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This chapter should be cited as follows:
McMicking J, Lam AYR, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.416413

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 8

Maternal medical health and disorders in pregnancy

Volume Editor: Kenneth K Chen, MD, Alpert Medical School of Brown University, USA Originating Editor: Professor Sandra Lowe

Chapter

Epidemiology and Classification of Diabetes in Pregnancy

First published: November 2021

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By completing 4 multiple-choice questions (randomly selected) after studying this chapter readers can qualify for Continuing Professional Development awards from FIGO plus a Study Completion Certificate from GLOWM
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INTRODUCTION

Epidemiology

Worldwide, the number of people living with diabetes has more than doubled over the last 20 years, from 108 million in 1980 to 422 million in 2014.1 This equates to 8.5% of adults living with diabetes.

It is estimated that 16.9% of pregnancies globally are affected by hyperglycemia in pregnancy using the WHO criteria, equating to 21.4 million of 127.1 million live births to women.2,3,4,5 The incidence is increasing, attributed by the combination of higher obesity rate, advanced maternal age, and changes in screening and diagnostic criteria.2,6,7,8 The differences between low-, middle-, and high-income countries are reported in Appendix 1.5 The International Diabetes Federation (IDF) estimated in 2019 (9th edition) that globally the overall prevalence of diabetes in pregnancy was 15.5% of which 12.8% was GDM, 1.3% was pre-existing diabetes 1.3% and 1.3% was diabetes first detected in pregnancy.9

Pre-existing diabetes was recorded as early as ancient Greek times with the word “diabetes” meaning to siphon or pass through, and “mellitus” meaning honey or sweet. It was not until 1922 that the first human received insulin to treat the condition. In 1936, research was published that differentiated between type 1 and type 2 diabetes. The classification of gestational diabetes dates to White’s classification in 1949.10 It was a simple system which classed diabetes according to its favorability from "A" to "F", which incorporated the age of onset, duration of diabetes, and presence of metabolic and vascular complications.10 From there, further work on screening for gestational diabetes was performed in the 1960s.

In the UK, up to 5% of pregnancies in women are complicated by either pre-existing or gestational diabetes (GDM).7,11 Of this cohort, approximately 87.5% have gestational diabetes, 7.5% type 1 diabetes and 5% type 2 diabetes.7 Over the last 17 years a large epidemiological study of over 400,000 pregnancies showed that prevalence of type 1 diabetes increased from 1.56 to 4.09 per 1,000 pregnancies, and type 2 diabetes 2.34 to 10.62 per 1,000 pregnancies.11 In particular, the increase was more rapid from 2009. In Scotland, there was a 44% increase in type 1 pregnancies from 1998–1999 to 2012–2013, and 90% increase in type 2 diabetes (p<0.001).12

In Australia, statistics from 2005–2007 show that pre-existing diabetes affects up to 1% of pregnancies, and GDM 5%.1 In the US, the prevalence of GDM has been estimated at affecting 7.6% pregnancies between 2007 and 2014. Southeast Asia has the highest prevalence of GDM with an estimated prevalence of 23–25%, in addition to its high population prevalence of type 2 diabetes.3,13 It is worth emphasizing that in South East Asian populations, the prevalence of GDM is considerably higher at lower BMI ranges compared to other populations.3 In New Zealand the GDM rates are as high as 10% in some populations.14

The prevalence observed in part reflects a variation in the diagnosis of GDM internationally, contributed by the difference in screening and diagnostic criteria used. This was apparent in the HAPO study where the reported prevalence was 9–26%, while other population studies reported 1–28%.15,16 Pre-existing diabetes is also being detected opportunistically in women due to GDM screening.

CLASSIFICATION

Pre-existing diabetes refers to a chronic metabolic disease that has been diagnosed prior to pregnancy. Type 1 diabetes mellitus, previously known as juvenile onset or insulin-dependent diabetes, accounts for 5–10% of diabetes outside of pregnancy. It results from autoimmune beta cell destruction, leading to absolute insulin deficiency.11,17 The onset is typically in the first three decades of life, but can occur at any age, even into the 8th and 9th decade of life. Type 2 diabetes mellitus accounts for 90–95% of all diabetes. Patients with type 2 diabetes mellitus have peripheral insulin resistance and relative insulin deficiency.17 This condition tends to be associated with poor nutrition, being overweight or obese, and later age of onset. In addition, there is a strong hereditary component with this disease, with a positive first degree family member resulting in three times increased risk of developing the disease.18

Maturity onset diabetes of the young (MODY) refers to a group of monogenic disorders, which accounts for 1–2% of diabetes..17,19,20 It is a heterogenous group of disorders due to single gene mutations affecting the beta-cells of the pancreas resulting in impaired insulin production.19 The most common type of mutation is of the glucokinase gene (GCK), and is designated MODY-type 1. It is hard to accurately report the incidence of GCK-MODY, as it is higher in different ethnic populations, but it is estimated to be between 10 and 60% of the MODY cohort.21 Clinical characteristics of MODY include onset of diabetes before age 25 years, a strong family history of diabetes, insulin independence, absence of autoantibodies for pancreatic antigens, and an absence of features usually associated with insulin resistance (e.g. being overweight or obese, acanthosis nigricans, high triglyceride levels, low high-density lipoprotein cholesterol).19

Gestational diabetes refers to glucose intolerance resulting in hyperglycemia of variable severity with onset or first recognition in pregnancy, that usually resolves following the pregnancy.2,17 In normal pregnancy, insulin sensitivity declines with advancing gestation due to placental factors such as progesterone, estrogen and placental lactogen, resulting in a compensatory increase in insulin secretion to maintain glucose homeostasis. Gestational diabetes develops if the pancreatic B cells cannot keep up with insulin demand, in tandem with the progressive increase in insulin resistance.

What constitutes gestational diabetes or glucose intolerance in pregnancy has historically created much controversy.6 Current recommendations have suggested using the term “diabetes in pregnancy” for women who meet non-pregnant screening criteria for diabetes and “gestational diabetes” for women meeting the lower screening criteria used in pregnancy. This has not been universally adopted with others referring to “diabetes in pregnancy” as any woman with diabetes in pregnancy. Others have used the term “overt diabetes” to describe women diagnosed with diabetes early in pregnancy, given the likelihood of being pre-existng and reserving “gestational diabetes” for those diagnosed in second or third trimester.2,17 There is also a lack of clarity in the definition of abnormal glucose tolerance in early pregnancy as both glucose and insulin levels are lower physiologically early in pregnancy.6 Fasting plasma glucose levels decrease with advancing gestation, with contributing factors including increased utilization by the fetoplacental unit. In addition this is accompanied by a decrease in insulin sensitivity from early in the first trimester, with the quantitative amount variable according to BMI.22

The definition still stands, given that all forms of diabetes in pregnancy is associated with significant adverse perinatal outcomes. It is however a heterogenous group of women with a wide range of glucose abnormalities and varying metabolic profiles.2,6

MATERNAL AND FETAL CO-MORBIDITIES AND OUTCOMES

Maternal

Women with pre-existing diabetes have a higher prevalence of essential hypertension. In addition, there is a 40–45% risk of developing hypertensive disorders of pregnancy.2,22 Type 1 diabetes is more strongly associated with development of pre-eclampsia, and type 2 with essential hypertension.2

Diabetes and its complications can also accelerate in pregnancy with poor glycemic control leading to worsening retinopathy and nephropathy. The risk of retinopathy progression is dependent on numerous factors, including glycemic control preconception and during pregnancy, presence of pre-existng retinopathy, and pregnancy outcomes.23 Factors that have correlated with a higher degree of retinopathy deterioration include greater difference in HbA1c between the first and third trimester and development of hypertensive disorders of pregnancy.23 Gestational diabetes can also lead to hypertensive disorders of pregnancy and pre-eclampsia. Intrapartum adverse outcomes include the need for early induction of labor, preterm delivery, assisted vaginal delivery, and cesarean section.24

Women with type 1 diabetes also carry a risk of hypoglycemia in the first trimester, due to physiological changes that occur in combination with efforts for tight glucose control to achieve normoglycemia.8,26 Enhanced insulin sensitivity is also seen following the delivery of the placenta and therefore adjustments to the usual insulin regime are critical to avoid hypoglycemia. Women are also at risk of diabetes ketoacidosis, due to pregnancy creating a "ketogenic state", as well as being able to develop ketoacidosis insidiously at lower blood glucose thresholds than the non-pregnant state due to higher glomerular filtration rate and lower renal threshold for glucosuria.26

Long-term outcomes for women with GDM include markedly increased risk in developing type 2 diabetes mellitus, metabolic syndrome, as well as cardiovascular disease.8,24,27,28 A population-based retrospective cohort study, which examined more than 9,000 women in the UK showed that GDM women were 20 times more likely to develop type 2 diabetes mellitus and 2.8 times more likely to develop ischemic heart disease.29 They were also two times more likely to develop hypertension.29

A recent meta-analysis looking at 28 studies and 170,139 women found that following GDM, the risk for type 2 diabetes increased linearly (9.6%) with every year following completion of pregnancy. At 10 years, the risk for type 2 diabetes was 19.72%, 20 years 29.36%, and 39.00% at 30 years. In addition, women of Asian ethnicity, advanced age, and higher body mass index were at greater risk.30

Fetal

Adverse fetal outcomes in pregnancies complicated by type 1 and 2 diabetes are greater than the background population.4,31 The most profound effect is an increased risk of congenital malformations, which occurs as a consequence to hyperglycemia in preconception, periconception and weeks 2–8 of the first trimester.24,26,32 The most common malformations are neural tube defects, congenital heart disease, and musculoskeletal disease.4

The National Birth Defects Prevention Study recently published results from population-based birth defects case control study that looked at nearly 42,000 pregnancies from 1997 to 2011. The study concluded that a strong relationship existed between pre-existing diabetes and fetal congenital anomalies, versus gestational diabetes. In particular, 24 cardiac defects included had an association of statistical significance with pregestational diabetes. Table 1 provides a summary of the key findings from this study.32

1

Diabetes and selected birth defects. Adopted from the National Birth Defects Prevention Study, 1997–2011.32

Birth defect

Total

Pregestational

Gestational diabetes

n

Odds ratio (95% CI)

n

Odds ratio (95% CI)

Anencephaly

  627

17

 3.5
(1.9–6.5)

 22

0.7
(0.5–1.1)

Spina bifida

1,236

12

 1.4
(0.8–2.7)

 62

0.9
(0.6–1.2)

Cleft palate alone

1,570

42

 4.3
(2.9–6.5)

 96

1.4
(1.1–1.8)

Cleft lip with or without cleft palate

3,046

58

 3.0
(2.1–4.3)

161

1.1
(0.9–1.3)

Renal agenesis/hypoplasia

 180

11

 8.1
 (3.9–16.9)

  3

0.4
(0.1–1.1)

Sacral agenesis

  104

33

80.2
 (46.1–139.3)

  6

1.7
(0.6–4.8)

Tetralogy of Fallot

1,181

40

 5.3
(3.5–8.0)

 81

1.5
(1.1–1.9)

Atrioventricular septal defect (ASD)

  359

20

10.5
(6.2–17.9)

 15

1.1
(0.6–1.8)

Coarctation of aorta

1,149

30

 4.5
(2.8–7.1)

 72

1.3
(1.0–1.8)

Ventricular septal defect and ASD

  747

34

6.9
(4.4–10.8)

 48

1.4
(1.0–1.9)

Hyperglycemia in the first trimester is also associated with an increased miscarriage rate, with HbA1c >97 mmol/mol (11%) carrying 44% miscarriage rate.26

There is also an increased risk of large-for-gestational-age (LGA) fetus or macrosomia (birth weight >4,000 g) due to maternal glucose crossing the placenta, a phenomenon described by Pedersen’s hypothesis.27,28 This leads to fetal hyperglycemia and subsequent hyperinsulinemia, which result in increased fat and protein stores from anabolic hormone effects and anabolic fuel.33 Associated polyhydramnios also occurs in this setting.28 Macrosomia increases the risk of shoulder dystocia, which can have significant perinatal morbidity and mortality, including brachial plexus injury, fetal hypoxia, and poor Apgar score.4,28,33 The mechanism supporting the link between diabetes in pregnancy and shoulder dystocia is the central growth and adiposity that accompanies these fetuses, with large trunk measurements in comparison to the head.33,34

Table 2 summarizes data from Scottish population data between 1998 and 2013 on pre-existing diabetes and obstetric outcomes.

2

Obstetric outcomes for type 1 and type 2 diabetes.12

Variable

Type 1

Type 2

No pregestational diabetes

Stillbirths, n
(n per 1,000 births)

63***
(19.5)

36***
(24.8)

3,966
(4.9)

Perinatal mortality, n
(n per 1,000 births)

65***
(20.1)

39***
(26.9)

5,154
(6.4)

Mean birthweight, g

3,466.7 +/− 802.8*

3,474.4 +/− 793.1*

3,398.8 +/− 587.9*

LGA, % (n)

50.9 (1,623)***

38.4 (549)***

10.5 (84,141)

*p < 0.001 versus type 2 diabetes; ***p < 0.001 versus no diabetes.

The risk of perinatal mortality in pre-existing diabetes in pregnancy is four times higher compared to pregnancies without diabetes.2,31,35 This is due to major structural anomalies, stillbirth, fetal hypoxia, and preterm birth.35,36 Poor glycemic control prior to and during pregnancy is associated with a higher rate of adverse outcomes.2,36 This was demonstrated in a North England Study looking at all diabetic pregnancies versus population data between 1996 and 2008, where preconception HbA1c levels >6.6% (49 mmol/mol) (aOR 1.02), pre-pregnancy retinopathy (aOR 2.05) and third trimester HbA1c >6.1% (aOR 1.06) carried increased risk of perinatal mortality in those with pre-existing diabetes with normally formed singleton pregnancies.2,35 Women with type 2 DM had the highest risk of stillbirth.25,37

Data from Scotland published in 2019 examined this in more detail, looking at stillbirth amongst 5392 singleton type 1 and type 2 diabetes between 1998 and 2016 (3,778, 1614, respectively).37 Women with type 1 diabetes had a stillbirth rate of 16.1 per 1,000 births (95% CI 12.4–20.8) (n = 61), with pregnancies characterized by higher HbA1c before pregnancy (OR 1.03, 95% CI 1.01–1.04, p = 0.0003). Over one-third (38%) of stillbirths occurred at term, highest in the 37th and 38th week (5.1 per 1,000 ongoing pregnancies, 95% CI 2.8–9.1 versus 7.0, 95% CI 3.7–12.9). Only 11% of this cohort delivered over 38th week. Type 2 diabetic women had a stillbirth rate of 22.9 per 1,000 births (95% CI 16.4–31.8), with the cohort having a higher maternal BMI (OR 1.07, 95% CI 10.01–1.08, p = <0.0001) and higher pre-pregnancy HbA1c (OR 1.02, 95% CI 1.00–1.04, p = 0.016). Stillbirth rate was the highest in 39th week at 9.3 per 1,000 ongoing pregnancies (95% CI 2.4–29.2). Overall, the risk of stillbirth was highest for birthweights <10th centile (type 1 diabetes sixfold higher, type 2 diabetes threefold higher), and birthweight >95th centile (type 2 diabetes twofold higher).

Diabetes in pregnancy can also lead to fetal complications such as neonatal hypoglycemia immediately after delivery, when glucose input from mother is disrupted and the neonate at this stage is hyperinsulinemic.4,24 There is also risk of polycythemia, hypocalcemia, hyperbilirubinemia, and respiratory distress syndrome.24,26

A large review published in 2013 looked at 12 population studies over the past 10 years, compared women with type 1 diabetes (14,099) and non-diabetic women (4,035,373). It looked at four complications specifically for risk of adverse pregnancy outcome, as demonstrated in Table 3.38

3

Outcomes for type 1 diabetes versus non-diabetes population.


Type 1 diabetes

Non-diabetes

Relative risk (RR)

Congenital malformations

 5.0%

 2.1% 

2.4

Perinatal mortality

 2.7%

 0.72%

3.7

Preterm delivery

25.2%

 6.0% 

4.2

Large for gestational age infants

54.2%

10.0% 

4.5

In addition, a Swedish population-based study compared 5,089 type 1 diabetic women to 1,260,207 controls and examined the obstetric and fetal complications.39 This large study was able to capture both pregnancy and fetal complications, and demonstrate rates consistent with other high-income countries.

4

Pregnancy complications and mode of delivery in type 1 diabetes versus control population.39


Type 1 diabetes (%)

Non-diabetes (%)

Adjusted OR (95% CI)

PIH

 1.6

 0.87

1.53 (1.18–1.99)

Pre-eclampsia mild

9.7

 2.0 

4.30 (3.83–4.83)

Pre-eclampsia, severe

 4.3

 0.8 

4.47 (3.77–5.31)

Cesarean section

46  

12   

5.31 (4.97–5.69)

VE/forceps

 9.6

 6.6 

1.41 (1.25–1.58)

5

Fetal and neonatal complications in type 1 diabetes versus control population.39


Type 1 diabetes (%)

Non-diabetes (%)

Adjusted OR (95% CI)

Stillbirth

1.5

0.3

3.34 (2.46–4.55)

Fetal distress

14   

6.2

2.34 (2.12–2.58)

Perinatal mortality

20   

4.8

3.29 (2.50–4.33)

Neonatal mortality, 0–7 days

5.1

1.8

3.05 (1.68–5.55)

Neonatal mortality, 0–28 days

7.0

2.2

2.67 (1.72–4.16)

Birth <37 weeks

21   

5.1

4.86 (4.47–5.28)

Birth <32 weeks

2.3

0.7

3.08 (2.45–3.87)

Large for gestational age

31   

3.6

11.4 (10.6–12.4)

Small for gestational age

2.3

2.5

0.71 (0.55–0.91)

Major malformations

4.7

1.8

2.50 (2.13–2.94)

Apgar <7 at 5 min

3.1

1.1

2.60 (2.14–3.17)

Apgar <4 at 5 min

 0.80

 0.30

2.39 (1.64–3.51)

Erbs palsy

2.1

 0.25

6.69 (4.81–9.31)

Respiratory distress syndrome

1.0

 0.20

4.65 (2.20–9.84)

Respiratory disorders

9.5

2.6

3.42 (3.04–3.85)

There is also now increasing evidence to suggest children and adolescents with exposure to diabetes in pregnancy are associated with increased risk of obesity and diabetes in adulthood, due to the impact of the hyperglycemic intrauterine environment.40,41 A follow-up study in Denmark of 597 adult offspring born to mothers with either GDM or type 1 diabetes showed a higher prevalence of type 2 diabetes.40 When compared to background population, the adjusted odds ratio for type 2 diabetes in the GDM group was 7.76 (95% CI, 2.58–23.39) and 4.02 (95% CI, 1.31–12.33).40 In addition, the risk of being overweight was doubled in the offspring of GDM or type 1 diabetes in this same cohort, and risk of metabolic syndrome was 4 and 2.5 times, respectively.41

SCREENING STRATEGIES FOR GESTATIONAL DIABETES

Currently no screening strategy has been adopted globally for gestational diabetes as no single method meets the classic criteria of a screening test. In particular, issues related to cut-off values have been highly contentious, predominantly because the impacts of hyperglycemia follow a continuum without any obvious deflection point.42 Universal versus selected screening, timing of screening, and type of testing all continue to be debated between National and International interest groups. In addition, the WHO states “it is important to avoid imposing models from high-resource settings with advanced health systems on countries that lack the infrastructure and resources to achieve adequate coverage of the population. Screening programs require significant health resources, infrastructure and functional health systems to be effective”.43

Screening was introduced in the 1960s following work by O’Sullivan, which showed that screening, diagnosing, and treating hyperglycemia in pregnancy led to improved outcomes for mother and baby.6 The proposed diagnostic test was a 3-h 100 g glucose challenge, and the criteria cut offs used were based on successful treatment regimes to reduce LGA.6

The aim of screening in pregnancy can be divided into two main phases.27,28

  • Early pregnancy screening (up to 20 weeks) – to detect overt diabetes or diabetes that may have been present before pregnancy, given the increased risk of congenital anomalies and later maternal and fetal complications associated with pre-existing diabetes. Unfortunately, many women will only present for antenatal care well after the completion of embryogenesis.
  • Second-trimester screening (26–28 weeks) – to detect gestational diabetes.

Early pregnancy screening

This screening strategy is ideally performed after a woman’s initial prenatal visit and has been focused on women with risk factors for hyperglycemia.45 Risk factors for patient selection for early screening do vary internationally, however the most consistent is previous history of gestational diabetes.

Abnormal early diabetes screening has been shown to correlate with an increased risk of adverse pregnancy outcomes. A retrospective study in Israel involving 6,129 women looked at fasting glucose levels in the first trimester and pregnancy outcomes.45 Findings included a strong association with first-trimester maternal hyperglycemia and the development of GDM, with the highest category of 100–105 mg/dl (5.6–5.8 mmol/l) glucose having an AOR 11.92 (95% CI 5.39–26.37). In addition, as first-trimester fasting glucose increased, the rate of LGA and cesarean section also increased.

First-trimester screening may be directed to selected high-risk women or be universal, as demonstrated in the following table, which shows the variation that exists internationally. Many criticisms surround the differing approaches to early pregnancy screening for gestational diabetes. The primary aim is to detect undiagnosed diabetes, however given the physiological changes that occur during pregnancy, no consensus can be made on the most suitable test or diagnostic criteria.43,44

6

First-trimester screening.


NICE (2015)7

ADIPS (2014)46

IADPSG (2010)6

NZ (2014)13

Population screened

Women with risk factors only

Women with risk factors

Universal testing or those high risk

Universal screening

Test


OGTT (ideally)

Fasting plasma glucose, random plasma glucose or HbA1c

HbA1c

Criteria



≥5.1 mmol/l

≥11.1 mmol/l

HbA1c
≥48 mmol/mol
(6.5%)

HbA1c ≥50 mmol/mol
(6.7%)

The International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria uses the same criteria as the second-trimester screening, however one would argue that this would result in an under detection of GDM given the physiological decrease in glucose and insulin levels in early pregnancy.2 The HbA1c value in this criteria was based on the a previous expert committee that had recommended HbA1c ≥6.5% be used for diagnosis, based on data in a non-pregnant population.48 However it is likely that the optimal HbA1c in pregnancy is lower, given HbA1c levels fall in the first trimester, and are 0.5% lower by 14 weeks.47,48

The ADIPS screening strategy for early pregnancy screens only those women with risk factors present. These risk factors are shown in Appendix 1, which interestingly differ from other groups that employ a risk-factor screening approach. What is defined as high risk in this cohort does vary in comparison to other international population groups.46

The timing for screening in early pregnancy also poses difficulty. The aim is to diagnose as early as possible for optimization of management of the disease, however there is variability across health settings for timing for first health encounter and opportunity to screen.42 Given the feasibility of accessing a fasting glucose test, this has been questioned, which makes the HbA1c testing seem more favorable.48

First-trimester screening is therefore a highly debatable area, as discussed in the following sections, and is further confounded by the WHO, which does not consider or recommend HbA1c as a screening tool for diagnosis of overt diabetes in pregnancy.2,6,28

Second-trimester screening

Second-trimester screening is typically performed between 24 and 28 weeks’ gestation, through either universal or a selective screening pathway.

The HAPO study was designed to assess the relationship between the level of maternal hyperglycemia and adverse pregnancy outcomes (including macrosomia and fetal hyperglycemia).42 The conclusion of this study reported in 2009 was that there was a continuous and linear relationship between maternal hyperglycemia (as defined by the results of a 2-h 75 g OGTT) in pregnancy and adverse clinical outcomes, independent of other risk factors as shown in Table 7.9,42,49

7

HAPO: Adjusted odds ratios for associations between maternal glycemia on a 2-h OGTT with primary and secondary perinatal outcomes.

Plasma glucose level – odds ratio (95% CI) per 1 mmol increase at each time point of the OGTT

Fasting

1 h

2 h

Primary outcome

Birth weight >90th centile

1.38 (1.32–1.44)

1.46 (1.39–1.53)

1.38 (1.32–1.44)

Primary cesarean section

1.11 (1.06–1.15)

1.10 (1.06–1.15)

1.08 (1.03–1.12)

Clinical neonatal hypoglycemia

1.08 (0.98–1.19)

1.13 (1.03–1.26)

1.10 (1.00–1.12)

Cord blood serum C peptide >90th centile

1.55 (1.47–1.64)

1.46 (1.38–1.54)

1.37 (1.30–1.44)

Secondary outcome

Premature delivery (before 37 weeks)

1.05 (0.99–1.11)

1.18 (1.12–1.25)

1.16 (1.10–1.23)

Shoulder dystocia or birth injury

1.18 (1.04–1.33)

1.23 (1.09–1.38)

1.22 (1.09–1.37)

Intensive neonatal care

0.99 (0.94–1.05)

1.07 (1.02–1.13)

1.09 (1.03–1.14)

Hyperbilirubinemia

1.0 (0.95–1.05) 

2.0

1.11 (1.05–1.17)

1.08 (1.02–1.13)

Pre-eclampsia

1.21 (1.13–1.29)

1.28 (1.20–1.37)

1.28 (1.20–1.37)

The IADPSG consensus panel convened in 2010 and recommended new diagnostic thresholds for GDM based on the HAPO findings. In the absence of an obvious deflection point in the glucose continuum, the values selected were pragmatic, equating to a 1.75-fold increase in adverse outcomes, including large for gestational age, elevated C peptide, high neonatal body fat, or a combination of these factors.47 These have been adopted in some parts of the world, however, there has been reluctance from other parts of the world due to the perceived higher prevalence with the adopted criteria and associated economic strain on health resources.9 In addition, these criteria have not yet been tested in a prospective trial to determine if they improve outcomes compared with previous criteria or screening methods.

Despite IADPSG recommendations, there remains variation in clinical practice in screening and diagnosis of GDM as demonstrated in Table 6. A number of countries still recommend a two-step screening process utilizing a 1-h random 50 g glucose challenge test (GCT) as an initial step.

8

Second trimester.


IADPSG/
WHO (2010)6

NICE (2015)7

Canada (2013)2

ACOG (2013)8

NZ (2014)13

Description

75 g OGTT

75 g OGTT

Sequential

  • GCT
  • If positive, 75 g OGTT

Sequential

  • GCT
  • If positive:
    • 3 h 100 g OGTT

Two-step screening.

  • No risk factors – sequential GCT/75 g OGTT
  • If risk factors – 75 g-OGTT

Fasting

≥5.1 mmol/l

≥5.6 mmol/l

≥5.3 mmol/l

≥5.3 mmol/l

>5.5 mmol/l

1 h

≥10 mmol/l


≥10.6 mmol/l

≥10.0 mmol/l


2 h

≥8.5 mmol/l

≥7.8 mmol/l

≥9.0 mmol/l

≥8.6 mmol/l

>9 mmol/l

3 h




≥7.8 mmol/l


GCT, glucose challenge test; OGTT, oral glucose tolerance test.

Controversies in screening

Population screened and modality of screening

Variation still exists internationally for the adoption of universal screening versus selective risk-based screening, and one-step versus two-step sequential screening. Selective screening method is based on the presence or absence of selective risk factors, from maternal or obstetric history.50 This allows those at lower risk based on history to avoid the screening process.

In the UK, one-step selective screening is performed using a 75 g OGTT and risk factors defined in the NICE guidelines.7 Despite the values differing from IADPSG criteria, the argument proposed is that the selective approach combined with this criteria balance the benefits of increased detection against the economic cost and capacity limits of the health-care providers.7

In France, selective screening has been adopted with the test only recommended if there are one of four risk factors, which include raised BMI, age more than 35 years, first degree family history of diabetes, and previous history of GDM or macrosomia.51

In Australia, universal screening is recommended by the Australian Diabetes in Pregnancy Society (ADIPS), with all women undergoing a 75 g OGTT at 24–28 weeks’ gestation.44 The values set are from the IADPSG recommendations. One of the criticisms is that this universal screening method results in the diagnosis of a large GDM cohort and false-positive test results following one OGTT.49

Proponents of sequential screening argue that this strategy has its advantages, citing that the GCT is a simple test to conduct across a large population given its non-fasting state, and also has relatively acceptable sensitivity and specificity of 74% and 85%, respectively.28 Another study showed the FPG and GCT for screening for GDM carrying an overall sensitivity and specificity of 75.0% and 92.0% for GCT, and 88.8% and 95.2% for FPG. A large Canadian study showed the two-step approach was acceptable with good uptake by women, but also maintained equivalent diagnostic power when compared to one-step testing.2,52 Therefore, one could conclude GCT is acceptable for screening, but has limited diagnostic capacities.

Canada despite using the two-step approach has recognized that there is a GCT threshold for which the diagnosis of GDM can be made, avoiding OGTT having to be performed.2 This cut-off value is ≥11.1 mmol/l. From a retrospective study, these women were found to have a 3.7 increased rate of insulin treatment compared to women diagnosed as GDM by two-step criteria (GCT followed by OGTT), which demonstrates their high risk of increased adverse pregnancy outcomes.54

The use of HbA1c solely as a diagnostic test has been questioned. In earlier times, the HAPO study showed the associations with adverse outcomes significantly stronger with glucose measures than HbA1c.42 However more recently, a Spanish study involving 1,288 pregnancies was able to compare fasting plasma glucose and HbA1c in a prospective observational cohort.55 No association was found between fasting plasma glucose levels and adverse pregnancy outcomes, whereas HbA1c thresholds did correlate with macrosomia and pre-eclampsia.

A New Zealand study conducted in 2008–2010 across 16,122 pregnancies was in support of the use of HbA1c in the first trimester, however their results suggested diagnostic criteria of HbA1c ≥5.9%.48 If the cut off of 6.5% was used, it was shown to miss almost half of the women with positive OGTT in the second trimester versus all women being identified with revised HbA1c criteria of ≥5.9%. In addition, an early pregnancy HbA1c 5.9–6.4% correlated with increased risk of adverse pregnancy outcomes including congenital anomaly (RR 2.76, 95% CI 1.51–5.04), pre-eclampsia (RR 3.04, CI 1.97–4.70), shoulder dystocia (RR 2.48, 95% CI 1.21–5.10), and perinatal death (RR 2.24, 95% CI 0.75–6.69).

Risk factors for selective screening

There is inconsistency internationally for what is classed as a risk factor. In addition, when a risk-factor approach is used for screening strategies, further criticism has been directed at the lack of equivalent predictive value for different risk factors.

An observational retrospective study conducted in 2011 in Australia found the strongest independent risk factors using ADIPS criteria for GDM included past history of GDM (OR 10.7, 95% CI 5.4–21.1, p < 0.001), maternal age ≥40 years (OR 7.0, 95% CI 2.9–17.2, p < 0.001) and BMI ≥35 (OR 6.1, 95% CI 3.0–12.1, p < 0.001).50 The aim was to compare number of women screened, and sensitivity for GDM. Overall a greater number of women were screened positive using ADIPS criteria (2121 versus 1695, respectively), however ADIPS had a greater sensitivity 98.6% (95% CI 96.1–99.95) versus 92.7% (95% CI 88.5–95.5).

When risk factors are studied, the most consistent non-modifiable ones include increased parity, age, and ethnicity.28 With advancing maternal age, the risk of developing GDM increases from 2 to 7% if greater than 35 years of age.28 Assisted reproduction (ART) also carries increased risk, with an Australian study showing higher rates of GDM in women who had undergone ART (7.6%) compared to spontaneous conception (5%, p value 0.001).56

The recurrence rate for GDM in subsequent pregnancies is variable, reported to lie between 30 and 84%.57 The most significant modifiable risk factor is BMI, with obesity carrying twice the risk of developing GDM versus overweight category.2

Recently evidence has suggested that diagnostic thresholds for GDM should incorporate body mass index (BMI) of patients. A study published in 2015 highlighted that women with a lower BMI should have adjusted criteria.58 Although the number of participants was low (n = 527) in this cohort in Ireland, it suggests that using IADPSG criteria, a beneficial effect is observed with treatment (reduction of LGA and macrosomia rates) in obese GDM women but not for those with BMI <25. Women with a BMI <25 but GDM diagnosis as per IADPSG had the same outcomes as those with negative tests. The conclusion of this study suggested that these women could be managed in a low-resource setting.

Another study used a two-step screening strategy and demonstrated that GDM therapy had a positive impact on the control of fetal growth for those with class 1 and 2 obesity, but not normal weight or class 3 severe obesity.59 It was proposed that the reason there was no significant reduction in fetal growth in class 3 obesity in GDM setting was that other factors existed that contributed to fetal growth such as low-grade inflammation from the maternal obesity, leading to a shift in fetal muscle cells from myogenesis to adipogenesis.59

A population-based study in Norway published in 2012 highlighted the differences in prevalence of GDM with IAPDSG and WHO criteria amongst ethnic minority groups.15 When the modified IADPSG criteria was used, there was a 2.2 to 2.8 increase in GDM prevalence, highlighting the stark differences between the screening criteria.

Cost of different screening strategies

Major challenges that face the global adoption of IADPSG criteria is the increase in the diagnosed GDM population, the demand of services that accompany this increase, and the pressures on the health-care system.60 The CDC Diagnosing Gestational Diabetes Mellitus Conference estimated that applying the IADPSG criteria in the United States would result in 450,000 more patient education visits, 1 million more clinic visits, 1 million more prenatal testing appointments per year.59

However, the counter argument is that these costs can be mitigated if it results in better maternal and neonatal outcomes.14 One example was the St Carlos study in Spain where the application of IADPSG criteria resulted in tripling the GDM rate from 10.6% to 35.5%, however provided a cost savings of nearly E15,000 per 100 women.60 This study examined 1,526 women for 12-month period following introduction of IADPSG in 2012, compared to a similar cohort previously using two-step criteria. The savings were achieved through improvements in pregnancy outcomes, including a reduction in the rate of gestational hypertension, prematurity, cesarean section, NICU admissions, and rates of SGA and LGA babies.60

New Zealand recently published a study to provide justification for their two-step screening strategy. The estimated cost to their nation of adopting the one-step screening approach was estimated at NZ$1.36 million.61 This equated to NZ$12,460 per patient. The economic implications for different resource settings therefore do influence the type of screening strategy.

CONCLUSION

Significant progress has been made since the initial diagnostic criteria for GDM were established 50 years ago. There is still debate internationally given the barriers for the determination of a universal consensus on diagnostic criteria, timing, and methods.

In recognition of these challenges, it will almost certainly be necessary to accept some local variation in screening practices to ensure culturally and economically sensitive solutions to this enormous and growing problem.

PRACTICE RECOMMENDATIONS

  • We recommend using the single-step 75 g Oral Glucose Tolerance Test to screen and diagnose Gestational Diabetes as per IADPSG recommendations.
  • Women at high risk of pre-existing diabetes mellitus or early onset of diabetes in pregnancy should be screened by 14 weeks, to allow earlier diagnosis and treatment potentially minimizing adverse outcomes on pregnancy.
  • All women without diabetes should be screened between 26 and 28 weeks with a 75 g Oral Glucose Tolerance Test.
  • Universal third-trimester screening and management is associated with improved maternal and fetal outcomes. However, this does come with cost implications potentially requiring modification of these recommendations to best target higher risk women.


CONFLICTS OF INTEREST

The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.

APPENDICES

Appendix 1: Global estimates of hyperglycemia in pregnancy for 2013, according to income group5

Income group

No. live births (millions)

Cases of hyperglycemia in pregnancy (millions)

Crude prevalence (%)

Age-standardized prevalence (%)

Proportion of cases that may be due to total diabetes in pregnancy

High income

 12.0

 2.1

17.5

13.8

16.4

Upper middle

 16.6

 2.4

14.8

12.8

17.1

Lower middle

 71.2

12.7

17.8

17.6

13.4

Low income

 27.3

 4.2

15.5

14.5

16.7

World

127.1

21.4

16.9

14.8

16.0


Appendix 2: ADIPS risk factors for hyperglycemia in pregnancy46

Previous hyperglycemia in pregnancy

Previously elevated blood glucose level

Maternal age >40 years

Ethnicity – Asian, Indian, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African

Family history of diabetes mellitus – first-degree relative with diabetes mellitus or sister with GDM

Obesity (pre-pregnancy BMI >30)

Previous macrosomia (baby with birth weight >4,500 g or >90th centile)

Polycystic ovarian syndrome (PCOS)

Medications – corticosteroids, antipsychotics


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