DOI: 10.1111/1471-0528.

12964
www.bjog.org

A follow-up of a randomised study of metformin

and insulin in gestational diabetes mellitus:
growth and development of the children at the
age of 18 months
H Ijäs,a M Vääräsmäki,a T Saarela,b R Keravuo,c T Raudaskoskia
a
Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulu, Finland b Department of Paediatrics, Oulu University Hospital,
Oulu, Finland c Department of Obstetrics and Gynaecology, Kainuu Central Hospital, Kajaani, Finland
Correspondence: H Ijäs, Department of Obstetrics and Gynecology, Oulu University Hospital, PO Box 23, Oulu FIN-90029 OYS, Finland.
Email hilkka.ijas@ppshp.fi

Accepted 12 May 2014. Published Online 16 July 2014.

Objective To compare the growth and development of children
born to mothers with gestational diabetes mellitus (GDM)
requiring pharmacological treatment, and randomised to
treatment with metformin or insulin.
Design Follow-up of a randomised controlled trial (RCT)
comparing metformin and insulin treatment of GDM.
Setting Data were gathered during routine visits to child welfare
clinics at the ages of 6, 12, and 18 months, including weight and
height measurements, and assessment of motor, social, and
linguistic development.
Sample The children of mothers with GDM randomised to
metformin (n = 47) or insulin (n = 50) treatment during
pregnancy.
Methods Data were collected from the structured questionnaire
filled in at the child welfare clinics.
Main outcome measures The growth and development of the
children until the age of 18 months.
Results Children exposed to metformin were significantly heavier
(10.47 versus 9.85 kg, 95% CI 0.04–1.20) at the age of 12 months
and taller and heavier (83.9 vs 82.2 cm, 95% CI 0.23–3.03, 12.05
vs 11.32 kg, 95% CI 0.04–1.43) at the age of 18 months. The
mean ponderal index (PI) did not differ significantly. The motor,
social, or linguistic development evaluated at the age of
18 months did not differ between the groups.
Conclusions Children prenatally exposed to metformin were
heavier at the 12 months measurements and taller and heavier at
the 18 months measurements than those exposed to insulin, but
their body composition defined by PI did not differ. Over the
short term, metformin does not seem to be harmful with regards
to early motor, linguistic, or social development.
Keywords Gestational diabetes mellitus, metformin, offspring.
Linked article This article is commented on by Thom EA. To
view this mini commentary visit http://dx.doi.org/10.1111/
1471-0528.13092.

Please cite this paper as: Ijäs H, Vääräsmäki M, Saarela T, Keravuo R, Raudaskoski T. A follow-up of a randomised study of metformin and insulin in
gestational diabetes mellitus: growth and development of the children at the age of 18 months. BJOG 2014; DOI: 10.1111/1471-0528.12964.

dard in the management of GDM, today, oral agents are

Introduction
The incidence of gestational diabetes mellitus (GDM) seems
to be increasing worldwide, in parallel with increasing rates
of obesity and sedentary lifestyle.1 In 2012, 12.5% of all preg-
nant women in Finland were found to have GDM and needed
special counselling and follow-up in maternity care.2 Dietary
intervention is the cornerstone in the treatment of GDM. In
Finland, 13% of women with GDM need medical therapy to
reach normoglycaemia as well as intensive follow-up in the
delivery hospital.2 Although insulin has been the gold stan-
increasingly considered as treatment alternatives. Recently,
six randomised controlled studies (RCTs) comparing metfor-
min and insulin treatments in GDM have been published.
According to these studies, metformin has not been associ-
ated with a higher incidence of adverse pregnancy or perina-
tal outcome when compared with insulin treatment.3–8
Metformin crosses the placenta freely, and fetal serum
concentrations are comparable with maternal values.9–11 It
has not been found to be teratogenic.12,13 Although
exposure to antenatal metformin does not seem to be

ª 2014 Royal College of Obstetricians and Gynaecologists 1

 Ijäs et al.
harmful for the offspring over the short term, little is
known about its long-term effects.
The Metformin in Gestational diabetes (MiG) study is
the largest randomised trial comparing metformin with
insulin treatment in GDM.3 The MiG Offspring Follow-Up
(MiG TOFU) study at 2 years of age demonstrated no dif-
ference in the overall growth between the children exposed
to either metformin or insulin in utero, although there was
a tendency to a more favourable pattern of fat distribution
in the children exposed to metformin.14
We previously conducted an RCT to compare metformin
and insulin as a pharmacological treatment of GDM.4 In
our study these treatments were found to be equal in the
prevention of fetal macrosomy, and the incidence of
short-term perinatal adverse events did not differ between
the study groups. The aim of the present study was to
compare the growth as well as the motor, social, and lin-
guistic development of the children prenatally exposed to
metformin or insulin up to the age of 18 months.
Methods
Our RCT study protocol and pregnancy outcome has been
described in detail previously.4 Briefly, 100 pregnant
women with GDM were randomised to receive either met-
formin (n = 50) or insulin (n = 50) therapy when diet
turned out to be insufficient to achieve normoglycaemia. In
the metformin group, two women withdrew from the study
shortly after randomisation, and one woman was excluded
because of abnormal liver function tests. Out of the group
of 47 in the metformin group, 15 (32%) needed supple-
mental insulin to achieve normoglycaemia. One woman in
the study population was of Asian origin, and the rest were
white. The study was carried out in the tertiary-level Oulu
University Hospital, Oulu, and secondary-level Kainuu
Central Hospital, Kajaani. The study was approved by the
Ethics Committee of Northern Ostrobothnia Hospital Dis-
trict and the Finnish National Agency of Medicines.
In Finland, free primary health care is offered to all
mothers and children at maternal and child welfare clinics,
with practically 100% attendance. Until the age of 6 years,
children are offered a schedule of check-ups, where stan-
dardised weight and height measurements are performed
and the stage of development of the child is evaluated by a
general practitioner and/or a nurse specially trained in
child health care.
The mothers of this study returned a questionnaire
designed by a paediatrician (T. Saarela). The questionnaire
was filled in by a specially trained nurse at the child welfare
clinic at the check-up at 18 months of age, including data
on height, weight, and head circumference, as well as
motor, social, and linquistic development, examined by the
doctor. The nurse also filled in data on height, weight, and
2 ª 2014 Royal College of Obstetricians and Gynaecologists
head circumference at the ages of 6 and 12 months from
the clinic records. The check-up at 18 months of age
included: an examination of vision, with an examination of
corneal light reflex and red reflex using an ophthalmo-
scope; Hirschberg and cover tests, in the assessment of stra-
bismus; and pinch grip, which tests hand–eye coordination.
The evaluation of motor functions included the capability
of standing and walking without support, normal pinch
grip, and coordination of upper limbs. The social, emo-
tional, and language development of the child was evalu-
ated by testing the response to spoken commands, and the
ability to make understandable spoken words and recipro-
cal contact. The response rate of questionnaires was 96%,
as the questionnaire was returned by 45/47 mothers in the
metformin-treated group, and by 48/50 mothers in the
insulin-treated group (Figure 1).
The weight and height percentiles of the children at dif-
ferent ages were calculated using the recently updated Finn-
ish growth reference software.15 The number of children
growing above the 95–percentile or below the 5–percentile
lines was recorded. Weight-for-length (i.e. difference in
percentage to the median weight of the children of the
same length) was calculated by using the same software.
According to Finnish guidelines for childhood obesity, a
weight-for-length percentage of 10–20% defines overweight,
and a weight-for-length percentage of over 20% defines
obesity.16 To evaluate body composition, ponderal index
(PI) was calculated as weight in kg divided by height in m3
[1 000 000 9 (weight in kg)/(height in cm)³].
The primary outcome was weight and height of the
children at the ages of 6, 12, and 18 months. The second-
ary outcomes included motor, social, and linguistic
development of the children until the age of 18 months, as
well as the body composition of the children defined by PI,
and the incidence of overweight and obesity defined by
weight-for-length.
Study period: 2007-2011
Metformin n = 50 Insulin n = 50
Withdrawn
n=3
Metformin only Metformin +supplemental
n = 32 insulin n = 15
Not returned Not returned Not returned
the questionnaire the questionnaire the questionnaire
n=1 n=1 n=2
Offspring follow-up at Offspring follow-up Offspring follow-up at
the age of 18 months at the age of 18 months the age of 18 months
n = 31 n = 14 n = 48
Figure 1. Flowchart.
 A follow-up of children exposed to metformin or insulin

Statistical analysis difference in the length of the neonates between the

The analyses to compare the study groups were performed
with SPSS 22.0 for WINDOWS (IBM SPSS Statistics, Espoo, Fin-
land). Comparisons between the two groups were made
using the Student’s t–test for continuous variables with
normal distribution and the Mann–Whitney U–test for
continuous variables with non-normal distribution. For cat-
egorical variables the Fisher’s exact test was used according
to the expected frequencies. P < 0.05 was regarded as statis-
tically significant.
Multivariate analyses were performed with children’s
weight and overweight or obesity at the age of 18 months
as dependent variables, and with maternal pre-pregnancy
body mass index (BMI) and treatment option as predictive
variables.
[Correction added on 3 December 2014, after first online
publication: The sentence, ‘The subgroup analyses were
made using one-way analysis of variance (ANOVA) to
compare the three groups: children exposed to metformin,
metformin with supplemental insulin, and insulin.’ was
irrelevant to the statistical analysis section; and it has been
removed.]
Results
The baseline characteristics of the mothers did not differ
upon enrolment to the study. The gestational age and
the mean birthweight of the neonates were similar in
both of the study groups, but there was a significant
groups (Table 1).
At the postpartum follow-up visit, approximately
8 weeks after delivery, 67% of mothers in the metformin
group and 62% of mothers in the insulin group breastfed
their infants. There was no significant difference between
the groups according to mode of feeding (totally breastfed,
totally bottle-fed, or combined), and the BMI of the
women did not differ significantly between metformin and
insulin groups (30.4 versus 29.9 kg/m², P = 0.427, 95% CI
1.91 to 2.95, respectively) at this time point.
At the age of 6 months, the mean height or weight of the
infants did not differ between the groups. Children exposed to
metformin were significantly heavier at the age of 12 months
and taller and heavier at the age of 18 months than those
exposed to insulin (Table 2). However, there were no signifi-
cant differences between the groups in PI at birth or at any
time point (Table 2). Neither did the proportion of over-
weight, obese, or underweight infants determined by weight-
for-length differ between the study groups. The mean head
circumference was similar in both groups at every time point
(Tables 1 and 2).
The occurrence of any mild motor or linguistic develop-
mental delay at the age of 18 months was rare, and rates
were similar in both groups (Table 3).
The estimated mean weight at the age of 18 months was
12.039 kg (95% CI 11.557–12.521 kg) versus 11.330 kg
(95% CI 10.879–11.781 kg) in metformin and insulin
groups, respectively, when the mother’s prepregnancy BMI

Table 1. Maternal baseline characteristics and neonatal data at delivery

Metformin Insulin P Risk ratio 95% CI

n = 45 n = 48

Mothers
Age at randomisation (years) 32.1  5.5 31.9  6.2 0.872
Pre-pregnancy BMI (kg/m²) 31.0  6.2 30.6  5.4 0.744
Smoking 1 (2.2) 4 (8.3) 0.201 0.27 0.03–2.30
Gestational age at randomisation (weeks) 30.0  4.5 30.4  4.1 0.822*
GhbA1c at randomisation (%) 5.9  0.41 5.9  0.40 0.674
Gestational age at delivery (weeks) 39.3  1.2 38.9  4.1 0.355*
Infants
Male/female 21 (47)/24 (53) 22 (46)/26 (54)
Birthweight (g) 3694  426 3528  585 0.119
Height (cm) 50.8  1.8 49.9  2.2 0.047
PI (kg/m³) 28.4  2.4 28.6  3.0 0.710
Head circumference (cm) 35.2  1.4 35.2  1.7 0.888
LGA n (%)* 3 (6.7) 4 (8.3) 1.000 0.8 0.19–3.38

Data are means  SDs (Student’s t–test/*Mann–Whitney U–test) or n (%) (Fisher’s exact test).
[Correction added on 3 December 2014 after first online publication: the statistical data in Table 1 were miscalculated; and these have been
corrected.]

ª 2014 Royal College of Obstetricians and Gynaecologists 3

 Ijäs et al.

Table 2. Children’s growth at the ages of 6, 12, and 18 months

Metformin Insulin P Risk ratio 95% CI

n = 45 n = 48

6 months
Height (cm) 68.1  3.8 67.4  2.7 0.286 0.63–2.11*
≥95 percentile 1 (2.2) 0 (0) 0.484
≤5 percentile 0 (0) 8 (16.7) 0.006
Weight (kg) 8.281  0.99 7.925  0.99 0.071 0.03–0.79
≥95 percentile 4 (8.9) 3 (6.3) 0.709 1.42 0.34–6.00
≤5 percentile 1 (2.2) 4 (8.3) 0.363 0.27 0.03–2.30
Weight-for-length > 10% 9 (20.0) 8 (16.7) 0.790 1.20 0.51–2.84
Weight-for-length > 20% 3 (6.7) 2 (4.2) 0.671 1.60 0.28–9.14
PI (kg/m³) 26.8  8.0 25.8  2.4 0.827 1.43–3.39*
Head circumference (cm) 43.8  1.3 43.8  1.5 0.865 0.63–0.53*
12 months
Height (cm) 76.9  3.3 75.6  3.1 0.062 0.07–2.62*
≥95 percentile 7 (15.6) 1 (2.1) 0.027 7.5 0.95–58.32
≤5 percentile 2 (4.4) 4 (8.3) 0.678 0.53 0.10–2.77
Weight (kg) 10.466  1.49 9.847  1.26 0.038 0.04–1.20*
≥95 percentile 4 (8.9) 3 (6.3) 0.709 1.42 0.34–6.01
≤5 percentile 3 (6.7) 3 (6.3) 0.630 1.04 0.45–2.38
Weight-for-length > 10% 9 (20.0) 7 (14.6) 0.587 1.37 0.56–3.37
Weight-for-length > 20% 3 (6.7) 1 (2.1) 0.351 3.20 0.35–29.7
PI (kg/m³) 23.0  2.5 22.8  2.0 0.617 0.70–1.18*
Head circumference (cm) 46.9  1.6 46.8  1.7 0.979 0.65–0.67*
18 months
Height (cm) 83.9  3.6 82.2  3.1 0.023 0.22–3.02*
≥95 percentile 6 (13.3) 2 (4.2) 0.150 3.2 0.68–15.04
≤5 percentile 1 (2.2) 6 (12.5) 0.112 0.18 0.02–1.42
Weight (kg) 12.051  1.87 11.318  1.45 0.040 0.04–1.43*
≥95 percentile 5 (11.1) 1 (2.1) 0.104 5.33 0.65–43.91
≤5 percentile 3 (6.7) 4 (8.3) 1.00 0.80 0.19–3.38
Weight-for-length > 10% 10 (22.2) 6 (12.5) 0.275 1.78 0.70–4.49
Weight-for-length > 20% 1 (2.2) 3 (6.3) 0.618 0.36 0.04–3.30
PI (kg/m³) 20.4  2.1 20.3  1.7 0.895 0.75–0.86*
Head circumference (cm) 48.3  1.5 48.4  1.7 0.856 0.76–0.64*

Data are means  SDs (Student’s t–test) or n (%) (Fisher’s exact test).
*95% CI of the difference.
[Correction added on 3 December 2014, after first online publication: the statistical data in Table 2 were miscalculated; and these have been
corrected.]

was included in the model. In the multivariate regression
analysis, the strongest factor associated with weight of the
children at the age of 18 months was maternal pre-preg-
nancy BMI (P = 0.001, 95% CI 0.04–0.15), but metformin
treatment also predicted a higher weight at this time point
(P = 0.036, 95% CI 1.37 to 0.05). Maternal BMI was the
only risk factor predicting a child being overweight
(P = 0.013, OR 1.13, 95% CI 1.03–1.25) or obese
(P = 0.014, OR 1.27, 95% CI 1.05–1.55) at the age of
18 months.
[Correction added on 3 December 2014, after first online
publication: The sentence, ‘There were no differences in the
growth or development in the subgroup analysis comparing
offspring of mothers treated with metformin only and off-
spring of mothers treated with metformin plus supplemen-
tal insulin or with insulin alone.’ was irrelevant to the
results section; and it has been removed.]
Discussion
Main findings
In this randomised study we found that the children exposed
to metformin prenatally were heavier at 12 months measure-
ments and both taller and heavier at 18 months measure-
ments than those exposed to insulin; however their body
composition defined by PI did not differ. In addition, the

4 ª 2014 Royal College of Obstetricians and Gynaecologists


Table 3. Development of the children at the age of 18 months
Metformin
n = 45
Standing* (months) 11.0  2.0
Walking* (months) 13.3  2.3
Not walking unaided 1 (2.2)
Absent key pinch grip 0 (0)
Speech delay** 4 (9.1)
Any mild developmental delay 5 (11.1)
Strabismus 3 (6.7)
Hearing impairment 1 (2.2)
Data are means  SDs (Student’s t–test) or n (%) (Fisher’s exact test).
*Without support.
**No meaningful words.
[Correction added on 3 December 2014, after first online publication: the statistical data in Table 3 were miscalculated; and these have been
corrected.]
mean weight-for-length and the proportion of overweight
and obese children did not differ significantly between the
groups at 6, 12, and 18 months of age. Prenatal exposure to
metformin did not seem to affect the child’s motor, linguis-
tic, or social development, assessed at 18 months of age,
compared with exposure to insulin.
Strengths and limitations
Our study is the second randomised study and the first
European study comparing metformin and insulin treat-
ments in GDM. In addition to growth, we have assessed
the motor, social, and linguistic development of the infants
to the age of 18 months. The response rate in our study
was high, as the questionnaire was returned by 96% of the
women who participated in our primary study.
The limitation of our study is the considerably small sam-
ple size. As a result, we are not able to detect differences in
rare conditions, such as developmental delays, between the
groups. In the original study, power calculations were made
to detect a 30% difference in the incidence of macrosomy.
Power calculations were not performed in the present study.
Although the sample size is small, the results of the primary
study are comparable with other randomised studies and
they may be considered reliable.
We were unable to gather data on the total duration of
breastfeeding, known to affect the weight of the infants.
We did not have the opportunity to perform check-ups on
the infants ourselves; however, the Finnish national child
welfare clinics use standardised follow-up techniques and
calibrated equipment to assess the growth and neurological
development of children, and therefore the results can be
considered reliable. The nurses and general practitioners
evaluating these children were not blinded to the allocation
ª 2014 Royal College of Obstetricians and Gynaecologists
A follow-up of children exposed to metformin or insulin
Insulin P Risk ratio
n = 48 (95% CI)
11.1  2.0 0.786
13.0  1.9 0.841
2 (4.3) 0.999 0.52 (0.05–5.56)
0 (0)
3 (6.4) 0.708 1.42 (0.34–6.01)
5 (10.4) 1.000 1.07 (0.33–3.44)
1 (2.0) 0.356 3.13 (0.34–29.02)
0 (0.0) 0.484
of the study subjects, but they were not otherwise in touch
with our study.
Interpretation
According to our knowledge, only one randomised study
has prospectively evaluated the growth of the offspring of
mothers with GDM treated with metformin or insulin. In
the MiG TOFU study, at the age of 2 years, there was no
difference in the height or in the weight of children exposed
either to metformin or to insulin in utero.14 The study
reported larger subscapular and biceps skin folds in children
exposed to metformin, whereas the total fat mass of the
children did not differ between the groups. The authors
interpreted this finding as a more favourable pattern of
growth later in life. The study did not report weight-for--
length measures.14 Our study found that the children
exposed to metformin were significantly heavier at the age
of 12 months and both taller and heavier at the age of 18
months than children exposed to insulin. In the logistic
regression metformin treatment was a predictor for a higher
weight at the age of 18 months. We had no opportunity to
analyse the detailed body composition of the offspring by
Dual X-ray absorptiometry (DEXA) or other radiological
methods; instead, we used PI to assess the body composi-
tion of these infants. Neither mean PI nor the proportion of
overweight or obese children differed significantly between
the groups. There was a tendency to a higher rate of over-
weight at the age of 18 months in the metformin group,
but the difference did not reach statistical significance,
which may be linked to the small study population.
In a study of 199 children of mothers with polycystic
ovary syndrome (PCOS), and exposed to metformin or
placebo in utero, at the age of 1 year the children exposed
5
 Ijäs et al.
to metformin were found to be significantly heavier than
those in the placebo group.17 Unfortunately, the study did
not report the height of the infants.17 The results drawn
from the studies concerning women with PCOS and treated
with metformin should be interpreted with caution when
comparing them with those obtained from being treated
for GDM. In PCOS the treatment has usually been initiated
before pregnancy and has often continued throughout the
pregnancy. The intrauterine metabolic environment may be
completely different in women being treated for GDM
compared with women being treated for PCOS.
In a recently published study, both birthweight and
infant weight, as well as the BMI of children aged over
2 years, were strongly associated with overweight in later
childhood and adolescence.18 In light of this evidence we
cannot ignore the parallel results of our study and that
conducted by Carlsen et al., indicating that prenatal met-
formin exposure may have an impact on the future growth
and risks of the offspring.17
Maternal metabolism has an effect on fetal programming
in utero and may cause long-term metabolic consequences
in the offspring by epigenetic mechanisms.19 Both maternal
obesity and hyperglycaemia are reported to associate with
metabolic disturbance and obesity of the offspring, but the
role of pharmacological treatment of GDM in the future
growth and metabolism of the child has not been investi-
gated separately.20–22 We do not yet know if the glycaemic
control during pregnancy has more influence on the subse-
quent growth of the offspring than the mode of treatment.
According to the data from the MiG study, treatment type
is not an important variable in relation to neonatal out-
comes, compared with glycaemia.23
A cohort study of 126 children born to women with
PCOS receiving metformin treatment, begun before
fertilization, and continued throughout pregnancy to
decrease pregnancy complications, found no adverse
effects on the motor or social development of the chil-
dren, assessed at the ages of 3, 6, 9, 12 and 18 months
and compared with national gender-spesific data.24 These
findings are in line with our study: prenatal metformin
exposion seemed not to have adverse effects on children’s
motor, social or linquistic development.24
Metformin reduces insulin resistance and is associated
with beneficial fat redistribution from visceral depots to
subcutaneous deposits in adults.25 Rowan et al. suggested
that fetuses exposed to metformin in utero might have
improved insulin action, which may also lead to more ben-
eficial fat distribution and insulin sensitivity later in life.14
On the contrary, in a recent animal experiment on mice,
prenatal metformin exposure was associated with increased
body weight gain, a significant reduction in total body
water content, and an increase in mesenteric fat during a
high-fat diet phase. In the male offspring prenatal metfor-
6 ª 2014 Royal College of Obstetricians and Gynaecologists
min exposure was associated with impaired glucose toler-
ance and elevated fasting glucose during a high-fat diet.26
The importance of environmental factors on growth and
metabolism should not be ignored, however. Further stud-
ies are needed to investigate the body composition and
insulin sensitivity of the offspring exposed to either metfor-
min or insulin prenatally.
Conclusion
Our study found no adverse influence of prenatal metformin
exposure on motor, linguistic, or social development of the
offspring during the first 18 months of life, as compared
with insulin exposure. The relevance of the finding that
infants exposed to metformin were heavier at the age of 12
months and both taller and heavier at 18 months needs to be
settled in long-term studies.
[Correction added on 3 December 2014 2014, after first
online publication: To correct the statistical analysis, the
initial statement ‘children exposed to metformin were hea-
vier and taller at the age of 12 and 18 months than chil-
dren exposed to insulin’ has been changed to ‘children
exposed to metformin were heavier at the age of 12 months
and both taller and heavier at 18 months than children
exposed to insulin’ throughout the article.]
Disclosure of interests
There are no conflicts of interest to disclose.
Contribution to authorship
HI and MV initiated and designed the study, collected the
study population, interpreted the data, and wrote the arti-
cle. RK collected a part of the study population. TS
designed the questionnaire and participated in the writing
of the article. TR initiated and designed the study, collected
the study population, interpreted the data, and is responsi-
ble for the final version of the article.
Details of ethics approval
Ethics approval for the study was granted by the Ethics
Committee of Northern Ostrobothnia Hospital District on
20 June 2005 (66/2005).
Funding
Funding was provided by the Finnish Diabetes Association
and the Finnish Medical Society Duodecim (Oulu Divi-
sion).
Acknowledgement
We thank Risto Bloigu (Medical Informatics Group, Uni-
versity of Oulu) for his skilled assistance in univariate and
logistic regression analyses. &

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