Curr Diab Rep (2014) 14:461

DOI 10.1007/s11892-013-0461-1

DIABETES AND PREGNANCY (CJ HOMKO, SECTION EDITOR)

Perinatal Outcomes in Type 2 Diabetes

Niranjala M. Hewapathirana & Helen R. Murphy

# Springer Science+Business Media New York 2014

Abstract Over the past decade the prevalence of type 2

diabetes in pregnancy has continued to increase. It is vital that
health care professionals recognize that preconception care is
just as important for mothers with type 2 diabetes as it is in
type 1 diabetes. All women with type 2 diabetes should be
advised regarding safe effective contraception and the benefits
of optimal glycemic control, folic acid supplementation,
and avoidance of potentially harmful mediations before
attempting pregnancy. Glycemic control is the most
important modifiable risk factor for congenital anomaly
in women with type 2 diabetes, whereas maternal obesity and
social disadvantage are associated with large for gestational
age neonates. This review aims to bring the reader up to
date with the burden of perinatal outcomes and clinical
interventions to improve maternal and infant health. It
warns that the consequences of type 2 diabetes pregnancy do
not end at birth.
Keywords Congenital malformation (CM) . Large for
gestational age (LGA) . Macrosomia . Perinatal mortality
(PNM) . Stillbirth (SB) . Neonatal mortality (NM) .
Type 2 diabetes
This article is part of the Topical Collection on Diabetes and Pregnancy
N. M. Hewapathirana
MRCP, Queens Medical Centre, Nottingham University Hospitals
NHS Trust, Derby Road, Nottingham NG7 2UH, UK
H. R. Murphy
University of Cambridge Metabolic Research Laboratories and
NIHR Cambridge Biomedical Research Center, Addenbrookes
Hospital, Hills Road, Cambridge CB2 0QQ, UK
H. R. Murphy (*)
Level 4 Metabolic Research Laboratories, Institute of Metabolic
Science, Box 289, Addenbrookes Hospital, Cambridge
CB2 0QQ, UK
e-mail: hm386@medschl.cam.ac.uk

Introduction
Type 2 diabetes is a growing concern worldwide, with increasing numbers of new cases, particularly among in younger
age groups. With rising rates of overweight and obesity
among women of reproductive years, the increasing numbers
of pregnant women with type 2 diabetes poses a major public
health challenge [1, 2]. Although women with type 2 diabetes
have more obstetric risk factors in that they are older, more
overweight and obese, of higher parity, more likely to take
potentially harmful medications at conception (for treatment
of hypertension and/or hyperlipidemia), they also have a less
severe glycemic disturbance and a shorter duration of diabetes
[3]. However, despite their multiple health care professional
contacts, women with type 2 diabetes are less likely to use safe
effective contraception, and less likely to access preconception and/or specialist prepregnancy care programs [3]. More
effective community based screening and educational programs are required to facilitate optimum preconception management of type 2 diabetes, particularly in ethnic minority and
socially disadvantaged groups [4]. Of concern are emerging
data suggesting that the consequences of type 2 diabetes do
not end at birth. There is compelling evidence that in utero
programming influences long term offspring health [57],
further re-enforcing the importance of identifying and
supporting women with type 2 diabetes early enough to make
a difference .
Although at first, type 2 diabetes was perceived as a more
benign condition than type 1 diabetes, potentially modifiable
by diet and lifestyle interventions, the early reports of serious
adverse perinatal outcomes in type 2 diabetes pregnancy
rapidly dispelled this myth. The most serious adverse pregnancy outcomes, feared by women and clinicians alike, are
major congenital anomaly, stillbirth, and neonatal death.
Perinatal mortality includes both stillbirths (fetal death
after 24 weeks) and neonatal deaths (death of a live-born

461, Page 2 of 7

infant before 28 days). Studies from Denmark conducted

between 19802001 described alarmingly high rates of
perinatal mortality in women with type 2 diabetes; 4 times
higher compared with type 1 diabetes and 9 times higher
than the background maternity population [8]. Similar
findings were reported from a 1990-2002 UK study, which
described an 11 times higher risk of congenital anomaly, a
2.5 times increased risk of perinatal mortality and a 6-fold
increased risk of dying before the age of 1 year compared
with regional/national maternity data [9]. Our own cohort
study from the East of England highlighted the potentially
modifiable risk factors for poor perinatal outcomes in type
2 diabetes pregnancy. We documented that mothers with
type 2 diabetes received inadequate preconception care,
with lack of folic acid supplementation, and suboptimal
glucose control before pregnancy [10].
The relatively small number of type 2 diabetes pregnancies
in these early case series provided limited statistical power for
comparisons with type 1 diabetes and the background maternity population and precluded accurate risk estimates for congenital anomaly and perinatal mortality. Thus, a national population based study was performed during 2002-03, to document the true prevalence of congenital anomaly and perinatal
mortality among infants born to women with type 1 and type 2
diabetes. The UK Confidential Enquiry for Maternal and
Child Health (CEMACH) included 652 mothers with type 2
diabetes and 1707 with type 1 diabetes. It confirmed that the
perinatal mortality and prevalence of congenital anomalies
were comparable in the babies of women with type 1 or type
2 diabetes (32/1000 and 46/1000 births, respectively) [11].
Over the past decade the prevalence of type 2 diabetes
pregnancy has continued to increase, with a 58 % increase in
the UK 5 years after CEMACH, with absolute prevalence
rising from 26 % in 20022003 to 40 % in 20072008 [12].
Primary and secondary care clinicians have, thus, gained more
experience in managing type 2 diabetes before and during
pregnancy and more data has come to light with regard to
the perinatal outcomes. This review aims to bring the reader
up to date with the burden of perinatal outcomes and clinical
interventions to improve maternal and infant health.

Perinatal Outcomes in Type 2 Diabetes Compared

With Type 1 Diabetes Pregnancies
Perinatal Mortality
In 2009 Balsells et al reported the first systematic review
comparing the pregnancy outcomes of type 2 vs type 1
diabetes pregnancies [13]. This meta-analysis of 33 original
papers provided summary data on maternal /fetal outcomes
during a 20-year period from 19872008. The 4 main outcomes were major congenital anomaly, stillbirth, neonatal

Curr Diab Rep (2014) 14:461

mortality, and perinatal mortality. A further 15 secondary

outcomes; including diabetic ketoacidosis (DKA), hypoglycemic coma, pregnancy-induced hypertension, preeclampsia,
caesarean section, miscarriage, termination, preterm delivery,
macrosomia, large for gestational age (LGA), small for gestational age (SGA), minor congenital malformations, hypoglycemia, respiratory distress, and jaundice were evaluated. In
contrast to the CEMACH report, they found a higher risk of
perinatal mortality in type 2 diabetes offspring although with
no apparent differences in the individual rates of congenital
anomaly, stillbirth, and neonatal mortality. Women with type 2
diabetes had better glucose control, less DKA, and caesarean
section but no difference in any of the other secondary
outcomes. They concluded that despite a milder glycemic
disturbance, mothers with type 2 diabetes had no better
perinatal outcomes than those with type 1 diabetes. They
also commented on the suboptimal prepregnancy care and
late gestational age at booking in women with type 2
diabetes. Some limitations were noted, namely the lack
of prospective studies and incomplete data on potential
confounding factors such as maternal obesity.
Our own prospective population based study (The East
Anglia Study Group for Improving Pregnancy Outcomes
in women with Diabetes-EASIPOD) included a carefully
designed multivariate analysis examining the contribution
of different maternal clinical and socio-demographic factors
on perinatal outcomes [14]. We compared obstetric and
perinatal outcomes in 682 consecutive type 1 and type 2
diabetes pregnancies during 2006-09. We examined whether
serious adverse outcomes (congenital anomaly and perinatal
mortality) and perinatal morbidity (LGA, preterm delivery,
and neonatal care) were different between type 1 and type 2
diabetes offspring, after adjustment for maternal confounders
including age, obesity, ethnicity, social disadvantage, glycemic control and type of diabetes [14]. Of the 682 pregnancies, there were 408 (59.8 %) mothers with type 1 diabetes
and 274 (40.2 %) with type 2 diabetes. Not surprisingly
women with type 2 diabetes were older, heavier, more likely
to be on potentially harmful medications such as statins,
ACE inhibitors, and glitazones and less likely to have preconception counselling, folic acid supplementation, and
prepregnancy care. They did, however, have better glycemic
control, shorter diabetes duration, and less microvascular
complications compared with women with type 1 diabetes.
Despite having significantly better preconception glycemic
control with HbA1c an average 1 % lower [HbA1c52 mmolmol
(6.9 %) type 2 vs 63 mmol l (7.9 %) type 1 diabetes], there
was no difference in the combined congenital anomaly and
perinatal mortality rates (50/1000 type 2 vs 671000 type 1
diabetes; P=0.5). HbA1c at booking was the only independent risk factor for serious adverse pregnancy outcome in
mothers with type 2 diabetes (OR 1.45, 95 % CI 0.992.12;
P=0.05 per 1 % increase in HbA1c).

Curr Diab Rep (2014) 14:461

Cundy et al suggested different causes of perinatal mortality in type 1 and type 2 diabetes, from a 20-year study (1986
2005) in Auckland, New Zealand, a multi-ethnic region of
region of native Maori, people from various Pacific Island
nations, China, and South Asia [15]. Although overall rates of
perinatal mortality in type 1 and type 2 diabetes were similar,
the underlying causes were different. More than 75 % of
perinatal deaths in type 1 diabetes offspring were attributed
to congenital anomalies or complications of prematurity,
while deaths in type 2 diabetes were mainly due to stillbirth,
chorioamnionitis, or birth asphyxia. Among women with type
2 diabetes, the BMI of women with stillbirths was 2 kg/m2
greater than women with live born infants, suggesting that
obesity contributed significantly to pregnancy loss in this
study population. A recent examination of placental vascular pathology in type 1 and type 2 diabetes pregnancies
demonstrated that 1 in 5 type 2 diabetes placentas had
histological infarcts, consistent with a vascular insult
(22 % vs 6 % for type 2 vs type 1 diabetes) whereas
type 1 diabetes placenta showed more signs of abnormal
development related to hyperglycemia (12 % vs 29 % for
type 2 vs type 1 diabetes) [16].
Congenital Anomaly
The most frequent serious adverse outcome of diabetes pregnancy is congenital anomaly. Congenital anomalies are the
leading cause of infant mortality in developed nations. An
estimated 185,000 infants in the United States and about 8
million worldwide are born, each year with major birth defects
[17]. Approximately 1 in 3 major malformations are not
detected by routine antenatal ultrasound scanning [11], so
quantifying the precise rates in routine clinical care is challenging. The North of England has a dedicated register for
recording and reporting detailed congenital anomaly data.
They recently reported findings from a large series of singleton pregnancies (n=401,149) including 1677 pregnancies in
mothers with diabetes; 1314 (78.4 %) type 1 and 363 (21.6 %)
type 2 diabetes, collected between 19962008 [18]. Using
the same European surveillance of congenital anomalies
(EUROCAT) criteria as CEMACH and our own regional
studies [3, 1012, 14], they reported higher rates of congenital anomaly (71.6/1000 pregnancies), with a relative
risk of 3.8 compared with the background maternity population. There was no significant difference in risk of major
nonchromosomal congenital anomaly between type 1 and
type 2 diabetes; 82 and 58 per 1000/pregnancies, respectively. A major strength of this study is that it included data
for all congenital anomaly cases diagnosed to up to the age
of 12 years. However, a methodological limitation was that
the preconception glycemic control data included a combination of pre and post-conception HbA1c measurements; as
the post conception levels would have been lower [3].

Page 3 of 7, 461

Bell et al documented a 3- to 6-fold increase across all

common anomaly groups, confirming the wide range of
anomalies affecting both single and multiple organ systems
described by previous investigators. They confirmed that
periconception glycemic control is the most important modifiable risk factor for congenital anomaly in women with
diabetes, with a 30 % increased risk per 1 % (11 mmol/mol)
linear increase in HbA1c above 6.3 % (45 mmol/mol). The
authors suggested that even near-normal levels of HbA1c may
not eliminate risk but advised that women should aim for as
great a reduction in preconception HbA1c as possible. They
also demonstrated that prepregnancy nephropathy was associated with a 2-fold increased risk of congenital anomaly,
recommending that women with nephropathy be offered specialist prepregnancy care.
Various mechanisms have been implicated with maternal
hyperglycemia causing oxidative stress during early embryogenesis proposed as a key contributor to the development of congenital anomaly [19]. In the case of women
with underlying nephropathy, Bell et al speculated that
previously poor glycemic control, periconception exposure to potentially teratogenic medications [20, 21] and
dual role of oxidative stress in the development of
nephropathy and congenital anomaly as likely explanations. A review of the molecular pathophysiology of
diabetic embryopathy and potential interventions specifically targeted to key molecular targets highlights the
potential of dietary interventions including antioxidants
and specific fatty acid supplements [17]. The results of
early phase animal tests are eagerly awaited. Recent
genetic data suggest that maternal genetic variants associated
with glucose homeostasis and obesity may also modify the
risk of having a neural tube defect [22].
Perinatal Morbidity
A notable and unexpected finding in our EASIPOD study was
the improvement in perinatal morbidity with fewer large for
gestational age (LGA) offspring, fewer deliveries before 37
weeks gestation, and fewer neonatal care admissions in type 2
compared with type 1 diabetes. Using customized birth weight
percentiles (adjusted for maternal parity, ethnicity, BMI)
mothers with type 2 diabetes had significantly fewer LGA
infants (38 % vs 53 %; P<0.0008), fewer preterm deliveries
(17 % vs 37 %; P<0.0001), and fewer neonatal care admissions (30 % vs 43 %; P<0.001). Third trimester HbA1c and
social disadvantage were independent risk factors for LGA
among the whole cohort of women with type 1 and type 2
diabetes (n=682), whereas for mothers with type 2 diabetes
(n=274) social disadvantage and maternal obesity were significant predictors of LGA. This association between social
disadvantage, obesity, and LGA is important since it suggests
that additional dietetic support may be required for this group

461, Page 4 of 7

of high risk women. A summary of the maternal/fetal outcomes in type 2 diabetes pregnancy is shown in Table 1.
Our finding of improved perinatal morbidity with reduced
rates of LGA, preterm deliveries, and neonatal care admissions in type 2 diabetes offspring has since been confirmed in
a larger UK cohort of 1381 pregnancies; 812 (60 %) type 1
diabetes, 556 (40 %) type 2 diabetes, from the North,
North West, and East of England during 20072008 [12].
Cyganek et al similarly reported that macrosomic infants
were more than twice less frequent in type 2 diabetes
mothers, in 415 consecutive Polish pregnancies (345 type 1
and 75 type 2 diabetes) [23]. This was attributed to improved
glucose control at booking and less gestational weight gain
(14.1 vs 9.9 kg), highlighting the contributions of glycemic
control and maternal obesity. Near-normal periconception
glycemia was achieved by women with type 2 diabetes
who planned their pregnancies, again indicating the potential of prepregnancy care to improve pregnancy outcomes
in type 2 diabetes.
Knight et al reported a decreased incidence of adverse
neonatal events in type 2 diabetes infants [24]. The same
group also reported the perinatal outcomes of 213 women
with type 2 diabetes and 213 obese women without diabetes
matched by prepregnancy BMI, in which mean prepregnancy
BMI for both groups was 36.6. Mothers with type 2 diabetes
had higher rates of congenital anomalies and LGA offspring
with associated complications of neonatal hypoglycemia,
hyperbilirubinemia, respiratory distress, sepsis, and need for
intubation, further confirming the impact of maternal diabetes
independent of obesity [25]. A detailed study of fetal growth
(77 type 1, 68 type 2, 99 GDM pregnancies) described the
disproportionate growth patterns in both LGA and non-LGA
offspring [26]. Higgins et al described disproportionate
growth and high levels of leptin in type 2 diabetes offspring,
postulating that this early leptin resistance may be important
for appetite regulation in later life [27].

Impact of Obesity and Gestational Weight Gain in Type 2

Diabetes Pregnancy
Studies in women without diabetes have shown that high and
very high maternal weight gain in association with high
prepregnancy BMI increases the risk of LGA whereas low
maternal gestational weight gain could result in small-forgestational age (SGA) infants especially in underweight
women [28]. In 2009, the U.S Institute of Medicine (IOM)
published revised gestational weight gain guidelines based on
prepregnancy body mass index (BMI). They suggested weight
gain targets for underweight, normal weight, overweight, and
obese women but did not specifically address targets for
women with diabetes [29]. Yee et al [30], therefore, looked
at the effect of gestational weight gain on perinatal outcomes

Curr Diab Rep (2014) 14:461

Table 1 Summary of maternal/fetal outcomes in type 2 diabetes
pregnancy
Miscarriage/loss prior to 24 wk

Congenital anomaly

Prevalence comparable to type 1

diabetes pregnancy
Approximately 1 in 5 pregnancies
Prevalence comparable to type 1
diabetes pregnancy

Approximately 4 % (43 per

1000/type 2 diabetes pregnancies)
23 times higher than background
maternity population
30 % decreased risk per 1 %
(11 mmol/mol) decrease in
HbA1c
Perinatal mortality
Prevalence comparable to type 1
diabetes pregnancy
34 times higher than background
maternity population
Approximately 3 % (32 per 1000/
type 2 diabetes pregnancies)
Causes: stillbirth, chorioamnionitis,
birth asphyxia
Serious adverse outcome
Prevalence comparable to type 1
(congenital anomaly and
diabetes pregnancy
perinatal mortality)
Approximately 5 % (50 per
1000/type 2 diabetes pregnancies)
46 % decreased risk per 1 %
(11 mmol/mol) decrease in
HbA1c
Preterm delivery
Prevalence less than type 1 diabetes
pregnancy
Approximately 17 % type 2
diabetes pregnancies
Large for gestational age
Prevalence less than type 1 diabetes
pregnancy
Approximately 1 in 3 type 2
diabetes infants
Associated with glycemic control
and maternal obesity
Small for gestational age
Prevalence greater than type 1
diabetes pregnancy
Approximately 1 in 10 type 2
diabetes infants
Neonatal care admission
Prevalence less than type 1 diabetes
pregnancy
Approximately 1 in 3 type 2
diabetes infants
Longer term metabolic conditions Prevalence of insulin resistance,
obesity and type 2 diabetes
greater than type 1 diabetes
pregnancy
Neurodevelopmental conditions
Prevalence greater than background
population
Approximately 2 times increased risk
Neoplastic and circulatory system Prevalence greater than background
conditions
population
Approximately 2 times increased risk

Curr Diab Rep (2014) 14:461

in overweight or obese women with type 2 diabetes using

IOM guidelines. They showed that excessive gestational
weight gain was associated with increased risk of having a
LGA or macrosomic infant. They also demonstrated increased
rates of preterm delivery among type 2 diabetes women with
excessive gestational weight gain per week.
While the IOM recommends a total weight gain of 59 kg
for healthy obese women, lower targets may be applicable for
women with type 2 diabetes. A retrospective study from
Denmark recently examined the impact of restricted maternal
weight gain on fetal growth and perinatal morbidity in 58
singleton pregnancies in obese women (BMI30 kg/m2) with
type 2 diabetes pregnancy [31]. They recommended that
women with type 2 diabetes aim to gain 05 kg throughout
pregnancy. Although limited by its retrospective nature and
small sample size, the study results are encouraging in that
women who gained 5 kg or less had infants with more proportionate birth weight, fewer LGA infants, and lower perinatal morbidity without increased risk of SGA infants.

Role of Metformin in Type 2 Diabetes Pregnancy

Metformin is increasingly used before and during type 2
diabetes pregnancy, although there is controversy and a lack
of randomized trials evaluating maternal and neonatal outcomes [32, 33]. The UK National Institute for Health and
Clinical Excellence (NICE) guidelines advise that metformin
(FDA class B) may be continued during pregnancy if the
benefits to glycemic control outweigh any potential risks
[34]. Recent data from the large USA Medication Exposure
in Pregnancy Risk Evaluation Programme (MEPREP Study
Group) indicate the widespread increased use of metformin
before pregnancy from 2001-2007 but suggest that approximately two-thirds did not continue during pregnancy [35].
Our own EASIPOD study documented the widespread clinical use, with metformin used at conception by more than half
the women with type 2 diabetes without evidence of harm.
However, we were also unable to demonstrate any beneficial
impact on maternal glycemic control and/or perinatal outcomes, possibly due to limited statistical power [14].
Metformins mechanism of action with AMP-activated
protein kinase (AMPK) dependent actions to increase peripheral (mainly skeletal muscle) glucose disposal and AMPK
independent reductions in endogenous glucose production
[36, 37] are physiologically plausible. Metformin may also
modulate the incretin axis to reduce dipeptidyl peptidase-4
activity and increase glucagon-like peptide 1 (GLP-1) [38,
39], to assist postprandial glucose control. Both these actions
would be potentially beneficial in the management of type 2
diabetes pregnancy.
Metformin is also widely used albeit for shorter duration and
more typically confined to the third trimester in gestational

Page 5 of 7, 461

diabetes, but it is unknown whether women with type 2

diabetes, who are treated for longer periods, may require
additional vitamin B12 or other dietary supplementation
[40]. In an ancillary study of the Metformin in Gestational
diabetes trial, maternal triglycerides were higher at 36
weeks in the metformin-treated group (2.9 vs 2.6 mmol/L;
P=0.002), with maternal triglycerides related both to glycemic
control and ethnicity [41].
Some recent animal study data suggest that prenatal metformin exposure programs the adult metabolic phenotype
during high-fat diet, highlighting how little is known about
the longer term impact [42]. The mice data suggest that
metformin (at a human dose equivalent of 1.7 g per day)
was associated with a slight but significant reduction in
fetal weight, without effect on maternal body weight or
food intake. The long term effects became more apparent
during high fat diet in later life with higher body weight,
more mesenteric fat, increased liver mass, and progression to impaired fasting glucose and impaired glucose
tolerance in male offspring. These authors advise that the
potential for long-term programming be considered when
using metformin as a therapeutic agent during pregnancy.
The results of an ongoing Canadian study, aiming to
recruit 500 pregnant women, will help to determine the
clinical impact of metformin in type 2 diabetes pregnancy
(NCT01353391), with long term offspring follow up eagerly
anticipated (NCT01832181).

Longer Term Health Outcomes

While the focus of this review is on the immediate perinatal
outcomes, it is increasingly recognized that the consequences
of type 2 diabetes pregnancy do not end at birth. The adverse
intrauterine environment has an enduring influence on the
offsprings lifelong risk of cardiovascular and metabolic disease [57], with well documented increases in insulin resistance, obesity, and type 2 diabetes.
More recently concerns about increased risks of
neurodevelopmental and neoplastic conditions have emerged.
A Danish population based study suggests that susceptibility
to malignant neoplasm is also at least in part modified by fetal
programming, with increased risk of malignant neoplasm in of
type 2 diabetes offspring [43]. Children born to mothers with
metabolic conditions, including obesity and type 2 diabetes,
are also more likely to have neurodevelopment problems [44].
In a US population based, case control study of 1004 children,
developmental delay was more common among mothers
of children with metabolic conditions, obesity, gestational,
and type 2 diabetes. In California, where this study was
performed, pregnant women with type 2 diabetes were 2.3
times as likely to have a child with neurodevelopment
delay [45]. The authors postulated that fetal exposure to

461, Page 6 of 7

maternal hyperglycemia, resulting in prolonged fetal pancreatic

hyperinsulinemia could trigger increased fetal oxygen consumption leading to chronic intrauterine tissue hypoxia. The
resulting biological responses including fetal iron deficiency
and fetal hypoxia are biologically plausible contributors to
neurodevelopmental delay.

Conclusions
Primary and secondary care professionals have an important
role to play in improving the perinatal outcomes of type 2
diabetes pregnancies. As in type 1 diabetes, preconception
counselling and supportive prepregnancy care to avoid potentially harmful medications and optimize glycemic control is
important. Specific attention is required to overcome the cultural and language barriers, to improve pregnancy planning
and preconception care in women from ethnic minority and
socially disadvantaged groups. For women with type 2 diabetes, an additional focus on weight management before and
during pregnancy is required. Use of appropriate weight
guidelines with safe weight-gain and/or weight-restriction
targets, safe physical activity recommendations, targeted
nutritional support and role of oral hypoglycemic agents,
in particular metformin are required.
Acknowledgments Helen R. Murphy is a funder of Closed Loop
Pregnancy projects for Diabetes UK, and receives HRM salary support
from NIHR.
Compliance with Ethics Guidelines
Conflict of Interest Niranjala M. Hewapathirana declares that she has
no conflict of interest. Helen R. Murphy has received speakers honoraria
from Medtronic, Sanofi Aventis, and NovoNordisk, and for the European
Advisory Board from Medtronic. She also receives support in kind for
CGM and devices from CGM Medtronic and Abbott Diabetes Care. She
has received honoraria unrelated to CGM from NovoNordisk, and from
Medtronic (CGM manufacturer).
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.

References
Papers of particular interest, published recently, have been
highlighted as:
Of importance
Of major importance
1.
2.

Feig DS, Palda VA. Type 2 diabetes in pregnancy: a growing

concern. Lancet. 2002;359:16902.
Temple R, Murphy H. Type 2 diabetes in pregnancy an increasing
problem. Best Pract Res. 2010;24:591603.

Curr Diab Rep (2014) 14:461

3.

Murphy HR, Roland JM, Skinner TC, Simmons D, Gurnell E,

Morrish NJ, et al. Effectiveness of a regional prepregnancy care
program in women with type 1 and type 2 diabetes: benefits beyond
glycemic control. Diabetes Care. 2010;33:251420.
4. Dunne F. Type 2 diabetes and pregnancy. Semin Fetal Neonatal
Med. 2005;10:3339.
5. Dabelea D, Crume T. Maternal environment and the transgenerational
cycle of obesity and diabetes. Diabetes. 2011;60:184955.
6. Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations:
from pathophysiology to prevention and management. Lancet.
2011;378:16981.
7. Poston L. Intergenerational transmission of insulin resistance and
type 2 diabetes. Prog Biophys Molec Biol. 2010;106:31522.
8. Clausen TD, Mathiesen E, Ekbom P, Hellmuth E, MandrupPoulsen T, Damm P. Poor pregnancy outcome in women with type
2 diabetes. Diabetes Care. 2005;28:3238.
9. Dunne F, Brydon P, Smith K, Gee H. Pregnancy in women with
Type 2 diabetes: 12 years outcome data 1990-2002. Diabetes Med.
2003;20:7348.
10. Roland JM, Murphy HR, Ball V, Northcote-Wright J, Temple RC.
The pregnancies of women with Type 2 diabetes: poor outcomes but
opportunities for improvement. Diabetes Med. 2005;22:17747.
11. Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J,
Acolet D, et al. Perinatal mortality and congenital anomalies
in babies of women with type 1 or type 2 diabetes in England,
Wales, and Northern Ireland: population based study. BMJ
(Clinical research ed). 2006;333:177.
12. Holman N, Lewis-Barned N, Bell R, Stephens H, Modder J,
Gardosi J, et al. Development and evaluation of a standardized
registry for diabetes in pregnancy using data from the Northern,
North West, and East Anglia regional audits. Diabetes Med.
2011;28:797804.
13. Balsells M, Garcia-Patterson A, Gich I, Corcoy R. Maternal and
fetal outcome in women with type 2 vs type 1 diabetes mellitus: a
systematic review and meta-analysis. J Clin Endocrinol Metabol.
2009;94:428491. A definitive review of the type 2 diabetes
pregnancy literature before 2009.
14. Murphy HR, Steel SA, Roland JM, Morris D, Ball V, Campbell PJ,
et al. Obstetric and perinatal outcomes in pregnancies complicated
by Type 1 and Type 2 diabetes: influences of glycemic control,
obesity and social disadvantage. Diabetes Med. 2011;28:10607.
15. Cundy T, Gamble G, Townend K, Henley PG, MacPherson P,
Roberts AB. Perinatal mortality in Type 2 diabetes mellitus.
Diabetes Med. 2000;17:339.
16. Beauharnais CC, Roberts DJ, Wexler DJ. High rate of placental
infarcts in type 2 compared with type 1 diabetes. J Clin Endocrinol
Metabol. 2012;97:E11604.
17. Reece EA. Diabetes-induced birth defects: what do we know? What
can we do? Curr Diabetes Rep. 2012;12:2432. A comprehensive
review article summarizing causes and potential treatments for
congenital malformations.
18. Bell R, Glinianaia SV, Tennant PW, Bilous RW, Rankin J. Periconception hyperglycaemia and nephropathy are associated with
risk of congenital anomaly in women with pre-existing diabetes: a
population-based cohort study. Diabetologia. 2012;55:936947.
19. Fraser RB, Waite SL, Wood KA, Martin KL. Impact of hyperglycemia on early embryo development and embryopathy: in vitro
experiments using a mouse model. Hum Reproduction. 2007;22:
305968.
20. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S,
Gideon PS, et al. Major congenital malformations after firsttrimester exposure to ACE inhibitors. N Engl J Med. 2006;354:
244351.
21. Edison RJ, Muenke M. Central nervous system and limb anomalies
in case reports of first-trimester statin exposure. N Engl J Med.
2004;350:157982.

Curr Diab Rep (2014) 14:461

22.

23.

24.

25.

26.

27.

28.

29.
30.

31.

32.
33.

34.

Lupo PJ, Canfield MA, Chapa C, Lu W, Agopian AJ, Mitchell LE,

et al. Diabetes and obesity-related genes and the risk of neural tube
defects in the national birth defects prevention study. Am J
Epidemiol. 2012;176:11019.
Cyganek K, Hebda-Szydlo A, Skupien J, Katra B, Janas I,
Borodako A, et al. Glycemic control and pregnancy outcomes in
women with type 2 diabetes from Poland. The impact of pregnancy
planning and a comparison with type 1 diabetes subjects.
Endocrine. 2011;40:2439.
Knight KM, Thornburg LL, Pressman EK. Pregnancy outcomes in
type 2 diabetic patients as compared with type 1 diabetic patients
and nondiabetic controls. J Reprod Med. 2012;57:397404.
Knight KM, Pressman EK, Hackney DN, Thornburg LL. Perinatal
outcomes in type 2 diabetic patients compared with non-diabetic
patients matched by body mass index. J Matern Fetal Neonatal
Med. 2012;25:6115.
Hammoud NM, Visser GH, Peters SA, Graatsma EM, Pistorius L,
de Valk HW. Fetal growth profiles of macrosomic and nonmacrosomic infants of women with pregestational or gestational
diabetes. Ultrasound Obstet Gynecol. 2013;41:3907.
Higgins MF, Russell NM, Brazil DP, Firth RG, McAuliffe FM.
Fetal and maternal leptin in pre-gestational diabetic pregnancy. Int J
Gynaecol Obstet. 2012;120:16972.
Nohr EA, Vaeth M, Baker JL, Sorensen T, Olsen J, Rasmussen KM.
Combined associations of prepregnancy body mass index and
gestational weight gain with the outcome of pregnancy. Am J
Clin Nutrit. 2008;87:17509.
Institute of Medicine. Weight gain during pregnancy: re-examining
the guidelines. Washington, DC: National Academies Press; 2009.
Yee LM, Cheng YW, Inturrisi M, Caughey AB. Effect of gestational weight gain on perinatal outcomes in women with type 2 diabetes
mellitus using the 2009 Institute of Medicine guidelines. Am J
Obstet Gynecol. 2011;205(257):e16.
Asbjornsdottir B, Rasmussen SS, Kelstrup L, Damm P, Mathiesen
ER. Impact of restricted maternal weight gain on fetal growth and
perinatal morbidity in obese women with type 2 diabetes. Diabetes
Care. 2013;36:11026. Preliminary data suggesting that moderate
gestational weight loss <5 kg may be beneficial.
Hawthorne G. Metformin use and diabetic pregnancy-has its time
come? Diabetes Med. 2006;23:2237.
Hughes RC, Rowan JA. Pregnancy in women with Type 2 diabetes:
who takes metformin and what is the outcome? Diabetes Med.
2006;23:31822.
NICE guideline 63: Diabetes in Pregnancy. Management of
diabetes and its complications in pregnancy from the pre-

Page 7 of 7, 461
conception to the postnatal period. www.nice.org.uk. 2008.
Last accessed 25 Jan 2013.
35. Lawrence JM, Andrade SE, Avalos LA, Beaton SJ, Chiu VY, Davis
RL, et al. Prevalence, trends, and patterns of use of antidiabetic
medications among pregnant women, 2001-2007. Obstet Gynecol.
2013;121:10614.
36. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al.
Role of AMP-activated protein kinase in mechanism of metformin
action. J Clin Invest. 2001;108:116774.
37. Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux
G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic
energy state. J Clin Invest. 2010;120:235569.
38. Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates
the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia.
2011;54:33949.
39. Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL.
Mechanisms underlying metformin-induced secretion of
glucagon-like peptide-1 from the intestinal L cell. Endocrinology.
2011;152:46109.
40. Gatford KL, Houda CM, Lu ZX, Coat S, Baghurst PA, Owens JA,
et al. Vitamin B12 and homocysteine status during pregnancy in the
metformin in gestational diabetes trial: responses to maternal
metformin compared with insulin treatment. Diabetes Obes
Metab. 2013;15:6607.
41. Barrett HL, Nitert MD, Jones L, O'Rourke P, Lust K, Gatford KL,
et al. Determinants of maternal triglycerides in women with gestational diabetes mellitus in the metformin in gestational diabetes
(MiG) study. Diabetes Care. 2013;36:19416.
42. Salomaki H, Vahatalo LH, Laurila K, Jappinen NT, Penttinen AM,
Ailanen L, et al. Prenatal metformin exposure in mice programs the
metabolic phenotype of the offspring during a high fat diet at
adulthood. PloS One. 2013;8:e56594.
43. Wu CS, Nohr EA, Bech BH, Vestergaard M, Olsen J. Long-term
health outcomes in children born to mothers with diabetes: a
population-based cohort study. PloS One. 2012;7:e36727.
44. Tanne JH. Maternal obesity and diabetes are linked to children's
autism and similar disorders. BMJ (Clinical research ed). 2012;344:
e2768.
45. Krakowiak P, Walker CK, Bremer AA, Baker AS, Ozonoff S,
Hansen RL, et al. Maternal metabolic conditions and risk for autism
and other neurodevelopmental disorders. Pediatrics. 2012;129:
e11218. A reminder that the consequences of type 2 diabetes do
not end at birth.