JRSM >
Volume 94, Number 10 >
Pp. 502-509
Department of Endocrinology and Metabolic Medicine, Imperial College School of Medicine, Mint Wing, St Mary's Hospital, Praed Street, London W2 1NY, UK
Correspondence to: Professor D G Johnston
 | INTRODUCTION |
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 TOP INTRODUCTION RATIONALE FOR SCREENINGSCREENING POLICIES FOR...COST-EFFECTIVENESSCONCLUSIONREFERENCES |
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Diabetes in the first trimester is more likely to be type 2 DM that was present but undiagnosed before pregnancy. In these circumstances, glycosylated haemoglobin, giving an indication of average blood glucose concentrations over the previous six to eight weeks, is likely to be raised. Occasionally, the diagnosis of GDM will identify women with type 1 diabetes mellitus6. Indeed, the incidence of type 1 DM is greater in pregnancy than in the background population7,8.
One of the aims of the St Vincent Declaration is to ‘achieve pregnancy outcome in the diabetic woman that approximates to that of the non-diabetic woman’9. It is because of the adverse outcomes of diabetic pregnancy that screening is required.
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In different series, GDM occurs in 1-14% of pregnancies, with an estimated prevalence in the UK of 4%10. Its clinical importance is on three levels—first, the adverse consequences of poorly controlled GDM for the fetus and neonate; second, the increased risk of type 2 DM in later life for the infant; third, the adverse consequences for the mother, especially the predisposition to type 2 DM in later life.
Adverse consequences of GDM for the fetus and neonate
The principal complication for the baby is
macrosomia11. There
is no agreed definition: birthweight is a continuous variable with no obvious
dichotomy between normal and macrosomic. If the outcome of interest is birth
trauma, absolute weight may be appropriate, since this is the best predictor
of birth
trauma12,13,14.
If the outcome of clinical interest is neonatal metabolism or metabolism
subsequently, centile weights are appropriate since these predict neonatal
hypoglycaemia and later type 2 DM. In practice, an absolute weight of 4 kg or
4.5 kg is chosen, or a weight of >90th centile for gestational age
(according to ethnicity).
Many of the adverse features of the fetus in GDM are thought to result from fetal hyperinsulinaemia. The features of macrosomia include birthweight >90th centile for gestational age, abdominal circumference >75th centile from 29 to 33 weeks' gestation15 and increased abdomen/head ratio in the third trimester. Abdominal circumference reflects the size of the liver and amount of abdominal subcutaneous fat, structures that are sensitive to insulin action.
Although macrosomia is the major short-term anxiety in GDM pregnancy, most macrosomic infants are born to women with no history of GDM. Maternal obesity16,17 is the strongest predictor and maternal hypertriglyceridaemia is another16,18. Nonetheless, maternal glucose levels are an important determinant.
| Box 1 Screening tests for gestational diabetes mellitus
*All pregnancies screened between 24 and 28 weeks' gestation. Time and nature of last meal not taken into account. If positive screening test for GDM, women go on to have a diagnostic test.
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| Box 2 Diagnosis of gestational diabetes mellitus by ADA
criteria (Ref. 20)
Formal testing usually at 24-28 weeks' gestation. Standard 100 g oral
glucose tolerance test performed after overnight fasting (8-14 h). GDM
diagnosed if
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The Toronto Tri-Hospital Gestational Diabetes Project19, a large prospective study with more than 4000 women, was designed to examine pregnancy outcomes, including macrosomia, in women with varying degrees of glucose tolerance. Here the screening test was a glucose challenge test (GCT) (Box 1, discussed later), performed in the non-fasting state at 26 weeks' gestation. All women also had a 100 g 3-hour oral glucose tolerance test (OGTT) at 28 weeks' gestation. Macrosomia was defined as birth weight >4 kg. The relations of glucose values during the 100g 3-hour OGTT were examined in 3637 women without GDM according to American Diabetic Association (ADA) criteria (Box 2)20. For each time point of the test (fasting, 1 hour, 2 hours, 3 hours) the women were divided into quartiles, and the glucose interval for each quartile was recorded. Both OGTT values and GCT values by quartiles showed a graded relation to fetal size with no evidence of a glycaemic threshold. The risk gradient was strongest with the fasting plasma glucose (Figure 1), but the 1-hour and 2-hour glucose concentrations after oral glucose (and the 1 hour GCT value) were also significantly associated with macrosomia. The importance of maternal glucose concentrations is illustrated in Figure 2. The women were classified according to four grades of glucose tolerance—normoglycaemic, screen positive, ‘borderline GDM’ (Carpenter and Coustan criteria21, Box 3) and GDM (ADA criteria20, Box 2). The rate of macrosomia was higher in the untreated borderline GDM group (28.7%) than in the non-diabetic women (13.7%, p<0.001) and was also higher than in women with GDM on therapy to restore normoglycaemia (10.5%, p<0.001). No conclusions on treatment efficacy can be drawn since this was not a randomized controlled trial.
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The Diagest
study22 examined
women who did not meet ADA criteria for GDM (Box
2)20. A screening
test (50 g glucose challenge) was offered between 24 and 28 weeks' gestation,
plasma glucose being measured at 1 hour. If this was 
7.2 mmol/L, a 100 g
3-hour OGTT was performed. For this study ‘mild GDM’ was defined
as one abnormal value on the 100 g 3-hour OGTT. Women with mild GDM received
no treatment or specific advice during the pregnancy.
Large-for-gestational-age babies (defined as 90th percentile on standard
growth curves) were delivered in 21% of the 131 women in this group, compared
with 11% of 108 women in whom the 50 g GCT had been negative
(p<0.05). After adjustment for maternal body mass index (BMI),
age, parity and educational level, the relation between macrosomia and
diabetes persisted (odds ratio 2.5, confidence interval 1.16-5.40). An adverse
maternal or fetal outcome of some kind occurred almost twice as frequently in
this diabetic group as in the non-diabetic pregnancies.
The Hyperglycaemia and Adverse Pregnancy Outcome study (HAPO study), funded largely by the US National Institutes of Health, the ADA and the British Diabetic Association (BDA), aims to discover the glucose values on a diagnostic 75 g 2-hour OGTT at 28 weeks' gestation which predict adverse outcome23. This study will enrol 25 000 pregnant women from sixteen centres around the world, with an estimated 1000 women having ‘untreated GDM’ (2-hour plasma glucose between 7.8 and 11.1 mmol/L).
Macrosomia is the major adverse outcome for the fetus and neonate. Others, for which the evidence is less strong, include respiratory distress syndrome24, hyperbilirubinaemia25, polycythaemia25 and neonatal hypoglycaemia25,26. In addition, the likelihood of congenital malformation27 seems to be increased and admission to the special care baby unit is more likely26.
| Box 3 Diagnosis of gestational diabetes mellitus by Carpenter
and Coustan criteria (Ref.
21)
Formal testing usually at 24-28 weeks' gestation. Standard 100 g oral
glucose tolerance test performed after overnight fasting (8-14 h). GDM
diagnosed if
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The frequency of some of these complications, such as respiratory distress, has declined because the practice of early planned delivery for GDM women has lost favour; most patients now deliver at or near term. With good obstetric care, the perinatal mortality rate for a GDM pregnancy is similar to that in the non-diabetic population28.
Mechanisms of macrosomia in GDM
The Pedersen
hypothesis29 is an
attempt to explain the development of the diabetic fetus. Maternal insulin
deficiency is the primary abnormality, resulting in hyperglycaemia in the
mother, mainly post-prandial in the early stages. As glucose is transported
across the placenta down a concentration gradient, excess glucose is
transferred to the fetus in GDM, resulting in fetal hyperinsulinaemia. This
excess insulin limits fetal hyperglycaemia but results in an increase in fetal
triglyceride deposition, the major feature of macrosomia in a diabetic
pregnancy. The macrosomia is associated with shoulder dystocia and the need
for caesarean section. The fetal hyperinsulinaemia probably also contributes
to increased fetal erythropoiesis and thus
polycythaemia30.
After delivery, the neonate is at risk of hypoglycaemia, since insulin
concentrations may remain above normal at a time when maternal glucose
transfer has ceased. Neonatal hypoglycaemia in the first 3 hours after
delivery is therefore more frequent after GDM pregnancies, at least in some
studies, than after non-diabetic
pregnancies26.
The Pedersen hypothesis has been extended to include maternal aminoacid and triglyceride metabolism31,11. The relative hypoinsulinaemia and insulin resistance of GDM pregnancy is associated with an increase in maternal protein flux. Consequently there is excessive delivery of aminoacids to the fetus. From early pregnancy, some aminoacids are fetal insulin secretagogues and compound the increase in fetal insulin secretion. GDM is also associated with maternal hypertriglyceridaemia. Triglyceride is not transferred directly across the placenta, but the placenta contains abundant lipase enzyme activity32. The resultant non-esterified fatty acids may cross the placenta and contribute to fetal triglyceride synthesis and macrosomia33.
Implications of GDM for the future of the neonate
Diabetes during pregnancy may be a risk factor for diabetes and
hyperglycaemia in the offspring when older. A longitudinal epidemiological
study of diabetes and its complications has been conducted among the Pima
Indians of Arizona since
196534. From these
data the prevalence of type 2 DM was ascertained in over 1500 infants from
mothers who had received a 75 g 2-hour OGTT. The infants were followed
biennially from the age of 5 years with a 75 g 2-hour OGTT. Diabetes in the
next generation developed in 6.9% and 30.1% of breast-fed offspring of
non-diabetic and diabetic women, respectively, and in 11.9% and 43.6% of
bottle-fed offspring,
respectively35. It
is uncertain whether this risk extends to other ethnic populations.
The offspring may also be at increased risk of obesity in adolescence. In a prospective study of 139 singleton pregnancies from 1977 to 1983, children were reviewed annually36. By 14-17 years of age, the mean BMI was 24.6 SD 5.8 kg/m2 in the offspring of diabetic mothers versus 20.9 SD 3.4 kg/m2 in controls. Obesity in adolescence was also associated with maternal weight.
Simmons and Robertson37 looked at two groups of women with GDM, one treated with insulin, the other with diet. Although the insulin-treated women were older, more obese and more hyperglycaemic (despite insulin treatment) their offspring had significantly less adiposity at 2 years and 8 months. The study, though not controlled, suggests that insulin treatment influences neonatal outcome.
Adverse consequences for the mother
During pregnancy, GDM carries an increased risk of operative delivery. This
may be due partly to the frequency of macrosomia but probably also reflects
tradition, with operative delivery more likely to be undertaken in a diabetic
than in a non-diabetic
pregnancy19,38.
The frequencies of induced labour, of
pre-eclampsia39,40
and of hydramnios are all above average in GDM pregnancies.
GDM also has implications for the mother's later life. Type 2 DM is a major cause of morbidity and mortality and has substantial economic implications41. Women with previous GDM constitute one of the groups at risk of developing type 2 DM in later life. Other at-risk groups for type 2 DM are shown in Box 4. For women with previous GDM and normal glucose tolerance post-partum, the lifetime risk of type 2 DM is 40-60%, with obese women having a higher prevalence in later life than lean women42,43. Furthermore, even women with previous GDM and normal post-partum glucose tolerance have abnormalities of both insulin secretion and insulin sensitivity44 and there are differences between ethnic groups45.
WHO has recommended that women with GDM have a 75 g 2-hour OGTT performed 6 weeks post-partum and be classified accordingly1. The ADA also recommends a 75 g 2-hour OGTT post-partum46. There is as yet no evidence that the long-term incidence of type 2 diabetes can be altered through case detection in gestation and subsequent intervention.
| Box 4 At-risk groups for development of type 2 diabetes
mellitus Low birth weight (<2.95 kg) (Ref. 71) Low weight at 1 year (<9.2 kg) (Ref. 72) Non-Europids (Refs 45, 47, 73) Polycystic ovary syndrome (Refs 74, 75) Family history of type 2 diabetes mellitus (Refs 81,82,83)
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Risk factors for GDM
GDM is more prevalent in older than in younger women. In women over 40
years, GDM is ten times more likely to occur than in the 20-24
age-group47. GDM is
also more likely in the presence of
obesity42,47.
It is sixteen times more likely to develop with a BMI at booking of 35-39
kg/m2 than in women with a booking BMI of 20-24 kg/m2.
Ethnic origin is a major determinant. In our West London population, the
adjusted odds ratio for women from the Indian subcontinent, in comparison with
those of Europid origin, was 11.3 (95% confidence interval 6-8-18.8). In black
women the odds ratio was 3.1 (1.8-5.5). All non-Europid ethnic groups are at
greater risk than Europid
women47,48.
Groups defined as at high risk for the development of GDM by WHO1 are shown in Box 1. Increased parity47,49, multiple versus singleton pregnancy50, and weight gain between pre-pregnancy and post-partum examination47 are additional risk factors. With regard to parity, it is possible that the period of hyperglycaemia during GDM leads to deterioration in maternal pancreatic ß-cell function. Subsequent pregnancies appear to have an additive deleterious effect on the ß-cell function, culminating in a potentially earlier onset of type 2 DM.
| SCREENING POLICIES FOR GESTATIONAL DIABETES |
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25 years, family history
of diabetes, previous large-for gestational-age baby or stillbirth) caused 38%
of gestational diabetes to go unidentified in one
study51. Several
groups have tried other risk factors (previous neonate >9 lb [4 kg],
neonatal death, congenital anomaly, prematurity, family history of diabetes)
and clinical findings during pregnancy (obesity, excessive weight gain,
glycosuria, proteinuria, hypertension). About half the women with GDM were
identified by these
means52,53,54.
In the USA, the GCT, first proposed by O'Sullivan, is the most widely used
screening test and is recommended by the
ADA20. This is
performed without regard to time or nature of the last meal, at 24-28 weeks'
gestation. Women are given 50 g of glucose by mouth and plasma glucose is
measured at 1 hour. A positive test is a plasma venous glucose concentration
7.8 mmol/L (Box 1). In O'Sullivan's original studies of 752 women, all
had a 50 g GCT and a 100 g 3-hour
OGTT55. The
challenge test (with a screen cut-off of 7.8 mmol/L) had a sensitivity of 88%
and a specificity of 82% in those 25 years. Since then, researchers have
not agreed on the threshold values for the GCT, the range of suggested values
being 7.2-8.3
mmol/L21. There are
controversies over whether women should be tested fasting or
fed56: the Toronto
Tri-Hospital study showed pronounced differences of plasma glucose in the two
states. Adjustment of the thresholds to 8.2 mmol, 7.9 mmol, and 8.3 mmol/L for
elapsed post-prandial times of < 2, 2-3 and > 3 hours, respectively,
increased the positive predictive value of the test from 14.4% to
18.7%19. The ADA
has subsequently recommended that screening of a pregnant woman is unnecessary
if she fulfils all the following
criteria57: <25
years old; normal body weight; no family history (i.e. first degree relatives)
of diabetes; and not a member of an ethnic/racial group with a high prevalence
of diabetes (Hispanic, Native American, Asian-American, African-American, or
Pacific Islander). The Fourth International Workshop-Conference on GDM, under
the sponsorship of the ADA, further recommended that women should be screened
if they have a history of GDM or poor obstetric
outcome58.
The WHO recommends screening by means of maternal risk factor selection (Box 1)1. Formal systematic testing with a 75 g 2-hour OGTT for GDM between 24 and 28 weeks of gestation is recommended for older women, those with a previous history of glucose intolerance, those with a history of large-for-gestational-age babies, women from certain high-risk ethnic groups, and any pregnant woman who has a raised fasting or casual blood glucose. Also there may be a case for screening pregnant women from high-risk populations during the first trimester to detect previously undiagnosed diabetes mellitus.
In some populations risk-factor screening excludes only a small proportion of pregnant women (<20%)59, such that universal screening has been recommended. This is our policy for our multi-ethnic population in West London.
Diagnosis of GDM
For diagnosis of GDM there is no consensus on the glucose load to be used
or the timing and type of blood sample. The two widely used criteria are
outlined in Boxes 2 and 5.
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These tests are usually performed between 24 and 28 weeks' gestation. Early
criteria for abnormal glucose tolerance in pregnancy, proposed by O'Sullivan
and Mahan in 1964, were based on data obtained from the 100 g 3-hour OGTT
performed on 752 pregnant
women55. Abnormal
glucose tolerance was defined as 2 blood glucose values, out of 4, that
were greater than or equal to 2 standard deviations above the mean. The
requirement for two values to be abnormal was based on a desire to
‘avoid misclassification due to laboratory error or occasional single
high peaks resulting from unusually rapid absorption of
glucose’55.
These criteria for abnormal glucose tolerance were validated by their
prediction of later non-pregnancy glucose intolerance when applied to a second
group of 1013 women who had been tested during pregnancy and followed for 5-10
years post-partum. In 1979 the National Diabetes Data Group (NDDG) revised the
O'Sullivan and Mahan criteria, converting the whole-blood glucose values to
plasma glucose values by upward adjustment of
15%60 and the ADA
later adopted
this20. Carpenter
and Coustan suggested that the NDDG conversion factor was too high and
proposed alternative cut-off
values21 (Box
3).
The WHO recommends a standard OGTT, performed after overnight fasting (8-14 hours); 75 g anhydrous glucose is given in 250-300 mL water, and plasma glucose is measured fasting and after 2 hours. Pregnant women who meet criteria for diabetes mellitus or impaired glucose tolerance in the non-pregnant state are classified as having GDM (Box 5)1. Unlike the O'Sullivan and Mahan thresholds, the WHO criteria were not developed specifically for use in pregnant women, nor were they validated by their ability to identify pregnancies at increased risk for adverse outcome. A major advantage of the WHO criteria is that the 75 g 2-hour OGTT is used as for non-pregnant individuals.
The WHO and ADA criteria for GDM have been compared; 127 Pima Indian women with no previous history of type 2 DM were studied with both protocols. It was found that 11 women who met the WHO diagnosis of GDM also included 2 women with GDM by the ADA criteria. The other 9 patients with GDM by WHO criteria had an excess of macrosomic babies and caesarean sections: 16 of the 127 women had infants > 4 kg, of whom 6 were correctly identified as abnormal by the WHO criteria compared with 1 out of the 16 by the ADA criteria. Of the 7 delivering by caesarean section, 4 had abnormal glucose tolerance by WHO criteria, none of them by ADA criteria61. Although the numbers in this study were small, there is now a move towards using the diagnostic 75 g 2-hour OGTT in pregnancy62,63 and the results from the HAPO study are awaited for definitive evidence.
Subtle differences within the range of normal glucose homoeostasis may nonetheless have clinical importance. It is known, for example, that patients with an abnormal GCT but a normal OGTT are at increased risk of adverse perinatal outcome19, as are those with one abnormal OGTT value rather than the two required by ADA criteria64.
Treatment policies
There is no consensus on treatment of those women with an abnormal GCT and
normal diagnostic tests. Likewise, the implication of impaired fasting
glycaemia, a term defined by
WHO1 as fasting
plasma glucose 6.1 < 7.0 mmol/L and 2-hour post 75 g OGTT < 7.8
mmol/L, are uncertain during pregnancy. WHO recommends a formal 75 g 2-hour
OGTT in these
circumstances1.
All women with GDM should receive nutritional counselling and be advised on a diet with a limited intake of sucrose.
There is no consensus on when to start insulin treatment in GDM; the ADA
have recommended that treatment should begin when fasting plasma glucose is
5.8 mmol/L and the 2-hour post-prandial glucose is 6.7 mmol/L on two
or more occasions within a two-week interval. There is no position statement
from the WHO. It is difficult to be prescriptive with regard to insulin
treatment since this is partly dependent on gestational age and the presence
or absence of macrosomia. In our unit, we aim for a fasting glucose < 6
mmol/L and post-prandial glucose < 8 mmol/L.
It is noteworthy that insulin treatment during pregnancy results in a sharp reduction in macrosomia, a reduction in maternal complications, and a reduced neonatal and maternal stay19 with long-term benefit for the offspring. Other indices are being studied in the Australasian Carbohydrate Intolerance Study in Pregnancy65, which will follow 1000 women prospectively. This study aims to ascertain whether treatment improves outcome in terms of neonatal bilirubin levels, admissions to the special care baby unit, caesarean section and induction of labour. Treatment with diet plus or minus insulin will be compared with no treatment. This study, however, has not been powered for macrosomia.
| COST-EFFECTIVENESS |
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TOPINTRODUCTIONRATIONALE FOR SCREENINGSCREENING POLICIES FOR...COST-EFFECTIVENESSCONCLUSIONREFERENCES |
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| CONCLUSION |
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TOPINTRODUCTIONRATIONALE FOR SCREENINGSCREENING POLICIES FOR...COST-EFFECTIVENESSCONCLUSIONREFERENCES |
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| REFERENCES |
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