The ALPS Trial

The #OBGynInternChallenge is back! Enrollment will open Monday 4/18. Check out www.obgyninternchallenge.com/enroll.

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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?

• Intrauterine fetal demise

• Patient who hasn’t yet received antenatal corticosteroids

• Patient who received antenatal corticosteroids 10 days ago

• Patient who received antenatal corticosteroids previously at 24 weeks

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!

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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 

Thalassemias, feat. Dr. David Abel

Here’s the RoshReview Question of the Week!

A 31-year-old G1P1 woman of Southeast Asian descent with a history of intrauterine fetal demise presents to your office for preconception counseling. She also reports a history of mild anemia due to alpha-thalassemia. You order DNA testing. Which of the following is most likely her genotype?

• α-/--

• α-/α-

• α-/αα

• αα/–

Check if you got the right answer and get a special deal on the CREOG Q-Bank at link above!

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The Basics of Hemoglobin

• The major oxygen carrying pigments of the body. Carries oxygen from the lungs to the tissues to meet the needs of cells for oxidative metabolism.

  • We carry almost two pounds of hemoglobin at any given time!

• The hemoglobin molecule is a tetramer.

  • Typically, this tetramer is composed of two alpha chains and two non-alpha globin chains.

  • The molecular mass of a hemoglobin tetramer is large, approximately 64,000 daltons. 

  • The primary structure of a particular hemoglobin is determined by its covalent bonds between the amino acids that form these polypeptide globins, and it is this primary structure that determines the behavior of a particular hemoglobin.

• Hemoglobin synthesis is controlled by two multigene clusters, the alpha and beta globin genes.

  • The alpha genes are on chromosome 16.

    • Both genes for alpha globin are duplicated, thus there are four genes at the alpha globin locus, with two genes inherited from each parent.

  • The beta genes are on chromosome 11.

    • The beta globin gene consists of two genes, one inherited from each parent. 

  • Each of these two gene clusters also contain other genes!

Common Hemoglobin Molecules and Embryology of Hemoglobin

• Hemoglobin changes during fetal development.

  • The switch from embryonic to fetal to adult hemoglobin synthesis is a major mechanism by which the developing fetus adapts from the hypoxic intrauterine environment, as each hemoglobin has its own oxygen dissociation curve.

• In the embryonic stage of development, there exists both zeta and epsilon globin chains that are synthesized by yolk sac erythroblasts.

  • The zeta gene is part of the alpha globin gene cluster, and the epsilon gene is part of the beta globin gene cluster.

    • Hb Gower-1: two zeta and two epilson chains

    • Hb Gower-2: two alpha and two episilon chains

    • Hb Portland: two zeta and two gamma chains. 

• After the first trimester, the zeta and epsilon globin chains are replaced by hemoglobin F, the dominant hemoglobin in-utero.

  • Hb F is composed of two fetal gamma globin chains and two alpha globin chains.

    • The gamma gene is a fetal gene that is part of the beta globin gene cluster.  

• Hemoglobin F declines in the third trimester of pregnancy and is slowly replaced by hemoglobin A, which consists of two alpha and two beta chains.

  • Also keep in mind that expression of delta globin begins near birth. The delta gene is also part of the beta globin cluster, and contributes to hemoglobin A2 (two alpha, two delta globins).

• At birth, hemoglobin F accounts for approximately 75-80 percent of hemoglobin and hemoglobin A accounts for 20-25 percent.

  • Postnatally, hemoglobin F is slowly replaced by hemoglobin A so that infants do not rely heavily on normal amounts and function of hemoglobin A until they are between 4 and 6 months old. 

• In adults, hemoglobin A makes up approximately 97%, hemoglobin A2 approximately 2.5% and less than 1% consists of hemoglobin F. 

The Basics of Hemoglobinopathy and Thalassemias

• Hemoglobinopathies arise when a change occurs in the structure of a peptide chain or a defect compromises the ability to synthesize a specific polypeptide chain.

  • Can be qualitative or quantitative defects.

    • Thalassemias are quantitative disorders. 

• Thalassemia is derived from a Greek term that roughly means “the sea” (Mediterranean) in the blood.  

  • It was first applied to the anemias frequently encountered in people from the Italian and Greek coasts and nearby islands. 

  • Individual syndromes are named according to the globin chain whose synthesis is adversely affected.

    • Alpha thalassemia represents either a reduction or complete absence of production of alpha globin chains

    • Beta thalassemia is a reduction or complete absence of beta globin production. 

  • Among the most common autosomal recessive disorders worldwide. More than 100 genetic forms of alpha thalassemia have been identified. 

• By contrast, conditions such as sickle cell anemia represent a structural hemoglobinopathy, a qualitative defect.

Beta Thalassemias

• Hemoglobin electrophoresis can be used to diagnose beta thalassemia. This can reveal:

  • Reduction in the expression of beta globin (b+) or

  • Complete absence of beta globin expression (b0).

• Complete absence of beta globin expression is referred to as beta thalassemia major, aka Cooley’s anemia or transfusion-dependent thalassemia.

  • Little to no beta globin chain production and thus minimal to absence of hemoglobin A.

  • Symptoms usually manifest 6-12 months of life.

  • Since there is no hemoglobin A due to the lack of beta globin, hemoglobin F persists.

    • On a hemoglobin electrophoresis, you will see at least 95% of hemoglobin F, and  hemoglobin A2 will usually range between 3.5 and 7%.

    • The circulating red blood cells are very hypochromic, abnormal in shape, and the hemoglobin is markedly reduced, somewhere around 3-4 g/dl. 

  • Anemia of beta thalassemia major is so severe that long-term blood transfusions are usually required for survival.

    • The severe anemia results in extramedullary erythropoiesis, delayed sexual development and poor growth.

    • Death may occur by age 10 unless treatment with periodic blood transfusions is initiated.

• Beta thalassemia intermedia, now referred to as non-transfusion dependent beta thalassemia, presents as a less severe clinical phenotype.

  • A moderate microcytic anemia is present.

    • On hemoglobin electrophoresis, up to 50% of hemoglobin F will be noted and just as in beta thalassemia major, hemoglobin A2 will usually range between 3.5 and 7%.

  • May result from different mechanisms:

    • I.e., inheriting both a mild and severe beta thalassemia mutation, or

    • The inheritance of two mild mutations, or,

    • The inheritance of complex combinations of mutations.

• Beta thalassemia minor, also referred to as beta thalassemia trait, is caused by the presence of a single beta-thalassemia mutation and a normal beta globin gene on the other chromosome.  

  • Significant microcytosis with hypochromia on the blood smear but a mild anemia.

  • In general, thalassemia minor has no associated symptoms.

    • On hemoglobin electrophoresis, hemoglobin F is present up to 5%, and hemoglobin A2 at 4% or more. 

Alpha Thalassemias

• The alpha thalassemias are more difficult to diagnose because the typical elevations in hemoglobin F and A2 that are seen in the beta-thalassemias we have just discussed do not occur. This makes hemoglobin electrophoresis difficult to use for diagnosis.

  • Instead, molecular testing (DNA sequencing) is required for diagnosis.

  • More than 100 genetic forms of alpha thalassemia have been identified, with phenotypes ranging from asymptomatic to lethal.

  • The severity of this disorder is usually well correlated with the number of non-functional copies of the alpha globin genes (a one, two, three, or four-gene deletion).

• Silent Carrier: one alpha globin gene deletion.

  • Essentially has no clinical consequences.

  • On the CBC, the MCV is usually normal or perhaps mildly decreased.

• Alpha Thalassemia Minor: two gene deletion.

  • If two genes on the same chromosome are deleted, this is known as a cis deletion.

    • More commonly seen in those of southeast Asian ancestry.

    • If both parents carry a cis deletion, their offspring will have a 25% chance of having no functional alpha globin genes.

  • If the two deleted genes are on different chromosomes, this is trans deletion.

    • More common in those of African descent

    • If both parents have a two gene deletion in trans, their offspring will always have the same two gene deletion in trans.

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• Hemoglobin H: three gene deletion, which results in a moderate microcytic anemia.

  • When the alpha chains are reduced, the beta chains pair together and form beta globin tetramers, which is what this hemoglobin H represents.

  • In some cases, instead of the three gene deletion, a two gene deletion occurs with a mutant (i.e., non-functional) alpha globin mutation, such as hemoglobin Constant Spring.

    • This is referred to as nondeletional hemoglobin H.

    • Individuals with this nondeletional hemoglobiin H have a higher percentage of hemoglobin H, more splenomegaly and more advanced disease.

  • Most individuals with hemoglobin H don’t require regular transfusions. The anemia is typically mild; however, the phenotype is variable

    • With the dilutional anemia that occurs during pregnancy, the need of a transfusion may be increased. 

• Alpha thalassemia major, or hemoglobin Barts: Four gene deletion that results in a gamma tetramer.

  • Normal Hb A and Hb F are totally absent.

  • Hemoglobin Barts is incompatible with life and results in hydrops in-utero and stillbirth.

    • Its oxygen dissociation curve is markedly shifted to the left, so it holds onto oxygen and very little is released to the tissues.

    • Usually, the fetus or newborn will have marked anasarca and hepatosplenomegaly, with a hemoglobin level of 3-10 g/dL.

  • If a fetus is known to have alpha thalassemia major, multiple intrauterine transfusions can help these fetuses survive.  

    • Prenatal diagnosis of the thalassemias can be performed using either chorionic villi from CVS or using cultured amniocytes obtained from an amniocentesis.

  • A study at the University of California at San Francisco is looking at the use of in utero stem cell transplantation during pregnancy to essentially cure the fetus before birth. 

Take Home: When to Work Up for Thalassemia

• If the MCV is decreased (<80), a hemoglobin electrophoresis is very reasonable.

  • Ferritin to assess for iron deficiency is also something that can be performed at the same time.

    • Hemoglobinopathy and iron deficiency can coexist!

• If the MCV is decreased, and both a ferritin and hemoglobin electrophoresis are normal, molecular studies to assess for alpha thalassemia would be appropriate. 

Postpartum IUD Placement, with Dr. Sarah Prager

This week we are joined by Dr. Sarah Prager, a professor at the University of Washington in OB/GYN and Complex Family Planning. She shares with us some particular expertise in an ever-more common procedure - the postpartum IUD placement. There’s definitely a few pearls in the podcast that are worth listening for!

Definitions: 

• Immediate postplacental insertion: within 10 minutes of placental extraction

• Immediate postpartum insertion: 10 minutes to 48 hours after delivery

• Delayed postpartum insertion: 48 hours to 6-8 weeks after delivery

• Interval placement: IUD placement not related to recent delivery

• Trans-cesarean insertion: IUD placed through the hysterotomy at the time of cesarean delivery

Exclusion criteria:

• Chorioamnionitis/uterine infection

• Prolonged rupture of membranes (18-24 hours)

• Excessive postpartum bleeding that is unresolved

• Extensive genital trauma that would be negatively impacted by IUD placement

Expulsion rates: 

• 10% if placed in the first 10 minutes

• Up to 25-30% if placed after 48 hours

• Limited data on 10 minutes to 48 hours

  • Pilot study in Zambia showed 4% expulsion with “morning after delivery” IUD placement

• Provider experience matters!

  • Study from 1985 showed providers cut their expulsion rates almost in half comparing the beginning to the end of the study

• Take home message: don’t get discouraged! Your expulsion rate will decrease with experience!

Copper vs. LNG-IUD

• Most older data is with various copper IUDs (primarily the Copper T 380A – ParaGard)

• Some limited data with specifically Mirena brand LNG-IUD.

• Recent data often pooled LNG-IUD, without separating different IUDs

• Limited comparative data

  • Possibly higher expulsion rates with LNG-IUD than Copper IUD

  • Could be due to method used for insertion – inserter vs. no inserter

  • LNG-IUD inserters are long enough to reach the fundus of a PP uterus, ParaGard IUD inserters are not

  • There is a dedicated PP inserter for Copper IUD (longer, stiffer, but not available in USA at this time); unclear if it changes outcomes

• Recent study out of Kaiser showed slightly lower expulsion rates for breastfeeding vs. non-breastfeeding people.

  • Largest study to date with mostly LNG-IUD

  • Expulsion rates:

    • 10.7% expulsion by 5 years with placement 0-3 days

    • 3.9% for 3 days to 6 weeks

    • 3.2%for 6-14 weeks postpartum

    • 4.9% for interval placement

Medical Eligibility Criteria:

• CDC: category 1 or 2 at any time, regardless of type of IUD or breastfeeding status.

  • Of course, category 4 if uterus is infected

• WHO: category more nuanced depending on type of IUD and timing of placement

Method of placement:

• With the inserter

  • Need a long enough inserter

  • Often can use the LNG-IUD inserters

  • Also need the inserter to be stiff enough – sometimes doesn’t work with LNG-IUD inserters

  • Dedicated copper IUD inserter both longer and stiffer

• With an instrument

  • Can use a ring forceps

  • Can use a Kelly placenta forceps (longer)

• With your hand

  • No difference in expulsion seen compared with instrument

  • Personal bias – WAY more painful! No-one likes a hand in their uterus

    • Not reported in the early studies that compared this to using a ring

Clinical tips and tricks for successful insertion with an instrument:

• Place a ring on the anterior lip of the cervix

• Hold the IUD gently in a ring forceps (don’t click down if LNG-IUD – don’t want to disrupt the LNG delivery system!)

• Know the orientation of the IUD with respect to the orientation of the ring handles to make sure you place IUD with the proper orientation in the uterus!!!

• Once the IUD is in the lower uterine segment, gently let go of the ring on the cervix and place the non-dominant hand on the uterine fundus

• Drop your wrist! Drop your shoulder! Aim for the fundal hand

  • Angle different from interval insertions – basically aim for the umiblicus

  • Will not go wrong if you aim for the fundus! Feel it with your fundal hand!

• Let go of the IUD and gently remove the ring without pulling on the IUD or strings

• If strings are visible, cut at the os

  • Can also pre-cut the strings of LNG-IUDs so they are about 10 cm

  • Cutting strings can sometimes pull the IUD lower or out

• Can use ultrasound if you want!

If using an inserter: 

• Pre-deploy the IUD – you do not need the narrow profile with an open cervix!

• Personal bias – don’t use the inserter

If using your hand:

• Change your gloves

• Precut the strings

• Hold between the index and middle fingers with the strings laying across your palm

• Make sure you don’t pull it out when you remove your hand!

If trans-cesarean placement:

• Close 1/3 – ½ the hysterotomy then place

• Precut the strings shorter before directing down into the cervix

• Personal bias again toward instrument placement, but usually hand and inserter also work fine

Follow-up care:

• See patients at 1-2 weeks postpartum and trim strings as needed.

  • May need to do this again at 6-week visit

• If strings not visible at follow-up, do an ultrasound to verify presence of IUD in the uterus

  • If IUD there, NO NEED FOR ROUTINE ULTRASOUND TO CHECK CONTINUED PRESENCE OF THE IUD

  • Counsel patient that efficacy unchanged, but removal may be more complicated if strings don’t emerge from the cervix

    • This should have been a counseling point during consent!

Financial Wellness with Michael Foley, CFP, CSLP

We have a special Wednesday episode this week, brought to you in part by the SMFM Thrive Initiative! SMFM Thrive is a wellness program for MFMs - but we hope that this week’s podcast will be helpful even to those outside of MFM land!

Our guest is Michael Foley. Michael is a comprehensive financial advisor who runs his practice out of Scottsdale, Arizona, under North Star Resource Group. Michael was trained at Duke University and holds his Certified Financial Planner designation alongside his Certified Student Loan Professional designation. Although Michael serves a diverse group of clients with their financial and student loan needs, with two physician parents, Michael has found a specialty in working with those in the healthcare space. 

DISCLOSURE: Michael is a registered representative and investment advisor representative of Securian Financial Services. Securities and investment advisory services offered through Securian Financial Services, Inc. Member FINRA/SIPC. North Star Resource Group is independently owned and operated. 6720 N Scottsdale Rd Ste 290, Scottsdale, AZ 85253

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Check out some additional resources from Michael:

My Bio: https://www.northstarfinancial.com/advisors/michael-foley/

CSLP Blog: https://cslainstitute.org/blog/

Student Aid Updates: https://studentaid.gov/h/announcements-events

Medical Economics articles: https://www.medicaleconomics.com/authors/michael-foley-cfp-cslp?page=3

And to schedule an initial consultation with Michael click here.

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?