Clinical trial NCT03867383
Conditions: Uterine Atony Uterine Atony With Hemorrhage Cesarean Section Complications
Sponsor: Stanford University
Start date: 2019-03-15; Completion date: 2021-08-15
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this pilot study, investigators will administer calcium chloride or placebo to pregnant women undergoing Cesarean delivery who have been identified as high risk for hemorrhage due to poor uterine muscle contraction, or atony. They will assess whether a single dose of calcium given immediately after the delivery of the fetus decreases the incidence of uterine atony and bleeding for the mother. The pharmacokinetics of calcium chloride in pregnant women will also be established. Data from this pilot study of 40 patients will be used to determine sample size and appropriateness of a larger randomized clinical trial.

Detailed description:
Poor contraction of the uterus, also known as uterine atony, is the leading cause of severe blood loss during Cesarean section, both in the US and worldwide. Exogenous calcium has been shown to increase uterine muscle contraction in in vitro and in animal studies. Calcium is also an essential factor in normal blood clotting. Anesthesiologists commonly administer intravenous calcium chloride during Cesarean as well as other types of surgery, but formal randomized studies to determine efficacy in improving uterine tone have not been performed.

In this pilot, randomized controlled study, the anesthesiologist will administer a one-time dose of intravenous calcium chloride 1gram versus placebo at the time of fetal delivery to women identified as having high risk of hemorrhage during Cesarean delivery. Primary outcome assessed will be a composite measure of uterine atony. Data from the pilot study will be used to perform power and sample size calculations for a larger study. Secondary outcomes assessed will include total blood loss, subjective assessment of uterine tone by the blinded obstetrician performing surgery, safety, side effects, and pharmacokinetic profile of calcium chloride in pregnant women.

Arms: arm 1: Non-participating anesthesiologist prepares the drug solution, which is 1 gram of calcium chloride diluted into a total volume of 60 milliliters normal saline, labeled only with the study ID number. The solution is administered intravenously utilizing an Alaris syringe pump and microbore tubing, with infusion starting immediately at the time of fetal delivery at a rate of 360 milliliters per hour (for a calcium infusion rate of 100 milligrams /minute until the full 1 gram dose is administered).

This is a one-time administration. Patients continue to receive all standard care during the Cesarean including 1 unit oxytocin bolus at the time of fetal delivery + continuous oxytocin infusion at 7.5 units per hour per our institution's protocol. arm 2: Non-participating anesthesiologist prepares the placebo solution, which is 60 milliliters normal saline, labeled only with the study ID number. The solution is administered intravenously utilizing an Alaris syringe pump and microbore tubing, with infusion starting immediately at the time of fetal delivery at a rate of 360 milliliters per hour.

This is a one-time administration. Patients continue to receive all standard care during the Cesarean including 1 unit oxytocin bolus at the time of fetal delivery + continuous oxytocin infusion at 7.5 units per hour per our institution's protocol.
Interventions: intervention 1: Calcium Chloride intervention 2: Placebo
Intervention descriptions: intervention 1: All included in intervention description.

1 gram of calcium chloride in total 60 milliliters normal saline intervention 2: 60 milliliters normal saline

Protocol documents:
Prot_SAP_001.pdf: 
Protocol Version 2.1 September 10, 2018 
1
Calcium chloride for the prevention of uterine atony during 
cesarean in women at increased risk of hemorrhage 
A pilot randomized controlled trial and pharmacokinetic study 
 
Jessica R. Ansari, MD 
Neil Kalariya, MD 
Brendan Carvalho, MBBCh, FRCA 
Pamela Flood, MD, MA 
Nan Guo, PhD 
Edward Riley, MD 
 
Stanford Institutional Review Board # 43076 
Clinical trial registry NCT03867383 https://clinicaltrials.gov/ct2/show/NCT03867383 
 
KEYWORDS: calcium chloride, calcium pharmacokinetics, maternal hemorrhage, 
obstetric hemorrhage, uterine atony 


Protocol Version 2.1 September 10, 2018 
2
Summary 
 
Uterine atony is the leading cause of obstetric hemorrhage. Low calcium levels diminish 
uterine muscle contractility and response to oxytocin. Our aim is to assess the 
effectiveness and pharmacokinetics of intravenous calcium chloride to prevent uterine 
atony. This will be a single-center, double blind, randomized controlled pilot trial. 
Women with at least 2 risk factors for uterine atony at the time of caesarean delivery will 
be randomized in 1:1 ratio to receive 1-gram dilute calcium chloride or saline placebo in 
addition to oxytocin after umbilical cord clamping. The primary outcome will be 
incidence of uterine atony, defined as second-line uterotonic requirement, uterine 
balloon, or estimated blood loss (EBL) >1000 mL.  
 
 


Protocol Version 2.1 September 10, 2018 
3
 
Introduction: 
Postpartum hemorrhage (PPH) is the leading cause of maternal mortality 
worldwide.1 Uterine atony, defined as failure of the uterus to adequately contract after 
placental delivery, causes at least 70-80% of PPH.2 Current management of uterine 
atony involves prophylaxis with oxytocin and treatment with second-line uterotonics 
including methylergonovine, carboprost, and misoprostol. However, these medications 
all carry significant limitations of poor efficacy, adverse side effect profiles, expense, or 
contraindications to use.3 For example, methylergonovine is contraindicated in women 
with preeclampsia or hypertensive diseases, and carboprost, which may cost up to 
$1000 per dose, is contraindicated in women with asthma. As such, additional 
prevention or treatment modalities for uterine atony are needed. 
Calcium has an important physiological role in uterine contractility. Uterine 
myometrial contractility is dependent upon an influx of calcium from intracellular stores 
in the sarcoplasmic reticulum as well as extracellular calcium.4 A number of in vitro 
studies have established that myometrial contraction amplitude diminishes in the setting 
of low extracellular calcium.4-7 Oxytocin’s efficacy in inducing myometrial contraction 
diminishes by 60-75% in the setting of low or absent extracellular calcium levels in in 
vitro studies with human uterine strips.7 Although the safety and lack of hemodynamic 
consequences of intravenous calcium infusion in parturients has been assessed in one 
study,8 no clinical studies have been designed to assess the potential role for 
intravenous calcium in preventing or treating uterine atony or PPH as a primary 
outcome. 


Protocol Version 2.1 September 10, 2018 
4
. This pilot study was designed to assess whether intravenous calcium chloride 
warrants future study as an agent for prevention of uterine atony and maternal 
hemorrhage. Our primary aim is to assess whether calcium, administered in addition to 
standard oxytocin to women with risk factors for developing uterine atony during 
caesarean delivery, warrants a large study for efficacy in the prevention of uterine 
atony. We hypothesize that providing calcium will augment uterine contraction and 
decrease the incidence of atony. Secondary aims include assessment of atony and 
hemorrhage-associated outcomes including estimated blood loss, fluid requirement, 
obstetrician assessment of tone. Other secondary aims assessed include potential side 
effects of calcium infusion including hemodynamic changes, discomfort at the site of the 
intravenous catheter, nausea, and vomiting. Finally, population pharmacokinetics will be 
assessed as a secondary aim to guide dosing in future studies.  
 
 


Protocol Version 2.1 September 10, 2018 
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Methods: 
Inclusion criteria: Cesarean delivery with at least two of the following established 
risk factors for uterine atony: intrapartum delivery, oxytocin infusion for 4 hours or 
longer, magnesium infusion, chorioamnionitis, multiple gestation, polyhydramnios, 
premature preterm rupture of membranes (PPROM), preterm at <34 weeks gestation, 
and prior history of postpartum hemorrhage.  
Exclusion criteria: renal dysfunction with serum creatinine >1.0 mg dL-1, maternal 
treatment with digoxin, maternal treatment with a calcium channel blocker, and maternal 
history of cardiac condition including arrhythmia, congenital cardiac disease, or 
coronary disease.  
Patients admitted to the labor and delivery ward will be provided a brief 
informational sheet regarding the study. Women who meet inclusion criteria for the 
study will be subsequently approached by the clinical staff for written informed consent 
as long as the obstetrician agrees that this discussion will not interfere with case 
urgency. Not all women who meet study inclusion criteria will be approached; the 
patients included in this pilot study will be a convenience sample approached when the 
clinical service allows.  
As part of consent, women will be asked if they will permit the team to draw 3 
blood specimens for ionized calcium assessment and nested pharmacokinetic analysis; 
however, women who declined phlebotomy are still allowed study participation.  
Patients will be informed about possible side effects including intravenous line 
discomfort during the consent process and asked to inform the anesthesiologist if they 
experience this at any point during the delivery course. The anesthesiologist is 


Protocol Version 2.1 September 10, 2018 
6
instructed to assume all patients are receiving a 1 gram bolus of calcium chloride, and 
to immediately discontinue the infusion if any concerns for medication extravasation, 
arrhythmia, hemodynamic disturbance, or for severe nausea or vomiting. 
Patients will be sequentially assigned to one of two computer-generated random 
groups (Microsoft Excel, Microsoft Corporation, Redmond, WA, USA) using in a sealed, 
opaque envelope system. Patients will either receive 1 gram of intravenous calcium 
chloride or saline placebo diluted to a total volume of 60mL with normal saline in 
addition to our institution’s standard oxytocin regimen (2 U bolus and 7.5 U hr-1 infusion 
for 4 hours). All participants including the obstetrician, supervising and resident 
anesthesiologists, patient, and study investigator collecting data will be blinded to the 
study solution received. An anesthesiologist with no further involvement in patient care 
will prepare the study solution in a different operating theater. 
Upon entering the operating room, standard noninvasive monitors will be applied: 
pulse oximetry, electrocardiography (ECG), heart rate (HR), and baseline non-invasive 
blood pressure (NIBP). Mean arterial blood pressure (MAP) will be measured with an 
automated, non-invasive sphygmomanometer (Dinamap, Critikon Inc., Tampa, FL, 
USA) at 1 minute intervals until fetal delivery and hysterotomy closure and then at 2.5 
minute intervals at the discretion of the clinical anesthesiologist.  
All patients will have an 18-gauge peripheral intravenous cannula in place at the 
time of cesarean delivery per standard protocol. Lactated Ringers solution will be 
administered at the discretion of the clinical anesthesiologist with general guidelines not 
to exceed 3 L during the caesarean delivery. Total administered fluid volume will be 
recorded. Colloid infusion with 6% hydroxyethyl starch in 0.9% sodium chloride or 5% 


Protocol Version 2.1 September 10, 2018 
7
albumin is also recorded. Patients receive prophylactic phenylephrine infusion (starting 
at 0.5 mcg kg-1 min-1) and phenylephrine (50-100 mcg) or ephedrine (5-10 mg) bolus 
doses as needed at the discretion of the clinical anesthesiologist to maintain MAP within 
20% of baseline. The total phenylephrine infusion dose received as well as total bolus 
doses of vasopressors will likewise be left to the discretion of the clinical 
anesthesiologist and recorded. 
Following fetal delivery and umbilical cord clamping, patients will receive 2 U 
oxytocin bolus, and oxytocin infusion will be initiated at a rate of 7.5 U hr-1. At this same 
time point, the 60 mL study drug infusion will be administered over 10 minutes using an 
Alaris syringe infusion pump (BD Alaris syringe module, Beckton, Dickinson and 
Company, Franklin Lakes, NJ, USA) through microbore infusion tubing connected to the 
intravenous injection port most proximal to the patient. Adequacy of uterine tone (yes or 
no) will be formally assessed at 3, 6, and 10 minutes after delivery by the operating 
obstetrician. If tone is deemed inadequate at 3 minutes or 6 minutes, a 2 U bolus of 
oxytocin will be administered, and the oxytocin infusion rate doubled. If at 10 minutes, 
tone is still deemed inadequate, a second-line uterotonic agent of intramuscular 
methylergonovine 200 mcg, intramuscular 250 mcg, or buccal misoprostol 600 mcg will 
be chosen at the discretion of the obstetrician and clinical anesthesiologist and 
recorded. After leaving the operating theater, all patients receive our institution’s 
standard protocol of oxytocin 7.5 U hr-1 for 4 hours. 
 
 
 


Protocol Version 2.1 September 10, 2018 
8
Primary outcome: 
The primary outcome will be incidence of uterine atony, a binary composite 
outcome defined as any of the following: second-line uterotonic requirement, EBL 
>1000 mL, placement of a Bakri balloon, B-lynch suture, or O’Leary sutures by the 
obstetrician, uterine artery embolization or hysterectomy. For this pilot study, any P 
value less than 0.2 is defined a priori as indicating potential for efficacy, and thus 
warranting a future, larger study.  
 
Secondary outcomes: 
Several secondary outcomes related to uterine atony and hemorrhage will be 
assessed. At completion of study drug infusion (10 minutes after umbilical cord clamp), 
the operating obstetric attending will be asked to assess and grade the uterine tone 
based upon palpation of the fundus using a verbal numerical scale score from 0-100 
(0=completely atonic, 100=fully contracted). Blood loss will be estimated by visual 
examination of the graduated suction jars, surgical sponges, drapes, table and floor. 
The difference in preoperative and postoperative day 1 hematocrit gathered as standard 
of care at our institution will be calculated. The total volume of intravenous fluid given 
from start to conclusion of the surgical procedure will be recorded.  
For patients who consent to phlebotomy, blood specimens will be collected into a 
non-heparinized syringe at three different time intervals: once in the operating room 
prior to fetal delivery for a baseline value, once within 1-30 minutes of completing study 
drug infusion, and once 30 minutes to 3 hours after completing study drug infusion. To 
allow for painless sample collection for patients with a surgical lumbar neuraxial block, a 


Protocol Version 2.1 September 10, 2018 
9
tourniquet will be placed at the patient’s lower calf, and a 21-gauge winged blood 
collection needle was utilized to collect a 3 mL venous specimen from the foot or 
saphenous vein. The ionized calcium level and pH will be immediately determined with 
an i-STAT 1 system (i-STAT Corp., Princeton, NJ, USA). 
 
Calcium pharmacokinetics will be analyzed with NONMEM (Nonlinear Mixed-
Effects Modeling; Globomax, Ellicott City, MD) using PLT Tools (PLT Soft, San 
Francisco, CA). We will evaluate calcium kinetics using a 1-compartment model with 
administration into the central compartment. We will use an exponential model for 
interindividual variability on the volume of distribution and clearance and an additive 
model of interindividual variability on the baseline calcium concentration. The model 
parameters will be estimated by NONMEM using the first order conditional estimation 
approach. Confidence intervals for each parameter will be assessed using log likelihood 
profiling and bootstrap analysis.  
 
Hemodynamic variables analyzed will include heart rate and mean arterial 
pressure at baseline, at fetal delivery, and at 5 minute intervals for the next 30 minutes. 
This will be used to calculate a maximal increase and decrease from baseline 
calculation for each patient. The clinical anesthesiologist will fill out a checklist prior to 
exiting the operating theater at case conclusion answering whether the patient 
experienced nausea, vomiting, intravenous line discomfort, changes in heart rate or 
blood pressure, any arrhythmia, or other possible side effect (with a free-text field) 
during or following the study drug infusion. 
 
 
 


Protocol Version 2.1 September 10, 2018 
10
Statistical analysis: 
A sample size of 40 parturients was selected for this pilot study as most likely 
feasible to perform in approximately one year or less at our institution. Internal quality 
improvement data at our institution revealed that in patients with more than one atony 
risk factor, incidence of EBL >1000 mL or second line uterotonic use was >60%. If 
calcium were to halve the rate of uterine atony, we estimated that a sample size of 20 
subjects in the calcium and 20 subjects in the placebo group should allow sufficient data 
to show a difference between groups with 75% power and a two-sided type I error 
probability of 0.2. 
For analysis of the primary outcome, the relative risk (RR), and its 95% 
confidence interval will be calculated according to Altman.13 The number needed to treat 
(NNT) will be defined and calculated using the terminology suggested by Altman.14 The 
95% confidence interval for NNT will be calculated according to Daly,15 and P-value 
calculated according to Sheskin.16 Bootstrap analysis for sample size calculation for 
future studies will be performed using R programming and 10,000 replicates of the pilot 
dataset. 
Demographic and baseline characteristics will be reported as mean ± standard 
deviation (SD) or median and interquartile range [IQR] as appropriate for continuous 
variables. Categorical variables will be presented as percent. The mean differences and 
their 95% confidence intervals (CI) will be presented for outcomes of interest. Univariate 
comparisons between groups will be performed using Chi-square analysis or the 
Kruskal–Wallis test, as appropriate for categorical or continuous variables, respectively. 


Protocol Version 2.1 September 10, 2018 
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Statistical analyses will be performed using STATA version 14.0 (StataCorp, 
CollegeStation, TX, USA).  
 
 
 


Protocol Version 2.1 September 10, 2018 
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References:  
 
1. Say L, Chou D, Gemmill A, Tunçalp Ö, Moller A-B, Daniels J, Gülmezoglu AM, 
Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. 
Lancet Glob Health. 2014 Jun;2(6): p. e323-33 
2. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin: Clinical 
Management Guidelines for Obstetrician-Gynecologists Number 183, October 2017: 
Postpartum Hemorrhage. Obstet Gynecol, 130 (2017), p. e168-e186 
3. Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology of postpartum 
hemorrhage in a large, nationwide sample of deliveries. Anesth Analg 2010;110:1368-73 
4. Luckas MJ, Taggart MJ, Wray S. Intracellular calcium stores and agonist-induced 
contractions in isolated human myometrium. Am J Obstet Gynecol. 1999 Aug;181(2): p. 
468-76 
5. Papandreou, Chasiotis, Seferiadis, Thanasoulias, Dousias, Tsanadis, Stefos. Calcium 
levels during the initiation of labor. European Journal of Obstetrics and Gynecology and 
Reproductive Biology. 2004 July;115(1):17-22 
6. Talati C, Ramachandran N, Carvalho JCA, Kingdom J, Balki M. The Effect of Extracellular 
Calcium on Oxytocin-Induced Contractility in Naive and Oxytocin-Pretreated Human 
Myometrium In Vitro. Anesth Analg. 2016 May;122(5): p. 1498-507. 
7. Papandreou L, Chasiotis G, Seferiadis K, Thanasoulias NC, Dousias V, Tsanadis G, 
Stefos T. Calcium levels during the initiation of labor. Eur J Obstet Gynecol Reprod Biol. 
2004 Jul 15;115(1):17-22. 
8. Farber MK, Schultz R, Lugo L, Liu X, Huang C, Tsen LC. The effect of co-administration 
of intravenous calcium chloride and oxytocin on maternal hemodynamics and uterine 
tone following cesarean delivery: a double-blinded, randomized, placebo-controlled trial. 
Int J Obstet Anesth. 2015 Aug;24(3):217-24 
 

ICF_002.pdf: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 1 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
STANFORD CONSENT FORM with HIPAA 
 
Are you participating in any other research studies? _____ Yes _____No 
 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study of the effects of calcium on 
uterine tone and blood loss at the time of Cesarean section.  
 
Calcium is an electrolyte that is present and abundant in the body. Calcium is 
important for normal functioning of many parts of the body including the heart, 
the brain, and blood clotting. Calcium has also been shown to help uterine 
muscles contract in laboratory studies. Anesthesiologists commonly administer 
calcium to patients through the IV during many types of surgeries.  
 
We hope to learn whether giving a single dose of calcium (an IV solution 
called calcium chloride) after delivery of your baby or babies can help your 
uterus contract and prevent severe blood loss.  Although calcium is 
commonly administered at this dose, using calcium to try to help the uterus 
contract would be considered “investigational” as studies have not been done for 
this indication. You were selected as a possible participant in this study because 
you have been identified as having an increased risk of blood loss during your 
Cesarean. 
 
Intravenous calcium chloride is approved by the FDA for administration to treat 
low calcium levels. Anesthesiologists also frequently administer calcium to patients 
to help with low blood pressure, poor blood clotting, elevated magnesium, or 
elevated potassium levels.  Anesthesiologists have described using calcium to help 
the uterus contract as animal studies show that calcium is helpful, but adequate 
studies have not been performed to see how effective this actually is in humans. 
Studies have not been done to address whether administering calcium to a 
pregnant woman crosses the placenta or affects the fetus. However, for this 
study, no calcium would be given to you until your baby had already been 
delivered. 
 
If you decide to terminate your participation in this study, you should notify Dr. 
Jessica Ansari at 650-721-0866.  For any urgent questions or concerns regarding 
the study, you can call 650-723-5403 and ask to speak with an Obstetric 
anesthesiologist at Lucile Packard Children’s Hospital 24 hours, 7 days per week. 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 2 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
This research study is looking for 40 patients undergoing Cesarean section at 
Lucile Packard Children’s Hospital Stanford who have been identified as having 
more than one risk factor for increased bleeding.  Enrollment will only occur at 
Lucile Packard Children’s Hospital Stanford. 
 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to 
participate will not have any negative effect on you or your medical care.  You 
can decide to participate now, but withdraw your consent later and stop being in 
the study without any loss of benefits or medical care to which you are entitled. 
 
DURATION OF STUDY INVOLVEMENT  
 
This research study is expected to take one to two years to recruit and enroll all 
patients.  You will only be an active participant in the study during your Cesarean 
section and up until the day after delivery. You will NOT be contacted after your 
delivery and will NOT need to attend any appointments as part of this study. 
 
PROCEDURES 
 
If you choose to participate, Dr. Ansari and her research study team will give the 
anesthesiologist caring for you a bag of medicine to deliver in the IV after your 
baby is born. This bag will either contain calcium chloride 1 gram or simple saline 
(also known as a placebo). 50% of patients will receive the calcium, and 50% of 
patients will receive the saline (placebo). Your anesthesiologist, your surgeon, 
and you will NOT know whether you are receiving calcium or the plain saline.  
 
The experimental treatment for this study is the calcium chloride solution 
administered in the IV. Regardless of whether you receive calcium or saline 
solution, you will receive all of the standard medications and treatments during 
your Cesarean.  We will record all the doses of medications you receive during 
your Cesarean, as well as how much blood is lost during your surgery.  We will 
also record the values from the routine labs that are done before and after any 
Cesarean. 
 
This study does NOT require you to undergo any additional procedures or lab 
testing.  However, if you are willing, we are asking all of our research 
subjects to supply up to 3 small tubes of blood, less than 3 teaspoons in 
total, to allow us to measure the calcium levels in the blood. Whenever possible, 
we will draw these blood samples simply by drawing back on your IV.  When this 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 3 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
is not possible, we may do a standard lab draw with a small needle.  You will not 
be charged for any lab studies related to this research. If you agree to blood 
sampling, the labs will be drawn  
1) In the preoperative area 
2) In the operating room after the medicine has been administered 
3) In the recovery room after your Cesarean 
 
If you agree to provide blood samples, these samples will not be saved or stored 
for any future research. Blood calcium level will be assessed, and the remaining 
blood will be discarded. 
 
You may still participate in this study even if you choose not to 
undergo any additional laboratory studies. All the rest of your care 
including lab draws and medications administered will follow the standard of care 
and will be determined by your anesthesiologist and obstetrician. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 4 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
 
 
 
 
 
20 women receive 1 gram of 
intravenous calcium chloride in 
50ml saline after delivery of the 
baby 
As well as oxytocin and all other 
standard of care medications and 
interventions at the discretion of 
the anesthesia and surgical teams 
20 women receive 60ml 
intravenous saline placebo after 
delivery of the baby 
As well as oxytocin and all other 
standard of care medications and 
interventions at the discretion of 
the anesthesia and surgical teams 
40 women with >1 risk factors 
for bleeding are enrolled prior 
to Cesarean. A computer has 
randomly assigned each 
woman to receive calcium or 
simple saline.  The patient, the 
anesthesiologist, and the 
surgeon will NOT know 
whether she is receiving 
calcium or saline. 
Patients are assessed for the following, all 
of which are standard-of-care assessments: 
-presence or absence of uterine atony (low 
uterus muscle tone) 
-total blood loss (estimated and measured) 
-change in hematocrit on standard 
preoperative and postoperative labs 
-blood pressure and heart rate recorded 
during Cesarean 
-amount of medication needed to maintain 
a normal blood pressure 
-any possible side effects of calcium 
 
  
If patients agree, they will undergo 
a maximum of 3 lab draws to 
assess serum calcium levels. All 
consented patients will be asked if 
willing to undergo the additional 
lab draws.   
If patients agree, they will undergo 
a maximum of 3 lab draws to 
assess serum calcium levels. All 
consented patients will be asked if 
willing to undergo the additional 
lab draws.   
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 5 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, if you have agreed to be in the group of patients supplying 3 
small blood samples, your only responsibility is to allow us to perform a total of 3 
lab draws: 1 before, 1 during, and 1 after your Cesarean. 
 
If you have elected to participate without lab draws, you have no significant 
responsibilities, other than receiving either calcium or placebo during your 
Cesarean, and consenting to us gathering data from your chart. 
 
• Follow the instructions of the Protocol Director and study staff. 
• Tell the Protocol Director or research study staff about any side effects, 
doctor visits, or hospitalizations that you may have. 
• Ask questions as you think of them. 
• Tell the Protocol Director or research staff if you change your mind about 
staying in the study. 
 
WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your 
decision will not affect your ability to receive medical care for your pregnancy 
and postpartum period, and you will not lose any benefits to which you would 
otherwise be entitled.  
 
If you decide to withdraw your consent to participate in this study, you should 
notify Dr. Edward Riley at 650-498-7787.  For any urgent questions or concerns 
regarding the study, you can call 650-723-5403 and ask to speak with an Obstetric 
anesthesiologist at Lucile Packard Children’s Hospital 24 hours per day, 7 days per 
week. 
  
If you withdraw from the study, or the calcium medication is stopped for any 
reason: 
• We will record the reason for stopping the medication and/or 
withdrawing from the study 
• We will follow you for any side effects, questions, or concerns 
• We will still analyze anonymous information about your blood loss 
during Cesarean if the calcium medication is stopped 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 6 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
The Protocol Director may also withdraw you from the study and the calcium 
medication may be stopped without your consent for one or more of the 
following reasons:   
o Failure to follow the instructions of the Protocol Director and 
study staff. 
o The Protocol Director decides that continuing your 
participation could be harmful to you. 
o The study is cancelled.  
o Other administrative reasons. 
o Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research 
study.  These deserve careful thought.  You should talk with the Protocol 
Director if you have any questions. 
• Calcium chloride infusion is generally very well tolerated, especially 
when diluted and administered slowly as will be done for this study.  
Most common reported side effects include mild discomfort in the 
IV, a funny taste in the mouth or sensation in the tongue, and 
nausea. 
• In rare cases, rapid intravenous injections of calcium chloride may 
cause excessively high calcium levels in the blood, which can 
result in vasodilation, abnormal heart rhythms, decreased blood 
pressure, and bradycardia (slow heart rate).  
• If the IV used to administer the calcium does not function properly, 
the calcium can cause significant inflammation and discomfort in 
the hand or arm. In very rare cases, this can lead to significant 
damage to the tissues of the arm requiring medical attention. Your IV 
will be assessed carefully by the anesthesiologist (as a working IV is 
essential for ANY patient undergoing Cesarean) before administering 
calcium. If you experience pain or discomfort in your IV at any point, 
the anesthesiologist will carefully inspect your IV site and pause the 
infusion if there is any concern. 
• All patients are monitored continuously during Cesarean on EKG (heart 
rhythm) monitors, and the anesthesiologist is present at all times. If 
you are having any signs of intolerance, the infusion will be 
discontinued.  Any side effects are expected to be short-lived. 
• It is always possible that there could be other risks of administering 
calcium during a Cesarean, which are currently unforeseeable.  
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 7 of 15 
 
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Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
POTENTIAL BENEFITS                              
 
One potential benefit of the study is that the calcium administered to patients 
may help the uterus to contract and decrease the amount of bleeding during 
Cesarean.  This is the goal of the study. 
 
We cannot and do not guarantee or promise that you will receive any benefits 
from this study. 
 
ALTERNATIVES 
 
The alternative is not to participate in the study.  All patients who participate in 
the study will receive the same standard of care medications, surgical procedure, 
follow up, and labs that any other patient will receive. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell 
the Protocol Director.   
 
You will be told of any important new information that is learned during the 
course of this research study, which might affect your condition or your 
willingness to continue participation in this study. 
 
ClinicalTrials.gov 
 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law.  This Web site will not 
include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time. 
 
CONFIDENTIALITY 
 
The results of this research study may be presented at scientific or medical 
meetings or published in scientific journals.  Your identity and/or your personal 
health information will not be disclosed except as authorized by you or as 
required by law.  However, there is always some risk that even de-identified 
information might be re-identified.  
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 8 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
Patient information may be provided to Federal and other regulatory agencies as 
required.  The Food and Drug Administration (FDA), for example, may inspect 
research records and learn your identity if this study falls within its jurisdiction. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 9 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
Authorization To Use Your Health Information 
For Research Purposes  
Because information about you and your health is personal and 
private, it generally cannot be used in this research study without 
your written authorization.  If you sign this form, it will provide that 
authorization.  The form is intended to inform you about how your 
health information will be used or disclosed in the study.  Your 
information will only be used in accordance with this authorization 
form and the informed consent form and as required or allowed by 
law.  Please read it carefully before signing it.   
 
What is the purpose of this research study and how will my 
health information be utilized in the study? 
This study is investigating whether giving a single dose of calcium 
(an IV solution called calcium chloride) can help the uterus contract 
and prevent severe blood loss during Cesarean surgery. This 
medication is routinely administered by anesthesiologists during 
many types of surgery, including studies in pregnant patients. 
However, it has not been studied in patients at risk for bleeding 
during Cesarean surgery. If you are willing, you may have also been 
asked to provide 3 blood samples to allow us to measure the blood 
calcium levels and assess whether the calcium helps the blood 
clotting. 
 
You were selected as a possible participant in this study because you 
have been identified as having some risk factors for blood loss during 
your Cesarean. As part of this study, information will be collected 
from your chart including how much blood is lost during the surgery, 
what other medications are administered, and how the routine lab 
values after surgery change.  This anonymous information may be 
used in publication in academic journals or at academic meetings; 
however, no personal information that identifies you in any way will 
be used. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 10 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, 
you will not be able to participate in this research study including 
receiving any research-related treatment.   
 
Signing the form is not a condition for receiving any medical care 
outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your 
authorization regarding the use and disclosure of your health 
information (and to discontinue any other participation in the study) 
at any time.  After any revocation, your health information will no 
longer be used or disclosed in the study, except to the extent that 
the law allows us to continue using your information (e.g., necessary 
to maintain integrity of research).  If you wish to revoke your 
authorization for the research use or disclosure of your health 
information in this study, you must write to:  
Dr. Jessica Ansari, Stanford Obstetric Anesthesia 
300 Pasteur Drive, Room H3580, Stanford, CA 94305,  
Mail Code 5640 
 
What Personal Information Will Be Obtained, Used or 
Disclosed? 
Your health information related to this study, may be used or 
disclosed in connection with this research study, including, but not 
limited to: 
• Your name and medical record number will be recorded upon 
enrollment in the study, but will be kept confidential and WILL 
NOT be shared in any publications about the results of this 
study 
• Your age, weight, and number of prior pregnancies 
• Your current medications and any past medical conditions 
• Information about your pregnancy and/or labor that can impact 
the risk of bleeding during Cesarean 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 11 of 15 
 
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IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
• Your baseline preoperative hemoglobin and hematocrit levels, 
which are drawn in all patients before Cesarean 
• Medications administered during your Cesarean 
• Your blood pressure and heart rate values during Cesarean 
• Estimated blood loss during Cesarean surgery 
• Hemoglobin and hematocrit labs drawn as routine care after 
Cesarean 
• Any complications during your delivery or hospital stay 
• Any possible side effects of calcium or saline infusion 
• Lab calcium measures drawn as part of the study, if you agreed 
to undergoing the 3 lab draws 
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your 
health information in connection with this research study: 
• The Protocol Director, Dr. Jessica Ansari 
• The Stanford University Administrative Panel on Human 
Subjects in Medical Research and any other unit of Stanford 
University as necessary 
• Research Staff 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your 
health information to the following persons and organizations for 
their use in connection with this research study:  
• The Office for Human Research Protections in the U.S. 
Department of Health and Human Services 
• The Food and Drug Administration (FDA) 
 
Your information may be re-disclosed by the recipients described 
above, if they are not required by law to protect the privacy of the 
information. 
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 12 of 15 
 
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IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health 
information will end on December 31, 2050 or when the research 
project ends, whichever is earlier.  
 
 
________________________________             
  ______________ 
Signature of Adult Participant                                        Date 
 
 
________________________________             
 
Print Name of Adult Participant                                         
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 13 of 15 
 
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Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
FINANCIAL CONSIDERATIONS 
 
Payment 
You will not be paid to participate in this research study. 
 
 
Costs 
There is no cost to you for participating in this study. If you are undergoing the 
lab calcium and blood clotting studies, the anesthesia department will pay the 
cost of those labs.  Neither you nor your insurance will be billed for the calcium 
administered or the labs drawn as part of the study. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental 
– involve some risk of injury.  In spite of all precautions, you might develop 
medical complications from participating in this study.  If such complications 
arise, the Protocol Director and the research study staff will assist you in 
obtaining appropriate medical treatment.  In the event that you have an injury or 
illness that is directly caused by your participation in this study, reimbursement 
for all related costs of care first will be sought from your insurer, managed care 
plan, or other benefits program.  You will be responsible for any associated 
co-payments or deductibles as required by your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, 
managed care plan or other benefits program, you may be responsible for these 
costs.  If you are unable to pay for such costs, the Protocol Director will assist 
you in applying for supplemental benefits and explain how to apply for patient 
financial assistance from the hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
 
Questions, Concerns, or Complaints:  If you have any questions, concerns or 
complaints about this research study, its procedures, risks and benefits, or 
alternative courses of treatment, you should ask the Protocol Director, Dr. 
Jessica Ansari, at 650-721-0866. You should also contact her at any time if you 
feel you have been hurt by being a part of this study.  
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 14 of 15 
 
SU_MainICF_HIPAA rev022316 
IRB Use Only 
Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
For any urgent questions or concerns regarding the study, you can call 650-723-
5403 and ask to speak with an Obstetric anesthesiologist at Lucile Packard 
Children’s Hospital / Stanford 24 hours, 7 days per week. 
 
If you are not satisfied with how this study is being conducted, or if you have 
any concerns, complaints, or general questions about the research or your rights 
as a participant, please contact the Stanford Institutional Board Review (IRB) to 
speak to someone independent of the research team at 650-723-5244 or toll free 
at 1-866-680-2906.  You can also write to Stanford IRB, Stanford University, 
3000 El Camino Real, Five Palo Alto Square, 4th Floor, Palo Alto, CA 94306. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but 
are not limited to the patient's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably 
to be expected;  
• 
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices 
that might be advantageous to the subject, their relative risks and 
benefits; 
• 
be informed of the avenues of medical treatment, if any available to the 
subject after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or 
the procedures involved;  
• 
be instructed that consent to participate in the medical experiment may 
be withdrawn at any time and the subject may discontinue participation 
without prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a 
medical experiment without the intervention of any element of force, 
fraud, deceit, duress, coercion or undue influence on the subject's 
decision. 
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Jessica Ansari 
Protocol Title:   Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk 
of Hemorrhage: a pilot randomized controlled trial and pharmacokinetic study 
 
 
Page 15 of 15 
 
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Approval Date:   April 9, 2018 
Expiration Date: October 17, 2018 
Participant ID: 
Signing your name means you agree to be in this study and that you will receive 
a copy of this signed and dated consent form.  
 
 
_____________________________________                ____________ 
Signature of Adult Participant 
 
 
 
   
   Date 
 
 
_____________________________________             
Print Name of Adult Participant                                         
 
 
The following witness line is to be signed only if the consent is provided as a 
summary form and accompanied by a short form foreign language consent. 
 
 
_____________________________________                     ____________ 
Signature of Witness                                                              Date 
 
 
__________________________________             
 
Print Name of Witness                                         
 
(e.g., staff, translator/interpreter, family member, or other person who speaks both 
English and the participant's language) 
• Translated short form must be signed and dated by both the participant AND the 
witness. 
• The English consent form (referred to as the "Summary Form" in the regulations): 
− Must be signed by the witness AND the Person Obtaining Consent (POC). 
− The non-English speaking participant does not sign the English consent. 
− The non-English speaking participant should not sign the HIPAA participant line 
− If the participant is non-English speaking, the Person Obtaining Consent (POC) must 
ensure that any questions or options presented by the consent form are documented 
and initialed by the POC on the Summary Form, per the participant's wishes, as they 
are understood during the consent process.