in vitro, magnesium-mediated, impairment of myometrial contractility, by a poorly understood mechanism presumably involving blockage of calcium ion cellular influx and complex modification of intracellular calcium ion binding, molecular interaction, and distribution. It was almost 10 years later that the first clinical study of magnesium as a single agent tocolytic appeared in the American literature. 13 In all probability, the reason for this in-

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troduction of magnesium into clinical practice, before systematic clinical testing, was the fact that the American obstetric community already had extensive experience with its use in preeclampsia. Perhaps because magnesium sulfate appeared to be generally safe in the setting of preeclampsia, it was thought that there was little reason to question its safety when used for tocolysis. Since that time, numerous studies relating to the tocolytic efficacy of magnesium sulfate have been published. Most of these studies, unfortunately, are observational, or have not been properly controlled. The only randomized trials, to date, comparing magnesium to saline control, failed to show any measure of tocolytic efficacy, or any measure of improvement in perinatal outcome. 14,15 Additionally, systematic reviews and meta-analyses by experts in the United States, 7.s Canada, 6 and the United Kingdom, 16 have all failed to detect evidence of tocolytic benefit, while each has raised concern over maternal and fetal safety.

Putative Nontocolytic Benefits of Magnesium Sulfate: The Cerebroprotective Hypothesis Although the tocolytic efficacy of magnesium sulfate has been called into serious question, the possibility of a nontocolytic benefit of magnesium infusion (in the setting of anticipated pretelan delivery) has recently received considerable attention. This putative benefit was suggested after 2 recent epidemiological studies independently reported an association between antenatal intravenous magnesium sulfate exposure and a reduction in cerebral palsy. These important studies, having generated an intriguing "cerebroprotective hypothesis" and extensive ongoing international research activity, deserve careful consideration. The first study, by Nelson and Grether, 17 was a case-control design using population-based data from the California Birth Defects Surveillance Program. In that data set of more than 150,000 children followed from birth to at least $ years of age, 42 cases of cerebral palsy were diagnosed among the very low birth weight (<1500 g) surviving neonates. Only 3 of these 42 cases (7%) had been exposed to intravenous antenatal magnesium sulfate (either for seizure

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prophylaxis in preeclampsia or for tocolysis). This is compared with 27 magnesium-exposed infants among 75 randomly selected gestational age matched controls (36%) that did not have cerebral palsy (odds ratio [OR] 0.14, 95% Confidence Interval [CI] .05 to .51). Among the subgroup of women who were not preeclamptic, the apparent protective effect of magnesium was less profound, but still protective (OR 0.25, 95% CI .08 to .97). This latter finding is important because preeclampsia, for reasons that are not well understood, is protective against the outcome of cerebral palsy, even in the absence of exposure to magnesium sulfate. TM The second epidemiological study, reported by Schendel et al, 19 was a cohort study conducted at the United States Centers for Disease Control and Prevention, Atlanta, in which a subset of children was followed to at least 3 years of age. Among Atlanta-born survivors, those exposed to magnesium appeared to have a lower prevalence of cerebral palsy (crude OR 0.11, 95% CI .02 to .81). However, when these data were adjusted for confounding, in a multivariable model, the finding no longer achieved statistical significance. A similar, but also not statistically significant, trend was found for the outcome of mental retardation in which nearly 6% of unexposed children were affected, whereas only about 2% of those exposed to magnesium sulfate were found to be retarded (crude OR 0.3, 95% CI .07 to 1.29). For the entire cohort, no association was found between antenatal magnesium sulfate exposure and infant mortality (adjusted OR 1.0, 95% CI .83 to 1.25). However, when the data were restricted to children from metropolitan Atlanta, arguably the subset with the best follow-up data, an estimated 20% excess risk for mortality following antenatal magnesium sulfate exposure was found, although this did not quite reach statistical significance (OR 1.2, 95% CI .95 to 1.50). Thus Schendel et al's studya9 supported the apparent association between antenatal magnesium exposure and a reduction in prematurityrelated neurodevelopment injury, which was reported initially by Nelson and Grether. 17 It also began to address a concern, raised by critics of the first study, that magnesium may have reduced the prevalence of cerebral palsy simply by increasing the death rate among susceptible fetuses and infants. However, because of the birth

certificate based source of the data used, neither of these studies could evaluate possibly relevant fetal deaths, an important component of total pediatric mortality that needs to be considered to fully address that concern (an issue to be discussed later). Nonetheless, the findings of both studies were compelling, and initiated an optimistic research effort internationally. Several very large, randomized clinical trials, designed to test the magnesium cerebroprotective hypothesis, are ongoing, and the results are eagerly anticipated.

Possible Adverse Effects of Tocolytic Magnesium Maternal Adverse Effects Numerous maternal complications are associated with intravenous magnesium sulfate administered for the purposes of tocolysis. Unpleasant side effects include flushing, nausea with or without vomiting, diplopia, blurred vision, and headache. More serious physiologic perturbations, not infrequently seen in clinical practice, include ileus, and hypocalcemia. Hypoxia, secondary to pulmonary edema, is the most hazardous of the common maternal complications, and appears to be more often seen when magnesium is used in combination with one or more other tocolytic agents a n d / o r corticosteroids. Rarely, extremely high serum magnesium concentrations, seen with accidental over dosage or in the setting of poor maternal renal function and clearance, have resulted in subendocardial ischemia, cardiac arrest, and even maternal death.

Fetal Adverse Effects Fetal serum levels of magnesium sulfate quickly equilibrate with,2~and ultimately exceed, (Pryde PG, Borg MJ, Mittendorf R, Elin RJ. Cord-blood ionized magnesium [iMg] levels exceed maternal levels in both untreated and tocolytic magnesium sulfate treated preterm neonates. Am J Obstet Gynecol 180:S106, 1999 [abstr]) those of the mother undergoing prolonged tocolysis. Clearly established neonatal adverse effects include transient lethargy and often-profound hypotonia. 21 Concerns about bone mineralization abnormalities, subsequent to prolonged exposure, also have been raisedY 2 Additionally, several basic science investigators have published reports questioning the safety of tocolytic dos-

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ages of magnesium sulfate. These reports include: 1) The finding of elevated cardiac troponin levels (a marker of cardiac injury) in magnesium exposed neonates, 23 2) Dose-related excess mortality among magnesium-exposed fetal sheep u n d e r conditions of physiologic stressfl 4 and 3) Potentially deleterious physiologic responses related to magnesium sulfate administration in a newborn piglet meconium aspiration model. 25 Fetal Adverse Effects: The MagNET Trial It was in the context of the epidemiological studies discussed above, indicating a possible neuroprotective benefit of magnesium, that the Magnesium and Neurologic Endpoints Trial (MagNET) was conducted in Chicago. The purpose of this randomized clinical trial was to systematically test the cerebroprotecfive efficacy of magnesium sulfate. However, quite unexpectedly, early data monitoring suggested that there might be heretofore-unrecognized deleterious fetal effects of tocolytic magnesium sulfate. The results of the MagNET, although still controversial (Correspondence, "Tocolytic magnesium sulphate and paediatric mortality." Lancet 351: 290-292, 1998), will frame our further discussion regarding, not beneficial, but rather possible adverse fetal effects of magnesium sulfate when used in the very high doses employed for tocolysis. MagNET, funded by the United Cerebral Palsy Research and Educational Foundation, was actually 2 parallel trials with four arms. In the tocolyfic portion of the trial, gravidas in preterm labor at <34 weeks' gestation and (4-cm dilated were randomized to receive either tocolytic dosages of magnesium sulfate versus clinician's choice of an alternative tocolytic (ritodrine, terbutaline, nifedipine, or indomethacin). In the preventive portion of the trial, women in preterm labor, but with cervical dilatation too advanced to be tocolyzed were randomized to either a 4 g bolus of intravenous magnesium sulfate (a putative "neuroprotective dosage") versus an equivalent volume of physiological saline as control. Mothers with preeclampsia were excluded because all such women in the United States routinely receive magnesium as prophylaxis. Unfortunately, after only 15 months of enroll-

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ment, MagNET was suspended by the Institutional Review Board because of excess mortality in the arms randomized and exposed to magnesium sulfate. Overall, there were 10 pediatric deaths among 75 randomizations to magnesium sulfate compared with a single pediatric death among 75 randomizations to "other" tocolytics or saline control. By intent-to-treat analysis, the difference was statistically significant (risk difference 10.7%, 95% CI 2.9% to 18.5%; two-sided Fisher exact test, P =.02). In the tocolytic arms, 8 pediatric deaths occurred in 46 randomizations to magnesium sulfate and no pediatric deaths occurred in 47 randomizations to other tocolytics (risk difference 15.2%, 95% CI 4.4 to 26.0%; P =.01). On testing the randomization for balance, we f o u n d no differences in the groups with the exception of exposure to magnesium sulfate. Among the 9 total deaths that occurred after randomization and actual exposure to magnesium, one death occurred immediately before delivery, 4 were in the neonatal period, and 4 occurred in the postneonatal period. At the request of the Data Monitoring and Safety Committee of the United Cerebral Palsy Research and Educational Foundation, these mortal outcomes were reported as a Research Letter in Lancet, ~6 which was accompanied by a separate Commentary 12 requested independently by the L o n d o n editors. The autopsy findings for the 9 dead children are shown in Table 1. Although the Institutional Review Board suspended MagNET, the suspension was meant to be temporary pending further evaluation concerning the safety record of magnesium sulfate in its use as a tocolytic. To satisfy this request, we did an in-depth analysis of the English language literature focusing on maternal and fetal safety data from randomized controlled trials involving tocolytic magnesium sulfate. As it turned out, despite its initiation for use in preterm labor, in the 1960s, there were no randomized controlled trials of magnesium as a single-agent tocolytic until 1977 is (Table 2). Even more striking, 6 of the first 7 trials of tocolytic magnesium sulfate did not collect data on pediatric mortality, aa,27-s1 In fact, the first randomized controlled trial of magnesium, as a tocolytic, in which any perinatal mortality data were reported was 1984, a2 followed by 2 other randomized controlled trials that collected incomplete aspects of perinatal

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Table 1. Deaths Associated With MgSO 4 Exposure

Age Birth Weight(g)

Age at Death(days)

Attributable Cause, Place of Death

1

28 wk 4 d 1035

128

2

31 wk 0 d 1620

96

3*

30 wk 2 d 1442

41

4*

30 wk 5 d 1585

24

5t

26 wk 6 d 692

3

Sudden infant death, DOA at other ER Sudden infant death, in other ER Sudden infant death, in other ER Congenital anomalies; NICU Twin-to-twin transfusion recipient: NICU

6t

26 wk 6 d 400

IUFD

7

33 wk 3 d 1825

8*

25 wk 0 d 568

Case

9-0 2 6 w k l d 8 8 5

16 260 I

Necropsy Finding Petechial haemorrhages of epicardium and pleura; mild pulmonary oedema Bronchopneumonia (? aspiration induced); pulmonary petechiae Focal myocardial necrosis; bronchopulmonary dysplasia Permission for necropsy not given Focal myocardial necrosis and cardiomyopathy: bronchopulmonary dysplasia Immaturity; no other findings

Twin-to-twin transfusion donor; labour and delivery Neonatal apnoea; in ER Pulmonary congestion; and focal alveolar haemorrhage Respiratory arrest; in Bronchopulmonary dysplasia with necrotising PICU pneumonia and hypertensive pulmonary vasculopathy; atrial septal defect Cardiopulmonary arrest; Subepicardial haemorrhage labour and delivery

* Twin death without death of sibling. t Twin death with death of sibling; w = weeks; d =days; Abbreviations: DOA, dead on arrival; ER, emergency room; NICU, neonatal intensive care unit; IUFD, intrauterine fetal death; PICU, paediatric intensive care unit. Reprinted from Mittendorf R, et al: Is tocolytic magnesium sulfate associated with increased total paediatric mortality? Lancet 350:1517-1518, 1997, with permission,z6

mortality data.3~, 34 T h e only 2 r a n d o m i z e d trials of tocolytic m a g n e s i u m sulfate versus saline control, in which total pediatric mortality (fetal + neonatal + postneonatal) data were collected, are the Parkland studyTM a n d MagNET. In the c o m b i n e d data f r o m these 2 trials, 12.3% (15 o f 122) exposures to tocolytic m a g n e s i u m sulfate were associated with d e a t h in children, whereas only 1.6% (2 o f 127) exposures to saline or o t h e r tocolytics led to death. A random-effects m o d e l a5 meta-analysis of these 2 trials shows a highly significant association between magnesium sulfate a n d total pediatric death (risk difference 10.7%, 95% CI 3.9 to 17.6; P = .002). Fetal Adverse Effects: N e w Data

A strong association between excess total pediatric mortality a n d tocolytic m a g n e s i u m exposure, as observed in the MagNET a n d retrospective analyses o f the Parkland trial, does not prove causality. In addition to a strong association, a n d reproducibility, showing causality requires additional s u p p o r t i n g evidence such as biological plausibility a n d evidence of a dose effect. Since

c o m p l e t i n g the MagNET trial, o u r research group, by using retrospective data (not including the MagNET cohort) collected over a 13-year p e r i o d at Chicago Lying-in Hospital, f o u n d a statistically significant association between the use o f high doses ( > 4 8 g) o f m a g n e s i u m sulfate a n d the o u t c o m e o f perinatal mortality. 36 Additional evidence, suggestive o f a dose-response effect in m a g n e s i u m related toxicity, c o m e f r o m secondary analyses o f MagNET data d e m o n s t r a t i n g a statistically significant association between high (>0.70 m m o l / L ) umbilical cord s e r u m ionized m a g n e s i u m levels collected at birth, a n d the o u t c o m e of total pediatric mortality. 37 Finally, we recently p r e s e n t e d new data at the 2001 Annual Meeting of the Society for Materual-Fetal Medicine indicating an association between higher levels o f ionized magnesium at delivery and the o u t c o m e o f s u b s e q u e n t neonatal intraventricular h e m o r r h a g e (Mittend o f f R, K h o s h n o o d B, Lee KS, et al: Association between m a g n e s i u m a n d intraventricular h e m orrhage. Am J Obstet Gynecol 184:S188, 2001 [abstr]). This latest finding is particularly dis-

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32 1

Table 2. English Language, Randomized-controlled Trials of Single-agent Tocolytic Magnesium for Preterm Labor Year

Investigators

Drugs Randomized (No. in Each Arm)

Trials in which no data were collected on pediatric mortality 1977 1982 1984 1985 1987 1988

Steer CM, Petrie RH 13 Miller JM, Jr, et al e7 Tchilinguirian NG, et a128 Beall MH, et a129 Hollander DI, et al~0 Wilkins IA, et a131

MgSO4 (31) MgSO 4 (14) Mg804 (36) MgSO 4 (46) MgSO 4 (31) MgSO4 (66)

versus ethanol (31) versus terbutaline (15) versus ritodrine (31) versus ritodrine (45) vs. terbutaline (40) versus ritodrine (30) versus ritodrine (54)

Trials in which neonatal (<--28 days of age) and fetal, but not postneonatal (>28, <365 days of age), mortality data were collected or derivable (numerator is the number of deaths): 1984

Cotton, et a132

1993 1993

Morales, et a133 Glock, et a134

MgSO4 (1/16) versus terbutaline (1/19) versus 5% dextrose in lactated Ringer's (4/19) MgSO 4 (1/51) versus indomethacin (1/49) MgSO 4 (0/41) versus nifedipine (2/39)

Trials in which total pediatric (fetal, neonatal, and posmeonatal) mortality data were collected (numerator is the number of deaths): 1990 1997

Cox, et al TM MagNET26

MgSO4 (8/76) versus saline control (2/80) MgSO 4 (7/46) versus other tocolytics (0/47)

Abbreviation: MgSO4, magnesium sulfate. Reprinted with permission from the American College of Obstetricians and Gynecologists (Mittendorf R, et al: Obstet Gynecol 92:308-311, 1998)

turbing in view o f the i n d e p e n d e n t observations, recently r e p o r t e d by the N I C H D Neonatal Research Network. This g r o u p f o u n d an increased incidence of periventricular leukomalacia in a large c o h o r t of p r e t e r m neonates e x p o s e d prenatal to magnesium, c o m p a r e d to gestational age m a t c h e d u n e x p o s e d neonates ( L e m o n s JA, Stevenson DIL Poole K, et al: In utero magnesium exposure: Effects in extremely low birth weight (ELBW) infants. Pediatr Res 45:207A, 1999 [abstr]). Subsequently, with longitudinal observation, they have f o u n d an i n c r e a s e d m n o t d e c r e a s e d - - r i s k for cerebral palsy after exposure to magnesium sulfate, even after adjustment for other risk factors, in the same cohort (LemonsJA, Vohr BR, Stevenson DK, et al: In utero magnesium exposure: Effects on ELBW infants at 18 m o n t h s o f age. Pediatr Res 49:388A, 2001 [abstr]).

MagNET Trial: Beneficial Effects? Despite o u r inability to e n t e r new patients into MagNET because of the suspension by the Institutional Review Board, we were p e r m i t t e d to c o n t i n u e follow-up o f the children who were already enrolled. We m a i n t a i n e d the c o h o r t a n d evaluated m o r e than 120 children at 18 m o n t h s of age to d e t e r m i n e whether or not cerebral

palsy was present (Mittendorf R, Bentz L, Borg M, Roizen N. Does exposure to antenatal magnesium sulfate prevent cerebral palsy? A m J Obstet Gynecol 182:$20, 2000 [abstr]). By using intent-to-treat analysis, in the tocolytic arms, 0% (0 of 37) of children exposed to tocolytic magnesium sulfate developed congenital cerebral palsy, whereas 8% (3 o f 36) o f children exposed to o t h e r tocolytics h a d cerebral palsy (two-sided Fisher exact test, P = .11). In the preventive arms, 15% (3 o f 20) o f children exposed to a 4 g bolus dose of intravenous m a g n e s i u m sulfate got cerebral palsy, whereas 0% (0 of 20) of children exposed to a saline control developed cerebral palsy (two-sided Fisher exact test, P = .09). Analyzing the data according to a hypothetical "sufficient" exposure to m a g n e s i u m suffate (defined as > 4 g), 0% (0 o f 37) children exposed to m a g n e s i u m got cerebral palsy, while 8% (6 o f 79) of children who were n o t exposed to a "sufficient" dose o f m a g n e s i u m sulfate got cerebral palsy (two-sided Fisher exact test, P = .17). Thus, although not statistically significant, and thereby inconclusive, there was a possible trend toward r e d u c e d cerebral palsy a m o n g high-dose magnesium exposed survivors c o m p a r e d with unexposed p r e m a t u r e l y delivered children.

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We must, therefore, return to concerns expressed after the publication of the initial Nelson and Grether article, 17 and the niggling doubt raised by the subsequent work of Schendel et al. 19 Does magnesium sulfate provide apparent "cerebroprotection" among exposed fetuses, by a mechanism that involves unexpected mortality in perhaps more fragile fetuses and infants that otherwise may have survived, but with cerebral palsy? Neither the Nelson and Grether 17 study nor the Schendel et a119study could include information on fetal death since only liveborns were included in their data sets. Thus, the relevant fetal death contribution to overall perinatal, or "total pediatric mortality" was not part of their analyses. In contrast, our experience in MagNET, as well as our more recent work, suggest that the fetal component of perinatal death may play a significant role in the possible relationship between use of tocolytic magnesium sulfate and the outcome of total pediatric mortality. An additional limitation of the initial Nelson and Grether 17 and SchendeP 9 studies is the unavailability of information on the total dose of magnesium received by infants in the cohorts. As discussed above, our data suggest that mortality, in exposed fetuses, may be limited to cases with higher exposures of the drug. Along these lines, it is feasible that, like many drugs, there is a "therapeutic window" in which magnesium sulfate provides cerebroprotection (presumably at lower dosages), but above which it is toxic to susceptible fetuses. On the other hand, it is somewhat discouraging that the most recent work published by Nelson and Grether 3s and others a9 no longer detect any association between tocolydc magnesium sulfate and reduced risk for cerebral palsy in prematurely born children. Thus, the evidence supporting the hypothesis of a cerebroprotective effect for magnesium sulfate is less compelling today than it was several years ago.

Ongoing Research Although many research questions may go unresolved, it is conceivable that the seemingly competing antenatal magnesium "cerebroprotective" and "toxicity" hypotheses may be answered. As we have alluded to, these hypotheses are not necessarily mutually exclusive and may be a matter of sufficient cerebroprotective dos-

ages as opposed to higher toxic dosages. Large, randomized controlled trials using intermediate doses of magnesium sulfate are now underway. The Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) assesses the effect of magnesium sulfate given to the mother immediately before preterm birth (<30 weeks' gestation) on the risk of cerebral palsy at age 2. The total prophylactic dose being used in the ACTOMgSO 4 trial is just 28 g, and women previously exposed to magnesium sulfate are excluded from the trial. In the United States, the Beneficial Effects of Antenatal Magnesium (BEAM) Trial, currently being conducted by the National Institute of Child Health and Human Development, is a randomized controlled trial in which the prophylactic magnesium dose being employed is 30 g. However, in the BEAM Trial, women previously exposed to tocolytic magnesium sulfate remain eligible to be randomized to the 30 g dose of magnesium or to saline control. Thus, because its design allows considerably higher total exposure in some patients than does the Australasian protocol, it is conceivable that BEAM may answer both questions: That is, are higher doses of magnesium sulfate associated with total pediatric mortality, while smaller or intermediate doses provide neuroprotection against the outcome of cerebral palsy? We anxiously await the findings of these 2 important studies as they come to completion in the near future.

Betamimetics The first reported use of beta-adrenergic agonists for tocolysis was in 1961 with the drug isoxsuprine. 4~ Since then, numerous other beta-adrenergic agents have been evaluated for this indication including terbutaline, hexoprenalone, salbutamol, albuterol, ritodrine, and others. In 1980, 42 after extensive review, the Federal Drug Adminstration (FDA) granted its approval for one of these agents, ritodrine hydrochloride, for the purposes of tocolysis. Interestingly, ritodrine remains, to this day, the only FDA approved tocolytic, although all other drugs being used for tocolysis are so employed through "off label" use. Ritodrine (Yutopar, Philips DuPhar, Netherlands), however, is not the best accepted of tocolytics. Although there are convincing data indicating effective prolonga-

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tion of pregnancy, the betamimetics have the most undesirable side effect profile of all currendy employed tocolytics.

Clinical Efficacy Beta-adrenergic agonists, also called "betamimetics," inhibit myometrial contractions by interacting with uterine smooth muscle cell membrane /31 receptors that activate adenylate cyclase. Activated adenylate cyclase then enzymatically increases intracellular cyclic-AMP (cAMP), which in turn phosphorylates, and thereby inactivates, myosin light chain kinase. The inactivation of myosin light chain kinase markedly decreases the sensitivity of the myosin and actin contractile elements to the contraction promoting influence of both calcium ions and prostaglandins. 4~,44 However, after prolonged stimulation the membrane receptors for these agents down-regulate, a process called tachyphylaxis, and uterine smooth muscle cells become insensitive to the tocolytic action of the betamimetics.45,46 There have been numerous clinical studies assessing the efficacy of betamimetics in the acute treatment of preterm labor. 47-5~ Unfortunately, because of heterogeneity of study design, and highly variable quality, many of these studies are difficult to compare with one another or even interpret in the greater context of preterm labor management. Still, critical evaluation of existing randomized clinical trials allows relevant evidence-based conclusions. A large 1980s meta-analysis of 16 controlled, randomized trials concluded that beta adrenergic agents are successful in postponing preterm delivery for 24 to 48 hours. However, in that analysis, there was no detectable improvement in 1) prolongation of pregnancy to term, 2) perinatal mortality rate, or 3) any measure of perinatal morbidity. ~a A subsequent large multicentered randomized clinical trial, conducted by the Canadian Preterm Labour Investigation Group, confirmed a delay in delivery of 24 to 48 hours with intravenous ritodrine acute tocolysis, compared with saline placebo. Again, similar to the findings reported in the previous meta-analysis, there was no significant difference between ritodrine and placebo in prolongation of pregnancies to term, birth weight, perinatal mortality, or perinatal morbidity. D~

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Once contractions have been arrested with parenteral betamimetic agents, it is c o m m o n practice to initiate "maintenance therapy" with an oral preparation of the same medication (or one of its congeners). The oral medication then is typically continued until 35 to 37 completed weeks of gestation. Several small studies initially implied that this strategy might be successful in prohibiting recurrent preterm contractions. 52-54 However, larger randomized controlled trials have failed to show any pregnancy prolongation, or reduction in incidence of recurrent preterm labor, from maintenance oral betamimetic therapy. 55,56 Likewise, a large meta-analysis of randomized clinical trials confirmed no measurable pregnancy prolongation, no reduction in recurrence of preterm labor, and no improvement in perinatal outcomes, using oral "maintenance" beta-adrenergic agents compared with observation alone. ~7

Adverse Effects There are 2 types of beta-adrenergic receptors distributed with varying emphasis within h u m a n tissues. For example, the heart, small intestine, and adipose tissues have a predominance of/31 receptor representation with fewer/3~ receptors, while /32 representations predominate in the myometrium, vascular smooth muscle, bronchioles, diaphragm, renal parenchyma, and hepatocytes. When stimulated,/32 receptors decrease contractile tone and strength in the uterus, but simultaneously cause generalized vasodilatation, bronchiolar dilatation, activation of the reninangiotensin-aldosterone system, and promotion of both gluconeogenesis and glycogenolysis.58 Stimulation of/31 receptors, on the other hand, causes increase of cardiac rate and stroke volume (hence increased cardiac output), as well as decreased motility of the bowel, induction of lipolysis, and facilitation of potassium transport intracellular. The betamimetics, used for tocolysis, are epinephrine derivatives formulated to maximize/32 adrenergic activities and minimize /31 activity. Unfortunately, however, there are no pure /32 agonists, so that all betamimetic tocolyric drugs have some/31 activity, in addition to their more potent /32 effect. For this reason, along with the desired clinical effect (uterine smooth muscle relaxation), there are myriad potential maternal and fetal toxic side effects with these drugs.

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Maternal Adverse Effects Cardiovascular. Because all betamimetics used

for tocolysis have /31 activity, they consistently increase heart rate and stroke volume leading to considerable increase in cardiac output (often 50% higher than the already elevated cardiac output induced by normal pregnancy alone). ~9,6~At the same time, the /32 effect on vascular smooth muscle leads to decreased peripheral vascular resistance, frequently causing reduced blood pressure. 61 Also, /32 stimulated renin release increases aldosterone leading to sodium and water retention, 62 increased plasma water, and decreased plasma osmotic pressure. Taken together these predictable pharmacological effects can, in some cases, lead to cardiac arrhythmia, pulmonary edema, and rarely myocardial ischemia. Fur obvious reasons, the use of beta-adrenergic agents is contraindicated in patients with pre-existing restrictive cardiac disease or known cardiac dysrrhythmia. 6~ However, cardiac arr h y t h m i ~ such as sinus tachycardia, supraventricular tachycardia, and ventricular ectopy, are commonly reported, although atrial fibrillation has occasionally been reported, in exposed patients even with previously normal hearts. Also, it is not u n c o m m o n for patients receiving these agents in tocolytic dosages to complain of chest pain. In such cases, ST-segment depression may occur and therapy should be discontinued. However, cardiac enzyme elevations and bonafide myocardial injury are rare. 64 Pulmonary edema, reported in 0.3 % to 9% of treated pregnancies, is a relatively c o m m o n complication of betamimetic tocolysis. This potentially severe complication, in fact, accounts for the majority of maternal deaths (more t h a n 25 have b e e n reported) attributed to betamimetic tocolytic therapy. 5s.6s Pulmonary e d e m a is more c o m m o n l y seen in multifetal gestations, probably because of the increased maternal blood volumes as c o m p a r e d with singleton pregnancies. There also appears to be an association with iatrogenic fluid volume overload. Careful assessment of fluid and electrolyte status, therefore, is extremely i m p o r t a n t in m a n a g i n g all patients who receive tocolytic betamimetics.

Metabolic Effects /3 adrenergic receptor stimulation has wide-ranging metabolic effects. Accordingly, the tocolytic use of betamimetics c a n cause p r o f o u n d metabolic derangement in susceptible women. 5s Glycogenolytic and gluconeogenic effects promote rapid rises in plasma glucose levels, while lipolytic and ketogenic effects can promote ketosis and, in some instances, ketoacidosis. W o m e n with insulin-dependant diabetes mellitus, and even gestational diabetes, are especially vulnerable. For this reason, betamimetic tocolysis is relatively contraindicated in this group of patients. However, it should be recognized that cases of overt glucose intolerance have been described even in nondiabetic patients after prolonged betamimetic tocolysis.65 Finally, virtually all women receiving parenteral beta-agonist therapy develop transient serum hypokalemia. Because this p h e n o m e n o n results from insulin induced intracellular shift of potassium, 66 and urinary potassium excretion is not increased, the total body potassium remains unaltered. Therefore, most authorities agree that it is unnecessary to "replace" potassium, under these circumstances, unless maternal serum levels fall below 2.0 to 2.5 m e q / d L . 5s,67

Neuromuscular System Central nervous system stimulation occurs as a direct/31 effect, and commonly manifests as resting tremor when betamimetics are given at tocolytic dosages. More concerning, patients with pre-existing cerebral vascular disorders, such as migraine with history of transient ischemic attacks, may experience cerebral vasospasm. Transient ischemic attacks, although rare, have been reported in such patients during betamimetic tocolytic therapy. 6s

Gastrointestinal System Nausea and vomiting are common betamimetic side effects, probably due to decreased bowel motility associated with /31 stimulation. 69 Paralytic ileus, by the same mechanism, is rarely observed but can be even more troublesome. Also, an idiosyncratic, drug induced hepatitis (clinically manifest by elevated transaminases with or without pruritus secondary to elevated bilirubin levels) has been reported subsequent to longterm beta adrenergic agonist therapy. 70,71

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Adverse Fetal and Neonatal Effects All of the beta-adrenergic agents used for tocolysis readily cross the placenta and appear to invoke much the same side effects in the fetus as those seen in the mother. The most c o m m o n observable fetal effect is tachycardia produced by direct /31 stimulation of the fetal myocardium. 79 Much more infrequently, fetal cardiac hypertrophy has been described. This finding may be related to a hypertrophic response to long-term myocardial adrenergic stimulation in susceptible fetuses. However, some investigators have speculated a mechanism for tocolytic-associated fetal hypertrophic cardiomyopathy involving fetal hyperinsulinism, similar to the transient condition seen in fetuses and infants of poorly glycoregnlated diabetic mothers. 7s,74 Along these lines, neonatal hypoglycemia is occasionally observed in preterm infants born to mothers undergoing beta-agonist tocolysis, an effect thought to be related to residual neonatal hyperinsulinemia in response to transplacental, adrenergically driven fetal hyperglycemia. 75 Other complications including hypocalcemia, hypotension, and ileus, have also been reported in the immediate neonatal period when the newborn was delivered within 48 hours of exposure to beta agonists. 76 Hypokalemia, on the other hand, has not been shown to be significant in the newborn population. There have been retrospective analyses 77'78 suggesting an association between neonatal intraventricular hemorrhage and exposure to beta adrenergic tocolysis. The most concerning of these reports, 77 a review of intraventricular hemmorhage (1VH) among nearly 3,000 preterm delivered neonates, found more than a doubling of risk for infants of mothers treated with betamimetics compared to those that were not treated or were treated with a different tocolytic. Other studies did not identify this association. 79 Also, a separate small study raised the possibility of increased learning disabilities among schoolage children who were exposed to these drugs in uteri. 8~ Although neither of these observations came from the more bias-free study design of randomized clinical trials, the findings cannot be discounted outright. On the other hand, it is reassuring that most longitudinal studies of child development subsequent to prenatal

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betamimetic exposure, have failed to detect long-term adverse effects. 81-8a

Summary of Beta-adrenergic Agonists The body of clinical evidence suggests that parenteral betamimetics are effective in slowing uterine contractions, and delaying preterm delivery, but 0nly for a relatively short time interval (24 to 48 hours), However, there is little evidence supporting the "tocolytic maintenance" use of these agents, particularly by oral route, with the intention of prolonging pregnancy beyond that interval. Although fraught with potential pharmacologically predictable mechanisms for both maternal and fetal toxicity, in practice these drugs appear to be relatively safe when administered to appropriately selected patients, for short intervals, and with judicious attention to fluid and electrolyte status. Therefore, the beta agonists are likely to be most useful, and their use most justified, in clinical strategies designed 1) to prolong pregnancy long enough to allow for the maternal administration of corticosteroids in order to induce fetal lung maturation, and 2) to stabilize preterm laboring patients for transport to tertiary care centers. Nevertheless, it should be emphasized that whether even this limited use of the beta agonists is truly beneficial, in terms of measurable perinatal outcomes, remains to be proven in proper trials.

Prostaglandin Synthetase Inhihitors The use of prostaglandin synthetase inhibitors, for tocolysis, was first reported in 1974 when Zuckerman published his experience administering indomethacin to 50 women diagnosed with preterm labor. 84 In the ensuing 27 years, several studies of indomethacin tocolysis have been published and, although its tocolytic efficacy has been generally recognized, its acceptability as a tocolytic remains unsettled. 85 Although it is clearly well tolerated by mothers, its fetal safety is less well established. Although the potential for fetal toxicity from long-term use has been supported by prospective studies, and convincing data proscribe against use of these agents at later gestational ages, the risk-benefit balance for "limited" (short-term use at gesta-

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tional ages < 32 weeks) remains highly controversial. 4,86

Tocolytic Efficacy and Beneficial Effects Prostaglandins are thought to have a critical role in the initiation and maintenance of both normal and premature human labor. Recognized mechanisms for this role are 2-fold. 87 First, the prostaglandins (particularly E2 and F2,~ appear to facilitate myometrial cytoplasmic influx of calcium both from extracellular sources (via calcium ion channels), and from stored calcium ion available for release from the intracellular sarcoplasmic reticulum. This increased cytoplasmic calcium ion, in turn, activates myosin lightchain kinase eventuating in the actin/myosin interaction that allows individual myometrial cell contraction. Second, the same prostaglandins potentiate the propagation of myometrial gap junctions that are essential for whole organ synchronization of the otherwise disorganized individual myometrial cell contractile activity. Thus, a prostaglandin rich milieu increases the contractile activity of individual myometrial cells while it simultaneously organizes the uterine activity into coordinated whole organ, or laborlike, contractions. Unfortunately, as we have noted with other tocolytic agents, the majority of indomethacin studies have been scientifically lacking, usually being poorly controlled, having variable study designs rendering comparison between trials difficult, having small sample sizes, or giving insufficient attention to strict perinatal outcome criteria. Nevertheless, prostaglandin synthetase inhibitors (mainly indomethacin), presumably by reversibly blocking the prostaglandin-mediated activities described above, have been found effective in prolonging pregnancy. Evidence supporting this conclusion includes 3 small placebo controlled trials of variable quality,s8-9~several trials testing indomethacin as a supplement to other tocolytics,91-93 and trials comparing indomethacin to other tocolytics. 33'94"95 Recent meta-analyses, too, have concluded that indomethacin is effective in delaying delivery by at least 48 hours, for 7 to 10 days, and even beyond 37 weeks.6,96 Moreover, one of these meta-analyses,6 evaluating the current standard tocolytics (magnesium, betamimetics, indomethacin, atosiban, and ethanol), implied that indo-

methacin may be the most potent of tocolytics if evaluated according to magnitude of pregnancy prolongation compared with saline placebo. Whether prolonging pregnancy with indomethacin has resulted also in improved perinatal outcomes has not been clearly shown, although some data are encouraging. In a large meta-analysis of evaluable trials, Keirse96 found nearly a 40% reduction in both respiratory distress syndrome (RDS) and fetal/neonatal death, among the indomethacin exposed infants, although these differences from the comparison group did not reach statistical significance. More recently, in a case control study, Gardner and colleagues reported siguificantly fewer cases of RDS in a tocolytic indomethacin exposed cohort of premature infants compared with a gestational age matched group that was not exposed to indomethacin (48% versus 77%; P = .001). 97 It can only be speculated whether earlier studies, had they taken full advantage of steroid use to induce pulmonary maturation during tocolysis, would also have demonstrated reduced perinatal morbidity and mortality.

Adverse Effects of Prostaglandin Syntehetase lnhibitors Prostaglandin synthetase inhibitors operate by nonselective inhibition of the enzyme cyclooxygenase, thereby blocking its action to convert arachodonic acid to prostaglandin G2, the precursor to all other prostaglandins. Accordingly, the prostaglandin synthetase inhibitors effectively block production of all prostaglandins including prostaglandins E2 and F2,~, (powerful facilitators of uterine contractility), as well as thromboxane (a potent vasoconstrictor with platelet aggregating activity) and prostacyclin (a vasodilator). 87,98 These various prostaglandins, under normal circumstances, have wide-ranging physiologic regulatory function in both the fetus and its mother. It is therefore not surprising that, in addition to their desirable pharmacologic effects, the prostaglandin synthetase inhibitors have numerous potential adverse side effects as well. Aspirin, one type of prostaglandin synthetase inhibitor, blocks cycl0oxygenase irreversibly by acetylation of the enzyme. In contrast, indomethacin, and its congeners (sulindac, naproxen, ibuprofen), reversibly inhibits cyclooxygenase allowing full enzymatic recovery

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as soon as the drug is metabolized and excreted. 87,95 The reversibility of indomethacin's effect, as will be discussed later, may be clinically important in monitoring for, and managing, undesired side effects. Maternal Adverse Effects

Serious maternal complications, attributable to indomethacin tocolysis, appear to be extremely rare. 7 In fact, studies comparing indomethacin to other tocolytics have generally favored indomethacin as better tolerated from the standpoint of maternal adverse effects. 94,9~ Still, indomethacin, and other prostaglandin synthetase inhibitors, have wide ranging pharmacological influence and clinically important adverse effects have been observed in the gastrointestinal, renal, hematological, immunological, and vascular systems.87,95 The most c o m m o n complication of indomethacin when given in tocolyitic dosages is gastrointestinal irritation manifest by exacerbation of pre-existing peptic ulcer disease, or minor de-novo gastritis in susceptible women not previously having gastrointestinal disease. Proctitis with hematochezia also has been described subsequent to repetitive rectal administration. These gastrointestinal effects appear to be caused by reduction of prostaglandin E 2 whose multifold role in protecting the gastrointestinal mucosa includes 1) regulation of gastrointestinal microcirculation, 2) modulation of gastric acid release, and 3) participation in the maintenance of the gastrointestinal mucosal barrier. 99 Although the prostaglandin synthetase inhibitors should be avoided in women with known peptic ulcer disease, cases of gastritis in the remainder of women appear to be mild, and generally are self limiting. A more severe side effect of indomethacin is impaired renal function presenting as oliguria, rising serum creatinine, and hyperkalemia. 87,1~176 Extreme cases with acute renal failure, anuria, and volume overload have also been reported. These effects are attributed mainly to the pharmacological reduction of prostaglandins involved in the maintenance of renal blood flow. It is thought that, in susceptible patients, indomethacin induces renal hypoperfusion leading to reduced glomernlar filtration, decreased urine production, and electrolyte derangement. Fortunately, maternal renal toxicity from toco-

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lytic indomethacin is rare. Because this complication appears to be seen most commonly among patients predisposed by already impaired glomernlar filtration (due to underlying renal disease or plasma volume contraction) the prostaglandin synthetase inhibitors are relatively contraindicated in such patients. 1~ The platelet function inhibiting effect of the prostaglandin synthetase inhibitors is well known and appears to be caused mainly by reduction of the platelet aggregating prostaglandin, thromboxane. This effect is detectable by significantly prolonged bleeding times, although prothrombin times and partial thromboplastin times are not affected. 1~ Fortunately, excessive maternal bleeding complications have not been observed in most trials focusing on matemal effects of indomethacin. One exception, the recent placebo controlled randomized clinical trial of Panter et al90 did find a statistically significant increase in postpartum hemorrhage (defined as estimated blood loss > 500 mL) among women randomized to indomethacin, although this was not a primary outcome variable, nor was bleeding assessed in a scientific way. Also, by virtue of the anti-inflammatory nature of this class of medications, immunologic alterations might be expected. However, despite the observation that prolonged indomethacin therapy has been associated with altered T-cell suppressor activity in both m o t h e r and neonate, 1~ no clinical relevance of this effect has been recognized. Along these lines, allergic reactions to indomethacin are quite unusual, but cross-sensitivity to indomethacin among women having aspirin allergy, or aspirin induced asthma, is important to recognize and avoid. Finally, the antipyretic effects of these agents may theoretically mask an occult chorioamnionitis. Fetal Adverse Effects

Although the initial clinical experience with indomethacin tocolysis appeared reassuring with respect to fetal and neonatal complications, 84,1~176 its recent expanded clinical use has led to concerns about previously undetected adverse effects. Initial anecdotal reports have been followed by disturbing results of retrospective cohort studies 1~176 indicating possibly increased risk, a m o n g indomethacin exposed fetuses, for a variety of fetal and neonatal corn-

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plications. While there is theoretical concern about relevant decreases in uterine blood flow, u n d e r the influence of prostaglandin synthetase inhibition, this has n o t b e e n verified in Doppler studies o f h u m a n uterine arteries subsequent to tocolytic indomethacin exposure, n0 Nor has there b e e n any observable adverse effects on immediate indicators o f fetal and neonatal well being such as fetal biophysical activity, m umbilical artery Dopplers, 11~ or Apgar scores. 1~ O n the o t h e r hand, there is n o d o u b t that the prostaglandin synthetase inhibitors, particularly indomethacin, do cross the placenta. Accordingly, it appears that many fetal effects o f these drugs mirror those seen in the mother. More importantly, there are physiologic activities, unique to the fetus, which appear to be particularly vulnerable to prostaglandin synthetase inhibition. One o f the first recognized fetal complications with indomethacin tocolysis was oligohydramnios, xx3 Subsequently, numerous incidents of indomethacin related oligohydramnios have been reported, and several aspects of the complication- have b e e n characterized. 114-11a T h e p h e n o m e n o n has b e e n attributed to reduction o f renal vasodilator prostaglandins causing diminished renal blood flow and urine output, a7 Doppler studies of exposed h u m a n fetuses, however, have failed to prove altered renal perfusion and o t h e r factors may be contributory, n9 Although oligohydramnios is generally detected after p r o l o n g e d therapy, beyond 48 to 72 hours, some investigators have reported decreases in amniotic fluid volume m u c h earlier. 1~ Additionally, several r e p o r t e d cases of neonatal renal failure subsequent to fetal exposure have raised the possibility of ongoing renal toxicity after birth. 117.12~ Overall, the p h e n o m e n o n of indomethacin induced fetal/neonatal renal toxicity (manifest by r e d u c e d urine production) appears to be m o r e likely to occur with prolonged therapy, and in older fetuses. Finally, n u m e r o u s observers have r e p o r t e d that the problem appears to resolve, in most cases, with discontinuation o f therapy. The normal patency o f the fetal ductus arteriosus depends on local vasodilator prostaglandins (prostacyclin and PgE2). Indomethacininduced reduction of these prostaglandins, resulting in p r e m a t u r e ductal constriction, is another well-known potential consequence o f fetal

indomethacin exposure. This sometimes dramatic effect may be observed in as many as 10% to 50% o f exposed fetuses, but appears to be most prevalent after prolonged (more than 48 to 72 hours) exposure, a21 It also appears to be gesrational-age related, such that the likelihood of indomethacin induced ductal constriction increases with advancing gestational age, particularly beyond 32 weeks. 122 Fortunately, ductal constriction resolves completely, in most cases, within 24 hours after discontinuation o f therapy. 123a24 However, in severe or neglected cases, ductal constriction can lead to endocardial ischemia, papillary muscle and cardiac valvular dysfunction, heart failure, hydrops, and even fetal death. Along these lines, the dangers o f tocolytic indomethacin, in pregnancies also complicated by ducal-dependent fetal cardiac disease, have b e e n emphasizedA 25 A m o n g premature neonates evaluated in two separate retrospective case-control studies, 107,~09 there was a higher incidence of pathologically p r o l o n g e d patent ductus arteriosus a m o n g those exposed antenataUy to indomethacin c o m p a r e d to gestational age matched controls not exposed to indomethacin. Furthermore, some o f these infants were reported to be unusually refractile to the i n t e n d e d therapeutic ductal-closure effect o f neonatally administered prostaglandin synthetase inhibitors. A possibly related complication, persistent fetal circulation, or p u l m o n a r y hypertension, subsequent to indomethacin tocolysis was also f o u n d to be m o r e prevalent in the exposed cohorts. Although this later complication was initially described subsequent to neart e r m e x p o s u r e s , 126,1~7 the association has since b e e n r e p o r t e d after long term exposures in pr e mature neonates as well.a07a 2~la0 A mechanism involving chronic in utero constriction o f the ductus arteriosus, with attendant redirection o f cardiac outflow into the pulmonary circulation, and consequent hypertrophy of the fetal pulmonary vasculature has been hypothesized. T h e real magnitude of risk for this life-threatening complication, however, is disputed. While the likelihood is thought to increase following fetal exposures longer than 48 to 72 hours, and at gestational ages m o r e than 32 weeks, 124 cases have also been r e p o r t e d in association with short tel'In t h e r a p y . 1~ On-the-other-hand, most prospective studies (which include large numbers o f exposed pregnancies in aggregate) have not

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f o u n d this complication. 92,94,1s1,132 Likewise, Gardner et a197 and later Vermillion and Newman, lsa in similarly designed (carefully matched, comparatively large sample sized) retrospective case-control analyses, did not observe detectable increases in either patent ductus arteriosus, or pulmonary hypertension, a m o n g p r e m a t u r e infants delivered at gestational ages <32 completed weeks with exposures limited to < 72 hours. O t h e r clinically important adverse neonatal effects, putatively associated with fetal indomethacin exposure, include necrotizing enterocolitis (NEC), IVH, and b r o n c h o p u l m o n a r y dysplasia (BPD). Norton et all07 in 1 of the case control studies partially discussed above initially rep o r t e d the first 2 of these possible latent toxic effects. T h e finding o f increased NEC, but not IVH, was e c h o e d in a subsequently published, small case control study, 1~ while increased IVH, but not NEC, was f o u n d in a third case control study. 1~ Finally, a randomized clinical trial of indomethacin versus nylidrin (a betamimetic agent) resulted in significantly increased rates o f BPD and NEC, b u t not IVH, a m o n g the indomethacin treated group. TM While physiologic explanations for increased WH, NEC, and BPD may reside in the potential for indomethacininduced 1) alteration in splanchnic, pulmonary, and cerebral blood flow, causing vascular instability with or without transient localized ischemia; or 2) altered fetal platelet hemostatic function allowing localized hemorrhagic injury, these hypotheses are n o t proven. Once again, in contrast to these worrisome reports, o t h e r investigators in older case-control and observational studies, 84 prospective trials, 92,94 and meta-analysis, 96 did not find significant increases in any of these measures of neonatal mortality or morbidity. Similarly, the 2 most recent, and largest case control studies, failed to detect increases in NEC, IVH, respiratory distress syndrome, or BPD, in the indomethacin exposed cohorts compared to the u n e x p o s e d matched controls. 97,13s Why the discrepancy between these studies? An excellent contemporary review has suggested that the putative associations between indomethacin and these multiple adverse effects may actually represent "confounding by indication. "8~ This type of confounding may occur in case control studies when a clinical situation (in this case, failure of first-line tocolysis) itself is a risk

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factor for the adverse consequences in question (complications o f prematurity), and is, at the same time, the indication for the unique treatm e n t (switching from first-line tocolytic to indomethacin) of the c o h o r t in question. U n d e r these circumstances it may be impossible to distinguish the adverse effects attributable to the clinical circumstances that indicate the use of the drug in question, from the adverse effects attributable to the drug itself. Perhaps supporting this concept is a recent, and very large, case control analysis that f o u n d n o relationship between antenatal indomethacin m o n o t h e r a p y and NEC, while combination tocolysis was highly associated (leading the authors to speculate that recalcitrant p r e m a t u r e labor requiring multiple tocolytic agents may be a marker for subclinical infection, the m o r e likely cause of NEC). 135 Recently, sulindac (Clinoril, Merck, West Point, PA), a drug with structural similarity to indomethacin, ls6 has b e e n introduced as a tocolyric agent. Potential advantages of sulindac over indomethacin include maternal renal sparing by virtue of hepatic conversion, la7 and from the fetal point of view, there appears to be less placental transfer o f active drug metabolite, la8 Thus, in theory, sulindac could have m u c h the same tocolytic efficacy as indomethacin, but with considerably less potential for the critical maternal and fetal adverse effects. So far, however, data on the actual pharmacokinetics of sulindac in h u m a n pregnancy are limited. Preliminary clinical experience with sulindac found minimal alterations in amniotic fluid dynamics and ductus arteriosus velocities. 7 Subsequently, a small, randomized clinical trial comparing sulindac with indomethacin for refractile preterm labor, f o u n d similar tocolytic efficacy, without marked changes in amniotic fluid volume estimates or ductal flow velocities in the sulindac group. 139 Similarly, in a blinded comparison, sulindac was found to cause some ductal constriction but "only mild" as c o m p a r e d with indomethacinA 4~ However, a more recent Doppler study did not support this view and raised similar concerns about ductal constriction that were previously observed with indomethacinA 41 Nonetheless, the potential of sulindac to effectively treat preterm labor, without producing undesirable maternal and fetal side effects, or doing so in a less p o t e n t way, warrants further investigation. Also, newer prostaglandin synthetase inhibitors de-

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signed to selectively block cyclooxygenase-2, are now available, and await careful trials to assess whether they may selectively delay premature delivery without untoward maternal-fetal effects. Preliminary data, however, suggest that the COX-2 inhibitors promote fetal ductus constriction in sheep, m and in a small trial in humans, oligohydramnios evolved after prolonged therapy (3 to 9 days), but reversed after discontinuation of the drug. 143

Smnmary of Indomethacin and Related Prostaglandin Synthetase inhibitors Indomethacin, the best studied of the prostaglandin synthetase inhibitors for the purposes of tocolysis, appears to be among the most efficacious of currently available drugs for delaying preterm delivery. As with other tocolytics, howeverz the data supporting this conclusion are somewhat tentative because of generally less than optimal, and heterogeneous, study designs. Similarly vexing, the question of whether prolongation of pregnancy from indomethacin tocolysis translates into improved perinatal outcomes remains unclear. On one hand, some studies show a trend toward improved perinatal outcomes. Moreover, several experts have speculated that combining the short-term pregnancy prolongation benefit of indomethacin, to allow time for the multiple beneficial effects of a full 48-hour course of corticosteroids (including reduced IVH, NEC, RDS, and death) may have an overall beneficial effect. On the other hand, there are studies implicating indomethacin in several severe adverse fetal and neonatal effects. Although one group of authors has convincingly argued that the observed associations, between indomethacin and these putative adverse neona, tal effects, may be attributable to the bias of confounding by indication, the magnitude of fetal risk from indomethacin therapy remains unknown. The only way to properly evaluate this question is through a large prospective randomized clinical trial with sufficient power to compare adverse fetal, neonatal and infant outcomes. The National Institute of Child Health and Human Development has funded such a trial, but the results are unlikely to be available soon. Meanwhile, in view of these uncertainties, several clinical observations can guide clinical decision making. First, the predominance of

data suggest that fetal amniotic fluid volume effects, and ductal constriction, each appear to be related to dosage, duration of therapy, and gestational age. Therefore, limiting treatment to no more than 48 hours (during which corticosteroids should be administered), using conservative dosage protocols, and only at gestational ages less than 30 to 32 weeks' gestation seems a reasonable approach. A recently published, scholarly decision analysis, with currently published data related to tocolytic benefits as well as putative adverse fetal/neonatal effects, calculated that the potential fetal benefits likely exceed risks using such an approach, s6

Calcium Channel Blockers The use of a calcium antagonist, nifedipine, for tocolysis, was initiated in 1980 with the report of Ulmsten and associates of their experience abolishing preterm contractions in 10 patients. T M Since then, although considered a legitimate tocolytic among obstetricians in Europe and the Americas, nifedipine has remained second-line in popularity, behind magnesium sulfate in North America,5 and behind the betamimetics in Europe) 45 This is surprising in that the tocolyric experience with calcium channel blockers has revealed a much more tolerable maternal side-effect profile than is found with either of the more popular agents, and with few reported fetal adverse effects. Moreover, nifedipine has performed well in comparison trials with both the betamimedcs, and magnesium sulfate. Recent data, in fact, suggest that nifedipine may be not only the safest of these 3 tocolytics, but it may even be the most effective.

Tocolytic Efficacy The calcium channel blockers, such as nifedipine, nicardipine, and verapamil, appear to be relatively potent uterine relaxants. They act by blockade of voltage-dependent calcium channels in myometrial cells, 146,147 resulting in decreased intracellular calcium ion. This effect leads to reduction in myosin light-chain kinase activity thereby diminishing actin/myosin interaction and causing myometrial cell relaxation. Studies of human myometrium, in vitro, verify this action, as do numerous studies in experimental animal models. However, human trials,

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until recently, have suffered from small sample sizes limiting power for assessing outcomes such as pregnancy prolongation, and neonatal morbidity. Unfortunately, there is but a single, small trial of nifedipine that includes a placebo-control group. 14a However, even with small numbers of subjects, that trial demonstrated a statistically significant improvement in pregnancy prolongation, more than 48 hours, among nifedipine treated patients compared with controls. There are numerous small-randomized trials comparing nifedipine to other tocolytics including ritodrine (betamimetic), 148-1~~ terbutaline (betamimetic),'51 or magnesium sulfate. 152 Most of these trials showed a trend toward improved pregnancy prolongation in the nifedipine group compared with the altemative tocolytic group, but were insufficiently powered to show a statistically significant difference. Recently, however, a large multicenter randomized clinical trial comparing nifedipine to ritodrine, found a significantly improved rate of postponement of delivery in the nifedipine treated patients, l~a This finding was statistically significant at 24 hours, 48 hours, 1 week, and even 2 weeks after enrollment. In a subsequent publication, the same group reported a detailed analysis of the neonatal outcomes data from the trial demonstrating that nifedipine, compared with ritodrine, was associated with significantly fewer neonatal intensive care unit admissions, and significantly lower incidences of respiratory distress syndrome, intracranial hemorrhage, and neonatal jaundice. T M Further supporting these findings, a recent, high quality meta-analysis of the comparison trials between nifedipine and the betamimetics, also found markedly superior tocolytic efficacy of nifedipine. 145 Pregnancy prolongation, as well as neonatal outcome indicators including neonatal intensive care unit admission, and incidence of RDS indicated this superior performance of nifedipine. Maternal Adverse Effects

The calcium channel blockers, by the same mechanism that relaxes uterine smooth muscle, are potent vascular smooth muscle relaxants. 1~5 Accordingly, their main side effects, when employed at tocolytic dosages, are related to widespread vasodilatation. These effects include mild to moderate decreases in blood pressure, with a

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compensatory increase in pulse that also is typically mild. In some instances, however, there can be significant hypotension with secondary tachycardia, particularly in patients having reduced preload from dehydration. Although these cardiovascular effects are similar in type to those of the betamimetics, they are far less prominent during calcium channel blocker tocolysis. In fact, virtually all tocolytic studies comparing the 2 classes of drugs, have favored the calcium channel blockers as safer, and better tolerated, from the maternal perspective. 14~ Unlike the betamimetics, the calcium channel blockers have minimal metabolic effects. Drug-induced hypokalemia is not described, in the setting of calcium channel blockade, and upward excursions of serum glucose are mild and not clinically relevant. 156 Maternal symptoms associated with nifedipine tocolysis also tend to be mild; if present at all. 145 these include headache, cutaneous flushing, dizziness, nausea, and occasional palpitations. A more worrisome side effect, that fortunately is not commonly encountered, is marked hypotension. Because severe drops in maternal blood pressure can result in diminished uterine blood flow, it is important to monitor the fetus during initiation of nifedipine tocolysis. Also, in rare cases of pregnant women suffering from underlying coronary artery disease, or cerebral vascular disease, such hypotensive episodes could theoretically be dangerous potentially eventuating in myocardial infarction~7 or stroke. 158 Fortunately, nifedipine induced hypotension typically responds rapidly to maternal positional change (left lateral recumbent with feet elevated) and maternal vascular volume repletion using judicious volumes of intravenous crystalloid. An idiosyncratic case of hepatotoxicity attributed to nifedipine tocolysis has been reported, although that complication has not been encountered in any of the larger trials of tocoIysis. 159 Finally, several reports have described profound hypotension, cardiac toxicity, neuromuscular blockade (with skeletal muscle paralysis), and instances of maternal death, resulting from the combination of nifedipine and intravenous magnesium sulfate given for tocolysis.160-162 Although clinical experience over the past decade has shown that the magnitude of risk using this combination is probably limited, 165 most experts advise caution when con-

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sidering combination tocolysis, and probably it should be avoided altogether. Additional concerns about the calcium channel blockers have been raised, in the medicalhypertension literature, that are of questionable relevance to the general obstetrical population. A 1995 meta-analysis of nifedipine for cardio prophylaxis among adults with coronary artery disease, found a small, but statistically significant risk of mortality among nifedipine treated compared with untreated controls, a63 Case reports, too, have pointed out the risk of abrupt hypotension subsequent to short acting nifedipine, mostly in elderly patients, causing ischemic cardiac or cerebral eventsJ ~s,159 Obstetrical experts have concluded that these data do not generalize well to the broad population of obstetrical patients. 154a6m62 They do acknowledge, nevertheless, that caution should be exercised administering calcium channel blockers (especially short acting preparations) to older gravidas having chronic hypertension or long-standing diabetes or other risk factors for occult coronary artery disease) 61 One final issue that remains to be settled relates to a 1996 report of modestly increased cancer risk among long-term nifedipine treated hypertensives compared with pat e n t s managed with other antihypertensive regimens2 64 The study has been criticized for numerous reasons, however, and a more recent analysis of available data, a65 as well as large follow-up observational studies, 1~,a67 have contradicted the original finding and concluded that there is not convincing evidence of increased cancer risk in these patients.

Fetal Adverse Effects It has been speculated that some of the hesitancy, among obstetricians, to accept nifedipine as a tocolytic might be explained by concerns over initial animal data suggesting that calcium channel blockers reduce uteroplacental blood flow, with attendant fetal bradycardia, and hypoxic myocardial depression. 67,16s However, such effects were not observed with nifedipine unless very high, toxic range, dosages were used. Furthermore, Doppler studies of the fetal and uteroplacental circulation in humans, have not found significant changes in blood flow characteristics during tocolytic exposures to nifedipineJ 69 Likewise, tocolytic trials comparing ni-

fedipine to betamimetics, or magnesium suffate, find no detectable differences in immediate indicators of neonatal well being such as cord pH, or Apgar scores. T M Finally, as emphasized in the nifedipine "tocolytic efficacy" discussion above, clinical tocolytic trials suggest that nifedipine improves several indicators of perinatal outcomes without significant findings suggestive of fetal-neonatal toxicity, a4~354

Summary o f Nifedipine Tocolysis There is accumulating evidence that nifedipine is a safe and effective tocolytic. In fact, it should be emphasized that nifedipine is the only tocolytic drug, to date, in which a large randomized trial and a subsequent meta-analysis, have found, not only pregnancy prolongation, but more importantly, improvement in perinatal outcomes in treated patients compared with alternatively managed comparison groups. Thus, although rare cases of short-acting nifedipine induced hypotension may theoretically impact fetal wellbeing acutely, and could, in unusual circumstances, injure susceptible mothers; such events should be avoidable in most instances. Precautions to avoid such complications include: 1) Proper patient selection, and 2) Attention to clinical indicators of reduced maternal preload. Women should be treated with nifedipine only after excluding risk factors for occult coronary or cerebrovascular disease, and establishing reasonable assurance o f euvolemia. In all treated cases, careful monitoring of the mother and fetus are indicated until contractions have abated and a stable treatment regimen is established. With this approach, the drug appears to be extremely well tolerated without, as yet, idendried direct fetal toxicity.

Oxytoein Antagonists In 1986, Melin et aP 7~ reported the developm e n t of a new oxytocin/vasopressin antagonist with contraction inhibiting activity on h u m a n in vitro gravid myometrial strips. The drug, now known as atosiban, subsequently underwent preliminary clinical trials that revealed reduction in contraction frequency without significant maternal or fetal adverse events, aT1 Since then, large randomized clinical trials have indicated that atosiban may be as effective as the betarnimetics

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for short-term prolongation o f pregnancy, but apparently with considerably fewer clinically important maternal side effects, and with similar fetal-neonatal outcomes. 172,17s In view o f these generally favorable data, some experts have advocated a more p r o m i n e n t role for atosiban in the contemporary treatment o f p r e m a t u r e labor. Tocolytic Efficacy of Atosiban Oxytocin appears to have at least two mechanisms whereby it potentiates myometrial contractions. 174 Its main action is binding to the myometrial cell surface oxytocin receptor causing production o f soluble intracellular second messengers, these molecules ultimately increase intracellular calcium, thus potentiating contractions. Additionally, decidual oxytocin receptors have b e e n identified that increase p r o d u c t i o n o f contraction stimulating prostaglandins E and F when stimulated by oxytocin. By blocking these receptors, both in the myometrium and the uterine decidua, it is t h o u g h t that atosiban exerts a 2-fold mechanism to reduce uterine contractions. However, although there is evidence that the frequency o f normal pulsatile oxytocin release is increased during normal labor, the role and importance o f oxytocin in p r e t e r m labor is not well understood. 175 Oxytocin r e c e p t o r concentrations, in the myometrium, are known to increase with advancing gestational age but are quite sparse at gestational ages less than 28 to 32 weeks. This may explain why one recent study, to be discussed, has shown pregnancy prolongation with atosiban at gestational ages beyond, but not before, 28 weeks, a76 T h e r e have now been n u m e r o u s trials evaluating atosiban in comparison with placebo or betamimetics. From a purist perspective, it is unfortunate that even the "placebo controlled" trials have, for ethical reasons, allowed initiation o f alternative tocolytics in the event of treatment failure beyond a specified duration after starting the primary randomized treatment. Thus, a long-term, substantive, placebo controlled efficacy and outcomes trial is not available, and will not be for the foreseeable future. Nevertheless, data from a recent placebo "controlled trial ("with tocolytic rescue") still were able to demonstrate a statistically significant prolongation of pregnancy for up to 7 days in atosiban treated pregnancies enrolled beyond 28 weeks. 176 Inter-

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estingly, in that trial, efficacy at gestational ages <28 weeks was not shown. A more recent multicenter randomized clinical trial, the largest to date comparing atosiban to betamimetics (ritodrine, terbutaline, or salbutamol), showed indistinguishable efficacy in terms o f pregnancy prolongation beyond 48 hours, although there was not a placebo control group, x7s In this study, efficacy was not stratified according to gestational age at trial entry to evaluate the possibility raised by the former trial of less effectiveness among patients requiring tocolysis at earlier gestational ages.

Maternal Safety Because atosiban also is a p o t e n t blocker of the receptors to vasopressin, there is theoretical potential for undesired side effects during tocolytic administration. However, a b u n d a n t data, including thousands o f tocolytic exposures, indicate that the drug is extremely well tolerated by pregnant women. C o m p a r e d with placebo, side effect profiles were virtually identical with the exception o f a slightly higher rate o f injection site reactions that o c c u r r e d during tocolytic maintenance among patients receiving atosiban. 176 In studies comparing atosiban to betamimetics, the safety profile o f atosiban was far more favorable than betamimetics with as many as 15% o f patients randomized to betamimetics having to discontinue therapy due to intolerence, c o m p a r e d to 1% o f those treated with atosiban. 172,17s Furthermore, life threatening tocolytic complications, such as p u l m o n a r y e d e m a or myocardial ischemia, occurred a m o n g the betamimetic treatment arms, while they have not been observed a m o n g atosiban exposed women. Also, theoretical concerns about potential impact o f atosiban on lactation, have b e e n allayed by clinical experience showing no effect on maternal breast-feeding S u c c e s s . 174

Fetal Safety Animal studies evaluating fetal tolerance o f atosiban have b e e n reassuring with no demonstrable adverse effects even at fetal drug levels three times those observed in tocolytic exposed h u m a n fetuses. 174 Likewise, most h u m a n trials indicate that atosiban is tolerated as well by the fetus as it is by mothers. In the largest randomized trial, c o m p a r e d with betamimedcs, there was no difference in fetal or neonatal outcomes

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except for an increased incidence of fetal tachycardia among betamimetic treated fetusesA 73 On the other hand, one placebo controlled (with "tocolyfic rescue") randomized clinical trial f o u n d a higher rate of fetal-infant deaths in the atosiban group (13 of 250) compared with the placebo group (5 of 251). 176 Although there was an inadvertent imbalance in randomization, in that trial, such that there were significantly more atosiban exposures among patients enrolled at the early gestational ages (<26 weeks) where most of the deaths occurred, the authors concluded that fetal atosiban related adverse effects could not be definitively excluded. They speculated that a mechanism involving vasopressin blockade in the fetus, leading to impairment of a critical homeostatic response to stress, might explain the excess deaths. However, they went on to cite numerous reasons that such a p h e n o m e n o n was deemed unlikely.

Summary of Atosiban Tocolysis Atosiban, the most recently introduced tocolyfic, has accumulating evidence of at least short-term tocolytic efficacy, with an extremely favorable maternal side effect profile. However, despite the margin of safety demonstrated by atosiban in mothers, in the United States, there is lingering concern about clinical use because of the questionable efficacy in early pregnancy, and uncertain fetal safety issues raised in the Phase III trial of Romero and associates, a76 On the other hand, based on extremely favorable results in comparative trials with betamimetics, regulatory bodies in Canada and Europe appear poised to approve atosiban for routine clinical use in their countries.

Conclusion Premature birth remains the leading cause of perinatal morbidity and mortality excluding fetal anomalies. 1 The likelihood of death or disability related to prematurity is influenced by several factors: Most importantly, is the impact of gestational age, whereby outcomes generally worsen with earlier gestational ages at delivery. Also important, is the location of delivery. Infants born at facilities expertly staffed, and equipped, for neonatal intensive care fare better than those delivered at nontertiary centers. Finally, the preparation of the fetus prior to

delivery by administering a full course of selected corticosteroids markedly reduces neonatal death, and morbidity, at all gestational ages ranging from approximately 24 to as late as 34 weeks. Accordingly, therapies that can safely prolong pregnancy, even if gaining only 48 to 72 hours, would be expected to improve individual perinatal outcomes when faced with bona fide preterm labor. Efforts to treat preterm labor, by way of tocolyric therapy, have not been as effective as had been hoped. In fact, several authors have comm e n t e d that there has been no impact on the rate of premature birth, by the advent of tocolyric drugs, for the past 30 to 40 years. 3,6,7 Some tocolyfics (including betamimetics, calcium channel blockers, prostaglandin synthetase inhibitors, and atosiban, but not magnesium sulfate), have now been shown, with a reasonable degree of certainty, to effectively stave off premature delivery by 48 to 72 hours. However, this accomplishment has not reduced the n u m b e r of preterm births (defined as birth at gestational age <37 weeks). More curiously, however, it has also been difficult to show any impact of this modest pregnancy prolonging effect on neonatal outcomes. Reasons for this paradox are unclear, but probably are multifold: First, the diagnosis of genuine preterm labor has been, and remains, elusive. Many patients that d o n ' t actually have premature labor are thereby enrolled, treated, and analyzed in tocolytic studies, a p h e n o m e n o n that necessarily dilutes any measurable indicator of efficacy. Secondly, etiologic mechanisms of preterm labor are not well understood preventing the targeting of perhaps more optimal therapies to specific causes. And finally, many of the older studies, even if they showed prolongation of pregnancy by 48 hours, did not overwhelmingly adhere to recommendations regarding steroid administration for fetal lung benefit. By not giving steroids to the majority of patients, they may not have maximally benefited fetuses during the brief delay of delivery that they achieved. Accordingly, they may have failed to demonstrate the neonatal outcome benefit that might have been realized, even with only 48 hours of pregnancy prolongation. The recent reports of pregnancy prolongation with improvement in neonatal outcomes, with nifedipine, may be in part because of the high rate of corticosteroids

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use d u r i n g the p e r i o d o f tocolysis in the t r e a t e d patients. I n addition to the questions raised a b o u t efficacy o f m a n y o f the tocolytics, c o n c e r n has a p p r o p r i a t e l y b e e n raised a b o u t the safety o f these drugs. A l t h o u g h physicians a n d patients are usually willing to a c c e p t s o m e d e g r e e o f risk f o r adverse effects with drugs p r o m i s i n g a s t r o n g t h e r a p e u t i c effect, they n e e d to be m u c h m o r e cautious if the benefits are m a r g i n a l o r unproven. Unfortunately, s o m e o f the tocolytics, m o s t notably the betamimetics a n d m a g n e s i u m sulfate, have b e e n f o u n d to have c o n s i d e r a b l e potential for adverse m a t e r n a l cardiovascular a n d respiratory effects. Likewise, a l t h o u g h n o t as clearly established, t h e r e a p p e a r to be relevant fetal a n d n e o n a t a l risks associated with s o m e o f the tocolytics as well. Most well established are the renal, a n d ductus arteriosus constricting, effects o f the p r o s t a g l a n d i n synthetase inhibitors w h e n give at gestational ages a p p r o a c h i n g o r b e y o n d 32 weeks, a n d in y o u n g e r fetuses exp o s e d to p r o l o n g e d t h e r a p y m o r e t h a n 48 to 72 hours. Also c o n c e r n i n g is the increasingly convincing reports o f fetal a n d n e o n a t a l adverse events s u b s e q u e n t to p r o l o n g e d h i g h dose tocolyric m a g n e s i u m sulfate. F o r the time being, t h e r e r e m a i n s l i n g e r i n g u n c e r t a i n t y a b o u t the best p h a r m a c o l o g i c a l app r o a c h to p r e m a t u r e labor. F r o m this perspecfive, we agree with H a n n a h ' s r e c e n t editorial suggestion that large prospective r a n d o m i z e d trials c o m p a r i n g the m o s t p r o m i s i n g tocolytic agents, with placebo, are u r g e n t l y n e e d e d . 4 Meanwhile, o u r review o f the data suggests that c u r r e n t t r e a t m e n t a p p r o a c h e s m a y n o t b e the m o s t evidence based. Specifically, we feel that c u r r e n t data s u p p o r t nifedipine as b o t h safest, a n d m o s t efficacious, as first line t r e a t m e n t for p r e m a t u r e labor. This is in o p p o s i t i o n to the c u r r e n t E u r o p e a n first-line a p p r o a c h using betamimetics, a n d the N o r t h A m e r i c a n first line app r o a c h with m a g n e s i u m sulfate. Until b e t t e r d a t a are available convincingly s h o w i n g imp r o v e d perinatal o u t c o m e s , a n d assuring ext r e m e l y low rates o f t r e a t m e n t related m a t e r n a l a n d fetal toxicity, o t h e r tocolytics (betamimetics, p r o s t a g l a n d i n synthetase inhibitors, a n d atosiban) s h o u l d p e r h a p s be d e e m e d second-line agents, o r investigational if e m p l o y e d at all. Magn e s i u m sulfate, o n the o t h e r h a n d , we believe,

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a n d as has b e e n r e c o m m e n d e d by others, 4,6,7 s h o u l d be a b a n d o n e d entirely as a tocolytic.

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