Continuous Glucose Monitoring for the Evaluation of

Gravid Women With Type 1 Diabetes Mellitus

Yariv Yogev, MD, Rony Chen, MD, Avi Ben-Haroush, MD, Moshe Phillip, MD,
Lois Jovanovic, MD, and Moshe Hod, MD
OBJECTIVE: Tocompare the dailyglycemic prole reectedby
continuous and intermittent blood glucose monitoring in
pregnant women with type 1 diabetes and to compare the
treatment protocols based on the two monitoring methods.
METHODS: The study sample consisted of 34 gravid patients
at gestational weeks 1632, with type 1 diabetes being
treated by multiple insulin injections. Data derived from
the continuous glucose monitoring system for 72 hours
were compared with ngerstick glucose measurements
performed 68 times per day. During the study period,
patients documented the time of food intake, insulin injec-
tions, and hypoglycemic events. Data on demographics,
gravidity, parity, body mass index, hemoglobin A1c, and
fructosamine levels were collected for each patient.
RESULTS: An average ( standard deviation) of 780 54
glucose measurements was recorded for each patient with
continuous glucose monitoring. The mean total time of
hyperglycemia (glucose level greater than 140 mg/dL) un-
detected by the ngerstick method was 192 28 minutes
per day. Nocturnal hypoglycemic events (glucose level less
than 50 mg/dL) were recorded in 26 patients; in all cases,
there was an interval of 14 hours before clinical manifes-
tations appeared or the event was revealed by random
blood glucose examination. Based on the additional infor-
mation obtained by continuous monitoring, the insulin
therapeutic regimen was adjusted in 24 patients (70%).
CONCLUSION: Continuous glucose monitoring can diagnose
high postprandial blood glucose levels and nocturnal hy-
poglycemic events that are unrecognized by intermittent
blood glucose monitoring and may serve as a basis for
determining treatment regimens. A large, prospective
study on maternal and neonatal outcome is needed to
evaluate the clinical implications of this new monitoring
technique. (Obstet Gynecol 2003;101:6338. 2003 by
The American College of Obstetricians and Gynecolo-
gists.)
The goal of management in type 1 diabetes is to maintain
blood glucose and hemoglobin (Hb)A1c levels as near to
normal as possible. This goal is difcult to achieve in all
patients and poses an even greater challenge in pregnant
women.
Improved glycemic control during diabetic pregnancy
has been found to decrease perinatal morbidity and
mortality,
1,2
as well as the congenital malformation rate.
3
On the one hand, however, too-tight glycemic control in
this patient group may be accompanied by a high inci-
dence of hypoglycemia, ranging from36%to 71%.
4,5
On
the other hand, as maternal glycemia increases, the risk
of macrosomia, the most common and signicant peri-
natal complication clearly associated with diabetes in
pregnancy, increases as well.
6
Patients with diabetic
pregnancy are treated with multiple insulin injections
and are advised to perform selfblood glucose monitor-
ing by ngerstick measurements 48 times per day. The
optimal frequency of blood glucose testing in gravid
patients with type 1 diabetes has not been established.
The selfblood glucose monitoring method has an
important limitation; it provides only a single value
during the day and does not allow for continuous, lon-
gitudinal monitoring. As such, it may be missing both
hypoglycemic and hyperglycemic events. To counter
this problem, a new technology of continuous glucose
monitoring was recently developed (Mastortotoro J,
Levy R, Georges LP, White N, Mestman J. Clinical
results from a continuous glucose sensor multi-center
study [abstract]. Diabetes 1998;47:A61). The system
measures interstitial glucose levels in subcutaneous tis-
sue, within a range of 40400 mg/dL. Glucose values
obtained with continuous glucose monitoring have been
shown to correlate with laboratory measurements of
plasma glucose levels
7
and with home glucose meter
values (Mastortotoro J, et al. Diabetes 1998;47:A61).
The purpose of the present study was to compare the
daily glycemic prole reected by continuous and inter-
mittent blood glucose monitoring in pregnant women
with type 1 diabetes and to determine whether treatment
From the Perinatal Division and The World Health Organization Collaborating
Center, Department of Obstetrics and Gynecology, Rabin Medical Center, Beilinson
Campus, and Institute for Endocrinology and Diabetes, National Center of
Childhood Diabetes, Schneider Childrens Medical Center of Israel, Petah Tiqva,
Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; and
Sansum Medical Research Institute, Santa Barbara, California.
633 VOL. 101, NO. 4, APRIL 2003 0029-7844/03/$30.00
2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier. doi:10.1016/S0029-7844(02)02714-X
strategy protocols based on the two monitoring methods
differ.
MATERIALS AND METHODS
The initial study sample consisted of 41 consecutive
gravid women with type 1 diabetes who were recruited
for this prospective study during a routine clinical visit to
the Diabetes in Pregnancy Center of the Perinatal Divi-
sion Unit, Rabin Medical Center between November
2001 and March 2002. Of these, 34 women (82.9%) gave
consent to participate after receiving a comprehensive
explanation of the study. The local ethics committee
approved the study protocol.
Inall cases, type 1diabetes mellitus was diagnosedbefore
the onset of the current pregnancy. Gestational age ranged
from 16 to 32 weeks. All patients were being treated with
insulin and were under the care of a registered dietitian for
individualized counseling and instructions.
At entry to the study, the patients chart was reviewed
for demographic data, gravidity, parity, and body mass
index (BMI). Prior to sensor placement, levels of HbA1c,
fructosamine, and plasma glucose were measured.
The MiniMed continuous glucose monitoring system
(MiniMed, Sylmar, CA) was used in all cases for 3 days.
The system measures glucose levels in subcutaneous
interstitial tissue. It is composed of a disposable subcuta-
neous glucose-sensing device and an electrode impreg-
nated with glucose oxidase connected by a cable to a
lightweight monitor, which is worn over the clothing or
on a belt. The systemtakes a glucose measurement every
10 seconds, based on the electrochemical detection of
glucose by its reaction with glucose oxidase, and stores
an average value every 5 minutes, for a total of 288
measurements each day. A communication device en-
ables the data stored in the monitor to be downloaded
and reviewed on a personal computer. The patients are
unaware of the results of the sensor measurements dur-
ing the monitoring period.
The same trained nurse placed all continuous glucose
monitoring sensors. Prior to placement, the site onthe ank
was prepared with an alcohol sponge, and the sensor was
calibrated according to the manufacturers instructions.
The patients were shown howto code the time of food
intake, insulin injections, exercise periods, and symp-
tomatic hypoglycemic events into the monitor.
Patients were instructed to wear the continuous glu-
cose monitoring device for 72 consecutive hours. During
this period, they also performed ngerstick capillary
glucose measurements in the morning after overnight
fasting and 2 hours after meals (68 times per day) using
a glucometer (Ames Glucometer Elite, Bayer Corp.,
Elkhart, IN) and self-coded the data into the monitor. At
the end of the study period, before the nurse discon-
nected the women from the sensor, plasma and glucom-
eter glucose values were measured. Quality control mea-
sures of glucose levels from the meter, sensor, and
plasma glucose were also performed at the time of con-
nection to the continuous glucose monitoring system
and again at study completion. The data collected by
selfblood glucose monitoring and continuous glucose
monitoring for each patient were evaluated separately by
a single experienced physician. The average time (in
minutes) per day of sensor glucose readings of less than
50 mg/dL and greater than 140 mg/dL was calculated
from the daily graphs. A hypoglycemic event was de-
ned as a greater than 30-minute asymptomatic reading
below 50 mg/dL or symptomatic hypoglycemia detected
by meter or monitoring records.
The decision regarding the insulin regimen was made
twice, rst on the basis of the selfblood glucose moni-
toring data and then on the basis of the continuous
glucose monitoring data. To prevent bias, the two types
of data were presented to the physician on different
occasions. The physician was blinded to the identity of
the individual patients.
Continuous parameters are given as means stan-
dard deviations. Pearson correlation coefcient (r) and
the signicance for it (P) were calculated between the
variables. Reliability coefcient was used to quantitate
the consistency of the two measuring methods (self
blood glucose monitoring and continuous glucose mon-
itoring) applied to each subject. Paired t test was used to
determine the statistical signicance of differences in
mean continuous parameters. A P value equal to or less
than .05 was considered statistically signicant.
RESULTS
Mean patient age was 26 4.7 years (range 2136
years), and mean gestational age was 25 6.2 weeks
(range 1632 weeks). Mean gravidity and parity were
2.4 1.1 and 1.2 0.9, respectively. Mean BMI was
26.2 4.7 kg/m
2
, mean HbA1c level 6.1 1.2% (nor-
mal range 4.55.7%), and mean fructosamine level 276
29 mg/dL (normal range 205285 mg/dL).
All patients completed the 3-day study. There were no
adverse events associated with the use of continuous
glucose monitoring. None of the patients experienced
irritation or infection at the insertion site. Although
patients were blinded to the continuous glucose monitor-
ing readings during the study period, they reported high
satisfaction using the device concerning potential future
benets of continual monitoring.
An average of 780 54 glucose measurements was
recorded for each patient with continuous glucose mon-
634 Yogev et al Glucose Monitoring, Gravidas, and Type 1 DM OBSTETRICS & GYNECOLOGY
itoring. The mean total time of hyperglycemia (glucose
level greater than 140 mg/dL) undetected by the nger-
stick method was 192 28 minutes per day. Nocturnal
hypoglycemic events (glucose level less than 50 mg/dL)
were recorded in 26 patients; in all cases, there was an
interval of 14 hours before clinical manifestations ap-
peared or the event was revealed by random blood
glucose examination. Mean glucose level by selfblood
glucose monitoring and continuous glucose monitoring
was 101 13 mg/dL and 121 13 mg/dL, respectively
(P .02). The individual glucose levels varied widely
during each 24-hour period, but the overall 3-day prole
of each patient remained consistent in many occasions
during this time period (Figure 1).
Analysis of the whole study group for the total 102
days of continuous monitoring showed that all 34 pa-
tients had undetected hyperglycemia by selfblood glu-
cose monitoring, with a range of 74303 minutes per day
(mean 192 28 minutes per day, median 166 minutes).
Nocturnal hypoglycemic events (at bedtime, during
the night, and in the early morning) were recorded in 26
of the 34 patients in 58 nights; symptoms occurred in 28
episodes in 17 patients. In all affected patients, there was
an interval of 14 hours before clinical manifestations
appeared or the event was revealed by random blood
glucose examination.
There was no statistically signicant correlation be-
tween HbA1c and fructosamine levels and the occur-
rence of hypoglycemic events.
Figure 2 demonstrates a 24-hour continuous record-
ing in one of the patients.
In 24 of the 34 patients (70%), the physician recom-
mended that the insulin regimen formulated on the basis of
the selfblood glucose monitoring data be changed on
subsequent evaluation of the continuous glucose monitor-
ing data. The most common change made was in decreas-
ing the long or intermediate-acting insulin dosage at night
(mean reduction by 25% in the nighttime dose of insulin).
The correlation coefcient (r) between the glucose mea-
surements by the sensor and meter was .93 .04, and
between the plasma glucose, meter monitoring, and sensor
recording, .91 .02. The reliability coefcient was .88.
DISCUSSION
Despite years of meticulous study, there is still a paucity
of information regarding the optimal level of glycemia in
diabetic pregnancy that clinicians should target to safely
Figure 1. Three-day continuous glucose monitoring prole in one of our patients, showing signicant variations in glucose
levels during the day but a similar daily glycemic prole for all 3 days.
Yogev. Glucose Monitoring, Gravidas, and Type 1 DM. Obstet Gynecol 2003.
635 VOL. 101, NO. 4, APRIL 2003 Yogev et al Glucose Monitoring, Gravidas, and Type 1 DM
reduce maternal and perinatal morbidity. Strict meta-
bolic control in patients with type 1 diabetes has been
associated with an increased risk of maternal hypoglyce-
mia. In our study, continuous monitoring of blood glu-
cose in women with diabetic pregnancies conrmed the
high occurrence rate of nocturnal hypoglycemia sus-
pected in earlier studies. Rosenn et al
5
reported signi-
cant hypoglycemia, dened as hypoglycemia requiring
assistance fromanother person, in 71%of gravid patients
with type 1 diabetes, with a peak incidence in the rst
trimester. The impact of maternal hypoglycemia on hu-
man fetal development and neonatal outcome has not
been extensively studied. Although concern about the
hazards of hypoglycemia is related primarily to the preg-
nant mother, the potential effects on the developing fetus
need to be considered as well.
Studies in rat and mice embryos point to a possible
fetal risk of malformations in the presence of short- and
long-term maternal hypoglycemia.
8
These ndings were not apparent with selfblood
glucose monitoring. Indeed, Data derived from continu-
ous glucose monitoring led the evaluating physician to
change the insulin regimen, usually by decreasing the
nighttime dose of intermediate-acting insulin. In more
than half the cases, the hypoglycemic events were sub-
clinical, diagnosed only by continuous glucose monitor-
ing, and in one fth of the patients, more than one
hypoglycemic event occurred during the night.
These ndings may indicate that continuous glucose
monitoring is a better monitoring method than self
blood glucose monitoring in detecting hypoglycemic
events, which are usually asymptomatic and occur at
night. Whereas stringent glycemic control may lead to
hypoglycemia, too-loose control poses a risk of macroso-
mia, the most common and signicant perinatal compli-
cation associated with diabetic pregnancy, which can
lead to an increased risk of birth injuries and asphyxia.
The risk of macrosomia rises as maternal glycemia in-
creases. In addition, intensied management of gesta-
tional diabetes reduces the rate of perinatal complica-
tions, normalizes birth weight,
9
and has a positive
inuence on the congenital malformation rate.
3
Our study showed that glucose levels were above the
upper normal threshold for many hours during the day.
These events were related to unscheduled meals and
between-meal snacks and were not detected by conven-
tional selfblood glucose monitoring protocols. Despite
the recent introduction of intensied treatment proto-
Figure 2. A 24-hour continuous glucose monitoring trace in one of our patients demonstrating a nocturnal hypoglycemia
event, with a latent phase of 1 hour before clinical symptoms appeared (marked by the patient and followed by a meal).
Note the undetectable hyperglycemia by the selfblood glucose monitoring method after the meal in early morning.
Yogev. Glucose Monitoring, Gravidas, and Type 1 DM. Obstet Gynecol 2003.
636 Yogev et al Glucose Monitoring, Gravidas, and Type 1 DM OBSTETRICS & GYNECOLOGY
cols, high rates of macrosomia and perinatal morbidity
have persisted. On the basis of our study, we speculate
that this may be due to the imperfect evaluation of the
daily glucose prole by selfblood glucose monitoring,
which underestimates hyperglycemic events. Polansky
et al
10
reported that a large dinner might be associated
with a sustained postprandial state for 4.7 hours. In
addition, the most rigorous monitoring protocols only
require postprandial glucose measurements three times
per day. Many patients indulge in large between-meal
snacks, and these may be the cause of the hidden hyper-
glycemia.
High levels of HbA1c and fructosamine and elevated
BMI (greater than 30 kg/m
2
) were all unrelated to the
total diurnal time of hyperglycemia. The lack of a strong
correlation between HbA1c and glucose levels by con-
tinuous glucose monitoring may indicate that plasma
blood glucose levels vary signicantly day by day, and
although continuous monitoring is more informative
than sporadic, nonlongitudinal glucose monitoring, it
cannot adequately describe daily glucose proles over an
810-week period. It is possible that HbA1c is a better
predictor of preprandial than postprandial glucose lev-
els, as more hours are spent in interprandial and noctur-
nal periods than in the postprandial periods.
In our study, we used continuous glucose monitoring
as a guide for therapy adjustment. Recently, Kaufman et
al
11
showed that continuous glucose monitoring could
serve as a clinical tool for clinical decision making and
glycemic control in children with type 1 diabetes. In
another recent work, Hershkovitz et al
12
demonstrated
the clinical implications of continuous glucose monitor-
ing use to assess and manage asymptomatic hypoglyce-
mic events in children with glycogen storage disease.
Parretti et al
13
assessed the daily glycemic prole of
nondiabetic, nonobese pregnant women using multiple
daily ngerstick measurements. A comparison by con-
tinuous glucose monitoring in our department in a non-
diabetic, nonobese gravid population yielded a remark-
ably similar glycemic prole (unpublished data).
The present prospective study is the rst to test the
application of continuous glucose monitoring on gravid
women with type 1 diabetes. It showed that the diurnal
glucose prole undergoes extreme changes, including
both hypoglycemic and hyperglycemic events, which are
unrecognized by the conventional selfblood glucose
monitoring technique. Continuous monitoring proles
allow the physician to identify glucose patterns and to
better target insulin treatment. The treatment changes in
our series would not have been made on the basis of
meter data alone.
At this point, we do not recommend that continuous
glucose monitoring replace selfblood glucose monitor-
ing, but we suggest that intermittent application of con-
tinuous glucose monitoring can be used to ne-tune
glycemic control, assess patient compliance, if necessary,
and prevent nocturnal hypoglycemic events.
Because the incidence of hypoglycemia is higher and
achieving strict glycemic control is more difcult in the
rst trimester of pregnancy, the frequency of continuous
glucose monitoring should be increased during this pe-
riod. Later applications vary individually.
Importantly, this study does not indicate a clinical
difference in outcome from selfblood glucose monitor-
ing, and the clinical utility of continuous glucose moni-
toring in improving perinatal outcome remains un-
known.
A large, prospective study on maternal and neonatal
outcome is needed to evaluate the clinical implications of
this new monitoring technique.
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Address reprint requests to: Y. Yogev, MD, Rabin Medical Cen-
ter, Beilinson Campus, Department of Obstetrics and Gynecol-
ogy, Petah Tiqva 49100, Israel; E-mail: ilanit@dlylaw.co.il.
Received June 4, 2002. Received in revised form August 27, 2002.
Accepted September 5, 2002.
638 Yogev et al Glucose Monitoring, Gravidas, and Type 1 DM OBSTETRICS & GYNECOLOGY