Randomized investigation of magnesium sulfate for prevention of preterm birth

Superiority of amniotic fluid index

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11. Moore TR, Brace RA. Amniotic fluid index (AFI) in the term ovine pregnancy: a predictable relationship between AFI and amniotic fluid volume. In: Proceedings of the thirty-fifth annual meeting of the Society for Gynecologic Investigation, Baltimore, Maryland, March 17-20, 1988. Baltimore: Society for Gynecologic Investigation, 1988. 12. Moore TR, Cayle]E. The amniotic fluid index in normal human pregnancy. AM] OBSTET GYNECOL 1990; 16: 11 6873. 13. Brace RA, WolfE]. Characterization of normal gestational changes in amniotic fluid volume. AM] OBSTET GYNECOL 1989;161:382-8. 14. Williams RL, Creasy RK, Cunningham GC, Hawes WE, Norris FD, Tashiro M. Fetal growth and perinatal viability in California. Obstet Gynecol 1982;59:624-8.

15. Rutherford SE, Smith CV, Phelan ]P, Kawakami K, Ahn MO. Four-quadrant assessment of amniotic fluid volume. Interobserver and intraobserver variation.] Reprod Med 1987;32:587-9. 16. Phelan]P, Ahn MO, Smith CV, Rutherford SE, Anderson E. Amniotic fluid index measurements during pregnancy. ] Reprod Med 1987;32:601-4. 17. Brar HS, Platt LD. Placental vascular resistance using umbilical velocimetry in patients undergoing cesarean section for fetal distress.] Ultrasound Med; 1989;8:211-4. 18. Sarno AP ]r, Ahn MO, Brar HS, Phelan ]P, Platt LD. Intrapartum Doppler velocimetry, amniotic fluid volume, and fetal heart rate as predictors of subsequent fetal distress. I. An initial report. AM] OBSTET GYNECOL 1989; 161:1508-14.

Randomized investigation of magnesium sulfate for prevention of preterm birth Susan M. Cox, MD, M. Lynne Sherman, RN, and Kenneth J. Leveno, MD Dallas, Texas One hundred fifty-six women with preterm labor between 24 and 34 weeks' gestation were randomized to receive either intravenous magnesium sulfate or no tocolytic therapy. Magnesuim sulfate infusions of up to 3 gmlhr were used in 76 pregnancies and resulted in a mean serum magnesium concentration of 5.5 ± 1.4 mEq/L (mean ± SEM). Compared with 80 control pregnancies, magnesium sulfate tocolysis had no significant effect on duration of gestation, birth weight, neonatal morbidity, and perinatal mortality. We conclude that clinically safe infusions of magnesium sulfate are ineffective when used to prevent preterm birth. (AM J OBSTET GVNECOL 1990;163:767-72.)

Key words: Magnesium sulfate, preterm labor

Effective methods for treatment of preterm labor have become major goals in modern obstetrics because preterm birth is the leading cause of infant morbidity and mortality. A significant cause of preterm birth, labor without ruptured membranes or other obstetric complications necessitating intervention, has been the focus of several pharmacologic approaches aimed at inhibition of uterine contractions. Agents that were used include ethanol,I-4 prostaglandin synthetase inhibitors,2. 5. 6 various J3-adrenergic sympathomimetics,7-13 calcium channel blockers,14 and magnesium sulfate."·n.15-17 Side effects and clinical conditions that contraindicate the use of J3-sympathomimetics have recently directed the focus of attention to the use of magnesium From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center. Presented at the Tenth Annual Meeting of the Society of Perinatal Obstetricians, Houston, Texas, January 23-27, 1990. Reprint requests: Susan M. Cox, MD, Department of Obstetrics and Gynecolo/sy, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9032.

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sulfate for the inhibition of preterm labor because high concentrations of magnesium ion inhibit uterine contractility. Specifically, concentrations of 8 to 10 mEq/L were observed to reduce the frequency of in vitro uterine muscle contraction, whereas magnesium levels of 20 mEq/L were necessary for complete cessation of activity. IS Several studies"- 13 • 15-17 have suggested that magnesium sulfate is a reasonably safe and effective agent for tocolysis, although no large randomized investigations comparing this therapy with untreated controls have been reported. We sought to determine if clinically safe magnesium concentrations (i.e., those <8 mEq/L, at which level skeletal muscle paralysis occurs) were effective in preventing preterm birth when compared with untreated controls.

Material and methods Subjects for study were from the population of women who came to the obstetrics service at Parkland Memorial Hospital in Dallas between October 1987 and May 1989. Criteria for enrollment included: (1) preterm labor defined by regular uterine contractions as-

767

768 Cox, Sherman, and Leveno

September 1990 Am J Obstet Gynecol

Table I. Clinical characteristics in pregnancies randomized to magnesium sulfate tocolysis compared with controls Control (%)

Magnesium sulfate Chnracteristic

No.

No. of pregnancies Twin gestations Total infants Maternal age, yr (mean ± SEM) Nulliparous women Black White Hispanic Prior preterm birth*

76 2 78 24 43 18 14 20

I 20.6 ± 0.5

%

No.

100 3

80 9 89

32 57 24 18 26

28 34 26 19 15

I

Comparison

% 100 11

21.3 ± 0.5

NS NS NS NS NS NS NS NS

35 43 30 23 19

*Birth weight <2500 gm.

Table II. Study entry characteristics in pregnancies randomized to magnesium sulfate tocolysis compared with controls Magnesium sulfate Entry chnracteristics Gestational age at entry, wk (mean ± SEM) Cervical dilatation Mean ± SEM (cm) 1 cm 2cm 3cm 4cm Cervical effacement Mean ± SEM (%) <25% 26%-50% 51%-75% 76%-100%

No.

I

Control

%

29.9 ± 0.3 16 29 20 7 23 38 9 6

sociated with cervical dilatation of at least I cm but <5 cm, (2) gestational age between 24 and 34 weeks; (3) intact fetal membranes, and (4) no maternal or fetal complications necessitating delivery. Women who fulfilled these criteria were asked to participate and those who gave informed written consent were enrolled in the investigation, which was performed under the auspices of the Institutional Review Board on Human Research for the University of Texas Southwestern Medical Center at Dallas and Parkland Memorial Hospital. The use of magnesium sulfate for tocolysis at our hospital was restricted to this investigation. Patients were assigned to treatment or control groups by means of a random number table with group allocation predetermined and placed in consecutively numbered and sealed envelopes. Those randomized to the treatment group received 4 gm of magnesium sulfate in a 20% solution as an intravenous loading dose followed by an infusion of2 gm/hr. The infusion rate was increased to 3 gm/hr if uterine contractions persisted

2.2 ± 0.1

45 ± 2.6

No.

I

%

NS

30.1 ± 0.3 21 38 26 9

13 35 23 5

30 50 12 8

18 37 13 12

2.3 ± 0.1

52 ± 2.7

Comparison

16 44 29 6

NS NS NS NS NS

23 46 16 15

NS NS NS NS NS

1 hour after commencement of therapy. Intravenous magnesium sulfate was continued for 24 hours and no other drug therapy was used during or subsequent to these infusions. Women with recurrent preterm labor at a later date were eligible for a second treatment with intravenous magnesium sulfate. Women assigned to the control group received intravenous physiologic saline solution at a rate of 80 ml/hr for 24 hours. All women enrolled in the study had continuous electronic fetal heart rate monitoring for 12 to 24 hours and were observed in the labor suite for a minimum of 24 hours. All women who were undelivered in both groups were hospitalized until 34 weeks' gestation in the antepartum pregnancy unit. Laboratory tests for all women included real-time ultrasonographic examination, urinalysis, hematocrit, serum creatinine, glucose, and electrolyte studies. Magnesium level determinations were repeated serially in women randomized to this treatment group. Therapy was considered unsuccessful if the fetal

Magnesium sulfate for preterm labor 769

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Table III. Selected outcomes in pregnancies randomized to magnesium sulfate tocolysis compared with controls Magnesium sulfate Selected outcomes

Gestational age at delivery mean ± SEM (wk) 24-26 wk 27-29 wk 30-32 wk 33-35 wk 236wk Time gained in utero Mean ± SEM (days) :::;1 day 2-7 days 8-28 days 228 days

No.

2 10 19 15 30 22 14

I 33.8 ± 0.5

26.6 ± 3.0

14

26

membranes ruptured, cervical dilatation progressed to >4 cm, contractions persisted longer than 30 minutes at the maximum magnesium dose with continued cervical dilatation, or maternal side effects necessitated discontinuation of the drug. Maternal side effects such as muscle weakness and symptomatic hypotension prompted a reduction in magnesium dose. If a progressive reduction in dosage was ineffective in relief of these symptoms, or if maternal respiratory depression was noted, use of magnesium sulfate was discontinued. Entry characteristics and outcome variables were analyzed with Student's t test, X2 analysis, or Fisher's exact test of probability. Results in which the probability of a type 1 error were <0.05 were considered significant.

Results A total of 156 pregnancies were included during the I9-month study; 76 were randomized to receive magnesium sulfate and 80 to the control group. The clinical characteristics of the two study groups are shown in Table I. There were no significant differences between the two groups with respect to maternal age, parity, or racial composition. Similarly, there was no significant difference in the incidence of prior preterm birth defined as birth weight <2500 gm. Table II shows gestational age, cervical dilatation, and effacement at entry into the study for pregnancies randomized to receive magnesium sulfate compared with controls. There were no significant differences in any of these study entry characteristics. Table III summarizes selected pregnancy outcomes including gestational age at delivery and days gained in utero. Significantly fewer pregnancies randomized to magnesium sulfate were delivered between 33 and 35 weeks' gestation (p = 0.02) compared with the control group. However, all other comparisons were not significant, including rates of cesarean section, which

Control

%

No.

3 13 25 20 39

4 11 14 30 21

29 18 18 34

22 7 23 28

I 33.0 ± 0.5

22.4 ± 2.5

%

Comparison

5 14 18 38 26

NS NS NS NS 0.02 NS

28 9 29 35

NS NS NS NS NS

were 16.4% and 17.8%, respectively, for magnesium sulfate and control groups. Selected neonatal outcomes according to maternal treatment group are summarized in Table IV. Results in pregnancies randomized to receive magnesium sulfate did not differ significantly from the control group with respect to birth weight, 5-minute Apgar scores, or number of days of neonatal intensive care. Similarly, indices of serious neonatal morbidity, such as respiratory distress, intracranial hemorrhage, and necrotizing enterocolitis, were not affected by preterm labor management. Two intrapartum fetal deaths occurred in pregnancies randomized to magnesium sulfate; one resulted from abruptio placentae several weeks after tocolytic therapy, and multiple anomalies were present in the other stillbirth. As shown in Table V, there were a total of six neonatal deaths; 5 occurred in the magnesium sulfate group. Factors implicated in these deaths included complications of immaturity (n = 4) and congenital malformations (n = 2). One death occurred in each treatment group after 28 days of life but before discharge. Of the 76 women randomized to receive magnesium sulfate, 62% received the maximum dose of 3 gm/hr. The mean serum magnesium concentration in the treatment group was 5.5 ± 1.4 (SEM) mEq/L. This value reflects the mean of at least three measurements per pregnancy at the maximum magnesium sulfate infusion rates. Magnesium infusions were discontinued in eight women (11 %) because of toxicity that included generalized muscle weakness (n = 6), respiratory depression (n = 1), and systemic hypotension (n = 1).

Comment Side effects, in addition to the clinical conditions that contraindicate the use of J3-sympathomimetics, have

770 Cox, Sherman, and Leveno

September 1990 Am J Obstet Gynecol

Table IV. Selected neonatal outcomes in pregnancies randomized to magnesium sulfate tocolysis compared with controls Control

Magnesium sulfate Neonatal outcomes

I

No.

Birth weight (gm) Mean ± SEM (gm) 750-1000 gm 1001-1250 gm 1251-1500 gm 1501-1750 gm 1751-2000 gm 2001-2250 gm 2251-2500 gm ~2501 gm 5 min Apgar score (mean ± SEM) Neonatal hospital Mean ± SEM (days) Intensive care Respiratory distress None Required ventilator Intracranial hemorrhage Necrotizing enterocolitis Stillbirth Neonatal death Infant death*

3 4 6 12 8 5 8 31

2264 ± 93

%

No.

4 5 8 16 11 7 11 41

4 2 6 6 9 14 10 28

13.8 ± 1.9

3 15 4 4 2 5 1

2204 ± 77

%

Comparison

5 3 8 8 11 10 13 35

NS NS NS NS NS NS NS NS NS

8 ± 0.2

8 ± 0.2 5

I

7

12

4 20 5 5 3 7 1

10 15 4 3 0 1 1

19.7 ± 3.1

NS NS NS

15 13 19 5 4

NS NS NS NS NS NS NS

*After 28 days of life but before discharge.

Table V. Descriptions of neonatal deaths Gestational age (wk) Case

Study group

I

At entry

I

At delivery

I

Days gained

Comment

1150 gm, Apgar scores 11119, RDS, died day 4 740 gm, Apgar scores 4/5, immaturity, died day 3 895 gm, Apgar scores 11417, IVH, immaturity, died day 3 1515 gm, Apgar scores 7/4/4, diaphragmatic hernia, died day 6 1625 gm, Apgar scores 4/6, mUltiple congenital anomalies, died day 10 800 gm, Apgar scores 21111, immaturity, died day 1

Magnesiun sulfate

27

27

0

2

Magnesiun sulfate

25

25

2

3

Magnesiun sulfate

28

28

4

4

Magnesiun sulfate

32

33

6

5

Magnesiun sulfate

32

32

5

6

Control

24

25

11

RDS, Respiratory distress syndrome; IVH, intraventricular hemorrhage.

served to focus attention on the use of magnesium sulfate given intravenously as an alternative tocolytic drug. In 1959 Hall et al. 18 demonstrated that strips of human gravid uterine muscle had reduced contractility in the presence of magnesium ion. Specifically, concentrations of magnesium approximating 8 to 10 mEq/L were observed to reduce the frequency of in vitro uterine muscle contractions. Complete inhibition of uterine activity, however, required magnesium concentrations of approximately 20 mEq/L. Other investigators have shown

in humans that concentrations of 8 to 10 mEq/L result in loss of patellar reflexes with respiratory depression occurring at 10 mEq/L and respiratory arrest at 12 mEq/L or higher concentrations. 19 The first centers in the United States to use magnesium for tocolysis were the Columbia-Presbyterian Medical Center, where the drug has been used routinely since 1969, and the University of Virginia, where it has been used since 1970. 16 In 1977 Steer and Petrie 15 evaluated intravenous magnesium sulfate given for to-

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colytic therapy to 31 women for pre term labor and found such therapy effective in stopping uterine contractions for at least 24 hours. The magnesium sulfate dosage was 4 gm of a 10% solution followed by 2 gm/hr. Spisso et al. 17 subsequently also reported use of magnesium sulfate to be effective in delaying delivery 48 hours or longer in a nonrandomized study that included 119 pregnancies with pre term labor and intact fetal membranes. In a retrospective study Elliott20 reported successful use of magnesium sulfate for inhibition of preterm labor in 274 pregnancies. Magnesium sulfate was infused in dosages of up to 3 mg/hr with serum magnesium concentrations that ranged as high as lO mEq/L. The frequency of such toxic levels and the consequences were not specifically cited, although Elliott concluded that the side effects of magnesium infusions compared favorably with those reported for ~-sympathomimetics. He also observed empirically that magnesium serum levels of approximately 4 to 6 mEq/L were usually sufficient to inhibit uterine contractions. More recently Hollander et al. 13 evaluated the use of magnesium sulfate as a tocolytic agent with even higher dosages. In their study the efficacy of magnesium sulfate was analyzed in relation to ritodrine hydrochloride. The mean magnesium sulfate dosage required to achieve tocolysis was reported to be 4.5 gm/hr and the mean magnesium level resulting in tocolysis was 6.6 mg/dl (5.3 mEq/L). The dosage regimen used in this investigation included a 4 gm bolus injection of magnesium sulfate followed by 2 gm/hr intravenously. The infusion rate was increased at 30-minute intervals by 1 gm/hr and to a maximum infusion of 5 gm/hr. After successful tocolysis the infusion rate was decreased to the lowest effective rate required to maintain uterine quiescence and also maintain serum magnesium levels in the range of 6 to 8 mg/dl. Such infusions were then continued for a period of 12 hours. Among 33 women who were treated only with magnesium sulfate, the reported regimen necessitated a decrease in dosage because of lethargy in 15 women (45%). The experience of these investigators suggests that effective uterine contractioninhibiting concentrations of magnesium must be near toxic levels to anticipate a clinical uterine effect. The margin between safety and efficacy of magnesium sulfate infusions for tocolysis appears to be quite narrow. To date, there has been only one published randomized investigation in which magnesium sulfate tocolysis was compared with untreated controls. II Cotton et al. randomized a total of 54 women with preterm labor between 26 and 34 weeks' gestation to treatment with magnesum sulfate, placebo, or terbutaline. They defined successful tocolysis as postponement of delivery for at least 48 hours. Patients assigned to the magnesium sulfate group (n = 16) received 4 gm intrave-

Magnesium sulfate for preterm labor 771

nouslyover 15 minutes and then a continuous infusion of 2 gm/hr. They found no significant differences among the three treatment groups with regard to delay of delivery 48 hours or longer. Our study was prompted because magnesium sulfate is frequently used as a tocolytic agent but has not been studied extensively with randomization and untreated control subjects. During the study period 23,658 women were delivered at our hospital. On the basis of a previous survey of low birth weight at our hospital, we estimate that a maximum of 294 (1.3%) pregnancies were eligible for randomization during this investigation. However, patients commonly declined randomization and clinical developments before written consent could be obtained frequently excluded potential patients. It is important to note that women who met the study inclusion criteria were consistently offered participation in this investigation. Indeed, 156 randomized pregnancies may seem like a small number; however, this population represents the largest single center randomized study to compare a tocolytic drug with no treatment. We elected to use modest infusion rates of magnesium sulfate to avoid the unacceptably high incidence of toxicity reported with infusion rates in excess of 3 gm/hr. The majority (62%) of the women received infusions of 3 gm/hr and achieved serum magnesium concentrations well within the range of values previously reported to be effective for inhibition of preterm uterine contractions. Specifically, the maximum magnesium concentration in this study was 5.5 ± 1.4 mEq/L (mean ± SEM); this level compares favorably with the results of EllioteO (4 to 6 mEq/L) and Hollander et al." (6.6 mg/dl, equivalent to 5.3 mEq/L). We believe that magnesium ion in sufficient concentrations can inhibit muscle activity, including the uterus, but found that concentrations less than these levels do not effectively delay delivery in women with pregnancies complicated by preterm labor. Moreover, we were unable to document any perinatal benefit when magnesium sulfate infusions were used to prevent preterm birth compared with untreated control subjects. We therefore conclude that magnesium sulfate infusions resulting in maximum serum concentrations of magnesium equal to 5.5 mEq/L are ineffective in the prevention of. preterm birth. REFERENCES 1. Zlatnick FJ. Fuchs F. A controlled study of ethanol in threatened premature labor. AM J OBSTET GYNECOL 1971;112:6lO-2. 2. Spearing G. Alcohol, indomethacin, and salbutamol. A comparative trial of their use in preterm labor. Obstet GynecoI1979;53:171-4. 3. Schrock A, Fidi C, Low M, Baumgarten K. Low-dose ethanol for inhibition of preterm uterine activity. Am J PerinatoI1989;6:191-5.

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