CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 56, Number 4, 816–826
Insulin Analogues in
the Treatment of
Gestational Diabetes
Mellitus
CELESTE P. DURNWALD, MD
Department of Obstetrics and Gynecology, Division of Maternal
Fetal Medicine, The University of Pennsylvania, Philadelphia,
Pennsylvania
Abstract: Rapid-acting insulin analogues are the pre-
ferred choice for short-acting insulin due to their
superior pharmacologic profiles, leading to greater
flexibility and convenience of dosing. This has lead
to greater patient satisfaction and improved quality of
life. Clinical experience with rapid-acting insulin ana-
logues in pregnancy is increasing. Currently, there is
limited data available on the use of long-acting insulin
analogues in pregnancy. The focus of this review is to
discuss the role of insulin analogue therapy in the
treatment of the woman with gestational diabetes.
Key words: insulin analogues, gestational diabetes,
insulin lispro, insulin aspart, insulin glargine, insulin
detemir
Insulin Therapy in Women
With Gestational Diabetes
Mellitus (GDM)
The mainstay of GDM management is
dietary intervention. Approximately 50%
Correspondence: Celeste P. Durnwald, MD, Depart-
ment of Obstetrics and Gynecology, Division of Mater-
nal Fetal Medicine, The University of Pennsylvania,
Philadelphia, PA. E-mail: celeste.durnwald@uphs.
upenn.edu
The author declares that there is nothing to disclose.
CLINICAL OBSTETRICS AND GYNECOLOGY
816 | www.clinicalobgyn.com
r 2013, Lippincott Williams & Wilkins
of women will meet target values for glu-
cose control within the first 2 weeks of
dietary therapy, but only an additional
10% will achieve euglycemia by the fourth
week.1 Most clinicians use these general
guidelines to determine dietary failure as
to when to initiate pharmacologic therapy.
In the majority of GDM women, insulin
injections remain the gold standard for
treatment of those who fail to achieve
euglycemia on dietary management alone.
Institution of strict glycemic control has
been demonstrated to reduce neonatal
morbidity and mortality associated with
the diabetic pregnancy by decreasing the
incidence of stillbirth and macrosomia.2,3
Infants born to well-controlled diabetic
women also have fewer neonatal complica-
tions such as respiratory distress syndrome,
hypoglycemia, and hyperbilirubinemia.4
Insulin replacement is designed to mimic
the normal physiological release of insulin
by the pancreas. Women with GDM have
endogenous insulin production, but are
unable to mount the 2- to 3-fold increase
in insulin secretion required to maintain
/ VOLUME 56 / NUMBER 4 / DECEMBER 2013

euglycemia related to diabetogenic placen-
tal hormones. Insulin replacement is typi-
cally divided into basal and prandial
insulin. Basal insulin is designed to restrain
hepatic glucose production between meals
and in the fasting state. Prandial insulin
reduces glucose excursions associated with
feeding. Unlike women with preexisting
diabetes, insulin therapy for a woman with
GDM is often tailored to address the wom-
an’s individual glucose profile. The pre-
scribed insulin regimen may include as
few as 1 and as many as 4 insulin injections.
For example, in women with only post-
prandial glucose elevations, administration
of a prandial insulin would be most helpful.
In those with isolated fasting glucose
elevations, only basal insulin may be
necessary.
Insulin Analogues
Before the introduction of insulin ana-
logues, women with GDM were treated
with the standard insulins, neutral prot-
amine hagedorn (NPH), and regular insulin.
Basal insulin therapy for GDM should
continue to focus on the use of NPH insulin,
an intermediate-acting insulin. In many
cases, the greater insulin resistance associ-
ated with GDM and subsequent higher
insulin requirements cannot be adequately
treated with the long-acting insulin ana-
logues (LAIA), glargine and detemir, which
are peakless.
Conversely, rapid-acting insulin ana-
logues (RAIAs) are now the preferred
choice for prandial insulin dosing due to
their superior pharmacologic profiles, lead-
ing to greater flexibility and convenience of
dosing and thus, greater patient satisfac-
tion and improved quality of life. Over the
past few years, clinical experience with
insulin analogues in pregnancy has in-
creased dramatically. The majority of data
on insulin analogue therapy in pregnancy
pertains to the treatment of women with
preexisting diabetes, most specifically type
1 diabetes. However, the tenets of therapy
Insulin Analogues in GDM 817
and clinical experience with these newer
insulin formulations can be extrapolated
to the treatment of women with GDM.
Certain aspects of treatment, such as con-
genital malformation risk, are not as perti-
nent to GDM because the diagnosis occurs
beyond the period of organogenesis. How-
ever, transplacental passage, immuno-
genicity, and clinical efficacy in addition to
maternal and neonatal outcomes will be
discussed. The purpose of this article is to
review recent advances in insulin analogue
therapy as it pertains to the treatment of
women with GDM.
RAIAs
In the treatment of GDM, the mainstay of
prandial insulin has been regular insulin.
Regular insulin is formulated with the
addition of zinc atoms to the solution of
dimers which associate to form hexamers.
These hexamers diffuse slowly in the cir-
culation. Therefore, it has a slower onset
of action, peak action, and a longer dura-
tion of action than the newly developed
RAIAs. RAIAs are the result of recombi-
nant DNA technology. They quickly
dissociate into monomers in the subcuta-
neous tissue which allows for a shorter
onset of action, peak action, and duration
of action. Table 1 outlines the duration of
action of standard insulins and insulin
analogues. The pharmacokinetic and
pharmacodynamic properties of RAIAs
result in twice the maximum concentra-
tion of insulin in approximately half the
time compared with regular insulin
(Fig. 1), leading to less mean glucose
excursion in response to a food bolus
and less hypoglycemia between meals.
This superior drug profile allows maxi-
mum flexibility and convenience in dosing
resulting in greater patient satisfaction
and improved quality of life.5 Thus, in-
sulin analogues have emerged as the pre-
ferred choice for prandial insulin.
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818 Durnwald

TABLE 1. Pharmacologic Profiles of Standard Insulins and Insulin Analogues

Onset of Peak Duration of
Action Action Action (h)
Standard
Regular 30-60 min 2-3 h 8-10
Neutral protamine hagedorn 2-4 h 4-10 h 12-18
Rapid-acting analogues
Lispro 5-15 min 30-90 min 4-6
Aspart 5-15 min 30-90 min 4-6
Glulisine 5-15 min 30-90 min 4-6
Long-acting analogues
Glargine 2-4 h None 20-24
Detemir 3-4 h None 20

Insulin Lispro passage of these complexes with fetal

Insulin lispro, approved by the FDA in
1996, is the most studied insulin analogue
in pregnancy. Insulin lispro is the result of
a modification of the b-chain of human
insulin by inversion of lysine from posi-
tion B29 to B28 with proline from B28
to B29.
TRANSPLACENTAL PASSAGE/
IMMUNOGENICITY
Insulin can cross the placenta when it
complexes with immunoglobulins form-
ing an antigen-antibody complex. Pre-
vious studies have linked transplacental
overgrowth. Jovanovic et al6 first re-
ported on the immunologic effects and
placental transfer of insulin lispro in
women with GDM. In this study, anti-
insulin antibody levels were similar in
both groups, both at enrollment and de-
livery. Insulin lispro was undetectable in
the umbilical cord blood, including 4
women who received continuous intra-
venous administration of the drug during
labor. There were no cases of fetal anom-
aly, macrosomia, or neonatal hypoglyce-
mia. Two in vitro perfusion studies have
been published evaluating transfer of in-
sulin lispro across the human placenta.7,8

FIGURE 1. Pharmacodynamic profile of standard insulin and insulin analogues. NPH indicates
neutral protamine hagedorn.

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Boskovic evaluated placental transfer of
insulin lispro in term human placentas ex-
posed to a range of insulin lispro concen-
trations in which the maternal side of the
placenta was perfused with constant con-
centrations of the drug and the fetal circu-
lation was closed. Although there was a
possibility of transfer with concentrations
mimicking a single subcutaneous dose of
over 50 U which was maintained for over
60 minutes, there was no placental transfer
at single standard doses.7 Given the half-life
of insulin lispro, it is unlikely that this
physiological state could be reproduced in
the clinical setting. These findings were con-
firmed on a smaller scale by Holcberg et al.8
CONGENITAL MALFORMATIONS AND
FETAL OVERGROWTH
Most early diagnoses of GDM, especially
in the first trimester, represent women
with previously undiagnosed preexisting
diabetes. However, in the rare case of
early screening and diagnosis of GDM,
the topic of congenital malformation risk
will be discussed briefly. Over the past 10
years, multiple studies have been pub-
lished evaluating the use of insulin lispro
during pregnancy and the rate of congen-
ital malformations.9–12 The largest of
which was a multinational, multicenter
retrospective review of 496 women during
533 pregnancies resulting in the birth of
542 infants.12 Women with pre-GDM
who were treated with insulin lispro at
least 1 month before conception through
the first trimester of pregnancy were eval-
uated. More than 96% of the women
remained on insulin lispro for the remain-
der of the pregnancy. Glycemic control of
the population as measured by hemoglo-
bin A1c was 8.9% ± 4.2% at initial visit
with a decrease to 6.2% ± 2.4% in the
third trimester. Two dysmorphologists
reviewed all anomalies and found 27
(5.4%) of the offspring had major con-
genital malformations and 2 (0.4%) had
minor anomalies. This report is consistent
Insulin Analogues in GDM 819
with the previously published rates of
major congenital malformations of 2.1%
to 10.9% in women with preexisting dia-
betes requiring insulin therapy during
pregnancy. No study published to date
has reported a higher malformation rate
than the rates previously established for
the pregestational diabetic pregnancy.
Insulin lispro has a great homology
with insulin growth factor-1 (IGF-1) rais-
ing a concern for the possibility of in-
creased growth in fetuses of women
treated with this RAIA. With regard to
fetal overgrowth, similar rates of macro-
somia have been reported in pregnancies
treated with insulin lispro and regular
insulin.13–16 Table 2 shows the rates of
congenital malformations and fetal over-
growth in pregnancies treated with insulin
lispro, the majority of which are women
with pre-GDM. From the culmination of
these reports, insulin lispro is not associ-
ated with higher rates of congenital mal-
formations or fetal overgrowth compared
with standard insulin therapy.
CLINICAL EFFICACY
The superior pharmacologic profile of in-
sulin lispro including the shorter onset of
action and twice the maximal peak insulin
concentration compared with regular in-
sulin favor improved clinical outcomes
with lispro treatment. In the first study
of GDM women treated with insulin lis-
pro, areas under the curve for glucose,
insulin, and C-peptide were significantly
lower in the lispro group than those
treated with regular insulin, despite a sim-
ilar hemoglobin A1c level.6 Women
treated with lispro also experienced fewer
hypoglycemic episodes defined as symp-
toms and blood glucose concentration
<55%. Since this initial report, conflict-
ing results in women with pre-GDM have
been published with some analyses show-
ing no improvement in hemoglobin
A1c with the use of insulin lispro11,14
and others showing significantly lower
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820 Durnwald

TABLE 2. Insulin Lispro Treatment and Rates of Congenital Malformations and Fetal
Overgrowth
Mean A1c* Congenital Rate of
References N (%) Malformation (N) LGA (%)
Aydin et al13 27 Lispro 6.3 ± 2.2 0 7.4
59 Regular 7.1 ± 2.1 9 13.6
Lapolla et al16 72 Lispro 7.4 ± 1.7 3 55.1
298 Regular 7.4 ± 1.5 12 39.2
Durnwald and Landon15 58 Lispro 7.1 ± 2.2 2 32.8
49 Regular 8.3 ± 2.6 2 20.4
Cypryk et al14 25 Lispro 7.8 ± 1.4 0 43.5
46 Regular 7.5 ± 1.5 1 30.3
Masson et al10 71 Lispro 7.4 ± 1.7 4 35
Garg et al9 61 Lispro 7.2 ± 0.2 2 24
Persson et al11 16 Lispro 6.5 0 No difference
17 Regular 6.6 1

*First trimester or overall, if first trimester not reported.

predelivery A1c,5 without an increase in Rates of severe hypoglycemic episodes

hypoglycemic episodes. In the largest re-
port of insulin lispro use in pregestational
gravidas, hemoglobin A1c values im-
proved throughout gestation for an initial
mean of 8.9 ± 4.2 to 6.2 ± 2.4% in the
third trimester with a rate of hypoglycemic
episodes in each trimester (6.9, 6.6, 2.4,
respectively) similar to those seen with
regular insulin.12
In a prospective observational study of
58 pregestational women treated with in-
sulin lispro and 49 with regular insulin of
similar age, body mass index, and vascu-
lar complications, total insulin require-
ments in each trimester were lower in
women treated with insulin lispro.15 Yet,
the rate of increase in insulin between
trimesters was similar between groups.
Predelivery hemoglobin A1c was im-
proved in women treated with insulin
lispro compared with regular insulin
(5.9 ± 1.0 vs. 6.7 ± 1.3%, P = 0.02).
Conversely, a recent retrospective,
multicenter Italian study reported a sig-
nificant improvement in hemoglobin A1c
levels in the first trimester women treated
with insulin lispro compared with regular
insulin (6.7% ± 1.3% vs. 7.3% ± 1.4%,
P>0.001), but similar A1c levels in both
treatment groups in the third trimester.16
were similar.
Aydin and colleagues evaluated wom-
en with both pregestational and GDM
treated with insulin lispro and regular
insulin. Although mean hemoglobin A1c
during pregnancy for the entire popula-
tion was similar between groups, in the 53
women with GDM, those treated with
insulin lispro had lower hemoglobin A1c
levels compared with those treated with
regular insulin (5.25% ± 0.8% vs. 6.5% ±
2.0%, P = 0.013).13
MATERNAL/NEONATAL OUTCOMES
Two recent studies have evaluated maternal
obstetrical outcomes for women with pre-
existing diabetes undergoing lispro treat-
ment in pregnancy. Both studies have
shown similar rates of preeclampsia, pre-
term birth, and cesarean delivery in those
treated with insulin lispro compared with
regular insulin.15,16 Similarly, rates of
shoulder dystocia, neonatal intensive care
unit (NICU) admission, respiratory distress
syndrome, and neonatal hypoglycemia were
comparable.16 To date, only 1 study has
evaluated anthropometric characteristics
of newborns exposed to insulin lispro in
utero.17 This study enrolled 49 pregnant

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women with GDM, randomly assigned to
treatment with insulin lispro or regular in-
sulin, and 50 pregnant women with a nor-
mal glucose challenge test, matched for age,
parity, prepregnancy weight, and body mass
index. There was no difference between
groups in rate of LGA or SGA infants.
However, the rate of infants with a cranial-
thoracic circumference ratio between the
10th and 25th percentile was significantly
less in women treated with insulin lispro
compared with regular insulin (12% vs.
37.5%). This rate was comparable with the
rate seen in those with normal glucose tol-
erance (14%). In this study, 1-hour post-
prandial glucoses in the lispro group were
close to the physiological levels as demon-
strated by the normal glucose tolerance
women. In the regular insulin group, 1-hour
postprandial glucoses were higher than both
normal glucose tolerance women and those
GDM treated with lispro. This may have
contributed to the aberration in fetal growth
pattern seen in this group. Although inter-
esting, further investigation is needed on a
larger scale before any conclusive state-
ments can be made as to whether treatment
with insulin lispro is associated with any
measurable effect on anthropometric char-
acteristics of the newborn.
From the entirety of these studies, it can
be concluded that insulin lispro does not
offer a clear benefit for improved glycemic
control or less hypoglycemia. In contrast,
insulin lispro seems to have comparable
results to other short-acting insulins for
glycemic control in the pregnant diabetic
woman with the added advantage of im-
proved patient satisfaction likely related to
the flexibility in dosing. Greater patient
satisfaction may lead to improved compli-
ance with dosing regimens. Select perinatal
outcomes are similar in those women treated
with insulin lispro and regular insulin.
Insulin Aspart
Insulin aspart is formulated by substitut-
ing negatively charged aspartic acid for
Insulin Analogues in GDM 821
proline in position B28 on the b-chain of
human insulin. First approved in 1999,
there are a limited number of studies
addressing the use of insulin aspart in
pregnancy.
CLINICAL EFFICACY
In 2003, Pettitt et al18 were the first to
study the short-term clinical efficacy of
insulin aspart in comparison with regular
insulin in 15 women with GDM. Peak
insulin and glucose concentrations were
measured after eating a breakfast meal for
3 consecutive days: the first when no
insulin was given, the second with a ran-
dom assignment to either regular insulin
or insulin aspart, and the third when the
other insulin preparation was adminis-
tered. Peak insulin concentrations were
higher and peak glucose concentrations
were lower with both insulins compared
with no insulin. Glycemic control as
measured by the glucose concentration
under the curve above baseline was sig-
nificantly improved for insulin aspart
compared with no insulin. However, reg-
ular insulin did not show a significant
improvement compared with no insulin
administration. In a follow-up study of 27
gestational diabetic women randomized
to treatment with insulin aspart versus
regular insulin, a greater reduction in the
change from baseline average glucose val-
ues was seen in those treated with aspart
signifying better postprandial glycemic
control.19 However, there was a higher
number of hypoglycemic episodes (71%)
associated with aspart use, but no severe
hypoglycemic event requiring assistance
of another individual. Treatment with
aspart was associated with significantly
lower levels of C-peptide compared with
regular insulin, reflecting a lower demand
on b-cell function. This is likely attributed
to the higher peak insulin concentrations
that were achieved in this treatment
group. Insulin-specific antibody binding
was low in both groups (>1.5%).
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822 Durnwald
The largest evaluation of insulin aspart
use in pregnancy was an open-label,
randomized, parallel group study of 322
women with type 1 conducted at 63 sites in
18 countries.20 Study entry required a he-
moglobin A1c of r8% at pregnancy con-
firmation. In this study, the mean of the
difference between preprandial and post-
prandial plasma glucoses were lower for
those women receiving insulin aspart, de-
spite comparable hemoglobin A1c levels.
Although mean total daily insulin doses
were similar between groups, the mean
daily requirement of prandial insulin was
significantly lower in the insulin aspart
group. Rates of hypoglycemia were similar
between groups. Obstetrical outcomes such
as rates of preeclampsia, preterm labor,
and cesarean section were similar between
groups. In contrast, women treated with
insulin aspart reported significantly greater
satisfaction with their assigned treatment
as measured by the Diabetes Treatment
Satisfaction Questionnaire. In a second
report of these women, fetal and perinatal
outcomes were reported.21
CONGENITAL MALFORMATION
Rates of perinatal mortality were compa-
rable in pregnancies treated with insulin
aspart and regular insulin (14 vs. 22/1000
births, respectively). The frequency and
type of congenital malformations
were similar between groups (4.3% vs.
6.6%), with the majority involving the
cardiovascular system. Rates of LGA
and neonatal hypoglycemia were also
similar.
TRANSPLACENTAL PASSAGE/
IMMUNOGENICITY
In a subset of 95 women enrolled in the
randomized trial, analysis of maternal
and cord blood insulin antibody levels
demonstrated low levels of insulin-specif-
ic antibodies in both insulin groups both
at baseline and delivery.22 In addition,
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insulin aspart was undetectable in all cord
blood samples evaluated.
Although not as well studied as insulin
lispro, aspart use in pregnancy seems to be
comparable with regard to transplacental
passage, immunogenicity, and clinical ef-
ficacy. Reported data on fetal overgrowth,
maternal and perinatal outcomes are still
limited. It is expected that as clinical ex-
perience with insulin aspart increases, the
breadth of knowledge will continue to
expand.
Insulin Glulisine
Insulin glulisine is the newest RAIA ap-
proved for clinical use in the United States
in 2004. Insulin glulisine is formulated by
replacing asparagine at position B3 with
lysine and lysine at position B29 with
glutamic acid. It has a similar pharmaco-
logic action profile to both insulin lispro
and insulin aspart. Insulin glulisine has
been studied for use in both types 1 and 2
diabetes. There are currently no clinical
studies published addressing the use of
insulin glulisine in pregnancy.
LAIAs
The LAIAs are most commonly pre-
scribed using a once-daily dosing regi-
men, most commonly at night. The
relatively flat activity profile of glargine,
which is essentially peakless, is attractive
for women at risk for nocturnal hypogly-
cemia. These basal insulins are most often
used in women with type 1 diabetes. In
women with GDM, the nocturnal basal
rate of once-daily dosing is often inad-
equate to counteract the greater insulin
resistance and higher insulin requirements
during the daytime hours.
Insulin Glargine
Insulin glargine, created by adding 2 mol-
ecules of arginine to the C-terminal of the
b-chain of human insulin and replacing

aspartic acid with glycine in position A21,
was the first LAIA approved for clinical
use in 2001. These chemical changes lead
to a shift in the isoelectric point to a
neutral pH which makes the insulin mol-
ecule less soluble thereby allowing it to
form a depot which allows for slow re-
lease. The advantage of such a formula-
tion is a lengthy constant concentration of
insulin without a pronounced peak and
less hypoglycemia. This also allows for
once-daily dosing which may enhance
patient acceptance and satisfaction. How-
ever, it should be noted that insulin glar-
gine cannot be mixed with other insulin
formulations.
TRANSPLACENTAL PASSAGE
Results from human placental cotyledon
models of uncomplicated term pregnancies
have shown that there is no transplacental
crossage at maternal therapeutic concentra-
tions of insulin glargine.23 Transport across
the placenta was demonstrated at concen-
trations 1000-fold higher than clinically
therapeutic levels, yet there was a significant
difference in the rate of disappearance from
the maternal compartment compared with
the rate of appearance in the fetal compart-
ment. This suggests that the placenta may
sequester some amount of insulin glargine at
concentrations at this extreme level.
CLINICAL EFFICACY
Until 2008, experience with insulin glar-
gine in pregnancy was limited to case
reports of 1 to 6 patients each. Although
no conclusions can be made due to the
small number of women, glycemia was
comparable, if not improved with the
analogue, with no cases of congenital
malformation. Recent studies have pri-
marily evaluated the use of glargine in
pregnant women with type 1 diabetes
and are limited to retrospective reviews
and observational cohort studies. There
are no randomized trials comparing
Insulin Analogues in GDM 823
pregnancy outcomes of women assigned
to insulin glargine and NPH insulin.
Four studies have evaluated women
diagnosed with GDM treated with insulin
glargine.24–27 All of these studies evaluate
insulin glargine in a mixed population of
women with pregestational and GDM. In
a retrospective review of 114 pregnant
diabetic women, including 30 GDM,
there was no difference in gestational
age at delivery, birth weight, respiratory
distress syndrome, or admission to the
NICU in women treated with glargine
compared with NPH.26 In this analysis,
total dose of basal insulin was less in those
women treated with glargine. With regard
to maternal outcomes, rates of pree-
clampsia or cesarean delivery were similar
between groups. A larger retrospective
review in which 77% of the study popu-
lation was diagnosed with GDM eval-
uated the use of insulin glargine on select
maternal and neonatal outcomes.27 This
analysis reported a mean birth weight of
3142 ± 606 g for the study population,
with a 2% incidence of macrosomia in
GDM women. In a smaller retrospective
review of 112 women treated with glargine
compared with NPH, there was no sig-
nificant difference in maternal complica-
tions of preeclampsia, hypoglycemia, or
cesarean delivery between groups in the
59 GDM women studied.25 Rate of LGA
infants, Apgar scores, neonatal hypogly-
cemia, and hyperbilirubinemia, as well as
NICU admission were also similar be-
tween groups. Interestingly, this analysis
found fewer macrosomic infants and low-
er rates of neonatal hyperbilirubinemia in
the pregestational cohort treated with
glargine.
In a prospective observational cohort of
56 pregestational diabetic and 82 GDM
women, those with preexisting diabetes were
maintained on their preconception basal
insulin and those diagnosed with GDM
were randomly assigned to either glargine
or NPH. In the GDM women, those treated
with NPH had higher fasting glucose levels
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824 Durnwald
at 36 weeks gestation and required higher
doses of basal insulin compared with the
glargine group. Total lispro dose was similar
between groups. Those treated with NPH
had higher rates of hypertensive disorders of
pregnancy and more frequent hypoglyce-
mia. With regard to neonatal outcomes,
jaundice was more common in the NPH-
treated group, but no differences were noted
in rate of macrosomia or LGA, neonatal
hypoglycemia, respiratory distress syn-
drome, or 5-minute Apgar >7.
There has been concern raised about
the increased affinity to IGF-1 that is
demonstrated by insulin glargine com-
pared with human insulin with a potential
to stimulate fetal growth. The data that
exists in the current literature from pla-
cental cotyledon models23 and the studies
published do not demonstrate an increase
in the rate of LGA infants or fetal macro-
somia. Although a strictly GDM popula-
tion has not been studied, the risk of fetal
overgrowth and macrosomia are not
unique to abnormal glucose metabolism
of the GDM cohort.
Despite a clear benefit for better glyce-
mia and less hypoglycemia in the non-
pregnant diabetic women, current studies
are limited by small sample size, mixed
population of GDM, and pregestational
women studied and do not show a consis-
tent clinical benefit for the use of glargine
in the pregnant gravida. A randomized
controlled trial of insulin glargine and
NPH treatment would further elucidate
the perinatal outcomes of interest.
Insulin Detemir
Insulin detemir, approved in 2006, is a
LAIA that differs from human insulin by
the omission of the amino acid threonine
in position B30 and attachment of a C14
fatty acid chain to amino acid B29. In
contrast to other insulin analogues, insulin
detemir has a low affinity for the IGF-1
receptor (approximately 1/10 that of hu-
man insulin). In studies of nonpregnant
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diabetic women, insulin detemir has been
shown to have more consistent insulin
absorption compared with both insulin
glargine and NPH insulin.28 Compared
with insulin glargine, detemir is similarly
peakless but exhibits a slightly shorter
duration of action and therefore is dosed
every 12 hours in most diabetic individu-
als. Until recently, there were only 2 case
reports of 11 type 1 diabetic women
treated with insulin detemir in the precon-
ceptual period and continued throughout
the remainder of the pregnancy.29,30 All
women were maintained on this insulin
due to significant risk of nocturnal hypo-
glycemia. No adverse maternal effects or
neonatal effects were identified. There is
one randomized controlled trial compar-
ing the efficacy of insulin detemir with
NPH insulin in pregnant women with
Type 1 DM.31 In this trial, 152 women
were randomized to insulin detemir and
158 were given NPH insulin up to 12
months prior to pregnancy or within the
1st trimester. Hemoglobin A1c value at 36
weeks gestation, the primary outcome,
was similar between treatment groups
(6.27% detemir versus 6.33% NPH).
Although fasting plasma glucose levels at
both 24 and 36 weeks were lower in those
women treated with insulin detemir, the 8
point self monitored glucose profiles did
not differ. Further studies are needed to
adequately address efficacy and safety of
insulin detemir in pregnancy. No studies
have evaluated the use of insulin detemir
for the treatment of women with GDM.
Conclusions
Insulin lispro and insulin aspart are the
analogues most studied in pregnancy. Stud-
ies have consistently shown RAIAs to be
clinically effective, with insignificant placen-
tal transfer and low immunogenicity.
Although clinical experience in pregnancy
with LAIAs is increasing, significant gaps
remain in addressing their clinical use in
pregnancy. Further large-scale randomized

trials of glargine and detemir use in preg-
nancy are needed. However, the pharmaco-
dynamic profiles of the LAIAs make their
use impractical in women with GDM.
References
1. McFarland MB, Langer O, Conway DL, et al.
Dietary therapy for gestational diabetes: how
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