Original Research

OBSTETRICS
Treating hyperglycemia in early pregnancy:
a randomized controlled trial
Hilary A. Roeder, MD; Thomas R. Moore, MD; Ms. Tanya Wolfson, MA; Anthony C. Gamst, PhD; Gladys A. Ramos, MD

BACKGROUND: Treating women with gestational diabetes mellitus in
the third trimester improves perinatal outcomes. It is unknown whether
treating women with mild glucose intolerance earlier in pregnancy would
be beneficial in the reduction of maternal and neonatal morbidities.
OBJECTIVE: In women with hyperglycemia (hemoglobin A1c
5.7%
and/or fasting glucose
92 mg/dL) in early pregnancy, we sought to
determine whether immediate treatment improved maternal and neonatal
outcomes.
STUDY DESIGN: This unblinded randomized controlled trial enrolled
women with hyperglycemia at 15þ0 weeks gestation between 2013
and 2015. Participants were assigned randomly to early pregnancy or
third-trimester treatment of hyperglycemia that included nutrition coun-
seling, glucose monitoring, and medications as needed. Participants un-
derwent a blinded 2-hour glucose tolerance test at 24e28 weeks
gestation. Exclusion criteria were pregestational diabetes mellitus and
multiple gestations. The primary outcome was the proportion of infants
with neonatal umbilical cord C-peptide >1.77 nmoL (90th percentile).
Secondary outcomes were neonatal fat mass, infant World Health Orga-
nization weight-for-length percentile at birth, maternal gestational weight
gain, and diagnosis of gestational diabetes mellitus on glucose tolerance
test. Mann-Whitney-Wilcoxon test and Fisher’s exact test were used, as
appropriate.
RESULTS: A total of 202 women were assigned randomly; 45 women
dropped out before delivery, which left cases 157 for analysis (82 with early
pregnancy and 75 with third-trimester treatment). The trial was terminated
early because of low enrollment. Baseline characteristics were similar be-
tween groups. There was no difference in C-peptide >90th percentile
between groups (1 [1.5%] vs 4 [6.7%]; P¼.19) in the early pregnancy and
third-trimester groups, respectively). There was also no difference in fat
mass (0.370.16 vs 0.360.17 kg; P¼.91), weight-for-length percentile
at birth (25% vs 25%; P¼.46), or macrosomia (1.5 vs 5.0%; P¼.84).
Maternal gestational weight gain was 22.612.9 lb and 23.911.2 lb in
the early pregnancy and third-trimester groups, respectively (P¼.88).
Gestational diabetes mellitus was diagnosed in 19.0% of the cohort and did
not differ between groups (14.2% vs 25.8%; P¼.17).
CONCLUSION: In this population of women with hyperglycemia,
treatment in early pregnancy did not appear to improve maternal or neonatal
outcomes significantly. Given comparable results in both groups, caution
should be used in the initiation of an intensive diabetes mellitus treatment
protocol for women with the diagnosis of hyperglycemia in early gestation.
Key words: diabetes mellitus, gestational diabetes mellitus, gestational
weight gain, hemoglobin A1c, hyperglycemia, neonatal fat mass, pre-
diabetes, umbilical cord C-peptide

M aternal hyperglycemia (see glos-

sary) in pregnancy is linked to
fetal hyperglycemia and hyper-
insulinemia, somatic overgrowth, child-
hood obesity, and metabolic
syndrome.1,2 To evaluate these associa-
tions prospectively, the Hyperglycemia
and Adverse Pregnancy Outcomes
(HAPO) study enrolled nondiabetic
women and reported that, even low
levels of glucose intolerance, were
important contributors to fetal hyper-
insulinemia and adiposity.3 This can
have potential metabolic consequences
during childhood growth and
development.4,5
After this landmark trial, the Interna-
tional Association of Diabetes and Preg-
nancy Study Group (IADPSG) and the
American Diabetes Association (ADA)
2589-9333/$36.00
ª 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajogmf.2019.03.003
recommended that all pregnant women be
screened for pregestational diabetes mel-
litus at the first prenatal visit6-8 and be
referred for care immediately if diagnosed
with hyperglycemia (either a fasting
plasma glucose [FPG] of 100e125 mg/dL
or hemoglobin A1c [HbA1c] of
5.7e6.4%). The IADPSG additionally
recommended diagnosis and treatment
for gestational diabetes mellitus (GDM) if
the FPG is
92 mg/dL. The California
State Department of Health Service’s
“Sweet Success” Program recommended
that women who are diagnosed with either
an elevated HbA1c or FPG in the first
trimester be treated as GDM.9 However, it
is unknown whether early diabetes melli-
tus intervention in these patients will
improve outcomes
As outlined by the 2013 National
Institutes of Health GDM Consensus
Conference, there is a lack of random-
ized controlled data regarding the
potential health benefits or harms
of early treatment of women with
hyperglycemia as defined by the
IADPSG model. As such, the aim of this
study was to ascertain whether early
pregnancy treatment of pregnant
women with hyperglycemia improves
neonatal and maternal outcomes. We
hypothesized that early pregnancy
treatment (in contrast to traditional
third-trimester management) would
decrease fetal hyperinsulinemia
(measured by umbilical cord C-peptide
>90th percentile) and neonatal fat
mass. We also sought to measure dif-
ferences in maternal gestational weight
gain (GWG) and diagnosis of GDM.
Materials and Methods
Study participants
This study was performed at the Uni-
versity of California, San Diego
(UCSD) between July 2013 and August
2016. Before initiation, Institutional
Review Board approval was obtained
(#111685). Patients were dated at their
first visit by last menstrual period and

MONTH 2019 AJOG MFM 1

Original Research OBSTETRICS

bedtime), and exercise. They were also

AJOG at a Glance trained to use a glucometer to monitor
Why was this study conducted? fasting and 1-hour postprandial
Treatment of gestational diabetes mellitus in the third trimester of pregnancy blood glucose values (checking 4 times
improves maternal and neonatal outcomes. It is unknown whether treatment of daily). Glucose goals were fasting
hyperglycemia in early pregnancy improves outcomes. Organizations such as the values of 90 mg/dL and 1-hour post-
American Diabetes Association, the International Association of Diabetes and prandial values of 130 mg/dL.12,13 If
Pregnancy Study Group, and California Sweet Success recommend screening for >40% of these values were elevated after
and treatment of early hyperglycemia. The National Institutes of Health Gesta- 2 weeks of diet and exercise, pharmaco-
tional Diabetes Consensus Conference in 2013 requested more data before rec- therapy was initiated (neutral protamine
ommending global early screening. hagedorn and/or regular insulin, gly-
buride, or metformin). Patients were
Key findings seen every 2e4 weeks by their prenatal
There was no difference in umbilical cord C-peptide
90th percentile or neonatal provider (weekly after 36 weeks gesta-
fat mass between treatment groups. There were no differences in secondary tion), and their blood glucose values
outcomes that included maternal weight gain or diagnosis of gestational diabetes were sent to the CDE weekly for evalu-
mellitus. ation and medication titration for the
duration of the pregnancy.
What does this add to what is known? Differing from the usual instruction
There are no significant improvements in perinatal outcomes when women with sheet of foods to be avoided in all preg-
hyperglycemia are treated in early pregnancy. nancies, women who were assigned
randomly to the third-trimester group
additionally received a handout on a
balanced diet in pregnancy14 on enroll-
redated with ultrasound scans if early pregnancy (defined as after 15 ment in the trial. These women received
discordant from last menstrual period weeks gestation). routine prenatal care until 28 weeks
per the American College of Obstetri- gestation, by which time their interven-
cians and Gynecologists criteria.10 Per Study design and protocol tion was identical to the early pregnancy
protocol from California Sweet Success All eligible patients were contacted by group; they met with the CDE and were
Diabetes and Pregnancy Program the principal investigator and offered provided instruction regarding nutri-
(CDAPP), all pregnant patients had study enrollment. Patients who accepted tion, glycemic monitoring, and medica-
blood drawn for an HbA1c and a FPG participation in the study were contacted tion. Because of patient personal
in the first trimester (or as soon as the by the study coordinator, consented via schedules, this took place within a 2-
first prenatal visit was completed). an institutional review boardeapproved week window but after a glucose toler-
Patients with an abnormal result standard script, and randomly assigned/ ance test (GTT) was completed. Patients
(HbA1c
5.7% or FPG
92 mg/dL) enrolled. Randomization was performed were then seen every 2e4 weeks by their
were referred to the UCSD Diabetes in a 1:1 ratio (early pregnancy vs third- provider (weekly after 36 weeks gesta-
and Pregnancy Program (DAPP) by trimester group), and allocation tion), and their blood glucose values
their primary providers (medical doc- concealment was assured with the use were sent to the CDE weekly for evalu-
tor or certified nurse-midwife). of sequentially numbered opaque ation and medication titration for the
Women who met inclusion for the sealed envelopes in standard fashion.11 duration of the pregnancy.
study were identified by the DAPP- The study was not blinded to either From 24e28 weeks gestation, women
certified diabetic educators (CDEs), patient or study team. Written consent in both the early pregnancy and third-
and the principal investigator was was obtained at the next appointment trimester groups underwent a blinded
notified. Inclusion criteria for the (within 1 month of oral consent). (to patient, all providers, and all re-
study were (1) HbA1c 5.7e6.4% and/ Patients in both randomized searchers until the conclusion of the
or FPG 92e125 mg/dL, (2) pregnant controlled trial (RCT) arms received the study) 75-g, 2-hour GTT for research
women age
18 years, (3) singleton same intervention and treatment; what purposes and not for clinical use. This
pregnancy, and (4) planned prenatal differed was the gestational age at the was performed unless the patient had a
care and delivery at UCSD. Exclusion initiation of the intervention. history of gastric bypass surgery (bar-
criteria were (1) preexisting diabetes Patients in the early pregnancy group iatric patients were eligible for inclusion
mellitus or diabetes mellitus diagnosed immediately met with a CDE where they but did not participate in the GTT
in the first trimester by HbA1c of received education on monitoring their portion of the study). Participants had

6.5% or a FPG of
126 mg/dL, (2) diet, carbohydrate intake (goal; 15-g their weight measured at each prenatal
multiple gestations, and (3) blood breakfast, 30- to 45-g lunch/dinner, visit, had ultrasound scans for anatomy
drawn for HbA1c and FPG outside of and 15-g snacks between meals and at at 18e20 weeks gestation, growth

2 AJOG MFM MONTH 2019

 OBSTETRICS Original Research

ultrasound scans at 30 and 36 weeks

FIGURE 1
gestation, and twice weekly antenatal
Hyperglycemia in patient population
testing at 34e36 weeks. Timing of de-
livery was at the discretion of their pri-
A mary provider, but all patients were
scheduled for delivery by 41 weeks
gestation.

Outcomes
The primary outcome of the study was
an umbilical cord C-peptide >90th
percentile that was obtained at the time
of delivery. The blood was processed
onsite, and the serum was analyzed
offsite by quantitative chemilumines-
cent immunoassay (ARUP, Salt Lake
City, UT). The primary outcome was
fetal hyperinsulinemia; thus, as in the
HAPO study, C-peptide was used (as
opposed to insulin) because insulin and
C-peptide are secreted in a 1:1 ratio.
Additionally, this marker of fetal b-cell
function is not affected by hemolysis
during processing.3,15 Secondary
neonatal outcomes included fat
mass calculation, birthweight, and mac-
rosomia (defined as birthweight

4500 g). Within 2 days of delivery,
clinical research coordinators measured
anthropometric data (weight, length,
B and flank skinfold thickness) on the
neonates, based on the technique
described by Catalano et al.16 Also
similar to HAPO, research coordinators
and the authors (H.A.R. and G.A.R.)
underwent training by Dr Patrick Cata-
lano’s staff in reliably and validly
obtaining these measurements. Fat mass
was calculated with the use of a previ-
ously described regression model.16
Maternal secondary outcomes were
maternal GWG, proportion of women
who met diagnosis of GDM by GTT,
proportion of women who required
medications for glycemic control, and
mode of delivery. The initial body mass
index was calculated by weight at the first
prenatal visit and height. Weight gain
was calculated as final weight on

=
Frequency of A, abnormal hemoglobin A1c
values and B, fasting plasma glucose values.
FPG, fasting plasma glucose; HbA1c, hemoglobin A1c.
Roeder et al. Early pregnancy hyperglycemia RCT. AJOG
MFM 2019.

MONTH 2019 AJOG MFM 3

Original Research OBSTETRICS
FIGURE 2
Overview of sample enrollment and retention
6,066 HbA1c and/
or FPG reviewed
463 ELIGIBLE
and approached
N=202 enrolled
and randomized
N=99 Allocated to N=103 Allocated
FIRST THIRD
17 Early Exit 28 Early Exit
TRIMESTER TRIMESTER
TREATMENT TREATMENT
N=82 N=75
FIRST THIRD
TRIMESTER TRIMESTER
subject data subject data
analyzed analyzed
18 C-Peptide 64 C-Peptide 56 C-Peptide 19 C-Peptide
Not Collected collected/analyzed collected/analyzed Not Collected
The determination of eligibility from the overall population and breakdown of enrollment, random-
ization, and subjects available for analysis.
Roeder et al. Early pregnancy hyperglycemia RCT. AJOG MFM 2019.
admission to labor and delivery minus which 14% and 32%, respectively, of the
weight at the initial prenatal visit. The women had C-peptide elevations of
proportion of women with appropriate
90th percentile. With these assump-
GWG based on Institute of Medicine tions, 100 subjects per group would need
(IOM) guidelines by initial body mass to be enrolled to have at least 80% power
index was ascertained.17 After study to detect a difference between 14% and
completion, women were given a diag- 32% in the 2 groups at a .05 significance
nosis of GDM based on an abnormal level. Additionally, with 100 subjects per
blinded GTT determined by IADPSG group, we would have adequate power
criteria (FPG
92 mg/dL, 1-hour value (at least 80%) to detect a medium stan-

180 mg/dL, or a 2-hour value
153 dardized effect size (Cohen’s d¼0.5) on
mg/dL).8 the 2-sample comparison of the neonatal
fat mass.18 This power was computed at
Sample size estimation the significance level of .01 to adjust for
Given the lack of a specific interventional multiple comparisons. The target num-
trial that compared perinatal outcomes ber of subjects in each group was to be
in pregnant women with hyperglycemia, oversampled by 20% to control for
expected estimates based on the data missing data. Thus, the study goal was to
from the HAPO trial were used to power recruit and enroll 120 women per group
the study.3 We extrapolated that women (total, 240 participants). Finally, with the
in the early pregnancy group would be sample size of 100 subjects per group, we
similar to “Glucose Category 5” and that would have adequate power (at least
those in the third-trimester group would 80%) to detect an increase in the pro-
be similar to “Glucose Category 7,” in portion of women who adhered to IOM
4 AJOG MFM MONTH 2019
guidelines for GWG from 10e20% at a
.025 significance level.
Data safety and monitoring
An independent Data Safety and Moni-
toring Board periodically reviewed
enrollment numbers and whether any
adverse outcomes had occurred. When
just under one-half of the primary
outcome data had been collected, an
interim analysis was performed. The ef-
fect sizes were observed with the
enrollment at that point, and the power
was computed for the originally pro-
posed sample size of 240 participants,
with the use of the observed effect sizes.
It was deemed by the Data Safety and
Monitoring Board that, if the power was
inadequate (even without changing the
p-value as a penalty adjustment), the
study would be deemed futile and sub-
sequently terminated.
Statistical analysis
Statistical analyses were performed based
on intention-to-treat analysis with R
(version 3.3.1). Differences between early
pregnancy and third-trimester groups
were assessed with a 2-sample test (t-test
or Wilcoxon-Mann-Whitney, depending
on the distribution of the measure) in the
case of continuous measures, and a chi-
square test in the case of binary mea-
sures. A 2-sided probability value that
reached .05 indicated statistical signifi-
cance. Because the analysis of secondary
outcomes was considered largely explor-
atory, no adjustment for multiple com-
parisons was applied.
Results
From July 2013 to November 2015, 6066
women presented for obstetric care at
UCSD. Of these, 463 women (7.6%) were
identified as eligible for the trial based on
their HbA1c and/or FPG and were
approached regarding enrollment. The
median (interquartile range) gestational
age at testing for HbA1c and FPG was
10þ0 (8þ3, 11þ5) weeks and 10þ6
(9þ0, 11þ5) weeks, respectively, and
there were no differences between groups.
Of the 463 eligible patients, 202
women (43.7%) were enrolled, con-
sented, and randomized. Of the 202
women who enrolled, 137 met eligibility
 OBSTETRICS Original Research

criteria based on an HbA1c of 5.7-6.4%

TABLE 1
(Figure 1, A), 41 had an FPG of 92e125
Baseline patient characteristics
mg/dL (Figure 1, B), and 24 had both an
elevated HbA1c and FPG. Ninety-nine Overall Early pregnancy Third trimester P
women were allocated to early preg- Characteristic (N¼157) (n¼82) (n¼75) value
nancy treatment; 17 of the women exited Age at consent, ya 32.94.6 32.75.1 33.04.1 .78
early from the trial. One hundred three
Race, n (%) .26
women were allocated to third-trimester
treatment; 28 of the women exited early. Asian 19 (12) 8 (10) 11 (15)
The reasons for the early exits included African American 10 (6) 8 (8) 2 (3)
first- or second-trimester miscarriage White 85 (54) 45 (55) 40 (53)
(10 women), transfer of care (15
Other 43 (28) 21 (27) 22 (29)
women), refusal of written consent (6
women), and dissatisfaction with Ethnicity, n (%) .84
randomization group assignment (14 Hispanic 32 (20) 16 (20) 16 (21)
women). Non-Hispanic 125 (80) 66 (80) 59 (79)
At the time of the interim analysis, the 2a
Body mass index, kg/m 27.67.6 28.18.7 27.16.3 .73
total number of C-peptide samples that
were collected was 43% of the calculated Body mass index category, .42
n (%)
sample size. C-peptide data were avail-
able on 104 neonates; 1.8% of the early Underweight 3 (2.0) 2 (2.4) 1 (1.3)
pregnancy neonates and 6% of third- Normal 60 (38.2) 28 (34.1) 32 (42.7)
trimester neonates had a C-peptide Overweight 49 (31.2) 30 (36.6) 19 (25.3)
level at >90th percentile. Assuming 240
Obese 45 (28.6) 22 (26.9) 23 (30.7)
total enrolled subjects (120 per group),
a
there was 30% power to detect a differ- Weight at first prenatal visit, lb 163.144.0 166.247.9 159.739.4 .47
ence between these percentages with the Gravida, median 2 (1, 4) 2 (1, 3) 2 (2, 4) .32
use of the Fisher’s Exact Test. To detect a (interquartile range)
difference of 1.8e6% in 2 groups of Parity, median 1 (0, 1) 1 (0, 1) 1 (0, 1.5) .1
equal size, a total sample size of 700 (interquartile range)
women (350 per group) would have Family history diabetes 82 (52) 48 (59) 34 (45) .11
been required for 80% power. Because of mellitus, n (%)
this low enrollment, the Data Safety and
Personal history of gestational 12 (8) 8 (10) 4 (5) .37
Monitoring Board recommended stop- diabetes mellitus, n (%)
ping the trial early. Patients who were a
Data are given as meanstandard deviation.
still pregnant at the time of the interim Roeder et al. Early pregnancy hyperglycemia RCT. AJOG MFM 2019.
analysis remained enrolled for collection
of C-peptide at delivery.
At the time of the final analysis, there The primary outcome was an um- the groups; 31.0% and 27.0% of the
were 82 women (57 with abnormal bilical cord C-peptide >90th percentile; women had cesarean deliveries,
HbA1c, 12 with abnormal FPG, and 13 5 of the 125 cord blood samples that respectively (P¼.64).
with both abnormal HbA1c and FPG) in were collected reached this threshold. With regards to maternal outcomes,
the early pregnancy group and 75 There were no differences between early women who were enrolled in the study
women (60 with abnormal HbA1c, 5 pregnancy and third-trimester groups gained 23.011.9 lbs, and there were no
with abnormal FPG, and 10 with both (1 [1.5%] vs 4 [6.7%]; P¼.19). Like- differences in weight gain groups
abnormal HbA1c and FPG) in the third- wise, the meanstandard deviation C- (22.612.9 vs 23.911.2 lbs, respec-
trimester group with data available for peptide did not differ between groups tively; P¼.88; Table 3). There were also
analysis. Because some cord blood col- (0.80.35 vs 0.90.72 ng/mL; P¼.71). no differences in the number of women
lections were missed at the time of de- In the 119 neonates with anthropo- who met, adhered to, or exceeded the
livery, a total of 120 C-peptide samples metric data, the fat mass calculation IOM criteria for GWG based on initial
(64 early pregnancy and 56 third- was nearly identical between the early body mass index (Table 3).
trimester) were collected for calculation pregnancy and third-trimester groups Among the 102 participants who
of the primary outcome (Figure 2). (0.370.16 vs 0.360.17 kg; P¼.91) as completed the GTT, fewer women in the
The distribution of baseline patient were weight-for-length at birth, birth- early pregnancy group would have been
characteristics and demographics did weight, and macrosomia (Table 2). diagnosed with GDM based on the
not differ between groups (Table 1). Mode of delivery was similar between IADPSG criteria than women in the

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Original Research OBSTETRICS

TABLE 2
Primary and secondary neonatal outcomes
Outcome N Overall Early pregnancy Third trimester P value
Umbilical cord C-peptide >90th 120 5 (4) 1 (1.5) 4 (7.1) .19
percentile, n (%)
C-peptide, ng/mLa 120 0.850.55 0.800.35 0.900.72 .71
Neonatal fat mass, kga 119 0.370.16 0.370.16 0.360.17 .91
Weight-for-length World 122 25 (13, 50) 25 (15, 50) 25 (11, 63) .46
Health Organization percentage
at birth, median (interquartile range)
Birthweight, ga 122 3301851 3165445 34081130 .42
Macrosomia, n (%) 122 4 (3.2) 1 (1.5) 3 (5.0) .84
Cesarean delivery, n (%) 157 46 (29.3) 26 (31.0) 20 (27.0) .64
Gestational age at delivery, 157 39þ1 (38þ3, 40þ0) 39þ1 (38þ3, 39þ6) 39þ3 (38þ2, 40þ0) .97
weeksþdays, median (interquartile range)
a
Data are given as meanstandard deviation.
Roeder et al. Early pregnancy hyperglycemia RCT. AJOG MFM 2019.

third-trimester group; however, this did
not reach statistical significance (9 [.2%]
vs 15 [25.8%]; P¼.17). The GDM diag-
nosis did not differ among those who
had an abnormal HbA1c, FPG, or both.
Additionally, 28 women (34.2%) in the
early pregnancy group required either
oral medication or insulin vs 25 women
(33.0%) in the third-trimester group.
Thirty-one women (19.7%) used an oral
hypoglycemic agent, and 6 women
(3.8%) required insulin. There were no
differences in medication type between
those who were assigned randomly to
the early pregnancy and third-trimester
groups.
Comment
Principal findings
In this study of women with hypergly-
cemia who were assigned randomly to
early pregnancy intervention, there was
no significant reduction in the number
of infants born with umbilical cord C-
peptide at >90th percentile over those
who were treated in the third trimester.
Additionally, neonatal fat mass and
World Health Organization weight-for-
length percentiles were nearly identical
between groups. Secondary maternal
perinatal outcomes that included GWG
and adherence to IOM guidelines for
GWG were also similar. Twice as many
women in the third-trimester group
were diagnosed with GDM by a blinded
GTT when compared with early preg-
nancy group, but this was not statistically
significant.
Results
After the HAPO trial demonstrated the
continuum of adverse perinatal out-
comes with increasing glucose levels,3
researchers focused their attention on
early diagnosis of GDM to mitigate the
effects of hyperglycemia. HbA1c was
initially promising as a biomarker of
GDM and was selected by CDAPP to
channel patients into treatment. For

TABLE 3
Secondary maternal outcomes
Outcome N Overall Early pregnancy Third trimester P value
a
Gestational weight gain, lb 138 23.011.9 22.612.9 23.911.2 .88
Adherence to Institute of Medicine guidelines, n (%) 139 .75
Below 39 (28.1) 22 (30.6) 17 (25.4)
At 56 (40.2) 27 (37.6) 29 (43.2)
Exceed 44 (31.7) 23 (31.8) 21 (31.4)
Diagnosed with gestational diabetes mellitus 102 24 (23.5) 9 (14.2) 15 (25.8) .17
based on glucose tolerance test, n (%)
Required medication to control hyperglycemia, n (%) 157 53 (33.6) 28 (34.2) 25 (33.0) .84
a
Data are given as meanstandard deviation.
Roeder et al. Early pregnancy hyperglycemia RCT. AJOG MFM 2019.

6 AJOG MFM MONTH 2019

 OBSTETRICS Original Research

TABLE 4
Recent randomized controlled trials: early intervention of gestational diabetes mellitus or prediabetes
Secondary neonatal outcome(s)
Study Sample size, n Inclusion criteria Intervention analyzed
Osmundson 95 Hemoglobin A1c, 5.7e6.4%, Usual care vs treatment for Birthweight, birthweight
4000 g,
et al, 201620 at <14 wk gestation gestational diabetes mellitus umbilical cord C-peptide, umbilical cord
(diet, glucose monitoring, C-peptide >90th percentile
insulin, as needed) (no statistical differences)
Vinter et al, 304 in original Body mass index 30e45 kg/m2 Dietary counseling sessions Birthweight (z-score,
4000 g,
4500
201825 randomized controlled with gestational diabetes mellitus with dietitian (4 times) and g), large for gestational age, abdominal
trial; 90 with early (World Health Organization encouragement of moderate circumference, umbilical cord C-
gestational diabetes 2013 criteria) that was diagnosed physical activity (30e60 min peptide, and umbilical cord C-peptide
mellitus at 12e15 wk gestation daily)
90th percentile (no statistical
differences)
Harper et al, 954 Body mass index
30 kg/m2 Early 2-step screening at Macrosomia, neonatal hypoglycemia,
201926 presenting at <20 wk gestation 14e20 wk gestation, followed neonatal hyperbilirubinemia
by treatment if diagnosed vs (no statistical differences)
routine 2-step screening at
24e28 wk gestation
Roeder et al. Early pregnancy hyperglycemia RCT. AJOG MFM 2019.

example, a retrospective study by Fong
et al19 demonstrated a 3-fold increase in
the development of GDM if the HbA1c
was in the prediabetes (5.7e6.4%)
range; of note there were no differences
in mode of delivery, birthweight, or
macrosomia. However, in an RCT,
Osmundson et al20 found no significant
decrease in the diagnosis of GDM, um-
bilical cord C-peptide, or other neonatal
outcomes when instituting an interven-
tion at 14 weeks gestation in those pa-
tients with an elevated HbA1c. Our study
was consistent with these findings.
There was also enthusiasm for FPG as
a predictor of adverse outcomes, because
a recent secondary analysis of HAPO
demonstrated that FPG better predicted
high levels of umbilical cord C-peptide,
neonatal fat mass, birthweight, and body
fat than HbA1c.21 Riskin-Mashiah et al22
noted a higher risk of the development of
GDM and macrosomia in a retrospective
analysis of women with FPG
92 mg/dL
in the first trimester. Fadl et al23
randomly assigned patients with an
abnormal FPG in the third trimester
without GDM to diabetes mellitus
treatment or no intervention and noted a
significant reduction in large-for-
gestational-age infants (47e21%;
P<.05). Contrary to these findings, we
did not see a difference in outcomes;
however, only approximately 20% of our
population was diagnosed with hyper-
glycemia with FPG.
Strengths and limitations
To our knowledge, this is the first
clinical trial that randomly assigned
patients with hyperglycemia (diag-
nosed by HbA1c, FPG, or both) spe-
cifically to focus on neonatal
outcomes; it was designed to test the
2011 guidelines recommended by
CDAPP that affected the treatment of
almost 500,000 pregnant women per
year (the most of any state in the
nation).24 Despite this, the study may
not be strictly generalizable to other
protocols because the CDAPP algo-
rithm for diagnosis and management
of hyperglycemia is not currently
routine care per the American College
of Obstetricians and Gynecologists.
This RCT additionally may not be
generalizable because of the specific
breakdown of body mass index (ma-
jority nonobese), race, and ethnicity of
this San Diego university-based popu-
lation. A limitation to our findings is
that this RCT is underpowered to
detect a difference in umbilical cord C-
peptide at >90th percentile and GWG
between groups. During the interim
analysis, we calculated that 700 C-
peptide samples would be needed to
detect a statistically significant
difference between groups, which
would have extended the study for an
additional 5 years. Women who were
treated for GDM in the third trimester
who would have not failed a routine
glucose challenge could have biased
results towards the null hypothesis.
Furthermore, this group could have
been motivated particularly to alter
their diets and exercise on diagnosis of
hyperglycemia in early pregnancy.
Additionally, in consideration of the
ethics of withholding any intervention
until the third trimester, the decision
was made to provide basic information
on healthy eating in pregnancy to these
women who met a diagnostic criterion
for hyperglycemia. Last, inclusion of
women with hyperglycemia that was
diagnosed by either HbA1c or FPG
may have also biased the results to-
wards the null hypothesis.
Clinical and research implications
The optimal timing and diagnostic
modality of glucose intolerance in
pregnancy remains controversial. Once
a patient is diagnosed with GDM, she
undergoes a cascade of interventions
such as intensive glycemic control, ul-
trasound scans, antenatal testing, and
early delivery. In this cohort of patients,
approximately 26% would have failed a
2-hour GTT and been classified as

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Original Research OBSTETRICS
GDM. Intensive treatment in women
with hyperglycemia lowered the diag-
nosis of GDM by one-half, although
this did not reach statistical signifi-
cance. A larger, adequately powered
study is needed to address this ques-
tion. In an alternate approach, dietary
counseling alone may be sufficient in
this group until a definitive diagnosis of
GDM is made. Future studies should
aim to identify whether the subgroup of
women with hyperglycemia that was
diagnosed by an elevated FPG would
merit intensive early treatment to avoid
adverse outcomes. To date, no RCTs in
the realm of early GDM (or prediabe-
tes) diagnosis/treatment have been
published that are adequately powered
to assess differences in neonatal out-
comes such as birthweight, macro-
somia, umbilical cord C-peptide, or fat
mass; this is a needed area of study. The
few RCTs that have analyzed these dif-
ferences as secondary outcomes have
not demonstrated statistical significance
(Table 4).
Conclusion
In conclusion, this small study did not
demonstrate any significant improve-
ments in maternal or neonatal out-
comes in women with hyperglycemia
that was treated in early pregnancy over
those given third-trimester care.
Although this RCT was underpowered,
at this time, caution should be used in
the initiation of an intensive GDM
treatment protocol for women who are
diagnosed with more subtle glucose
intolerance. n Accessed December 10, 2017.
Acknowledgment
The authors thank Pamela O’Balle, RN, at Uni-
versity of California San Diego Health, for her
efforts in patient enrollment.
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Author and article information
From the Department of Reproductive Medicine, Division
of Perinatology, UC San Diego Health (Dr Roeder, Moore,
and Ramos), and the University of California, San Diego,
Computational and Applied Statistics Laboratory, San
Diego Supercomputing Center (Dr Gamst and Ms Wolf-
son), La Jolla, CA.
Received Nov. 26, 2018; revised Feb. 28, 2019;
accepted March 4, 2019.
Supported by The American Association of Obstetrics and
Gynecology Foundation and Society for Maternal-Fetal
Medicine Pregnancy Foundation and National Institutes of
Health/National Institute of Child Health and Human Devel-
opment R03: 5 R03 HD074826-02.
The authors report no conflict of interest.
Presented at as a poster at the Society for Maternal-
Fetal Medicine 37th Annual Meeting, Las Vegas, NV,
January 23e28, 2017.
Corresponding author: Hilary A Roeder, MD. alperth@
gmail.com
 OBSTETRICS Original Research

GLOSSARY
Anthropometry: The study of human body measurements, especially on a comparative basis
b-cell: An insulin-secreting pancreatic cell in the islets of Langerhans
C-peptide: A protein fragment that consists of 35 amino acid residues that are produced by enzymatic cleavage of proinsulin in the formation
of insulin
Chemiluminescent: Luminescence (emitting light) caused by a chemical reaction
Hemoglobin A1c: A stable glycoprotein formed when glucose binds to hemoglobin A in the blood; also, a test that measures the level of
hemoglobin A1c in the blood as a means of determining the average blood sugar concentrations for the preceding 2e3 months
Hyperglycemia: The presence of excess glucose in the blood
Immunoassay: A technique or test used to detect the presence or quantity of a substance (such as a protein) based on its capacity to act as
an antigen

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