Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 685e699

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Diabetes in pregnancy
David R. McCance, BSc, MD, FCRP, DCH, Professor, Consultant
Physician/Honorary Professor of Endocrinology *
Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland,
UK

Keywords:
diabetes
pregnancy
gestational diabetes mellitus
obesity
outcome

Diabetes in pregnancy is still considered a high-risk condition for

both mother and baby. Even in the best centres, malformation and
mortality rates are reportedly twofold to vefold higher than in
the background population, and pregnancy planning rates remain
obstinately poor. Increasing global rates of type 2 diabetes are now
extending into pregnancy, with similarly poor outcomes to type 1
diabetes, and excess maternal weight is adding to the complexity
of management. Over the last 5e10 years, several randomised
trials have offered new insight into the role of oral hypoglycaemic
drugs and insulin analogues in pregnancy, while continuous subcutaneous insulin infusion (CSII) pumps and continuous glucose
monitors (CGMs) are under scrutiny. The relevance of minor degrees of hyperglycaemia to adverse pregnancy outcome was
clearly demonstrated by the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study, but translation of these data into
clinical practice has proved challenging because of the continuum
of risk. Long-term metabolic and cardiovascular implications of
hyperglycaemia during pregnancy for mother and child are now
generally recognised with major implications for public health.
2015 Elsevier Ltd. All rights reserved.

* Corresponding author. Consultant Physician/Honorary Professor of Endocrinology, Regional Centre for Endocrinology and
Diabetes, Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland, UK. Tel.: 44 02890 633430; Fax: 44 02890 310111.
E-mail address: david.mccance@belfasttrust.hscni.net.
http://dx.doi.org/10.1016/j.bpobgyn.2015.04.009
1521-6934/ 2015 Elsevier Ltd. All rights reserved.

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Epidemiology
Globally, 21.4 million (16.9%) of 127.1 million live births to women aged 20e49 years are affected by
hyperglycaemia in pregnancy [1]. Approximately 16% of the 21.4 million may be caused by diabetes in
pregnancy (including known and previously undiagnosed diabetes). These statistics reect the
growing prevalence of the type 2 diabetes epidemic on pregnancy, and they vary signicantly with
ethnicity and location. 91.6% of cases are reported in low- and middle-income countries where access
to maternal care is often limited [1]. A UK survey in 2003 estimated the frequency of type 1 diabetes as
one in 364 (0.27%) and type 2 as one in 955 (0.10%) births [2]. The increase in hyperglycaemia in
pregnancy is compounded by overweight/obesity, which now affects about half of women who give
birth [3].
Adverse perinatal outcomes
A review of 12 population-based studies published within the last 10 years compared 14,099
women with type 1 diabetes with 4,035,373 women from the background population [4] reported a
twofold to vefold increased risk of adverse pregnancy outcomes as follows:





Congenital malformations, 5.0% versus 2.1% (relative risk (RR): 2.4)

Perinatal mortality, 2.7% versus 0.72% (RR: 3.7)
Preterm delivery, 25.2% versus 6.0% (RR: 4.2)
Large for gestational age (LGA) infants, 54.2% versus 10.0% (RR: 4.5)

In the UK Condential Enquiry into Maternal and Child Health (CEMACH), 4% of foetuses had at least
one major congenital anomaly (twice that of the general population). The most common anomalies
were congenital heart disease (1.7%; three times that of the general population) and musculoskeletal
(0.7%) [3]. At least one in two infants of mothers with type 1 diabetes has complications related to
glucose control [3].
Type of diabetes and outcomes
The outcomes of women with type 1 and type 2 diabetes are equally poor [5]. A recent metaanalysis of 33 studies involving 7966 type 1 and 3781 type 2 pregnancies showed that women with
type 2 diabetes had a signicantly higher risk of perinatal mortality but no difference in rates of
malformation [6].
Risks and risk factors
These are well established for both mother and baby, and are modied to some extent by the type
and duration of diabetes, glycaemic control and diabetes-related vascular complications [5]. Fifty per
cent of babies may need admission to neonatal care (10% intensive care) [7], and the following are the
risk factors:
 General risk factors: age, parity, weight, hypertension, smoking and drug abuse
 Obstetric risk factors: previous miscarriage, multiple pregnancy, nutritional deciency, late booking
and poor obstetric history
 Maternal risk: miscarriage, accelerated retinopathy and nephropathy, hypoglycaemia and hypoglycaemic unawareness, diabetic ketoacidosis (DKA), pre-eclampsia, hydramnios, operative delivery
and infection
 Foetal risk: stillbirth, perinatal mortality, congenital anomalies, small/large for gestational age (SGA/
LGA), preterm delivery, operative delivery, shoulder dystocia and birth injury, neonatal hypoglycaemia, polycythaemia, hypocalcaemia and respiratory distress syndrome

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Pathophysiology
Adaptation of maternal metabolism during pregnancy involves a greater fall in plasma glucose and
amino acids, and a greater rise in free fatty acids to overnight fasting than in the non-pregnant state
(accelerated starvation) associated with hepatic insulin resistance. In later pregnancy, a progressive
rise in postprandial glucose and its associated insulin response, associated with decreased insulin
sensitivity, parallels the growth of the foetal placental unit, and it rapidly reverses after delivery. This
facilitated anabolism brings about appropriate changes in carbohydrate, amino acid and lipid metabolism, and ensures adequate nutrients for the developing foetus.
Decient b-cell reserve, either absolutely, as in type 1 diabetes, or relatively, as in type 2 diabetes or gestational diabetes mellitus (GDM), will result in the abnormal adaptation of carbohydrate, protein and fat metabolism. In type 1 diabetes, sufcient insulin is required to compensate
for increasing caloric needs, increasing adiposity, decreasing exercise and increasing anti-insulin
hormones. The insulin dose to maintain normoglycaemia and prevent maternal ketosis may increase up to threefold in the course of pregnancy in type 1 diabetes, and women with type 2
diabetes will usually require insulin treatment, often at high doses, because of obesity and physical
inactivity.
The Pedersen hypothesis (proposed over 50 years ago) that maternal hyperglycaemia accelerates
foetal growth through foetal hyperinsulinaemia [8] is supported by animal and epidemiological data,
and has provided a basis for the concept of foetal programming. Other maternal fuels are also likely to
be implicated.
Type 1 and type 2 diabetes preceding pregnancy
Provision of care
A multidisciplinary team operating in a secondary- or tertiary-care setting is a commonly
adopted model for the care of pregnant women with diabetes [5]. Essential team members include
an obstetrician, a diabetes physician, a specialist nurse, a dedicated dietician and a diabetestrained midwife. Review is usually done fortnightly and initially focussed on diabetic rather
than on obstetric issues. Women are reviewed weekly as term approaches. Ideally, there should be
an open-access pregnancy-planning clinic with a seamless interface with the joint antenatal
diabetes clinic.

Rationale for pre-pregnancy care

Recognition that congenital malformations were increased in infants of diabetic mothers was rst
observed >40 years ago, and quickly linked with maternal periconceptional hyperglycaemia. Most
abnormalities occur in the teratologically sensitive period up till the seventh gestational week. A UK
population registry-based study between 1996 and 2008 involving 401,149 singleton pregnancies
(1677 in women with diabetes) showed that the odds of a malformation increased by 30% for each
percentage (11 mmol/mol) increase in booking HbA1c [9]. Periconception HbA1c was the most
important predictor of malformations with a linear risk between 6.3% and 11% (45e97 mmol/mol). A
meta-analysis of 14 studies of pre-pregnancy care showed a threefold reduction in the risk of major
congenital malformations among 1192 offspring who received such care compared with 1459 offspring
of mothers who did not [10]. It is important, however, for the mother to realise that these risks are
reduced with any improvement in HbA1c [11].

Pre-pregnancy counselling/pre-pregnancy care

Distinction is needed between the two major components of pregnancy planning.

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Preconception counselling
 Preconception counselling is the education of, and discussion with, women of reproductive age
about pregnancy and contraception, and it should be delivered annually in a primary and/or a
specialist care to all women of reproductive age
 Discussion includes future pregnancy plans, importance of pre-pregnancy care, relationship of optimal
glycaemic control to improved outcomes, possible need for revised treatment (e.g., substitution of
insulin in type 2 diabetes), efcient contraception, how diabetic complications may affect future
pregnancy, high-dose folic acid, teratogenic drugs (e.g., angiotensin-converting enzyme inhibitors
(ACEIs), angiotensin receptor blockers (ARBs) and statins) and urgent referral details if pregnant
Pre-pregnancy care
 Pre-pregnancy care is the additional care needed to prepare a woman with diabetes for pregnancy,
and involves a close partnership between the woman and health-care professional. Ideally, it should
begin at least 6 months before she embarks on a pregnancy.
 Discussion includes the use of contraception until optimal glycaemic control is achieved, relevant
maternal and foetal risks, individualised and realistic glycaemic targets, revision of drug therapy,
prescription of 5-mg folic acid daily, screening for and treatment of complications, nutritional and
lifestyle advice, smoking and alcohol cessation.
A regional UK pre-pregnancy care programme was associated with improved outcomes but only
27% of eligible women attended, and there was no improvement among women with type 1 diabetes
(50% access to preconception care) [12]. A similar lack of improvement was reported from Sweden and
Finland [12], but in Germany considerable improvements have been achieved with lower HbA1c levels
and reductions in preterm delivery and macrosomia/LGA, possibly associated with an increased use of
continuous glucose monitoring (CGMS) and continuous subcutaneous insulin infusion (CSII) [12].
The UK CEMACH survey [3] reported that women with type 2 compared with type 1 diabetes were
less likely to have received pre-pregnancy care (62% vs. 75%), to be taking folic acid preconception and
to have microvascular complications, but more likely to be ethnically diverse, to suffer from socioeconomic deprivation, to be hypertensive and overweight, and to have better glycaemic control both
at booking and during pregnancy.
Health-care provision is likely to differ for women with type 1 and type 2 diabetes, and hence the
need to promote awareness in whatever setting women are receiving routine diabetes care. Using
content analysis of transcribed groups, we have recently produced a DVD and an online resource tool
[13] (www.womanwithdiabetes.net) aimed at improving the reproductive knowledge of diabetes
among women of childbearing age. Signicantly improved pregnancy planning was observed
following regional distribution of this resource to all eligible women [14].
Maternal obesity and pregnancy
Obesity now affects one in ve women who give birth, and it may be one of the greatest threats to
childbearing women. In the UK survey, more than half of maternal deaths were in either overweight or
obese women (15% in women with a body mass index (BMI) above 35). Pregnancy may cause or worsen
obesity through excessive weight gain, and obesity may complicate pregnancy by increasing the risk of
fertility problems, LGA and maternal hypertensive and diabetic disorders. Maternal obesity has been
linked with a twofold to threefold increase in rates of malformation, perinatal mortality, caesarean
section and macrosomia, although in a recent meta-analysis, BMI was not a signicant independent
predictor of poor outcome in women with type 1 and type 2 diabetes [6].
The American Institute of Medicine (2009) [15] recommends gestational weight gain of:
 10e12.5 kg for normal weight women
 12.5e18 kg for underweight women (BMI <19.8 kg/m2)
 5e9.1 kg for obese women (BMI >30 kg/m2)

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Cedergren [16] suggested that obese women should gain <6 kg to reduce the risk of adverse
pregnancy outcomes. Current UK guidelines recommend that women with a pre-pregnancy BMI
>27 kg/m2 should restrict their calorie intake to 25 kcal/kg/day in the second trimester. High maternal
gestational weight gain in non-diabetic women increases the risk of LGA [17]. Concern remains that a
low maternal gestational weight gain is associated with SGA and preterm birth [18]. Preventive
measures by supporting women to lose weight and achieve a near-normal BMI before conception
remain the ideal, and practically the most feasible strategy.
Nutritional recommendations in diabetes
Few evidence-based dietary guidelines exist for women with diabetes with or without obesity. A
healthy lifestyle consisting of a well-balanced diet and moderate physical activity should be encouraged for all women during pregnancy. The aim is to reduce postprandial hyperglycaemia and to prevent hypoglycaemia between meals and nocturnally. Low glycaemic index foods may help to reduce
postprandial hyperglycaemia, but randomised trial evidence is lacking which shows that these foods
reduce adverse maternal/foetal outcomes [19].
As with a healthy non-pregnant diet, approximately 50% of the total energy is provided by carbohydrate and <35% from fat. Individual advice around appropriate carbohydrate intake and the
adjustment of insulin prior to exercise to avoid hypoglycaemia is necessary especially early in pregnancy. For women with type 2 and GDM, 30 min of walking once or twice a day after meals is realistic
and easily achievable, and this can lower fasting and postprandial blood glucose values as well as
reduce the need for insulin.
There are no specic weight recommendations, but minimising unnecessary weight gain in obese
women with type 2 diabetes and GDM women can improve maternal glycaemic control, reduce the risk
of macrosomia and improve pregnancy outcomes [20].
Glycaemic control
The importance of optimal glucose control for healthy infant outcomes is unquestioned. Recommendations are broadly similar across international bodies [21,22] and in the UK, and these include the
following [21,21a]:
 Target capillary glucose levels of below 5.3 mmol/l fasting and 1 hour after meals: 7.8 mmol/l or 2
hours after meals : 6.4 mmol/l
 Blood glucose should be measured up to eight times daily (before and after each meal, at bedtime
and, intermittently, in the middle of the night)
 If feasible, women planning pregnancy should aim for HbA1c below 6.5% (48 mmol/mol)
In a large multicentre UK cohort, <10% of UK women with type 1 diabetes had HbA1c <6.1% at rst
antenatal visit, increasing to around 25% at 26 and 34 weeks. At 34 weeks, 22% of women had an
HbA1c  7% [23]. We recently demonstrated a linear trend between increasing second and third
trimester HbA1c values (independent of rst trimester HbA1c) and adverse outcomes, supporting the
utility of HbA1c measurement in later pregnancy to indicate high-risk pregnancies, which need
intensive supervision [24] (Fig. 1).
There is a signicant risk of hypoglycaemia with intensication of insulin therapy, especially during
the rst trimester, and glycaemic targets should be individualised. Severe hypoglycaemia, affecting up
to 40% of women, causes substantial morbidity (seizures, fractures and road-trafc accidents), and it is
the leading cause of death in type 1 diabetic pregnancy [25].
Diabetic complications
Retinopathy
Ideally, all diabetic patients should have a detailed eye examination prior to pregnancy. This permits
relevant treatment (including photocoagulation) before optimisation of glycaemic control, and is

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Fig. 1. The odds ratios with 95% condence intervals (logarithmically transformed) for maternal and neonatal outcome indicators by
HbA1c categories at 24 and 36 weeks of gestation.

essential to reduce the risk of retinopathy progression during pregnancy. Risk factors for progression
include pre-existing retinopathy, poor blood glucose control preconception, longer diabetes duration,
rapid improvement of diabetes control during the rst trimester and previous or pregnancy-induced
hypertension. UK guidelines [21] recommend retinal assessment at the rst antenatal appointment
(if not performed in the previous 12 months), at 28 weeks, if the rst assessment is normal, and
additionally at 16e20 weeks if any retinopathy is present.
Nephropathy
The term includes microalbuminuria or proteinuria, with or without maternal hypertension, or
signicant impairment in the renal function. While recent retrospective data have reported perinatal
survival rates of 95%, these vary with the stage of nephropathy, and they are accompanied by high rates
of pre-eclampsia (32e65%), preterm delivery (57e91%) and foetal growth restriction (12e45%) [5].
Tight blood glucose and blood pressure control before and during pregnancy, close foetal surveillance
and timely delivery are needed to optimise pregnancy outcome. ACEIs/ARBs are teratogenic, and they
should be discontinued before or possibly at conception in patients with more severe nephropathy pre
pregnancy. Methyldopa and labetolol are alternative agents. Screening for microalbuminuria should
take place at booking (if not performed in the previous 12 months), and referral to a nephrologist
should be considered if serum creatinine >120 mmol/l or protein excretion >2 g/day [21]. Microalbuminuria in early pregnancy is associated with a fourfold increased risk of pre-eclampsia in type 1

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diabetic pregnancy. Women with increasing proteinuria during pregnancy need to be closely monitored particularly in late pregnancy.
Diabetic ketoacidosis
DKA presents a serious threat to maternal health and foetal viability. Precipitating factors include
hyperemesis, beta-mimetic drugs, failure to continue regular insulin therapy and infection. Every
mother should be taught how to monitor urinary ketones, and they should be given emergency contact
numbers. If unwell, with reduced oral intake/vomiting with hyperglycaemia and ketonuria, urgent
admission should be arranged especially if adequate hydration cannot be maintained.
Management
Insulin regimens
Most patients with diabetes before pregnancy are now using a multiple dose insulin (MDI) regimen
comprising a short-acting preprandial insulin and an intermediate-acting insulin up to three times
daily. Women with type 2 diabetes controlled on a twice-daily xed mixture insulin regimen before
pregnancy are often changed to an MDI regimen during pregnancy.
Rapid-acting analogue insulins, for example, aspart, lispro and glulisine, are frequently used as
they reduce postprandial hyperglycaemia, are less prone to cause hypoglycaemia and can be taken
immediately prior to meals. Data on their safety and efcacy have largely come from observational
data, but a large randomised controlled trial (RCT) of insulin aspart versus regular soluble insulin in
type 1 diabetes showed similar efcacy, with a tendency to lower rates of hypoglycaemia and
without apparent toxicity [26]. Insulin aspart and lispro are licensed for use during pregnancy (Food
and Drug Administration (FDA) category B and European Medicines Agency (EMA) approved); glulisine is FDA category C. Basal analogue insulins include insulin detemir and glargine. An RCT of 310
women with type 1 diabetes randomised to insulin detemir or neutral protamine hagedorn (NPH)
insulin (both with mealtime insulin aspart) revealed non-inferior HbA1c values, lower fasting plasma
glucose values with detemir in later pregnancy and similar perinatal outcomes [27]. Levemir is
approved by the FDA (category B) and the EMA for use in pregnancy. No large RCT data for insulin
glargine are available, but a review of observational studies did not show any excess of adverse
outcomes.
Continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGMS)
There is little evidence supporting the routine use of CSII in pregnancy. A meta-analysis of six
studies (107 CSII vs. 106 MDI) showed comparable glucose control and pregnancy outcomes [28],
although these studies were in the pre-analogue era and lacked power to detect differences in neonatal
outcomes. Observational data (CSII vs. MDI) are conicting, mostly retrospective and with striking
selection biases. It seems likely that capillary glucose monitoring reveals only a minor fraction of
hyperglycaemic excursions and day-to-day variability [29], and this may be relevant to adverse foetal
outcome.
An RCT, which compared continuous glucose monitoring system (CGMS) with or without conventional glucose monitoring every 4e6 weeks between 8e32 weeks of gestation in 46 type 1 and 25
type 2 women, showed an improvement in the mean HbA1c in late pregnancy (5.8% vs. 6.4%;
p 0.0007) with lower LGA rates (35% vs. 60%) compared with conventional monitoring [30]. A
subsequent Danish RCT of intermittent real-time CGMS (RT-CGMS) versus self-monitored plasma
glucose seven times daily showed no improvement in glycaemic control, or pregnancy outcome in
women with pre-gestational diabetes [31], although women were tightly controlled at conception
(HbA1c 6.6% vs. 6.8% (49 vs. 51 mmol/mol)). A multicentre trial is currently underway to determine if
RT-CGMS can improve HbA1c in women with type 1 diabetes who are pregnant or are planning
pregnancy without excessive hypoglycaemia (CONCEPTT). Future trials in pregnancy are likely to
focus on sensor-augmented pump therapy (CSII RT  CGMS) compared with optimal conventional
regimens given a meta-analysis reporting benet outside pregnancy [32]. However, the cost of this
technology is likely to limit the use to highly selected, educated, motivated women in experienced
centres.

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The closed-loop articial pancreas, by which glucose is sensed continuously and insulin delivered
by a computer algorithm, continues to evolve, and it has been shown to be successful in a laboratory
setting and preliminary clinical studies. Such methodology is undoubtedly attractive but perhaps
most feasible nocturnally given the variable insulin resistance and glucose absorption during
pregnancy.
Oral hypoglycaemic agents
Metformin is an insulin sensitiser, which inhibits gluconeogenesis and hepatic glucose output
while increasing muscle glucose uptake. Increasing numbers of women have conceived while
taking metformin for type 2 diabetes or polycystic ovary syndrome (PCOS). The drug crosses the
placenta, but no teratogenicity in animals has been reported. Human data on metformin in the rst
trimester are conned to small and often retrospective studies [33]. An RCT of 40 PCOS women
suggested better outcomes with metformin, while a cohort study of 214 women with type 2 diabetes showed no evidence of adverse outcomes with metformin. A small RCT in PCOS women
showed a ninefold reduction in GDM in those who continued metformin during pregnancy
compared with those who stopped treatment. An RCT of 360 women with PCOS showed that
treatment with metformin from conception to 12 weeks of gestation resulted in a higher pregnancy
rate (53.6% vs. 40.4%; p 0.06) and live birth rate (41.9% vs. 28.8%; p 0.014) compared with
placebo. A Canadian study (MITY) involving randomisation of women with type 2 diabetes to insulin with or without metformin is currently in progress. Follow-up data on longer-term neonatal
outcomes are also required.
In the UK, metformin is recommended for use in the preconception period [21], but in the US,
substitution of insulin is still recommended as the most effective and preferred agent to control
hyperglycaemia [22].
Obstetric surveillance
Accurate dating of the pregnancy is imperative, and is best achieved by an ultrasound examination
at 8e10 weeks. The goal of obstetric surveillance is to identify the foetus at risk, in order to intervene in
a timely and appropriate fashion to reduce perinatal morbidity and mortality. Given the limitations of
the available tests and lack of rigorous scientic trials, all protocols used for foetal surveillance are
empiric and all have limitations.
Foetal monitoring in women with diabetes is as per routine antenatal care, and includes a 20-week
anomaly scan and a foetal cardiac scan. The UK guideline [21] recommends ultrasound monitoring of
foetal growth and amniotic uid volume every 4 weeks from 28 to 36 weeks, and individualised
monitoring of foetal well-being for women at risk of intrauterine growth restriction (IUGR) and for
those with macrovascular disease or nephropathy. Tests of foetal well-being before 38 weeks are not
recommended unless there is a risk of IUGR.
Labour and delivery
The primary objectives are to avoid foetal death in utero and the hazards of obstructed labour or
shoulder dystocia associated with foetal macrosomia. As a consequence, caesarean section rates for
women with pre-gestational diabetes in most parts of the world are >50% (67% in the UK CEMACH
survey vs. 24% in the background population) [2]. Iatrogenic prematurity has resulted in high rates of
admission to neonatal intensive care unit (NICU) in type 1 diabetes.
The indications for caesarean section are often multiple and vary with individual hospital policy.
The rate tends to be lower in women with type 2, many of whom have had previous pregnancies at a
time when glucose tolerance was normal. For the obstetrician, the major consideration inuencing the
mode of delivery remains the risk of birth injury. Current UK guidelines advise that women with
diabetes should be offered elective delivery after 38 weeks assuming that no other signicant factors
have developed before this time. An individualised approach to the timing and mode of delivery is
essential. This is particularly so in pre-gestational and insulin-requiring GDM where many factors need
to be considered including glycaemic control, diabetes complications, past obstetric history, foetal
growth (macrosomia or IUGR) and the availability of health-care resources in labour. Preterm labour

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can be particularly hazardous for the infant of the diabetic mother. Beta-sympathomimetic agents used
to suppress uterine contractions, and corticosteroids used to accelerate foetal lung maturation, may
result in signicant and prolonged maternal hyperglycaemia, and even ketoacidosis, and the need for
supplementary insulin must be anticipated. A number of algorithms to guide glycaemic management
during steroid therapy have been developed [5]. Admission to hospital and close supervision are
essential.
The management of labour should follow standard practice as for the non-diabetic woman.
Given the desire not to prolong pregnancy unduly, the induction of labour is widely utilised, and
usually involves a combination of rst prostaglandins followed frequently by oxytocin. Careful
monitoring of progress is facilitated by a partograph and continuous electronic foetal monitoring by
cardiotocography. Management of diabetes during labour should follow an established protocol in a
dedicated centre with a neonatal care unit equipped and staffed to deliver the most sophisticated
level of care. UK guidelines recommend the maintenance of maternal blood glucose between 4 and
7 mmol/l during labour and delivery to reduce the incidence of both neonatal hypoglycaemia and
foetal distress [21]. Hourly capillary glucose measurements provide a ready guide to the success of
management and the need for insulin adjustment. Commonly used regimens (in the absence of a
consensus) include an intravenous glucose/insulin infusion supplemented by additional insulin
doses and a constant glucose infusion with insulin being infused separately by an infusion
pump [5].
Postnatal
In women with type 1 diabetes, the insulin dose is reduced approximately to half that prepregnancy as soon as the cord is cut, followed by subsequent active-dose titration. Regular capillary
glucose monitoring and intravenous uids are continued until the mother is able to eat normally.
Breastfeeding should be supported, and additional carbohydrate intake or further reduction in insulin
dosing to reduce the risk of hypoglycaemia may be needed. Glucose targets are relaxed to those prior to
pregnancy (4e7 mmol/l pre-meals).
In type 2 diabetes, insulin can usually be stopped at delivery with regular monitoring of capillary
blood glucose. UK guidelines recommend that women on metformin or on glibenclamide before
pregnancy may continue to take these drugs post partum while breastfeeding, but each case should be
reviewed on an individual basis [21]. Arrangements should be made for early midwifery community
follow-up and postnatal diabetes review at 6 weeks.
Care of the newborn
All neonates should receive feeding as soon as possible to minimise the risk of hypoglycaemia.
Monitoring of neonatal blood glucose pre-feeds should commence around 3e4 h of age and continue
for at most a few days until levels are persistently above 2 mmol/l. A low blood glucose associated with
abnormal clinical signs is a medical emergency requiring complete clinical evaluation and transfer to a
neonatal unit. Tube feeds may sufce in milder cases, but for a reduced level of consciousness or ts,
intravenous glucose should be instituted rapidly (5 mg/kg/min of glucose equivalent to 3 ml/kg per
hour of 10% dextrose increased as necessary). Blood sampling for hyperbilirubinaemia, polycythaemia,
hypocalcaemia and hypomagnesaemia is dictated by clinical examination. NICU admission should be
considered for symptomatic hypoglycaemia, jaundice, respiratory distress, cardiac failure, preterm
birth and where there is a need for intravenous uids, tube feeding or exchange transfusion for
polycythaemia. A neonatal echocardiogram is indicated in the presence of a heart murmur or if there
are symptoms and/or signs of congenital heart disease.
Contraception
Patient preference and health status are the two main factors that determine the choice of
contraception for diabetic women. Intrauterine contraceptive methods (IUDs) are particularly suited to
women who do not wish to become pregnant within the next year. In women without vascular disease

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who wish to conceive sooner, combined (oestrogen and progesterone) hormonal contraception is
considered safe. The lowest dose (oestrogen 35 mg) and potency formulation should be used as here
the absolute increase in arterial thromboembolism is very low (1/12,000) and comparable to that
among healthy users and non-users. Women with long-standing diabetes, hypertension, microvascular
or cardiovascular complications, those who are <6 weeks post partum, and probably also those who
smoke and who have a BMI >35 kg/m2 should not use oestrogen-containing contraceptives;
progesterone-only methods (injections, implants or tablets) may be used. Barrier and natural family
planning methods are less ideal because of high failure rates. Following completion of childbearing,
vasectomy and female sterilisation are available. When faced with an unintended pregnancy, women
with diabetes must receive additional guidance reecting their increased risk of major congenital
anomalies. Clinicians must understand the range of contraceptive options available and promote
effective methods.

Gestational diabetes mellitus

Screening and diagnosis
GDM is dened as carbohydrate intolerance, with onset or rst recognition during pregnancy,
although it is likely that a proportion of women will have had previously unrecognised type 2 diabetes.
For decades, its validity has been questioned and confusion generated by disparate approaches to
diagnosis and screening. Against this background, the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) [34] study was designed specically to examine the relevance of minor degrees of
hyperglycaemia during pregnancy, short of diabetes, for maternal/foetal outcome. This multicentre,
multicultural observational study involving 23,000 pregnant women undergoing a 75-g oral glucose
tolerance test (OGTT) at 24e32 weeks' gestation showed a continuous association between maternal
glucose levels during pregnancy and each of the primary outcomes (macrosomia, clinical neonatal
hypoglycaemia, primary caesarean section and cord C-peptide levels) (Fig. 1). The relationship of
hyperglycaemia to adverse outcomes was independent on the mother's BMI [35]. A 2013 systematic
review and meta-analysis of RCTs [36] found that the appropriate treatment of GDM (nutritional
therapy supplemented by insulin if needed and self-blood glucose monitoring) resulted in reductions
in the following:
 Pre-eclampsia (RR: 0.62; 95% condence interval (CI): 0.43e0.89) (7.2% vs. 11.7%) (three trials)
 Birth weight >4000 g (RR: 0.50; 95% CI: 0.35e0.71) (ve trials)
 Shoulder dystocia (RR: 0.42; 95% CI: 0.23e0.77) (three trials)
Two trials showed less maternal weight gain [37,38], and one trial showed a reduction in caesarean
section [38].
Given the continuum of risk, recommendations for the diagnosis and screening of hyperglycaemia
in pregnancy were reached by international consensus [39] (Table 1).
Table 1a
Recommendations for the diagnosis of Gestational Diabetes Mellitus (GDM) and overt diabetes in pregnancy by International
Association of Diabetes in Pregnancy Study Groups [39]

Fasting plasma glucose

1-hour plasma glucose
2-hour plasma glucose
HbA1c
Random plasma glucose*

Hyperglycaemia in Pregnancy
one or more of 75g oral glucose tolerance test thresholds
must be equaled or exceeded
 5.1 mmol/l
Or
 10.0 mmol/l
Or
 8.5 mmol/l

Overt diabetes

 7.0 mmol/l

 6.5%
 11.1 mmol/l

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Table 1b
Early detection of GDM
First prenatal visit
Fasting plasma glucose, HbA1c or random plasma glucose
*on all (or only on high risk women)

24-28 weeks gestation

75g oral glucose tolerance test after overnight fast

If results not diagnostic of overt diabetes, and

a) Fasting plasma glucose 5.1 and < 7 mmol/l
diagnose as GDM
b) Fasting plasma glucose < 5.1 mmol/l test at
24-28 weeks with 75g oral glucose tolerance test
On all women not already diagnosed as GDM or
overt diabetes at rst visit

* A random plasma glucose to diagnose diabetes during early pregnancy should be conrmed by a fasting plasma glucose or
HbA1c.
The 75g oral glucose tolerance test thresholds represent the average value at which the odds for birth weight and percent body
fat, and cord blood c-peptide (representing fetal insulin) exceeded 1.75 times the estimated odds of these outcomes compared
with mean glucose values for the whole HAPO population.

These guidelines have been endorsed by the World Health Organisation (WHO) [40] but not all
international bodies [21a, 41]. The 2015 NICE guidelines recommend glucose thresholds of 5.6 mmol/l
and 7.8 mmol/l fasting and 2h post 75g oral glucose load respectively based on an economic analysis
[21a]. Concerns regarding prevalence rates of approximately 20% with the new criteria can be justied
by similar rates of pre-diabetes in women of childbearing age, and most women with GDM are
managed by diet alone minimising medical intervention [42]. The International Association of the
Diabetes and Pregnancy Study Group (IADPSG) recommendations for universal 75-g OGTT screening
may be logistically difcult in some countries.
Current UK guidelines recommend screening by risk factors as follows:






Previous macrosomic baby (4.5 kg)

BMI >30 kg/m2
Previous GDM
First-degree relative with diabetes
Family history with high prevalence of diabetes (south Asian, black Caribbean and middle Eastern)

While logistically attractive, risk factors have only around 50% sensitivity and specicity, and customised strategies, guided by economic analysis, require exploration. The global increase in type 2
diabetes has implications for undiagnosed diabetes before pregnancy, and dictates the need for
screening for hyperglycaemia by venous sampling (fasting or random glucose or HbA1c) at the rst
antenatal booking [39].

Management
Following diagnosis (usually around 28e30 weeks of gestation), these women require education
and nutritional advice. Management and glycaemic targets are similar to those of diabetes preceding
pregnancy. Self-monitoring of blood glucose provides early warning of progressive hyperglycaemia and
the need for additional therapy, especially if associated with accelerated foetal growth. Two RCTs
highlighted that lifestyle change is sufcient to control hyperglycaemia in 80e90% of patients [37,38].
Women treated with diet alone are usually at a lower risk, and logistically they might be managed in a
less intense setting using a treatment algorithm.
If diet is insufcient to control maternal hyperglycaemia, insulin remains the mainstay of treatment
to prevent foetal complications, especially those related to foetal overgrowth. The goals of treatment
(including reduction of postprandial hyperglycaemia) are similar to type 1 diabetes, and MDI regimens
are frequently used. The starting dose of insulin is 0.1 m/kg/day, and with expert advice can easily be
commenced as an outpatient with active titration [5].

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Oral hypoglycaemic drugs in GDM

For women who cannot afford, or who do not wish to use insulin, metformin or glyburide
is approved as an alternative in the UK. Both cross the placenta, although glibenclamide crosses to a
lesser degree. Two systematic reviews [36,43] suggested no consistent evidence of adverse outcomes
with these drugs however, a recent review expressed reservation about glibenclamide [33].
In the largest trial [44] 751 Australian women with GDM at 20e33 weeks of gestation were randomised to metformin (1000e2000 mg daily), with insulin supplementation if needed, or insulin.
Perinatal morbidity (composite outcome) was similar in the two groups (32% vs. 32.2%, respectively).
Severe neonatal hypoglycaemia (<1.6 mmol/l) was lower with metformin (3.3% vs. 8.1%, p 0.008), but
preterm birth was more common (12.1% vs. 7.6%, p 0.04). Maternal weight gain was lower in the
metformin group (0.4 vs. 2.0 kg, p 0.001). Glycaemic control was similar between groups, although
46.3% of women in the metformin group required insulin. Two-year-old children of metformin-treated
patients had more subcutaneous upper limb fat, but no difference in the total body fat, implying a more
favourable pattern of fat distribution [33]. Seven more recent, but smaller trials, have largely conrmed
the safety and efcacy of metformin in GDM compared with insulin [33], while three trials comparing
metformin with glibenclamide suggested lesser maternal weight gain, lower birth weights and higher
neonatal blood glucose levels. In most of these trials, approximately half of metformin-treated women
required additional insulin; this is required generally in older women with a higher baseline BMI, more
marked hyperglycaemia and earlier hyperglycaemia, and earlier diagnosis and treatment of GDM.
The only large randomised trial of glibenclamide (an insulin secretagogue) [45] involved randomisation of 404 women with fasting hyperglycaemia despite diet at 11e33 weeks of gestation to
insulin or glibenclamide therapy (2.5e20 mg daily). Glycaemic control and neonatal outcomes were
similar between the two groups. Four per cent in the glibenclamide group needed insulin. Subsequently, four small RCTs comparing glibenclamide with insulin reported an increased rate of neonatal
hypoglycaemia, macrosomia and IUGR. Other retrospective observational studies have generally
conrmed the effectiveness of glibenclamide, but they variously reported increased rates of preeclampsia, macrosomia, a lower ponderal index, a lower Apgar score, the need for phototherapy,
neonatal hypoglycaemia, stillbirth (in those treated early in gestation) and NICU admission. Approximately 20% of women treated with glyburide needed to be switched to insulin.
The metformin studies (although small in number) indicate at least equivalent neonatal outcomes
compared with insulin while suggesting reductions in neonatal hypoglycaemia, maternal hypoglycaemia and weight gain and improved treatment satisfaction. The glibenclamide studies suggest
that it is effective in lowering blood glucose and generally well tolerated with possibly lower treatment
failure rates than with metformin. However, reports of several adverse outcomes require clarication,
and, consequently, at present, metformin would seem to be the safer oral agent. Follow-up data on both
drugs are needed. Practically, metformin doses should be escalated rapidly to minimise the duration of
hyperglycaemia and insulin started early (possibly even concurrently with metformin) in women with
high BMI, previous GDM and high baseline glucose suggesting likely failure with metformin as a single
agent.
Currently, the American Congress of Obstetricians and Gynaecologists (ACOG) and the UK National
Institute of Health and Care Excellence (NICE) approved the use of metformin or glibenclamide to treat
GDM, while the American Diabetes Association (ADA) recommends the substitution of insulin [22].
Delivery
This is similar to diabetes preceding pregnancy, particularly for women on insulin. In general,
glycaemic control during delivery does not require such intense monitoring or a glucose infusion.
Post delivery, the drug or insulin treatment that was started during pregnancy is discontinued in
anticipation that women will revert to normal glucose tolerance. This can be established provisionally before leaving hospital, but it should be conrmed by a fasting plasma glucose 6e7 weeks
after delivery. If a fasting plasma glucose test has not been performed by 13 weeks, a fasting plasma
glucose test, or an HbA1c test if a fasting plasma glucose test is not possible, should be offered after 13
weeks [21a]. GDM is a recognised risk factor for recurrent GDM (30e84% related to body weight and
ethnicity), type 2 diabetes (sevenfold increase) [46] and the metabolic syndrome. The postnatal visit
therefore provides a unique opportunity to offer lifestyle advice, to screen for cardiovascular risk

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697

factors and to remind women of the need for early referral in the eventuality of future pregnancy. An
annual HbA1c test should be offered to women who were diagnosed with gestational diabetes who
have a negative postnatal test for diabetes [21a].
Long-term outcomes
There is growing evidence that hyperglycaemic intrauterine environment has an enduring inuence on the offspring lifelong risks of cardiovascular and metabolic diseases, contributing to the public
health epidemic of obesity and type 2 diabetes [47]. As these risk factors develop early in life, the
offspring are at an increased risk of obesity during childhood and for developing GDM by the time they
reach childbearing age. The major public health challenge is to break this vicious cycle by the prevention of diabetes or by impaired glucose tolerance until after childbearing age, and possibly also by
better control of diabetes during pregnancy. Recent studies outside of pregnancy have shown that
lifestyle intervention (particularly in women with previous GDM), with or without pharmacological
measures, is effective at delaying type 2 diabetes in women with previous GDM, and is cost effective
[48]. The validity of the new GDM diagnostic criteria as predictors of long-term outcomes is now being
evaluated (HAPO Follow-Up Study).
Summary
Globally, it is estimated that 21.4 million (16.9%) of 127.1 million live births to women aged 20e49
years are affected by hyperglycaemia in pregnancy. These statistics reect the growing prevalence of
type 2 diabetes and obesity on pregnancy. Congenital malformation and perinatal mortality rates
remain several-fold higher than in the background population even in the best centres. Adverse outcomes are similarly poor in both type 1 and type 2 diabetes, and maternal obesity adds to the
complexity of management. Although the benets of pre-pregnancy care have been clearly demonstrated, the majority of women still do not plan for pregnancy. Over the last 5e10 years, several large
randomised trials have provided new insights into the role of oral hypoglycaemic drugs and insulin
analogues, while CSII and CGMS would appear best suited to problematic patients. The 2010 IADPSG
consensus recommendations for diagnosis and screening have been endorsed by the WHO but not by
NICE (2015) which has recommended different diagnostic thresholds based on a cost economic
analysis. Despite increased risks, the outcome of pregnancy for most women with diabetes is good, and
undoubtedly reects improved obstetric surveillance and better management of maternal hyperglycaemia over the last several decades. The aim is, through education and maternal empowerment, to
optimise blood glucose control both before and during pregnancy, so that pregnancy may proceed as
normally as possible and result in the birth of a normal baby at near term.

Practice points
 Congenital malformations and perinatal mortality rates remain twofold to fivefold higher in
pregnant women with diabetes compared with those in the general population
 Rates of type 2 diabetes, compounded by obesity, are increasing globally, and are associated
with similarly poor outcomes to type 1 diabetes
 Optimising glycaemic control remains challenging for both patient and clinician, and must be
constantly balanced against the risks of hypoglycaemia
 RCTs suggest that insulin aspart and detemir are safe to use in type 1 diabetic pregnancy, and
they have some benefits over conventional insulin
 New consensus recommendations for the diagnosis of GDM have been published and are
endorsed by the WHO
 Oral hypoglycaemic drugs are likely to be used increasingly to supplement or replace insulin
in the management of women with GDM and type 2 diabetes, especially in those who are
overweight

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Research needs
 Studies to examine how attendance for pre-pregnancy care can be improved
 RCTs to examine the role of sensor-augmented pump therapy in pregnant women with type 1
diabetes compared with optimal conventional regimens
 Better predictors of poor foetal outcomes in women with diabetes preceding pregnancy
 Studies to examine the cost-effectiveness of screening for GDM and the potential for selected
screening in certain populations
 RCTs to examine the most cost-effective way of producing lifestyle change in obese women
with GDM both during and after pregnancy

Conicts of interest
None.
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