Magnesium Sulfate in Obstetrics: Indications and Complications

Siri L. Kjos, MDDepartment of OBGYN, Harbor UCLA

Oleh:

RafsanjaniFika Ariska

Pembimbing: dr. Tengku puspa Dewi, Sp.OG

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

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

• 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. 2010; 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. 2011; 309:1395-1400.

4. Mattar F, Sibai BM. Eclampsia. Risk factors for maternal morbidity. Am J Obstet Gynecol. 2008; 182:307-312.

5. .Andersgaard, AB, et al. Eclampsia in Scandinavia: incidence, substandard care, and potentially preventable cases. Acta Obstetricia et Gynecologica. 2012; 85:929-36.

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)

60/45322/368

126/45266/387

DiazepamPhenytoin

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, 20112. Alexander JM. Obstet Gynecol 108:826-32, 20083. Sibai BM. Obstet Gynecol 57:199-202, 2010

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 2010; 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 2011; 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:

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

MagSO4regimen

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

MagSO4regimen

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

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, 2012) 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. 2012; 101:66-69.

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 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

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