The ALPS Trial

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Here’s the RoshReview Question of the Week:

A 21-year-old G1P0 woman at 36w2d gestation presents to L&D with preterm contractions. Which of the following is an indication for giving antenatal corticosteroids?

Check out the links above for the correct answer, and get more details on the group discount deal with RoshReview QBanks for CREOG and ABOG exam studying!

THE ALPS Study

Actual Title: Antenatal Betamethasone for Women at Risk for Late Preterm Delivery 

ALPS = Antenatal Late Preterm Steroids 

Some general background information 

  • Who did the study and who published it? 

    • Another study done by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, MFMU 

    • Published in the NEJM in 2016 

  • Why was the study done? 

    • Antenatal corticosteroids were widely used up to 34 weeks prior to this study 

    • Decided after consensus conference held by the National Institutes of Health in 1994 - strong evidence that corticosteroids reduce adverse neonatal outcomes (death, RDS, and other morbidities) 

    • Recommendation not given after 34 weeks because it was thought that babies usually do well after 34 weeks 

      • However, it became clear later that infants born in the late preterm period still have increased neonatal and childhood risks compared to term infants 

      • 8% of all deliveries occur in the late preterm time period 

  • Question we want answered: 

    • Does administration of betamethasone to women likely to deliver in the late preterm period (defined as 34w0d - 36w6d) decrease respiratory and other neonatal morbidities?

Methods 

  • Who participated and when? 

    • Done at 17 university-based clinical centers participating in the MFMU Network

    • Recruitment began in October 2010 - February 2015  

    • Eligibility criteria:

      • Live singleton pregnancy 34w0d- 36w5d 

      • High probability of delivery in the late preterm period

        • Preterm labor with intact membranes, at least 3 cm dilated or 75% effaced or

        • Spontaneous rupture of membranes 

        • If neither applied, expected preterm delivery for any other indication via IOL or CS between 24h - 7 days after planned randomization  

    •  Ineligible if: 

      • Expected to deliver in <12 hours for any reason

        • ROM with more than 6 contractions/hour or cervical dilation of 3 cm or more unless pit was withheld for at least 12 hours (but other induction agents were allowed) 

        • Chorioamnionitis 

        • Cervical dilation 8 cm or more 

        • Evidence of non-reassuring fetal status requiring immediate delivery  

      • Previously received steroids for fetal lung maturity in pregnancy  

      • Candidate for stress dose steroids 

      • Contraindication to betamethasone 

      • Pre-gestational diabetes 

      • Known major fetal anomaly 

  • How was the study done? 

    • After subjects were consented, they were allocated in 1:1 ratio to either course of 12 mg of BMZ (2 doses 24 hours apart) or placebo 

    • Stratified by clinical site and gestational age categories (34-35 weeks vs. 36 weeks) 

    • Double-blind (neither study participant nor investigator knew if BMZ or placebo)

    • Rest of labor/delivery managed per indication  

  • What outcomes did they look for?

    • Primary outcome 

      • Composite endpoint for need for respiratory support by 72 hours of age consisting of:

        • CPAP or HFNC for at least 2 consecutive hours 

        • O2 requirement with FiO2 of at least 30% for at least 4 continuous hours

        • ECMO or mechanical ventilation  

      •  Stillbirth and neonatal death before 72 hours were also included in both composite outcomes as they could be competing events 

      • Subgroup analysis for primary outcome and severe respiratory morbidity  for 34-35 vs 36 weeks gestation, indication for trial entry, planned CS vs planned VD, sex, and race/ethnicity 

    • Secondary outcomes 

      • Neonatal: many, but included severe respiratory morbidity; TTN, apnea, bronchopulmonary dysplasia, need for surfacntat, hypoglycemia, resuscitation, feeding difficulty, IVH, sepsis, death before discharge, etc.  

What were the results 

  • Who did they recruit?

    • Out of 24,538 screening, 2831 eligible were consented and randomized

      • 1429 got betamethasone 

        • Only 860 (60%) got both doses 

      • 1402 got placebo  - only 826 (59%) got both doses 

      • Reason those did not get a second dose: 95% delivered before 24 hours

  • What were their outcomes?

    • No stillbirths or neonatal deaths within 72 hours

    • 4 women lost to follow up (0.14%) 

    • Primary outcome: 

      • Occurred less frequently in the BMZ group than placebo 

        • 11.6% vs. 14.4% RR 0.8, 95% CI 0.66-0.97, p = 0.02 

        • Number needed treat to prevent one case was 35 

      • Unchanged in post-hoc analyses 

      • None of the subgroup analysis were significant 

    •   Secondary outcome 

      • Severe respiratory morbidity composite outcome also significantly reduced in BMZ compared to placebo

        • 8.1 vs. 12.1%, RR 0.67, 95% CI 0.53-0.84, P<0.001 

        • NNT 25 

        • Rate of TTN, need for resuscitation, and BPD were significantly less frequent in BMZ group  

      • No significant difference in chorio or endometritis 

    • Other findings of note: 

      • Significant difference in hypoglycemia of glucose <40

        • 343 (24.0%) vs 209 (14.9%) -  those that got BMZ more likely to have hypoglycemia, P<0.001 

What was the impact? 

  • Found that BMZ even up to 36w5d for initial can decrease respiratory morbidity 

  • Consistent with previous data from the ASTECs trial (Antenatal STeroids for Term Cesarean Section)

    • This did find dec NICU admission for respiratory distress

    • So babies in the UK do get steroids at term for CS not in labor!  

  • There is a recommendation from ACOG now to give single course of steroids to pregnant patients between 34w0d-36w6d at risk of preterm delivery within 7 days who have not previously received steroids 

The BEAM Trial

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We’re back this week to talk through another magnesium trial. This time, we explore the BEAM Trial, aka, “A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy.”

BEAM = Beneficial Effects of Antenatal Magnesium Sulfate 

Background

  • Who did the study and who published it?

    • Conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Strokes + The George Washington University Biostatistics Center 

    • Where was it published? The New England Journal of Medicine in 2008 

  • Why was the study done? 

    • Cerebral palsy is a huge cause of chronic childhood disability and preterm birth is a big risk factor 

    • Previous case-control study that showed that those infants who had cerebral palsy were less likely to be exposed to mag than those that didn’t 

      • But smaller trials had shown that maybe mag did not decrease infant death or cerebral palsy.

    • Biological plausibility: mag may reduce vascular instability, prevent hypoxic damage, and mitigate cytokine or excitatory amino acid damage 

  • What was the research question?

    • Will giving magnesium sulfate to women who are at high risk of preterm delivery decrease the risk of CP in their children? 

Methods 

  • Who participated and when?

    • Subjects were recruited from December 1997 - May 2004

    • Study conducted at 20 participating MFMU sites across the US 

    • Eligibility: 

      • Singletons or twins between 24-31 weeks of gestation and at high risk of delivery because of PPROM (22-31 weeks) or cervical dilation of 4-8 cm and intact membranes 

        • They say 24-31, but then mean 24w0d - 31w6d 

      • Indicated preterm delivery anticipated within 2-24 hours 

    • Exclusion criteria

      • If delivery was anticipated in <2 hours 

      • If cervix >8 cm 

      • PPROM <22 weeks 

      • Unwillingness for obstetricians to intervene for benefit of fetus 

      • Major fetal anomalies or IUFD 

      • Maternal hypertension or preeclampsia 

      • Maternal contraindication to mag sulfate 

      • Receipt of IV mag in the previous 12 hours 

  • How was the study done?

    • Double blind 

    • Subjects randomized to either IV mag (loading dose 6g for 20-30 min, then maintenance of 2g/hour) or placebo 

    • If delivery did not occur in 12 hours, and not imminent, infusion was stopped, and restarted if delivery became imminent again 

    • If >6 hours had passed since discontinuation of study med, then re-bolused 

    • Randomization was made with stratification for clinical center and in twin gestations, weeks of gestation (<28 or >/= 28 weeks)  

  • What outcomes were they looking for?

    • Primary outcome

      • Composite of stillbirth, infant death at 1 year of age, or moderate or severe cerebral palsy as assessed at or beyond 2 years of age (ages corrected for prematurity) 

        • They followed these babies out for >2 years! 

          • Had certified pediatrician or pediatric neurologist to make diagnosis of CP with criteria that they list 

          • If CP was diagnosed, then the Gross Motor Function Classification System (GMFCS) was used to assess severity 

        • Infants that had a normal neurological exam at 1 year, could walk 10 steps independently, and had bilateral pincer grasp were declared free of CP and were considered “normal” for purposes for primary outcome 

    •  Secondary outcomes

      • Maternal outcomes and complications 

      • Adverse events potentially attributed to study intervention 

      • Neonatal complications 

      • CP at 2 years of age that is mild, mod, or severe

      • Stillbirth

      • Infant death

      • Scores on the Bayley Scale of Infant Development II administered at 2 years of age 

      • Cranial ultrasounds were done on all neonates   

    • Analyses were done stratified according to if randomization occurred at <28 weeks vs. >/= 28 weeks 

  • A word on statistics

    • Power calculation

      • Assumed that primary outcome would occur in 14% of placebo group and assumed death rate of 6%, and that rate of mod to severe CP among survivors would be 8% 

        • One study in 2006 looking at survival without major morbidity was 92% at 30 weeks

        • These rates may have been much higher in 1997-2004 compared to now.

      • Deemed 2000 to be enough for detection of a 30% reduction in this outcome with Type I error of 5% and power of at least 80% 

Results

  • Who did they recruit? 

    • 2241 eligible women were enrolled

      • 1096 assigned to receive mag sulfate (1188 fetuses because they included twins!) 

        • Ultimately had 1087 women observed at delivery (1179 fetuses) 

        • 80 infants died before initial discharge home, and 18 infants died between discharge and 1 year 

        • 1133 fetuses and children included in primary analysis 

        • 1087 women included in maternal outcomes 

      • 1145 assigned to receive placebo (1256 fetuses) 

        • Ultimately had 1141 women observed at delivery (1252 fetuses) 

        • 71 infants died before initial discharge home, and 17 infants died between discharge and 1 year exam 

        • 1203 fetsues and children included in primary analysis 

        • 1141 women included in maternal outcomes analysis 

    • Baseline characteristics were similar in two groups 

    • Adherence to the protocol was very high! Only 1.4% had off-protocol use 

    • Median dose of magnesium was 31.5g (IQR 29-44.6g)

      • Just calculating that out: that’s like 12.75 hours of mag when used continuously!

  • Outcomes

    • Mod or severe cerebral palsy or death (primary outcome) - not different!

      • RR 0.97, 95% CI 0.77-1.23 

        • In mag group: 118/1041 pregnancies (11.3%) 

        • In placebo group: 128/1095 pregnancies (11.7%) 

    • Mod or severe cerebral palsy on its own - significant difference

      • 1.9% vs. 3.5% in mag vs. placebo 

      • RR 0.55, 95% CI 0.32 - 0.95

    • Risk of stillbirth

      • 9.5% vs. 8.5% in mag vs. placebo (RR 1.12, 95% CI 0.85 - 1.47), not different  

  • A word on the stratified outcome

    • No real difference in any outcome except for risk of mod or severe cerebral palsy 

    • In fact, when they stratified to <28 weeks and >/= 28 weeks: only difference was seen in the group that was <28 weeks

      • Mag 12/442 (2.7%) vs. Placebo 30/496 (6.0%) - RR 0.45 (0.23-0.87) 

      • If looking at >28 weeks: Mag 8/599 (1.3%) vs. Placebo 8/599 (1.3%), RR 1.0 (0.38-2.65) 

  • Secondary outcomes

    • Neonatal:

      • Percentages of mild, moderate, and severe cerebral palsy (not including dx at 1 year) were much smaller in the mag sulfate group compared to placebo (p= 0.004) 

        • Mild: 2.2% vs. 3.7% 

        • Mod: 1.5% vs. 2.0% 

        • Sever: 0.5% vs. 1.6%  

    •  Obstetric

      • Overall similar such as gestational age at delivery, antenatal steroid receipt, chorio, C/S, endometritis, pulmonary edema  

    • Adverse events

      • Significantly higher in the mag group!



What was the impact of all of this? 

  • We now give magnesium to people at risk of imminent delivery who are <32 weeks!

    • Committee Opinion 455: Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection

    • As with preeclampsia, your magnesium dosing may vary by institution for a number of reasons.

  • Some lingering questions:

    • How much time with mag is enough?

      • These researchers used 12 hours and then turned it off if no imminent delivery 

      • And then re-bolused if >6 hours from last mag 

      • But… how many people got 12 hours? How many people got only 3 hours? It seemed like the median number of hours was 12.75 (calculated based on dose of 31.5g, and based on 6g loading and 2g/hr) 

        • But IQR would make this about 11.5 h - 19.3 hours

    • How much time off of mag before effect wears off?

      • Study protocol redosed at 6 hours with loading dose but… what is the therapeutic range anyway? 

      • We have all these different doses from Crowther, Marret, and Rouse  

      • Did the Marret study not have any difference in effect because the numbers were small or because the mag dosing was too little?

The MAGPIE Trial

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We’re going to start dedicating a few episodes to landmark trials of obstetrics and gynecology. Have a suggestion for other trials we should review? Let us know!

The MAGPIE Trial

Do Women with pre-eclampsia, and their babies, benefit from magnesium sulfate? The Magpie Trial: a randomized placebo-controlled trial 

MAGPIE = MAGnesium sulfate for Prevention of Eclampsia

Find the trial text available here from The Lancet (2002)

Some general background information 

  • Magpie Trial Collaborative Group - huge group that spanned many continents and countries.

  • Funded by lots of people, but ultimately coordinated by the Resource Centre for Randomised Trials at the Institute of Health Sciences in Oxford, UK

  • Why was the study done? 

    • For many decades, anticonvulsant drugs were used on women with pre-eclampsia with the thought that it could prevent eclamptic seizures. Of these, magnesium sulfate was one of the medications 

    • However, in 1998, a systematic review looked at four trials compared anticonvulsants with no anticonvulsants, and of these, magnesium sulfate was thought to be the most promising choice for eclampsia prevention

    • At the time of the study, while magnesium was starting to be used more and more to prevent seizures in those that had preeclampsia, there were still those that used other medications like diazepam, other benzos, phenytoin, barbiturates, etc. 

  • What was the research question? 

    • Do women with pre-eclampsia or their babies (or both) “do better” if they are given magnesium sulfate compared to placebo, regardless of whether treatment is started before or after delivery and irrespective of any previous anticonvulsant therapies

Methods 

  • Who participated, and when?

    • Initial pilot trial ran from 2/23-7/14/1998 

    • Actual trial was from 7/15/1998-11/29/2001. 

    • Study was conducted in 33 countries and spanned 6 continents

    • Eligibility:

      • If they had preeclampsia and uncertainty about whether to use magnesium 

      • Had not yet given birth or <24 hr postpartum 

      • BP had to be >140/90 mmHg x2 , with proteinuria 1+ or more 

      • Note: their definition of severe preeclampsia were a little different 

        • Severe: DBP >110 mmHg x2 or SBP > 170 mmHg x2 or proteinuria >3+

          • Or DBP >100, or SBP >150, and proteinuria >2+ and at least two signs or symptoms of imminent eclampsia  

    • Exclusion criteria:

      • Hypersensitivity to magnesium, hepatic coma due to renal failure, or myasthenia gravis 

      • If urine output was <25 mL/hr, then the dose was halved  

  • How was the study done? 

    • Patients were randomized and groups were balanced for severity of preeclampsia, gestation at randomization, delivered or not, if given anticonvulsant drugs before trial entry, if multiple pregnancy, and country

    • Randomized to either magnesium or placebo

      • Magnesium: 4 g magnesium loading dose over 10-15 minutes; maintenance was then followed by infusion over 24 hours of 1g/hr

        • If areas of low resource needed to do IM, then it was an initial 4 g IV combined with maintenance of 5 g magnesium IM injected into each buttock (10g total) every 4 hours for 24 hours 

      • Placebo: similar looking pack, but was saline in the same mL amounts 

    • Monitoring:

      • Monitored reflexes - if these were depressed, then mag dose was adjusted to prevent toxicity 

      • Checked reflexes and respirations q30 minutes 

      • If eclamptic seizure: trial had to be stopped; eclamptic rescue pack was given with two packs; so those that had no mag were given 4 g mag total, and those with mag previously were given another 2g  

    • Outcomes of the trial:

      • Primary: eclampsia and death of baby before discharge from hospital (for women who were randomized before delivery)  

      • Secondary: serious maternal morbidity (won’t go through all of them, but essentially resp depression, resp arrest, pneumonia, cardiac arrest, coagulopathy, renal failure, liver failure, pulmonary edema, cerebral hemorrhage), toxicity (ie. need for ca gluconate, stopping or reducing mag), and other side effects of mag sulfate (ie. n/v, flushing, drowsiness, confusion, etc)

        • If women were randomized before delivery: also looked at complications of labor and delivery, neonatal morbidity 

      • Other: LOS, admission to ICU, NICU LOS 

What were the results? 

  • 10,141 women were randomized at 175 hospitals in 33 countries

    • 47% in Africa, 27% in the Americas, 15% in Asia, 10% in Europe 

    • Data was available for 10136 women, follow-up was available for 10,110 

  • Baseline characteristics (ie. age, primiparity, systolic BP at entry, severe preeclampsia, other problems of preeclampsia, gestational age at entry) were not different at entry 

  • Outcomes

    • Primary outcomes

      • Significantly fewer eclamptic convulsions among women with mag sulfate then those in placebo (reduction by about 58%) 

        • (0.8% vs. 1.9% - small numbers 40 vs 96), RR 0.42

        • This effect was seen in patients who had severe preeclampsia and those without severe preeclampsia (RR for both is 0.42) 

      •  No difference in baby death for those randomized before birth 

    • Maternal mortality - also lower among women allocated to mag sulfate (0.2% vs. 0.4%), Relative risk reduction of 45% 

    • Secondary outcomes

      • No clear difference in any measure of maternal morbidity or in composite measures of serious morbidity  

        • There WAS significantly increase in side effects of mag sulfate in mag group( ie. flushing, n/v, muscle weakness, headache, hypotension, dizziness, etc) 

      • No difference in neonatal morbidity 

What was the impact of all this? 

  • This was a huge landmark study in Ob/Gyn because of how many people it included across many countries, in both resource rich and resource poor settings 

  • Their data was very good: high compliance, high completion of the study 

  • Clearly demonstrated that mag sulfate decrease the risk of eclampsia from preeclampsia

  • No increased ill effects on babies 

  • Also provided a regimen (4g then 1g/hr) as well as timing (24 hours) 

What about now? 

At our institution, we only treat preeclampsia with severe features with magnesium.

But in this study, they included all patients with preeclamptics. Why the change? 

  • When looking at the MAGPIE trial, specifically at the women enrolled from high-resource settings in the Western world, the reduction rate of eclamptic seizures was not statistically significant 

    • RR 0.67, 95% CI 0.19-2.37 

  • A quarter of women reported adverse effects with magnesium sulfate, primarily hot flashes, and rate of CS was increased by 5% when mag was used 

  • Two small randomized trials that allocated women with preeclampsia without severe features to either placebo or mag → no cases of eclampsia among women allocated to placebo and no significant difference in proportion of women that progressed to severe preeclampsia (but small size limits this) 

  • Finally, rate of seizures in preeclampsia with severe features w/ mag is 4x higher than those without severe features (4/200 vs 1/100) 

  • Also, with calculations of previous data, it appears that 129 women need to be treated to prevent 1 case of eclampsia, but in those with symptoms (ie. headache, blurred vision, etc), NNT is 36 

  • What does the practice bulletin say?

    • Evidence less clear about preeclampsia w/o SF and mag 

    • Can be individualized by institution or by physician  

What about dosing? 

  • MAGPIE

    • Dosing is 4g loading followed by 1g/hr 

    • But at different institutions, we have seen 6g loading, 2g/hr or 4g loading, 2g/hr 

    • What’s right??  

  • The case for more vs. less magnesium

    • There is sparse data about the therapeutic range, which is usually 4.8-9.6 mg/dL or 4-8 mEq/L, but accurate mg concentration clinically effective in prevention of eclampsia has not been established 

    • Higher infusion rates increase potential for toxicity, and infusion rates >2g/hr have been associated with increased perinatal mortality in systematic review of randomized trials 

    • Lower starting bolus may increase time to therapeutic dosing 

    • Then.. there’s the BEAM trial…

      • Mg for cerebral palsy prophylaxis for babies from 24-31 weeks gestation  - regimen was 6g bolus followed by 2g/hr 

      • So many institutions will try and get two birds with one stone (6g bolus, 2g/hr for both CP prophylaxis and seizure prophylaxis if <32 weeks) 

    • … As well as the ACTOMgSO4 trial 

      • Doen in Australia and New Zealand for mag for fetal neuroprotection

      • Their dose was 4g bolus and 2g/hr 

    • Institution dependent, but we have seen a lot of combinations of both! 

Take away points: 

  • Magnesium sulfate can help decrease eclamptic seizures in patients with preeclampsia 

  • We have very good date to suggest it can decrease this rate by about 50% 

  • However, mag is not a benign drug - 25% have side effects

  • You should dose the mag somewhere between 4-6g loading dose and 1-2g/hr, but this is institution dependent 

  • It is also institution dependent regarding if preeclampsia without severe features needs mag (in MAGPIE, had same amount of decrease in eclamptic seizures as preeclampsia w/ SF) 

  • However, the number of those that get eclamptic seizures overall is low, and even lower in those with preeclampsia w/o SF, so there can be an argument for increased toxicity/side effects with increased NNT for those with PEC w/o SF and therefore forego it