Magnesium Sulfate in Obstetrics: Indications and Complications

Siri L. Kjos, MDDepartment of OBGYN, Harbor UCLA

Magnesium Sulfate in ObstetricsIndications and Complications: Objectives

• State mechanism of action on muscles and cells

• State the serum levels associated with side effects and toxicity—know how to monitor for toxicity

• State benefits and risks of use in preeclampsia and preterm labor

Seizure Prophylaxis in Preeclampsia/Eclampsia

Magnesium Sulfate and Effect on Musculature• Slows or blocks neuromuscular and cardiac conducting system

transmission– Inhibit release of acetylcholine from presynaptic nerve

terminal,• Depresses postjunctional membrane response and

response of underlying myofibrils• Result: Muscle weakness and respiratory depression

with overdose– Decreases smooth muscle contractility

• Uterine smooth muscle: tocolytic • ↓myocardial contractility, respiration

– Depress central nervous system irritability (anticonvulsant)– Little effect on Blood pressure in therapeutic ranges

Magnesium Sulfate and Effect on Musculature

Depression DTR’s [10 mEq/L] occur below levels of cardiac or respiratory depression– Use to monitor high levels but not to monitor therapeutic

levels—brisk reflexes do occur with anticonvulsant doses [4-6 mEq/l]. Do not need to monitor levels for efficacy

– Monitor DTR’s at least every 2 hours• Load: 4-6 g over 15-30 minutes → Continuous infusion 1-2

g/hr.• Impaired renal function: [Cr>1.0 mg/dl]

– Rate 1.0 g/hr; Obtain [Magnesium] • Calcium Gluconate (10ml of 10% solution given IV over 3

minutes)

Dosage for seizure prophylaxis: 1 g/hr or 2 g/hr:•both doses safe with normal renal function•1 g/hr appears equally effective (Magpie trial) without serious complications

•Neonatal serum [Mg] ~ maternal serum [Mg]•AFI levels increase with prolonged infusion secondary to fetal renal excretion but fetal serum [Mg] do not increase•Average newborn serum [Mg] 3.7 mEq/dl•No correlation of NN [Mg] and APGAR•No evidence of cumulative effects on neonate from prolonged magnesium infusion

• Volume distribution: beyond extracellular fluid, enters bones and cells

• Circulates largely unbound to protein• Exclusively excreted in the urine

– Reabsorbed in the proximal tubule, limited by transport maximum (Tmax)

– Excretion increases as filtered load increases above Tmax.

– T ½ time for excretion: 4 H (normal renal function)• Excretion prolonged in women with↓GFR

Pharmacology of Magnesium SulfatePharmacology of Magnesium Sulfate

Preeclampsia / EclampsiaPreeclampsia / Eclampsia• In the US, the frequency of eclamptic seizures in

preeclampsia is < 1%, with reported incidence in the Western world of 1/2,000- 1/3,000 deliveries 1

• Estimated < 1/200 for mild and 1/50 for severe disease 2

• Percentage of eclamptic fits that occur intrapartum:

- UK 18% 3; Tennessee 19% 4; Scandinavia 29% 5

• Incidence of intrapartum eclampsia: < 1/600 (0.17%) of cases of mild preeclampsia

1.Sibai BM. Magnesium sulfate is the ideal anticonvulsant in preeclampsia-eclampsia. Am J Obstet. Gynecol. 1990; 162:1141-45.

2.Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: Lessons learned from recent trials. Am J Obstet Gynecol. 2004. 190:1520-26.

3. Douglas KA, Redman CW. Eclampsia in the United Kingdom. BMJ. 1994; 309:1395-1400.

4. Mattar F, Sibai BM. Eclampsia. Risk factors for maternal morbidity. Am J Obstet Gynecol. 2000; 182:307-312.

5. .Andersgaard, AB, et al. Eclampsia in Scandinavia: incidence, substandard care, and potentially preventable cases. Acta Obstetricia et Gynecologica. 2006; 85:929-36.

Frequency of symptoms preceding Eclampsia

Sibai BM. Obstet Gynecol 57:199-202, 1981

Symptom Frequency ( %)HeadacheHyperreflexiaProteinuriaEdemaClonusVisual signsEpigastric pain

83808060464520

In the US, prophylactic anticonvulsant therapy for all women meeting criteria for preeclampsia is recommended

Intrapartum ManagementIntrapartum ManagementEclampsia: 1:300-1,000

Seizures are usually self-limited (1-2 minutes)Prevent aspiration of gastric contentsDiazepam or Ativan only if sustainedProlonged deceleration will recover after seizure

If possible, allow time for full fetal recovery

Cesarean only if vaginal birth not possible within a reasonable time frame

Treatment of severe preeclampsia with Magnesium Treatment of severe preeclampsia with Magnesium sulfate is supported by level I evidence, ACOG (level A)sulfate is supported by level I evidence, ACOG (level A)

Author (year) Magnesium Magnesium sulfate sulfate

Other BP Agents RR (CI)

Moodley (’94) 1/112 0/116 Dihydralazine Nifedipine

N/A

Chen (’95) 0/34 0/34 Hydralazine, Nifedipine

N/A

Belfort (’97) 5/324 11/303 Nimodipine, Hydralazine

0.43

(0.15-1.2)

Coetzee (’98)

placebo RCT

1/345 11/340 Hydralazine, Labetolol

0.09

(0.01-0.69)

Total 7/815

(0.9%)

22/793

(2.8%)

0.31

(0.13-0.72)

Seizure incidence

Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998; 92:883-9.

Treatment of eclampsia with Magnesium Treatment of eclampsia with Magnesium sulfate sulfate

Supported by level I evidence, ACOG (level A)Supported by level I evidence, ACOG (level A)

Author (year) Magnesium sulfate

Other Agent RR (CI)

Dommisse (’90) 0/11 4/11 Phenytoin N/A

Crowther (‘90) 5/24 7/27 Diazepam 0.8 (0.9-2.2)

Bhalla (‘94) 1/45 11/45 Cocktail 0.09 (0.01-0.7)

Friedman (’95) 0/11 2/13 Phenytoin N/A

Collaborative Trial (‘95)

60/453

22/368

126/452

66/387

Diazepam

Phenytoin

0.48 (0.4-0.6)

0.33 (0.2-0.5)

Total 88/932 (9.4%)

216/935

(23.1%)

Recurrent seizures

Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 1998; 92:883-9.

Magnesium Sulfate: Do women with mild preeclampsia need prophylaxis?

When does risk of Magnesium prophylaxis exceed seizure risk?

Magpie Study1: Magnesium safe and effective even in developing countries

Most had severe preeclampsia (75% needed anti-hypertensive Rx)

When Magnesium limited to severe disease → ↓ 50% in seizures2

Difficult to select which women with preeclampsia will progress to eclampsia based on symptoms3

1. Altman D, Lancet 359:1877-90, 2002 2. Alexander JM. Obstet Gynecol 108:826-32, 2006. 3.Sibai BM. Obstet Gynecol 57:199-202, 1981

Magnesium sulfate and Mild PreeclampsiaMagnesium sulfate and Mild Preeclampsia“Magpie Trial”“Magpie Trial”

Magpie Trial (n=10,141) 33 countries involved

• Double-blind, placebo RCT

• Criteria: SBP 140 or DBP 90 (x2), Proteinuria 1+

• Magnesium sulfate vs. Placebo

* All patients from US (43), and 248/251 patients from Cuba, had mild preeclampsia (severe cases not generally enrolled)

The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:1877-90.

The Magpie TrialThe Magpie Trial

Magnesium sulfate

Placebo RR NNT

All patients 0.8% 1.9% 0.42(0.3-0.6)

91

Iminent eclampsia*

1.0% 3.7% 0.26(0.1-0.6)

36

Severe preeclampsia

1.2% 2.8% 0.42(0.2-0.8)

63

Non-severe preeclampsia

0.7% 1.6% 0.42(0.3-0.7)

109

* Two or more of the following: hyperreflexia, frontal headache, blurred vision, epigastric tenderness (regardless of blood pressure and proteinuria)

The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:1877-90.

Seizure incidence

The Magpie TrialThe Magpie Trial

Eclampsia Magnesium sulfate

Placebo RR NNT

High PMR*>40/1,000

1.2% 2.8% 0.42(0.2-0.8)

63

Medium PMR20-40/1,000

0.7% 1.6% 0.42(0.3-0.7)

109

Low PMR<20/1,000 births

0.5%(4/778)

0.8%(6/782)

0.67 (0.2-2.4)

N/A

* Perinatal mortality rate

The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:1877-90

ConclusionsConclusions•Women with severe preeclampsia, imminent eclampsia, and those with preeclampsia in high PMR countries, appear to benefit the most.

• No benefit of Magnesium sulfate in countries with low PMR

•Magnesium sulfate is effective in reducing the risk of eclampsia in women with preeclampsia:

Placebo-controlled trials of Magnesium Sulfate in Placebo-controlled trials of Magnesium Sulfate in mild preeclampsia*mild preeclampsia*

Seizures Progression

to severe

preeclampsiaAuthor Magnesium Magnesium

Sulfate Sulfate Placebo Magnesium Magnesium

Sulfate Sulfate Placebo RR

(CI)

Witlin 0/67 0/68 12% 9.1% 1.35

(0.5-3.7)

Livingston 0/109 0/113 12.8% 16.8% 0.76

(0.4-2.4)

Total 0/176 0/181 12.5% 13.8% 0.90

(0.5-1.5)

*Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: lessons learned from recent trials. AM J Obstet Gynecol. 2004. 190: 1520-26.

Wtilin AG. The efect of magnesium sulfate therapy on the duration of labor in women with mild preeclampsia at term: A randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 1997; 176:623-27.

Livingston, JC. Magnesium sulfate in women with mild preeclampsia: a randomized control trial. Obstet Gynecol. 2003; 101:217-220.

AGOG Bulletin #33 January 2002AGOG Bulletin #33 January 2002

“Although there is no unanimity of opinion regarding the prophylactic use of magnesium sulfate for the prevention of seizures in women with mild preeclampsia or gestational hypertension,

a significant body of evidence attests to the efficacy of magnesium sulfate in women with severe preeclampsia or eclampsia.”

When should Magnesium Sulfate Therapy be When should Magnesium Sulfate Therapy be initiated in preeclampsia? initiated in preeclampsia?

Timing of Initiation in clinical triaTiming of Initiation in clinical trialsAuthor Pre-

eclampsiaInitiation of MagSO4

MagSO4

regimen

Duration of MagSO4

Witlin ’97

(n=135)

Mild Latent /

Active

6g / 2g 11.4 +/-

10.6 hr

Coetzee ‘98 (n=699)

Severe Latent / Active 4g / 1g -

Magpie ’02

(N=10,141)

Mild/

severe

Latent /

Active

4g / 1g Up to 24hrs

Livingston ’03 (N=222)

Mild Latent /

Active

6g / 2g -

Belfort ’03

(n=1650)

Severe Latent /

Active

6g / 2g

4g / 1g

Up to

24 hrs

In clinical trials, in which the methods were clearly described, Magnesium sulfate was always initiated

once the decision was made for delivery

Regardless of mild or severe status, no investigator has described waiting until the active phase of labor to start Magnesium sulfate

Magnesium Sulfate: Duration of prophylaxisMagnesium Sulfate: Duration of prophylaxis

Author Pre-eclampsia

Initiation of MagSO4

MagSO4

regimen

Duration of MagSO4

Witlin ’97

(n=135)

Mild Latent /

Active

6g / 2g 11.4 +/-

10.6 hr

Coetzee ‘98 (n=699)

Severe Latent / Active

4g / 1g -

Magpie ’02

(N=10,141)

Mild/severe Latent /

Active

4g / 1g Up to 24hrs

Livingston ’03 (N=222)

Mild Latent / Active

6g / 2g -

Belfort ’03

(n=1650)

Severe Latent / Active

6g / 2g

4g / 1g

Up to

24 hrs

ConclusionConclusion

•Magpie trial ’02 (N=10,141) limited Magnesium sulfate to 24hrs.

• After 24hrs, if delivery had not occurred, the decision for continued treatment was physician-dependent

• Concluded that exceeding 24hr limit has not been proven safe

• Belfort ’03 (N=1650), also limited Magnesium sulfate to 24hrs, and protocol called for C/S unless delivery imminent

Magpie Trial: Maternal MorbidityMagpie Trial: Maternal Morbidity

Outcome Magnesium Sulfate

Placebo

Any serious morbidity 3.9% 3.6%

Respiratory depression 0.9% 0.5%

Pulmonary edema 0.6% 0.7%

Placental abruption 2% 3%

Use of >1 Anti-hypertensives 25% 27%

C-section (in labor) 17% 16%

EBL>500cc after delivery 17% 18%

Hospital stay 6 d 6 d

Admit to ICU 2% 2%

Magpie Trial: Perinatal Magpie Trial: Perinatal morbidity

Outcome Magnesium SO4

Placebo

Perinatal death 11.4% 11.5%

Stillbirth 8.2% 8.6%

Apgar <7 at 5min 6% 6%

Intubated at delivery 4% 4%

Hospital stay 5d 5d

NICU >7d 19% 19%

Conclusion

• Magpie trial concluded that there was no difference in maternal or perinatal morbidity in patients receiving 24hrs Magnesium sulfate vs. placebo

• There are no large clinical trials evaluating the effects of Magnesium sulfate >24 hrs in preeclampsia

• Earlier observational studies had suggested risks of:

- postpartum hemorrhage

- pulmonary edema

- respiratory depression

Are Magnesium levels beneficial, or can we rely on clinical Are Magnesium levels beneficial, or can we rely on clinical symptoms to determine Magnesium Sulfate toxicity? symptoms to determine Magnesium Sulfate toxicity?

Therapeutic doseTherapeutic dose

• Zuspan initiated IV infusion : 4g load, and 1g/hr

• Pritchard identified therapeutic range :

-serum magnesium 4.2-8.4 mEq/L

• In study by Sibai, he found that with:

4g load, 1g/hr: 1.7% (2/115 ) in therapeutic range

4g load, 2g/hr: 5.1% (23/45 )in therapeutic range

6g load, 2g/hr: 100% within therapeutic range

Zuspan FP. Treatment of severe preeclampsia and eclampsia. Clin Obstet Gynecol. 1966;9:954-72.

Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet 1955; 100: 131-140.

Sibai BM. Magnesium sulfate is the ideal anticonvulsant in preeclampsia-eclampsia. Am J Obstet Gynecol. 1990; 162:1141-45.

Magnesium Sulfate: How do we monitor for toxicity?

• Most physicians rely on clinical signs/symptoms

• In Magpie trial respiratory signs were more telling than tendon reflexes:

Magnesium Placebo

Reduced tendon reflexes 1.2% 1.2%

Respiratory depression 1.0% 0.5%

Major differences were in minor symptoms:

-Flushing, N/V, muscle weakness The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002; 359:1877-90.

Magnesium Sulfate How do we monitor for toxicity?

• Many clinicians send level when concern for toxicity arises. However, levels >12 mEq/L are rare with proper infusion, and in the absence of renal disease.

Toxic levelsToxic levels:

N/V, flushing, weakness: 9-12 mEq/L

Loss of tendon reflexes: >12 mEq/L

Respiratory depression: >14 mEq/L

Paralysis, respiratory arrest: 15-17 mEq/L

Cardiac arrest: >25 mEq/L

Lindow SW. Magnesium sulphate: a review of clinical pharmacology applied to obstetrics. British Journal of Obstetrics and Gynecology. 1998; vol.105:260-68.

- When monitoring toxicity need to realize:

-Magnesium is cleared by the kidneys in concentration-dependent manner

- Usually, a higher Magnesium concentration leads to higher excretion from the body

- However, patients with oliguria, elevated creatinine, and/or chronic renal disease (e.g. DM, CHTN) should be monitored very closely due to impaired excretion

Magnesium SulfateMagnesium SulfateHow long should we treat postpartum?How long should we treat postpartum?

•12-24 hr regimen postpartum followed in most trials

• 27-65% of eclamptic seizures occur post-partum, and 38-84% occur within 48hrs

• However, studies on patients with eclampsia have concluded that postpartum eclampsia is usually self-limited and associated with decreased morbidity

• This has triggered desire to decrease post-partum Magnesium sulfate

Mattar F, Sibai BM. Eclampsia: Risk factors for maternal morbidity. Am J Obstet Gynecol. 2000; 182:307-312.

Is postpartum magnesium sulfate necessary?Is postpartum magnesium sulfate necessary?Postpartum magnesium sulfate: using maternal Postpartum magnesium sulfate: using maternal

clinical parameters to guide therapyclinical parameters to guide therapy

Study: (Isler, 2003) Prospective clinical trial (n=503)

• Gave Magnesium sulfate 2g/hr postpartum until:

•absence of persistent headache / visual changes

•absence of epigastric pain

•greater than 50% BP readings <150/100

•BP <160/110 preceding 2hrs

•diuresis of >100ml/hr for >2hrs consecutive

Isler CM, et al. Postpartum seizure prophylaxis: Using maternal clinical parameters to guide therapy. Obstet Gynecol. 2003; 101:66-69.

Postpartum magnesium sulfate: using maternal Postpartum magnesium sulfate: using maternal clinical parameters to guide therapyclinical parameters to guide therapy

Parameter Mild Pre-eclampsia

Severe

Preeclampsia

Superimposed preeclampsia

P-value

Antepartum

MagSO4 (hr)

11

(1-55)

10

(1-83)

9

(1-68)

0.69

Postpartum

MagSO4 (hr)

3.5

(2-72)

4

(2-77)

3

(2-33)

0.06

Time to diuresis (hr)

1

(1-18)

1

(1-13)

1

(1-12)

0.21

MagSO4

re-started

6.3% 5.7% 18.0% 0.02

Time to discharge (d)

3.1 3.2 3.0 0.69

Isler CM, et al. Postpartum seizure prophylaxis: Using maternal clinical parameters to guide therapy. Obstet Gynecol. 2003; 101:66-69.

Postpartum magnesium sulfate: using maternal Postpartum magnesium sulfate: using maternal diuresis to guide therapydiuresis to guide therapy

Study: (Fontenot , 2005). RCT to assess the use of diuresis as a determinant of postpartum MgSO4 therapy in severe preeclampsia

• Control group: MgSO4 2g/hr x 24 hrs

• Study group: MgSO4 until urine output >100 ml/hr x 2hrs

• Proposed that diuresis is indicative of diminishing vasospastic response

Fontenot et al. A prospective randomized trial of magnesium sulfate in severe preeclampsia: Use of diuresis as a clinical parameter to determine the duration of postpartum therapy. Am J Obstet Gynecol. 2005. 192:1788-94.

Postpartum magnesium sulfate: using maternal Postpartum magnesium sulfate: using maternal diuresis to guide therapydiuresis to guide therapy

Study: (Fontenot , 2005). RCT to assess the use of diuresis as a determinant of postpartum MgSO4 therapy in severe preeclampsia

• Control group: MgSO4 2g/hr x 24 hrs

• Study group: MgSO4 until urine output >100 ml/hr x 2hrs

• Proposed that diuresis is indicative of diminishing vasospastic response

Fontenot et al. A prospective randomized trial of magnesium sulfate in severe preeclampsia: Use of diuresis as a clinical parameter to determine the duration of postpartum therapy. Am J Obstet Gynecol. 2005. 192:1788-94.

Postpartum magnesium sulfate: using maternal Postpartum magnesium sulfate: using maternal diuresis to guide therapydiuresis to guide therapy

Variable Control

Group

Study

Group

P-value

Antepartum MgSO4 (hr) 19.3 19.4 0.99

Postpartum MgSO4 (hr) 24 8.5 <0.0001

Postpartum hospital stay 3.1 3.5 0.15

Eclampsia* 0 0 N/A

Re-intiation of MgSO4^ 0 0 N/A

Fontenot et al. A prospective randomized trial of magnesium sulfate in severe preeclampsia: Use of diuresis as a clinical parameter to determine the duration of postpartum therapy. Am J Obstet Gynecol. 2005. 192:1788-94.

*underpowered, to find a 2-fold difference would require 33,000 patients

^Study powered to find 20% increased risk of re-initiation of MgSO4 therapy

• Study was underpowered

•(powered to find a 20% difference in re-initation of magnesium sulfate therapy)

Cost differenceCost difference

•Difference in cost per day in lower acuity nursing unit (postpartum unit) is: $764

• Duration of treatment 65% less in study group

• Reduction in cost/patient: $495

• Total cost (n=98): $48,510

Postpartum Magnesium Sulfate and BreastfeedingPostpartum Magnesium Sulfate and Breastfeeding• Magnesium still elevated in colostrum x24hrs after infusion, but the level is considered safe in breastfeeding 1

• The decision to treat mild preeclampsia with magnesium sulfate, and the duration of post-partum treatment in severe preeclampsia can delay breastfeeding and infant bonding

• It is well studied that delayed initiation of breastfeeding leads to lower rates of long-term success 2

1. Cruikshank DP, et al. Breast milk magnesium and calcium concentrations following magnesium sulphate treatment. Am J Obstet Gynecol. 1982; 143:685-88.

2.Yamauchi Y, Yamanouchi I. Breastfeeding frequency during the first 24 hours after birth in full-term neonates. Pediatrics. 1990;86:171-75.

Summary: Magnesium sulfate use in Summary: Magnesium sulfate use in preeclampsia/eclampsiapreeclampsia/eclampsia

• Magpie trial supports use of magnesium sulfate in mild preeclampsia for countries with medium-high PMR

• RCT’s show no benefit of magnesium sulfate in mild preeclampsia in US and countries with low PMR

• Magpie trial (N=10,141) concluded no difference in maternal / perinatal morbidity between magnesium sulfate and placebo (24hrs)

• No clinical trial has been performed to evaluate the initiation of magnesium sulfate in active labor, or to evaluate its use >24hrs

Magnesium Sulfate for Tocolysis

Pharmocologic Therapy for Preterm Labor Contraindications to Magnesium Sulfate

Contraindications Complications

Hypocalcemia Renal failure Myasthenia gravis

Pulmonary edema Respiratory depression Cardiac arrest Maternal Tetany Profound Hypotension Profound muscular paralysis

Intravenous administrationLoad:4-6 g; 1-4 g/H--titrate to response

Complications from Tocolysis with Magnesium Sulfate

• Toxicity– Inhibition of myometrial contractility (5-8 mg/dl)– Loss of deep tendon reflexes (9-13 mg/dl)– Respiratory depression (>13 mg/dl)

• Pulmonary edema (similar to -adrenergics)– Twins (volume expansion); Anemia– Urinary output (renal excretion)– Tocolysis >24 hours ( colloid oncotic pressure)– Fluid overload (overhydration)

• Careful attention to fluids decreases risk:

– Corticosteroids do not affect risk

Administration of Magnesium Sulfate as a tocolytic

• Loading dose: 4-6 g in 10%-20% solution – Give over 30 minutes– 60 ml of 10% magnesium sulfate in D5NS

• Maintenance dose 2 g/hr– 40g magnesium sulfate to 1 L D5NS @ 50 ml/hr

• Increase dose by 1g/hr until <1 U.C. per Hour– Maximum: 4 g/hr

• Total fluids 125 ml/hr

Monitoring Tocolysis with Magnesium Sulfate

• Hourly monitoring of– Fluid status (>30 cc/hr); DTR’s– Vitals –respiratory rate

• Magnesium levels may be obtained – If suspected toxicity or impaired renal status ([Cr]>0.9

mg/dl]– Reduce or stop infusion if respiration or urine output

declines

• Calcium gluconate readily available to reverse effects of Magnesium sulfate

SummarySummary

““Magnesium sulfate is a familiar agent but its tocolytic Magnesium sulfate is a familiar agent but its tocolytic efficacy is poor.efficacy is poor.

Maybe a useful choice if the diagnosis of preterm labor Maybe a useful choice if the diagnosis of preterm labor is early and uncertain and in patients in whom other is early and uncertain and in patients in whom other

agents are contraindicated (e.g. diabetes)”agents are contraindicated (e.g. diabetes)”

Creasy & Resnik’s Maternal-Fetal Medicine 6Creasy & Resnik’s Maternal-Fetal Medicine 6thth Ed Ed

When to discontinue tocolysis with Magnesium Sulfate

• When U.C.s decreased < 1 every 10-15 minutes or have ceased

• Magnesium sulfate sometimes continued to arbitrary endpoint is reached (12 H after U.C.s stopped or until steroid course completed)– Not supported by data

Magnesium Sulphate for Preventing PTB Cochrane Meta-analysis 2002

Evaluated 23 RCTs: 9 RCTs included: Rx vs Control

:

Crowther CA, Hiller JE Doyle LW. Cochrane Collaboration 2002

Primary outcome RR (95% CI) NPreterm delivery <48 HrPreterm delivery <37 weeksPreterm delivery <34 weeksDifference in GA@ deliveryPerinatal DeathCVH

0.85 (0.58, 1.25)0.91 (0.75, 1.11)0.82 (0.45, 1.50)-0.43 (1.72, 0.87)2.82 (1.20, 6.62)1.07 (0.56, 2.05)

88142480

361727495

ConclusionConclusion

““Magnesium Sulfate is ineffective at Magnesium Sulfate is ineffective at delaying or preventing preterm birth delaying or preventing preterm birth

and its use is associated with and its use is associated with increased mortality for the infant.*”increased mortality for the infant.*”

*one trial only, subsequent RCTs for neuroprotective *one trial only, subsequent RCTs for neuroprotective have enrolled >30 times subjects without any have enrolled >30 times subjects without any

increased evidence of neonatal mortality/morbidityincreased evidence of neonatal mortality/morbidity

Inconsistent evidenceInconsistent evidence

A RCT (double-masked, placebo-controlled trial) of Magnesium Sulfate for Prevention of Cerebral Palsy

:

Study: N= 2241, multi-center (20 sites), 22-31 weeks, 6 g load, 2 g/H

Rouse DJ, et al. New Eng J Med 359:895-905

Primary outcome RR (95% CI)

Composite (CP or Death)

Moderate/severe Cerebral Palsy (> 2 y/o, among survivors)

Death (stillbirth or infant <2 yrs)

0.91 (0.75, 1.11)

0.45 (0.32, 0.87)

1.12 (0.85, 1.47)

11.3% vs. 11.7%

1.9% vs. 3.5%

9.5% vs. 8.5%

Conclusion of RCTConclusion of RCT““Fetal exposure to Magnesium Sulfate before anticipated Fetal exposure to Magnesium Sulfate before anticipated Early preterm deliver did not reduce the combined riskEarly preterm deliver did not reduce the combined riskof moderate or severe cerebral palsy or death, although of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduce in survivors.”the rate of cerebral palsy was reduce in survivors.”

May be a role for prenatally administered magnesium May be a role for prenatally administered magnesium sulfate as a neuroprotectant to infants born <32 weeks.sulfate as a neuroprotectant to infants born <32 weeks.Creasy & Resnik’s Maternal-Fetal Medicine 6Creasy & Resnik’s Maternal-Fetal Medicine 6thth Ed Ed

Magnesium Sulfate and Anesthesia• General anesthesia

– Neuromuscular blocking agents used to facilitate endotracheal intubation and relax abdominal musculature for cesarean delivery

– Magnesium potentiates and prolongs the action of depolarizing agents (succinylcholine) and non-deplorizing agents (rocuronium, vecuronium, atracurium).

• Need lower doses of these agents• Electronic monitoring of neuromuscular junction is helpful.

• End of surgery need to evaluate sufficient muscle strength to sustain ventilation

• Discontinue Magnesium during general anesthesia as drugs used during general anesthesia are anticonvulsants