The BEAM Trial

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?