Clinical trial NCT02835339
Conditions: Preeclampsia
Sponsor: Oregon Health and Science University
Start date: 2016-07-12; Completion date: 2019-06-30
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to learn how medications participant will receive in the course of their delivery are metabolized (broken down by the body). The investigators hope to learn more about the way drugs are metabolized by pregnant women, and how those drugs are distributed in the blood and body compartments and cleared in the urine, and how maternal body weight affects the metabolism. With this information the investigators will be able to develop a treatment regimen considering factors in the body that affect magnesium levels so that the investigators can improve treatment of pregnant women. The goal of the study is to understand how different dosing of magnesium sulfate affects blood levels of the magnesium in larger women.

Detailed description:
The purpose of this study is to learn how medications participant will receive in the course of their delivery are metabolized (broken down by the body). The investigators hope to learn more about the way drugs are metabolized by pregnant women, and how those drugs are distributed in the blood and body compartments and cleared in the urine, and how maternal body weight affects the metabolism. With this information the investigators will be able to develop a treatment regimen considering factors in the body that affect magnesium levels so that the investigators can improve treatment of pregnant women. The goal of the study is to understand how different dosing of magnesium sulfate affects blood levels of the magnesium in larger women.

Magnesium sulfate is generally given to patients to protect the mother against seizures in the case of preeclampsia. Different hospitals in the United States use different doses of magnesium sulfate. Participants will receive one of two accepted doses of magnesium sulfate for preeclampsia. The dose is usually 4g - 6g at the start, with another dose of 2-3 g every hour until 24 hours after delivery. Participants will be assigned to either a dose of 4 g at the start, followed by 1g every hour; or a dose of 6 g at the start, followed by 2g every hour until treatment for preeclampsia is complete. Participants will receive magnesium sulfate in the course of their normal clinical care whether or not they participate in this study.

Arms: arm 1: Once their obstetrician prescribes magnesium sulfate, participant will be assigned by 50/50 chance to one of two treatment regimens. Participant will be assigned to either a dose of 4 g at the start, followed by 1g every hour; or a dose of 6 g at the start, followed by 2g every hour until treatment for preeclampsia is complete. arm 2: Once their obstetrician prescribes magnesium sulfate, participant will be assigned by 50/50 chance to one of two treatment regimens. Participant will be assigned to either a dose of 4 g at the start, followed by 1g every hour; or a dose of 6 g at the start, followed by 2g every hour until treatment for preeclampsia is complete.
Interventions: intervention 1: Magnesium sulfate 4g loading dose, 1g/hr infusion intervention 2: Magnesium sulfate 6g loading dose, 2g/hr infusion
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Title
A Randomized Study of an Alternate Dosing Protocol for Magnesium Sulfate in 
Obese Preeclamptic Women
Objectives. In the current proposed study, we hope to identify pharmacokinetic (PK) 
drug effects (a therapeutic serum magnesium level) that an alternate magnesium sulfate 
dosing regimen will achieve in obese preeclamptic pregnant women.                             
Specific Aim 1: To determine if an alternate magnesium sulfate dosing regimen in 
preeclamptic pregnant women with BMI > 35 kg/m2 will result in a larger 
proportion of obese women who have therapeutic serum magnesium levels (> 4.8 
mg/dL) for seizure prophylaxis after 4 hours of administration.                                
Aim 1a: To determine if an alternate magnesium sulfate dosing regimen in preeclamptic 
pregnant women with BMI > 35 kg/m2 will result in a larger proportion of obese women 
who have therapeutic serum magnesium levels (> 4.8 mg/dL) for seizure prophylaxis at 
the time of delivery compared to a current standard dosing protocol.    
                                                                                                      
 Specific Aim 2: To determine if, and which, maternal side effects are more common 
at 1 hour, 4 hours, and time of delivery with an alternate magnesium sulfate dosing 
protocol in obese women.                                                                    
Hypotheses 
We hypothesize that a randomized trial of alternate dosing of intravenous magnesium in 
obese women will allow us to: 
1. Determine optimal antenatal magnesium dosing protocols to optimize therapeutic 
serum magnesium levels in obese preeclamptic women.
2. Determine significant covariates and correlations between maternal serum magnesium 
levels and maternal side effects and outcomes. 
3. Determine the optimal antenatal magnesium dose to minimize adverse drug effects 
while maintaining a therapeutic serum magnesium level in the mother. 
Background
Magnesium sulfate is one of the most commonly prescribed intravenous medications in 
contemporary obstetric practice.1,2 Magnesium is the drug of choice for preventing seizures in 
women with preeclampsia, a leading cause of maternal morbidity and mortality.3,4  More than 
77% of expectant mothers experience side effects related to antenatal magnesium 
administration.5  Magnesium may also negatively impact obstetric outcomes and lead to adverse 
neonatal effects.1,3,6-8  Current intravenous magnesium treatment for various indications 
(preeclampsia, tocolysis, neuroprotection) follows standardized protocols (4-6 g loading dose 
followed by an infusion at 1-2 g/h) based on institution preference. These protocols proposed by 
Prichard in 1979 were derived clinically to provide estimated serum magnesium levels necessary 
to treat eclamptic seizures.9 These standardized protocols are administered unaltered to all 
patients, without adjustment for maternal or fetal factors that may affect serum magnesium 
levels. The PI has previously constructed a detailed, robust pharmacokinetic (PK) model of 
intravenous magnesium sulfate administered antenatally to expectant mothers and exposed 
fetuses with the aim of optimizing maternal and fetal outcomes while preventing maternal and 
neonatal overdosing and morbidity associated with current magnesium treatment protocols.10 


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The PK data derived from this pilot study at another academic institution suggests obese 
pregnant women may require an increased dose of magnesium sulfate to maintain a therapeutic 
serum level for prevention of eclamptic seizures (> 4.8 mg/dL). In that pilot study, statistical 
modeling suggested more obese preeclamptic women take approximately twice as long as non-
obese preeclamptic women to achieve steady state levels of the drug.  
Study Design
The proposed study would use 1:1 allocation to randomize women with a BMI > 35 kg/m2 
treated with magnesium sulfate for preeclampsia to either standard dosing of the drug at OHSU 
(4g loading dose, followed by a 1 g/hr infusion) or to increased dosing (6g loading dose, 
followed by a 2 g/hr infusion). Maternal serum magnesium levels will be obtained at baseline, as 
well as after administration of magnesium sulfate at 1 hour, 4 hours, and at the time of delivery 
(within 20 minutes). We will exclude patients who are < 32 weeks gestation, as these women 
will automatically be administered a 6g loading dose, followed by 2g/hr infusion for fetal 
neuroprotection. The outcome will be a comparison of the proportion of preeclamptic women in 
each magnesium sulfate protocol group who have therapeutic serum levels 4 hours after 
administration, and at the time of delivery (serum magnesium level of > 4.8 mg/dL). We 
hypothesize that a significantly higher proportion of women with a BMI > 35 kg/m2 will be 
subtherapeutic at 4 hours and at the time of delivery when administered standard dosing of 
magnesium sulfate.  Findings from the proposed research can be used to tailor treatment for 
preeclampsia in obese pregnant patients. 
Study Population
Pregnant women between 32-42 weeks’ gestation who are prescribed magnesium sulfate for 
preeclampsia.
Number of Subjects
Based on a previous retrospective study conducted by Tudela et al11 and our own pilot data10, we 
estimate that 50% of obese women will be subtherapeutic for eclamptic seizure prophylaxis 4 
hours after magnesium sulfate administration.  Assuming 95% of normal weight women have 
therapeutic serum magnesium levels after 4 hours of administration, we anticipate that 18 
patients (36 total) are needed in each dosing group to detect a 50% difference in the proportion 
of women with a BMI > 35 kg/m2 who have therapeutic magnesium levels 4 hours after 
magnesium sulfate administration. Based on current patient load, which includes treatment of 
approximately 40 preeclamptic patients per month, and the additional inclusion criteria of the 
disease severity requiring magnesium sulfate administration, as well as a maternal BMI > 35 
kg/m2, and anticipated number of patients declining study participation, we anticipate potential 
enrollment of 1-2 women and their neonates per week. 
a. Inclusion and Exclusion Criteria
Pregnant women with preeclampsia admitted to OHSU hospital will be screened for 
eligibility using the institution’s electronic medical record – EPIC, on admission. 
Inclusion criteria:
Pregnant women who are ages 15 - 45 
32-42 weeks’ pregnant
Prescribed magnesium sulfate for preeclampsia


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BMI > 35 kg/m2
Exclusion criteria:
Pregnant women < 32 weeks’ pregnant
Women who are on dialysis
Women with pre-existing renal disease
Data collected in the course of a screen failure will be destroyed immediately.
b. Vulnerable Populations

Pregnant women will be included, as this is the primary study population. The pregnant 
women randomized in this study are already prescribed magnesium sulfate for preeclampsia 
and the dosing regimens proposed are doses that are already administered at hospitals in the 
United States, with every hospital utilizing its own specific dosing protocol.

Neonates (up to 28 days post birth) of uncertain viability or nonviable neonates will be 
included only to the extent of recording their birth outcome and birthweight. As the different 
dosing regimens follow United States guidelines and are already administered at hospitals in 
the US, there is no additional risk to neonates in this study.
For both pregnant women and neonates, there is a small chance of loss of confidentiality that we 
take every precaution to avoid. 
Children, decisionally impaired adults, and prisoners will not be specifically included in this 
study. 
c.
Setting

The research will take place at the OHSU Labor and Delivery Unit and Antepartum Unit and 
the study procedures will be carried out by OHSU personnel.
d. Recruitment Methods
When pregnant women with preeclampsia are identified at presentation to OHSU hospital 
through review of the medical record, the PI and research staff will screen for participation based 
on maternal age, gestational age, and whether or not magnesium sulfate will be prescribed as part 
of usual care.
Assistance with the initial screening process will take place through resident education sessions, 
as well as posting of study inclusion/exclusion criteria in the resident workroom as a reminder.  
A study factsheet and recruitment flyer will be posted on Labor and Delivery, Antepartum, and 
in the resident workroom to facilitate enrollment.  Recruitment outside of these areas is not 
anticipated due to the specific circumstances in which a potential research subject would qualify 
for enrollment (i.e. inpatient).  Additionally, a recruitment Grand Rounds will be presented to the 
Department of OB/GYN to educate them regarding the study enrollment criteria.
There will be no payment for participation in the study, however, laboratory studies requested for 
subjects that would not have normally been requested as part of usual care (i.e. blood, urine, and 
cerebrospinal fluid magnesium levels), will not be charged to the subject.


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e.
Consent Process
Once a potential participant has been identified, the PI or appropriate research staff will approach 
potential participants for consent while standard laboratory workup ensues for preeclampsia. 
Written informed consent will be obtained after having the purpose and details of the study 
explained in person by the PI or other research personnel.  Because study participation is limited 
to inpatients who are prescribed the study drug, no outside recruitment of subjects will take 
place.
After explaining the purpose of the study, the process of randomization, and obtaining informed 
consent, the PI /research personnel will use a random number generator from OpenEpi to assign 
the patient to one of two magnesium sulfate dosing regimens.
The PI/research personnel will review the list of daily obstetric service patients to identify 
possible participants for recruitment.
During the consent process, it will be emphasized to the potential research subject that the study 
drug is given in varying doses at different institutions and that if they choose not to participate, 
they will receive the dose that is standardly prescribed at OHSU for preeclampsia.
Non-English Speaking Subjects

Subjects who do not identify themselves as English speaking are eligible for consent if they 
identify as Spanish speaking and an interpreter is available to assist with the consent process 
and ongoing study requirements in a timely fashion. The primary study coordinator is 
Spanish speaking and will most often consent non-English speaking subjects.The English 
Consent and Authorization form will be translated into Spanish and submitted for IRB 
approval prior to use.  Only English and Spanish speaking patients will be eligible to 
participate.  The initiation of magnesium sulfate for preeclampsia will not be delayed to wait 
for the primary study coordinator or an in-person interpreter, and if the drug is ready to be 
administered prior to obtaining consent, the potential subject will no longer be eligible. 
2. Procedures Involved
After obtaining informed consent, the subject will by randomly assigned to one of two treatment groups: 
1.) a starting dose of magnesium sulfate of 4g, followed by 1g every hour until 24 hours after delivery 
(the current standard regimen used at OHSU), or 2.) a starting dose of magnesium sulfate of 6g, 
followed by 2g every hour until 24 hours after delivery. There will not be a placebo arm of the study; 
only a smaller dose or larger dose of magnesium sulfate administered. Although the study dosing is 
randomized, it is not blinded and both the investigator and the research subject may know what dose of 
magnesium sulfate is being administered.  If the subject is found to be symptomatic at any point in the 
study, the usual clinical care will be provided, which would include checking a serum magnesium level 
and decreasing the dose of magnesium sulfate, if needed.  Study participation will continue; however, 
the timing and details of the dosing change will be recorded and used for research purposes.
If there is an indwelling intravenous catheter in place for surgery, we will attempt to use it to draw 
blood. We will draw a sample from a vein if we are not able to collect the samples from an existing 
intravenous catheter.
Specimens will be collected as follows:
 


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
Serum magnesium before the administration of magnesium sulfate 

Serum magnesium at 1 hour, 4 hours, and delivery after the initial dose of magnesium 
sulfate 

Each sample will be 5-10 ml (approximately 1-2 teaspoon). The total drawn for all samples will 
likely not exceed 5 teaspoons.

Urine samples will be obtained if possible at these same time points.

If the patient requires spinal anesthesia for cesarean delivery, 0.5 ml (a few drops) of spinal fluid 
will be taken to check for magnesium levels at the same time the spinal anesthetic is being 
performed.
Visit 1
Day 1
Visit 2
Day 1
Visit 3
Day 1
Visit 4
Day 1
Consent Discussion, 
Screening tests and 
medical history 
X
Blood draw 
(1 teaspoon)
X
X
X
X
Urine sample (2 
teaspoons)
X
X
X
X
Time (after 
magnesium sulfate 
administration)
baseline
1 hour
4 hours
Time of 
delivery 
(within 20 
mins)
Information that may be abstracted from the subject’s chart includes maternal age, race, height, 
weight, renal function and creatinine clearance (if available), maternal heart rate variability, medical 
comorbidities, chorioamnionitis, labor duration, mode of delivery, gestational age, cord pH, and 
birthweight.  These covariates may be considered in the pharmacokinetic model. These covariates 
demonstrate biological plausibility, and have physiologic potential to significantly impact the optimal 
dosing of magnesium. Additionally, maternal side effects (flushing, sedation, nausea, vomiting, 
respiratory rate, oxygen saturations, blood pressure, heart rate, and patella tendon reflex depression) will 
be assessed prospectively by a physician or research assistant at the same time-points as the PK 
sampling. Neonatal data will include NICU admission, need for respiratory support, need for blood 
pressure support, electrolyte abnormalities, feeding difficulties, intraventricular hemorrhage, necrotizing 
enterocolitis, seizures, sepsis, respiratory distress syndrome, retinopathy, patent ductus arteriosus, 
fetal/infant death.
3. Data and Specimens
a. Handling of Data and Specimens
Blood, urine, and rarely cerebrospinal fluid specimens will be assigned a unique identifier that 
will be associated with the subject’s name and medical record number for initial laboratory 
analysis.  After the magnesium level is determined, only the unique identifier will be present in 
the research database.  The specimens are generally stored in the laboratory for approximately 5 
days and then stored in the MFM repository (eIRB#7285).  They will be transported to the 
laboratory through the pneumatic tube system at OHSU Hospital.  In the event a CSF sample is 


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obtained, this sample would be stored in laboratory space for the Department of Obstetrics & 
Gynecology – WHRU freezers.  The PI and research staff are responsible for transport of all 
specimens.
b. Sharing of Results with Subjects
Laboratory results that are part of the usual care and clinical decision making process will be 
shared with the subjects and providers, however, overall study results will take a much longer 
time to generate and will not be shared at the individual level.  The OHSU Hospital Laboratory 
responsible for testing the specimens is CLIA certified.
c.
Data and Specimen Banking
Specific data that may be banked includes maternal serum samples, urine samples, and CSF 
samples. While specimens will not be used for genetic research, they may be stored longer than 5 
days for the purpose of correlating tissue levels of magnesium with clinical events.  In the event 
the specimens are sent to the MFM Repository eIRB#7285, they will retain their unique 
identifier.  Only the PI will be able to access the specimens and they will be retained for an 
indefinite period of time.
4. Data Analysis
Univariate and multivariate mixed-effects modeling will be utilized to assess the impact 
of various covariates on the outcome of serum magnesium level at different time points after 
magnesium sulfate administration. As previously described, assuming 95% of normal weight 
women have therapeutic serum magnesium levels after 4 hours of administration, we anticipate 
that 18 patients (36 total) are needed in each dosing group to detect a 50% difference in the 
proportion of women with a BMI > 35 kg/m2 who have therapeutic magnesium levels 4 hours 
after magnesium sulfate administration. Based on current patient load, which includes treatment 
of approximately 40 preeclamptic patients per month, and the additional inclusion criteria of the 
disease severity requiring magnesium sulfate administration, as well as a maternal BMI > 35 
kg/m2, and anticipated number of patients declining study participation, we anticipate potential 
enrollment of 1-2 patients per week. 
5. Privacy, Confidentiality, and Data Security
All information collected as part of the study will be stored on an encrypted, password protected 
computer that will only be available to the PI and essential trained research personnel.  Hard 
copy data collection forms will be stored in a locked cabinet in the PI’s administrative office.  
Separation of identifiers from data and specimens will take place as soon as subjects’ 
participation has ended and only the PI and research personnel will be able to relink the data in 
the future if needed.


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Standard institutional practices will be followed as described in the OHSU Information Security 
and Research Data Resource Guide (http://ozone.ohsu.edu/cc/sec/isg/res_sec.pdf) to maintain the 
confidentiality and security of data collected in this study. Study staff will be trained with regard 
to these procedures. Paper files will be stored in locked filing cabinets in restricted access offices 
at OHSU. Electronic data is stored on restricted drives on the OHSU network. Access to 
data/specimens is restricted to study personnel. Access to data requires OHSU password 
authentication. Upon enrollment, subjects will be assigned a code that will be used instead of 
their name, medical record number or other personally identifying information. Electronic files 
for data analysis will contain only the subject code.
Codes will not contain any part of the 18 HIPAA identifiers (initials, DOB, MRN) The key 
associating the codes and the subjects personally identifying information will be restricted to the 
PI and study staff. The key will be kept secure on a restricted OHSU network drive a in a limited 
access folder.
6. Provisions to Monitor the Data to Ensure the Safety of Subjects
The investigators and study staff are responsible for recording the data, and they will be verifying its 
accuracy throughout the process. The PI will be reviewing the data in-depth periodically throughout 
the study. The PI will also be overseeing that the study procedures are being carried out as per the 
approved protocol via close supervision of the study visit and procedures and through frequent 
communication with the other investigators and staff. Anytime that an AE, SAE, UP or protocol 
deviation is reported by an investigator or study staff, the PI will review and assess the data, and 
proceed as per OHSU reporting policy. Otherwise, the PI entity will be reviewing the records 
periodically throughout the study. All adverse events will be assessed and reportable UPs will be 
submitted to the IRB, if judged related to the study protocol.  All data will be stored for future 
analysis and stored in the MFM Repository eIRB#7285
7. Risks and Benefits
a. Risks to Subjects.
The possible risks of obtaining blood samples from a vein in the arm are pain, bruising, fainting, and 
rarely, infection. This risk is extremely small as sterile supplies will be used, and all hospital protocols 
will be followed.
Magnesium sulfate is known to have associated side effects (i.e. nausea, flushing, palpitations, 
headache, malaise, sweating, pulmonary edema, and loss of reflexes.) There may be some side effects 
we do not expect because we are still learning about different dosing of the study drug. The study drug 
may be discontinued or the dosing changed if subjects experience serious side effects.
One risk to taking part in this study is that the study drug or the dose administered may not be effective 
in helping to treat preeclampsia. This is a risk for all patients who are administered magnesium sulfate.
There are several drugs (prescription and non-prescription) that may cause problems when taken with 
the study drug.  The investigator will carefully review all of the drugs a potential subject is taking before 
administering the study drug. 
Possible risks of the study include a low risk of breach of confidentiality.
b. Potential Benefits to Subjects
There are no benefits from participation in the study.


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8. Drugs or Devices                                                                                                                                                
Magnesium sulfate is approved by the FDA for treatment of preeclampsia.  It is not investigational.
All applicable Research Pharmacy policies and procedures will be followed for the study.  
The two possibilities for dosing of magnesium sulfate are already administered during 
pregnancy at OHSU for different indications and the study drug will be handled in the 
same way as would be usual clinical practice.
1. Pryde PG, Mittendorf R: Contemporary usage of obstetric magnesium sulfate: indication, contraindication, and relevance 
of dose. Obstet Gynecol 2009; 114: 669-73 
2. Fox NS, Gelber SE, Kalish RB, Chasen ST: Contemporary practice patterns and beliefs regarding tocolysis among u.s. 
Maternal-fetal medicine specialists. Obstet Gynecol 2008; 112: 42-7 
3. Duley L, Gulmezoglu AM, Henderson-Smart DJ, Chou D: Magnesium sulphate and other anticonvulsants for women with 
pre-eclampsia. Cochrane Database Syst Rev 2010: CD000025 
4. Duley L, Henderson-Smart DJ, Chou D: Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Syst Rev 
2010: CD000128 
5. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, Iams JD, Wapner RJ, Sorokin Y, Alexander JM, Harper M, 
Thorp JM, Jr., Ramin SM, Malone FD, Carpenter M, Miodovnik M, Moawad A, O'Sullivan MJ, Peaceman AM, Hankins GD, 
Langer O, Caritis SN, Roberts JM: A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. 
N Engl J Med 2008; 359: 895-905.
6. Greenberg MB, Penn AA, Thomas LJ, El-Sayed YY, Caughey AB, Lyell DJ: Neonatal medical admission in a term and late-
preterm cohort exposed to magnesium sulfate. Am J Obstet Gynecol 2011 
7. Riaz M, Porat R, Brodsky NL, Hurt H: The effects of maternal magnesium sulfate treatment on newborns: a prospective 
controlled study. J Perinatol 1998; 18: 449-54 
8. Yokoyama K, Takahashi N, Yada Y, Koike Y, Kawamata R, Uehara R, Kono Y, Honma Y, Momoi MY: Prolonged maternal 
magnesium administration and bone metabolism in neonates. Early Hum Dev 2010; 86: 187-91 
9. Pritchard JA: The use of magnesium sulfate in preeclampsia-eclampsia. J Reprod Med 1979; 23: 107-14 
10. Brookfield KF, Su F, Elkomy MH, Drover DR, Lyell DJ, Carvalho B. Pharmacokinetics and placental transfer of magnesium 
sulfate in pregnant women. Am J Obstet Gynecol 2016; epub ahead of print.
11. Tudela CM, McIntire DD, Alexander JM. Effect of maternal body mass index on serum magnesium levels given for 
seizure prophylaxis. Obstet Gynecol 2013; 121 (2 Pt1): 314-20.