The British Journal of Diabetes & Vascular

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Metformin treatment for gestational diabetes

Steve L Hyer, Jyoti Balani, Antoinette Johnson and Hassan Shehata
British Journal of Diabetes & Vascular Disease 2009 9: 220
DOI: 10.1177/1474651409346767

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Achieving best Practice
Metformin treatment for gestational
diabetes
Steve L Hyer,1 Jyoti Balani,1 Antoinette Johnson,2 Hassan Shehata2
Abstract
T
he prevalence of gestational diabetes mellitus
(GDM) is rising as the pregnant population becomes
older and more obese. This is concerning because
GDM is associated with increased perinatal morbidity
such as macrosomia and shoulder dystocia, and the need
for instrumental delivery. In addition, the offspring of
GDM women have increased long-term risks of obesity
and type 2 diabetes. There is no doubt that treating
women with GDM improves pregnancy outcomes.
Conventionally this has been by diet and insulin. Although
effective, insulin increases appetite leading to weight
gain. It increases the risk of hypoglycaemia and needs to
be given by injection. There is also a substantial cost in
terms of time for teaching and educating patients.
Metformin offers a logical alternative to insulin in GDM,
by reducing insulin resistance. Recent trial evidence indi-
cates it is safe and effective. We describe our experience
with metformin in GDM and review the evidence.
Br J Diabetes Vasc Dis 2009;9:220-225
Key words: gestational diabetes, macrosomia, metformin
Introduction
Currently, the number of pregnancies complicated by type 2
diabetes and GDM exceed those affected by type 1 diabetes.1
Although women with GDM do not have an increased risk of
congenital malformations,2 the risk of macrosomia is the same
as for women with pre-existing diabetes. Macrosomia is associ-
ated with an increased risk of intrauterine death, birth trauma
(especially shoulder dystocia), Caesarean section and neonatal
hypoglycaemia. Furthermore, large for gestational age babies
are at increased risk of obesity, metabolic syndrome and type 2
diabetes later in life.3
The best possible management of these patients to achieve
optimal glucose control and consistently good neonatal
1
Department of Diabetes & Endocrinology, St Helier Hospital,
Carshalton, Surrey, UK.
2
Department of Maternal Medicine, Epsom & St Helier Hospital
University Hospitals NHS Trust, Carshalton, Surrey, UK.
Correspondence to: Dr Hassan Shehata
Department of Maternal Medicine, Epsom & St Helier Hospital University
Hospitals NHS Trust, Wrythe Lane, Carshalton, Surrey, SM5 1AA, UK.
Tel/Fax: +44 (0)20 8401 9928
E-mail: hassan.shehata@nhs.net
© The Author(s), 2009. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651409346767 220
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Abbreviations and acronyms
ACHOIS Australian Carbohydrate Intolerance Study in
­pregnant women
CI confidence interval
FDA Food and Drug Administration
FGR foetal growth restriction
GDM gestational diabetes mellitus
GI gastrointestinal
HBGM home blood glucose monitoring
HOMA Homeostasis Model Assessment
OGTT oral glucose tolerance test
MiG Metformin in Gestational Diabetes
PCOS polycystic ovary syndrome
RR risk ratio
­ utcomes is not yet established.4-5 Although insulin therapy is
o
highly effective, it has the disadvantages of needing to be given
by injection and causing weight gain. Furthermore, insulin does
not address the fundamental problem in these patients which
is insulin resistance. For this reason, very large doses of insulin
are often required. A safe and effective oral agent would be
welcomed by patients and their healthcare professionals.
Conventional therapy
In the landmark ACHOIS study, women with GDM (glucose,
fasting < 7.8 mmol/L; 2-h 7.8–11 mmol/L) during a 75 g OGTT
were randomised to intervention (diet and/or insulin) or routine
antenatal care as for patients without diabetes.6 Serious perina-
tal morbidity was reduced in the intervention group (n5490)
compared with controls (n5510) (1% vs. 4%; RR 0.32, 95% CI
0.14 – 0.73). No infants died in the intervention group, but
there were five deaths in the control group (p50.06, two-
tailed). Infants born to the intervention group were less likely
to be large for their gestational age (13% vs. 22%; adjusted
treatment effect 0.62, 95% CI 0.47–0.81). Although anxiety
scores were similar in both groups, those in the intervention
group were less likely to experience depression (8% vs. 17% of
controls). This study reinforces previous uncontrolled studies
that treatment for GDM reduces serious perinatal outcomes.
The decision to start insulin is based on maternal glycaemia
taking into account foetal growth characteristics. Postprandial
glucose testing is recommended to optimise glucose control and
reduce macrosomia.7 However, there is controversy regarding
the optimal timing of home glucose testing with some ­evidence
to suggest that aiming for 1-h post-meals values of < 7.6 mmol/L

results in less macrosomia than when the 2-h target (6.6 mmol/L)
is used, although the difference in macrosomia rates did not
reach statistical significance.8 The most useful foetal growth
parameter is foetal abdominal circumference; if the abdominal
circumference is > 95th centile or is crossing centiles on serial
scans, insulin therapy is considered.
Insulin given with meals and at bedtime (basal-bolus insulin) is
more effective than twice daily insulin regimens; if control is still
not adequate, insulin by continuous infusion pump can be consid-
ered if a pump service with adequate support is available locally.
Both Diabetes UK and the American Diabetes Association
urge caution with the use of the new insulin analogues in preg-
nancy until more evidence becomes available on their safety.
However, rapid acting insulin analogues are particularly suitable
for pregnancy because they reduce postprandial glucose peaks
and have a low risk of hypoglycaemia. In a trial of 322 pregnant
women with diabetes, post-breakfast glucose peaks were sig-
nificantly reduced by insulin aspart compared with conventional
human insulin with similar pregnancy outcomes.9 In the same
trial, insulin aspart reduced the risk of major maternal hypogly-
caemia by 28% and major nocturnal hypoglycaemia by 52% In
the USA, the FDA classifies both insulin aspart and insulin lispro
as category B risk for pregnancy.10 By contrast, data on the use
of long acting insulin analogues in pregnancy are limited and
these should be used only if the potential benefit justifies the
potential risk to the foetus (category C risk in pregnancy). The
Detemir and Pregnancy Trial will complete in 2010. Of the 240
participants, 187 have delivered with one perinatal death and
there appear to be no concerns.11
Why metformin?
Metformin improves insulin sensitivity and would be expected
therefore to improve glucose tolerance in pregnancy by reduc-
ing the physiological rise in insulin resistance that occurs during
pregnancy. Indeed clinical studies show a reduction in insulin
resistance as assessed by HOMA of 46% when metformin is
started before conception and continued during pregnancy.12
Metformin is widely used outside of pregnancy for type 2 dia-
betes as it has a low risk of causing hypoglycaemia and is not
associated with weight gain. Data for metformin use in type 2
diabetes during pregnancy are beginning to emerge.13,14 In a
retrospective review of 214 pregnancies in women with type 2
diabetes, metformin had been continued in 93 patients, 23 of
whom had taken it for the duration of the pregnancy until
term.15 Compared with controls, i.e. women in the same series
who had not taken metformin, outcome measures including
pre-eclampsia, perinatal loss and neonatal morbidity were
similar between the groups. Theoretically, stopping metformin
in order to plan a pregnancy may result in a greater teratogenic
risk if there is deterioration of glycaemic control.
There is a wealth of experience with metformin when used
to treat infertility in PCOS from which there is no evidence that
metformin is teratogenic.16,17 In these women, observational
studies have shown reduced miscarriage rates in the first tri-
mester.16 The rate of pre-eclampsia in women with PCOS con-
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 221
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Achieving best Practice
ceiving on metformin is not increased despite being older and
heavier than controls.18 Long-term data are also reassuring. At
18 months, growth and motor social development of offspring
of mothers conceiving and continuing on metformin is no dif-
ferent to control babies.19 Metformin offers the advantage of
being in a tablet form and is usually well tolerated.
The MiG study compared insulin treatment with metformin
in a prospective randomised multicentre trial.20 Perinatal
­morbidity was compared in the metformin (n5373) and insulin
(n5378) groups. In the metformin and insulin treatment arms,
composite neonatal morbidity was 32.0% vs. 32.2%, RR (95%
CI) 1.0 (0.80–1.23), p50.95 and rates of large for gestational
age were 19.3% vs. 18.6%, p50.83. There was no increase in
hypertensive complications. However, women with small for
gestational age infants, i.e. with evidence of FGR, were
excluded from the study. The trial investigators concluded that
perinatal complication rates are similar and metformin was
safe. Women using metformin gained an average 1.6 kg less
weight from enrolment to term compared with the insulin
group, and a questionnaire assessing the acceptability of treat-
ment indicated that most women would be happy to take
metformin again in subsequent pregnancies. Long-term data in
the offspring are being collected.
Experience in gestational diabetes
In 2007, the data safety monitoring committee for the MiG trial
reported no safety issues in 550 patients enrolled in the trial and
no changes in protocol were needed. Reassured by this informa-
tion, we began using metformin in women with GDM whose
glycaemic control was not adequate despite lifestyle and dietary
changes. We defined suboptimal control as more than three
HBGM readings outside of target range which at that time was
fasting blood glucose > 6 mmol/L (now > 5.5 mmol/L), 1-h post-
prandial blood glucose > 8 mmol/L, 2-h postprandial blood
­glucose > 7 mmol/L. Patients tested before breakfast and again
1 or 2 h after meals.
Patients were given a written information sheet which
clearly stated that metformin was unlicensed for use in preg-
nancy. Those patients unhappy to take metformin in pregnancy
were treated with insulin as previously. We initiated metformin
at 500 mg twice daily with food and the dose was titrated to
a maximum of 2,500  mg/day according to HBGM results,
­consistent with the MiG trial protocol. If glucose control was
still not obtained, insulin was added and the metformin contin-
ued. Patients were asked to return to clinic one week after any
dose escalation and kept in close contact with the diabetes
specialist nurse by telephone.
Patients attended the joint antenatal diabetes clinic and we
collected outcome data prospectively during the clinics. We
subsequently audited the first 45 patients with GDM treated
with metformin and compared the data with 35 patients
attending the clinic in the previous year, matched for baseline
characteristics (weight, age, ethnicity) whose records had been
extracted from the diabetes register and who had been treated
with insulin.
Achieving best Practice

The mean age of the GDM patients was 31.4 years, 44% or impaired glucose tolerance discovered during pregnancy and
were Asian, 7% black, and the mean body mass index was 30.3. shown by a persistently abnormal OGTT post-partum. Mean
Mean baseline glycated haemoglobin A1C was 5.5% (4.5–7.2%). responses to metformin are shown in figure 2.
The responses to metformin are shown in figures 1 and 2. Baby growth and hence birth weight will be influenced
Some patients showed a rapid improvement within 1 week both by the severity of hyperglycaemia and its duration. Mean
(e.g. M.K.; figure 1). Others required higher doses or additional baby weight increases with gestation at which metformin is
basal insulin (figure 1). In a small number of patients there was commenced until 36 weeks with a small decrease after this
a poor response usually indicating pre-existing type 2 diabetes time. It is important that intensive monitoring occurs as soon as

Figure 1.   Illustrative case histories

Patient M.K.
100%
90%
High blood glucose readings

MF1500
80%
70%
60%
50%
40%
30%
20%
10%
0%
33 34 35 36 37
Weeks of gestation
Baby weight = 3,540 g

Key: MF 5 metformin

Figure 2.   Mean response to metformin (MF)

Patient S.S.
100%
90%
80%
High blood sugar readings

MF1500
70%
60%
50%
40%
MF 2000
30%
20%
10%
0%
24 25 26 27 28 29 30 31 32 33 34 35 36
Weeks of gestation
Baby weight = 3,196 g

Key: MF = metformin

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 Achieving best Practice

Figure 3.   Mean maternal weight gain in metformin (MF) only versus insulin-treated patients with gestational diabetes

Patient Z.H.
100%

90%

High blood glucose readings

80%

70%

60%

50%

40%
MF 1500
30%
MF 2000 MF 2500
20%

10%

0%
35 36 37 38
Week of gestation
Baby Weight = 4,389 g
Abnormal GTT
Key: MF = metformin

GDM is detected and drug treatment initiated immediately insulin-treated controls (p50.04; figure 3). Mean baby weight
after dietary measures fail. was reduced (3,491  g vs. 3,541  g) but this did not achieve
During pregnancy there is enhanced elimination of met- ­statistical significance (figure 4). We have since studied 100
formin, which might suggest a need to adjust doses especially metformin-treated GDM patients compared with 100 insulin-
in late pregnancy.21 Metformin is stopped after delivery and treated controls and confirmed the significant difference in
OGTT repeated at 6 weeks post-partum. In fact, metformin can maternal weight gain from enrolment to term.23,24 Although
be used safely during breastfeeding.22 baby weights were not significantly different, birth weight cen-
tile for gestational age was significantly reduced in the metfor-
Comparison with insulin min group using specific software that adjusts for maternal
In our early series, we found significantly less maternal weight height, maternal weight at booking, parity, ethnic group and
gain in the group treated with metformin compared with sex of baby.25

Figure 4.   Mean baby weight (g) and week of gestation at which metformin (MF) treatment commenced

Patient S.G.
100%
90%
High blood glucose readings

80%
70%
60%
MF + Insulin
50%
40%
30% MF 2000
MF 1000
20%
10%
0%
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
Weeks of gestation
Baby weight = 2,952 g
Key: MF = metformin

THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 223

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Achieving best Practice

Figure 5.   Neonatal outcomes in metformin-treated and insulin-treated groups

100

Mean percentage of high blood sugar

90
80
70
60
50 43%
40
30
20 12.6% 3.7% 5.5% 2.9% 3.7%
10
0
nt

eks

s
eks

eks

eks
tme

eek
we

we

we

we

0w
trea

1-2

3-4

5-6

7-8

9-1
Pre

Data for neonatal outcomes are shown in figure 5. We e­ uglycaemia (see figure 6 for treatment protocol). This has
found a significant reduction in the incidence of neonatal resulted in a considerable easing of the workload burden for
­jaundice (defined as requiring phototherapy) in the metformin- the diabetes specialist nurses who previously had large num-
treated group. This is probably accounted for by the increased bers of women at each clinic for initiation of insulin treat-
rate of prematurity in the insulin-treated group and their ment. Our neonatologists have reported a significant decline
increased frequency of admissions to the special care baby unit. in numbers of babies with hypoglycaemia and admissions to
Our recent data from the larger series confirm this finding. the special care baby unit. Our approach is in line with recent
Not all patients can tolerate metformin because of unpleas- NICE guidance (2008)26 for diabetes in pregnancy which
ant GI side-effects even at the lowest doses, despite being ­recommends that women with diabetes may be advised to
advised to take the drug with food and up-titration of the use metformin as an adjunct or alternative to insulin when
dose. In addition some patients on reflection decide not to take the likely benefits from improved glycaemic control outweigh
it for fear of adverse effects on the baby. We found five of the the potential for harm.
45 patients in our original series stopped metformin because of
fear of harm to their baby and one patient stopped because of
intolerable GI upset. Supplementary insulin was needed in Figure 6.  Treatment protocol for gestation diabetes mellitus (GDM)
addition to metformin in four patients to achieve glucose
­targets. In our larger series of 127 patients, 3.9% of women 3,692
discontinued metformin because of GI side-effects and 10% 3,700
required additional insulin. 3,600 3,540
This compares with data from the MiG trial in which 1.9% 3,500 3,412
of patients stopped because of adverse effects and 46% of 3,395
Baby weight

3,400
patients required insulin added to the metformin. The differ-
ence in the need for insulin may reflect the tighter glycaemic 3,300
3,196
targets used in MiG (fasting < 5.4  mmol/L, 1-h postprandial 3,200
< 6.7 mmol/L). 3,100

3,000
Conclusions
2,900
On the basis of randomised controlled data and our own 24-26 27-29 30-32 33-35 36-38
experience we now offer all GDM women metformin where Week of gestation

lifestyle measures are inadequate to achieve or maintain

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Key messages
● In our experience, compared with insulin, metformin
results in:
less macrosomia
fewer admissions to a special care baby unit
reduced incidence of neonatal jaundice and
­hypoglycaemia
● Metformin:
is a safe alternative to insulin when dietary and
­lifestyle measures are insufficient to achieve target
glucose levels
offers several advantages over insulin in the
­management of gestational diabetes including less
weight gain, no risk of hypoglycaemia, oral therapy,
and reduced costs including specialist nurse time
can be combined with basal insulin when fasting
glucose levels remain high
should not be used if FGR is present
is not licensed for use in pregnancy
The majority of our patients tolerate metformin and achieve
good control, avoiding the need for injections. To date we have
no experience with modified release metformin in pregnancy
which may be better tolerated. There remain occasional
patients who are unhappy about taking metformin in preg-
nancy and insulin alone (usually prandial insulin aspart and
basal isophane insulin) is used for this group. For women with
high fasting home glucose values (> 5.6 mmol/L) despite total
daily doses of 2,500  mg metformin, we add in basal insulin
such as isophane insulin. It is important to be vigilant for any
evidence of FGR. We do not use metformin if FGR is present
and if metformin has already been started, recommend discon-
tinuing it. Vigilance is also required for maternal changes, such
as development of a hypoxic state or reduced renal function,
which would warrant discontinuation of ­metformin therapy.
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