All the diagnostic criteria require women to be in fasting, but most of the time pregnant women do not come in the fasting state because of commutation and belief not to fast for long hours. Attending the first prenatal visit in the fasting state is impractical in many settings (Metzger et al., 2010). The dropout rate is very high when a pregnant woman is asked to come again for the glucose tolerance test (Seshiah et al., 2004; Magee et al., 2001).

of developing GDM compared to Caucasians (Dornhorst et al., 1992).

**3.1 Geographical variations in the prevalence of GDM**

**4. Rationale for universal screening**

**5. Diagnosis of GDM**

**5.1 A single step procedure to diagnose GDM**

For the successful implementation of universal screening, a test has to be casual and reliable. A procedure that does not impose any restriction would be ideal for universal screening. The test performed should be able to diagnose GDM, as they walk into the prenatal clinic or clinical laboratory irrespective of their last meal timings. Hence the authors undertook a study to evaluate, whether a 2-h 75g oral glucose test performed in a non-fasting state, irrespective of last meal timing, is as efficacious as 2-h 75g oral glucose test done in the fasting state recommended by WHO in detecting GDM (Anjalakshi et al., 2009).  Venous samples were collected at 2-h after oral glucose administration. They were advised to follow a diet containing atleast 150g carbohydrate daily and usual activity for atleast 3 days and come to the prenatal clinic after an overnight fasting of 10-12 h. At the second visit 800 of them responded and underwent 2-h 75g oral glucose test in the fasting state recommended by WHO. The observation in this study was, all women diagnosed as GDM (N=87) by 75g glucose test irrespective of the last meal timings also satisfied the diagnostic criteria of 75-g oral glucose test performed in the fasting state recommended by WHO. It was also found that there was no statistically significant difference (P > 0.05) between the PG levels of the 75g glucose test in fasting and non fasting state, irrespective of last meal timing, performed in the GDM and in NGT pregnant women.

The rationale behind this study outcome is that, a normal glucose tolerant woman would be able to maintain euglycemia despite glucose challenge due to adequate insulin response, whereas in a woman with GDM who has impaired insulin secretion (Kuhl, 1991)*,* her glycemic level increases with a meal and with glucose challenge, the glycemic excursion is expected to exaggerate. This cascading effect is advantageous as this would not result in false positive diagnosis of GDM. Performing this test procedure in the non-fasting state, irrespective of last meal timing, is prudent as glucose concentrations during the glucose tolerance are affected little by the time since the last meal (Gough et al., 1970)*.*

Pettitt et al. observed that WHO criteria based on the glucose concentration 2-h after 75g oral glucose administered to non-fasting women correctly identified subjects with GDM (Pettitt et al., 1994)*.* The non-fasting 2-h post 75g glucose concentration strongly predicts adverse outcome for the mother and her offspring (Pettitt et al., 1991)*.* Philips et al also observed that plasma glucose value with a glucose challenge test was unaffected by the time after a meal or time of the day in Normal Glucose Tolerant non pregnant subjects (Philips et al., 2009)*.* Thus, this single test procedure performed irrespective of the last meal timing is rational and a patient friendly approach, which causes least disturbance in her routine activities. This procedure is a modified version of WHO criteria in that, only 2-h PG is taken into consideration for the diagnosis of GDM and is being followed by the Diabetes In Pregnancy Study Group India (DIPSI) (Seshiah et al., 2009)

#### **5.2 Comparison of WHO and IADPSG criteria**

All the diagnostic criteria, except the existing diagnostic criterion of WHO 2-h plasma glucose (PG) ≥ 7.8 mmol/L with 75g oral glucose load (King, 1998), are country specific or recommended by various associations. Recently, based on the HAPO study, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) consensus panel recommended that GDM can be diagnosed, if any one value of fasting plasma glucose (FPG), 1-h and 2-h PG concentrations meet or exceed 5.1 mmol/L, 10.0 mmol/L and 8.5 mmol/L respectively, with 75g oral glucose tolerance test (OGTT) (Metzger et al., 2010).

India one of the most populous countries in the world was not part of the HAPO study. Hence the authors group undertook a prospective, collaborative study to ascertain whether

Gestational Diabetes Mellitus - A Perspective 27

**Specificity (95% CI)**

89.4 (87.6-91.0)

93.0 (91.4-94.3)

97.4 (96.3-98.2)

99.2 (98.5-99.6)

99.8 (99.4-100.0)

Table 2. Performance of FPG test for the predictor of gestational diabetes and macrosomia

**5.4 The validation of WHO criterion (DIPSI criterion) based on the fetal outcome**  The authors investigated whether the diagnosis of GDM by WHO criterion is rational based on the fetal outcome (N = 1463). Macrosomia was the end point of this study as this is the most common morbidity of GDM (Jovanovic, 2001). They observed that there was no statistically significant difference in the mean birth weight of neonates born to women in the normal glucose tolerance (NGT) and with intervention in GDM groups (P=0.705) (Balaji et al., 2011b). This was due to the medical nutrition therapy (MNT) and/or insulin in maintaining FPG ~ 5.0 mmol/L and 2-h post meal ~ 6.7 mmol/L in GDM women. Intervention helped in maintaining the pregnancy outcome in GDM women equivalent to that of NGT women. Gayle et al also observed that diagnosis of GDM with OGTT 2-h PG ≥ 7.8 mmol/L and treatment in a combined diabetes antenatal clinic is worthwhile with a decreased macrosomia rate and fewer emergency cesarean sections (Gayle et al., 2010). The distribution of birth weight of neonates born to GDM and NGT women were similar (Figure 2) in the study conducted by the authors, indicating that the intervention given to pregnant women with 2-h PG ≥ 7.8 mmol/L had a significant effect in obtaining neonatal birth weight appropriate for gestational age. The level of association between macrosomia and GDM status after controlling the factors: maternal age, gestational age, family history of diabetes and BMI was elucidated. It was found that, the GDM status (2-h PG ≥ 7.8 mmol/L) of the pregnant women after intervention was not associated with macrosomia (adjusted OR = 0.752; 95% CI (0.406-1.390); P=0.363). There are publications confirming that treatment of GDM women as defined by WHO criterion was associated with a reduced risk of pregnancy outcome (Crowther et al., 2005; Gayle et al., 2010). In pregnancy, the decision to perform a placebo controlled trial requires clinical equipoise (Gifford et al., 2001). Hence, in this study, the authors did not have a control group of untreated pregnant women with 2-h PG ≥ 7.8 mmol/L, as there are evidences confirming that the treatment of GDM women as defined by WHO criterion was associated with a reduced risk of pregnancy outcome (Crowther et al., 2005; Gayle et al., 2010)**.** The policy of not treating women with 2-h PG ≥ 7.8 mmol/L amounts to deliberately exposing the pregnant mothers to unphysiological glycemic level despite our extensive knowledge of the benefits of treatment of mild hyperglycemia during pregnancy (Seshiah et al., 2008a; Landon et al., 2009; Bevier et al.,

**Sensitivity (95% CI)**

(22.9-36.1)

(18.3-30.7)

(9.4-19.6)

(4.1-11.9)

(2.3-8.8)

2- h PG 7.8 13.4 13.6

**2- h PG value Macrosomia**

**Sensitivity (95% CI)**

21.2 (12.5-33.3)

15.2 (7.9-26.6)

6.1 (2.0-15.6)

1.5 (0.1-9.3)

0.0 (0.0-6.9)

(6.8-24.8)

**Specificity (95% CI)**

87.2 (85.0-89.2)

90.2 (88.2-91.9)

95.6 (94.1-96.7)

98.2 (97.1-98.9)

99.3 (98.6-99.7)

86.3 (84.0-88.3)

**FPG (mmol/L)**

**Test positive**

5.0 3.9 29.1

5.1 3.2 24.0

5.5 1.8 13.8

6.1 0.9 7.1

6.6 0.6 4.6

the present practice of diagnosing GDM by the guidelines recommended by Diabetes In Pregnancy Study Group India (DIPSI) (Seshiah et al., 2009) based on WHO criterion of 2-h PG ≥ 7.8 mmol/L can still be followed in India or adopt IADPSG recommendations. A total of 1,463 consecutive pregnant women with no previous history of GDM/pre GDM underwent a 75g OGTT and fasting, 1-h and 2-h PG were measured. Using the DIPSI criterion, 196 (13.4%) women were diagnosed as GDM. By applying IADPSG recommendation the cumulative prevalence of GDM was 14.6% (n=214). There was no significant difference (P > 0.05) in the discordant pair of diagnosing GDM by the two criteria which in turn implies, that the disagreement in diagnosing GDM by both criteria was not significant (P = 0.21, by Mc Nemar test). The difference in the diagnostic capability between IADPSG and DIPSI was 1.2% which was not significant (P>0.02) (Seshiah et al., 2011). IADPSG recommendation necessarily requires estimation of PG in three blood samples after administrating 75g oral glucose load.  Whereas, DIPSI criterion requires one blood sample drawn at 2-h following a 75g glucose load for estimating the PG. The cost involved in performing IADPSG recommended procedure is high, as this procedure requires three blood tests compared to one blood test of DIPSI. The cost will escalate further, if IADPSG diagnostic procedure is performed in each trimester in high risk population in whom GDM manifests in all trimesters of pregnancy (Seshiah et al., 2007). Among women with normal OGTT results in the first visit when tested in the subsequent visits, 28% of them were detected to have GDM (Seshiah et al., 2007). Hence, DIPSI procedure based on WHO criterion is feasible, sustainable, cost-effective and best buy to diagnose GDM in any country and particularly in less resource nations. IADPSG recommendations are suitable in clinical settings where financial and technical supports are available. The performance of both IADPSG and WHO criteria are similar as per GRADE ratings.

#### **5.3 Inadequacy of fasting plasma glucose to diagnose GDM**

The IADPSG criteria suggests FPG ≥ 5.1 mmol/L but ≤ 7.0 mmol/L to diagnose GDM in the first prenatal visit (Metzger et al., 2010) whereas the authors observed in their study that by applying this criterion of FPG ≥ 5. 1 mmol/L, only 24% (3.2% of the total population) of those diagnosed as GDM using WHO criterion 2-h PG ≥ 7.8 mmol/L would have been classified as GDM (Balaji et al., 2011a). Further, FPG of 5.1 mmol/L was not able to diagnose GDM in comparison to 2-h PG ≥ 7.8 mmol/L (Table 2). This is due to the ethnicity of Asian Indians who have high insulin resistance (IR) and as a consequence, their postprandial plasma glucose is higher compared to Caucasians (Mohan et al., 2007; Snehalatha et al., 2009). Asian and South Asian ethnicity are both independently associated with increased IR in late pregnancy (Retnakaran et al., 2006). Siddhartha Das et al documented an increased IR during pregnancy in Asian Indian Women and IR escalates further in GDM (Das et al., 2010). These studies provide evidence that FPG may not be an appropriate option to diagnose GDM in Asian Indian women. Further, in all GDM, the FPG values do not reflect the postprandial hyperglycemia (Valensi et al., 2009), which is the hallmark of GDM (Weiss et al., 2000). In addition, there is a paucity of data regarding the reproducibility of the FPG test (Sacks et al., 2010). Hence, administering 75g oral glucose load and measuring 2-h PG serves as a one-step definitive procedure to diagnose GDM in less serviced regions. Perucchini et al also suggest one-step diagnostic procedure, though their observation was based on different ethnic population (Perucchini et al., 1999).

the present practice of diagnosing GDM by the guidelines recommended by Diabetes In Pregnancy Study Group India (DIPSI) (Seshiah et al., 2009) based on WHO criterion of 2-h PG ≥ 7.8 mmol/L can still be followed in India or adopt IADPSG recommendations. A total of 1,463 consecutive pregnant women with no previous history of GDM/pre GDM underwent a 75g OGTT and fasting, 1-h and 2-h PG were measured. Using the DIPSI criterion, 196 (13.4%) women were diagnosed as GDM. By applying IADPSG recommendation the cumulative prevalence of GDM was 14.6% (n=214). There was no significant difference (P > 0.05) in the discordant pair of diagnosing GDM by the two criteria which in turn implies, that the disagreement in diagnosing GDM by both criteria was not significant (P = 0.21, by Mc Nemar test). The difference in the diagnostic capability between IADPSG and DIPSI was 1.2% which was not significant (P>0.02) (Seshiah et al., 2011). IADPSG recommendation necessarily requires estimation of PG in three blood samples after administrating 75g oral glucose load.  Whereas, DIPSI criterion requires one blood sample drawn at 2-h following a 75g glucose load for estimating the PG. The cost involved in performing IADPSG recommended procedure is high, as this procedure requires three blood tests compared to one blood test of DIPSI. The cost will escalate further, if IADPSG diagnostic procedure is performed in each trimester in high risk population in whom GDM manifests in all trimesters of pregnancy (Seshiah et al., 2007). Among women with normal OGTT results in the first visit when tested in the subsequent visits, 28% of them were detected to have GDM (Seshiah et al., 2007). Hence, DIPSI procedure based on WHO criterion is feasible, sustainable, cost-effective and best buy to diagnose GDM in any country and particularly in less resource nations. IADPSG recommendations are suitable in clinical settings where financial and technical supports are available. The

performance of both IADPSG and WHO criteria are similar as per GRADE ratings.

The IADPSG criteria suggests FPG ≥ 5.1 mmol/L but ≤ 7.0 mmol/L to diagnose GDM in the first prenatal visit (Metzger et al., 2010) whereas the authors observed in their study that by applying this criterion of FPG ≥ 5. 1 mmol/L, only 24% (3.2% of the total population) of those diagnosed as GDM using WHO criterion 2-h PG ≥ 7.8 mmol/L would have been classified as GDM (Balaji et al., 2011a). Further, FPG of 5.1 mmol/L was not able to diagnose GDM in comparison to 2-h PG ≥ 7.8 mmol/L (Table 2). This is due to the ethnicity of Asian Indians who have high insulin resistance (IR) and as a consequence, their postprandial plasma glucose is higher compared to Caucasians (Mohan et al., 2007; Snehalatha et al., 2009). Asian and South Asian ethnicity are both independently associated with increased IR in late pregnancy (Retnakaran et al., 2006). Siddhartha Das et al documented an increased IR during pregnancy in Asian Indian Women and IR escalates further in GDM (Das et al., 2010). These studies provide evidence that FPG may not be an appropriate option to diagnose GDM in Asian Indian women. Further, in all GDM, the FPG values do not reflect the postprandial hyperglycemia (Valensi et al., 2009), which is the hallmark of GDM (Weiss et al., 2000). In addition, there is a paucity of data regarding the reproducibility of the FPG test (Sacks et al., 2010). Hence, administering 75g oral glucose load and measuring 2-h PG serves as a one-step definitive procedure to diagnose GDM in less serviced regions. Perucchini et al also suggest one-step diagnostic procedure, though their observation was

**5.3 Inadequacy of fasting plasma glucose to diagnose GDM**

based on different ethnic population (Perucchini et al., 1999).

#### **5.4 The validation of WHO criterion (DIPSI criterion) based on the fetal outcome**

The authors investigated whether the diagnosis of GDM by WHO criterion is rational based on the fetal outcome (N = 1463). Macrosomia was the end point of this study as this is the most common morbidity of GDM (Jovanovic, 2001). They observed that there was no statistically significant difference in the mean birth weight of neonates born to women in the normal glucose tolerance (NGT) and with intervention in GDM groups (P=0.705) (Balaji et al., 2011b). This was due to the medical nutrition therapy (MNT) and/or insulin in maintaining FPG ~ 5.0 mmol/L and 2-h post meal ~ 6.7 mmol/L in GDM women. Intervention helped in maintaining the pregnancy outcome in GDM women equivalent to that of NGT women. Gayle et al also observed that diagnosis of GDM with OGTT 2-h PG ≥ 7.8 mmol/L and treatment in a combined diabetes antenatal clinic is worthwhile with a decreased macrosomia rate and fewer emergency cesarean sections (Gayle et al., 2010). The distribution of birth weight of neonates born to GDM and NGT women were similar (Figure 2) in the study conducted by the authors, indicating that the intervention given to pregnant women with 2-h PG ≥ 7.8 mmol/L had a significant effect in obtaining neonatal birth weight appropriate for gestational age. The level of association between macrosomia and GDM status after controlling the factors: maternal age, gestational age, family history of diabetes and BMI was elucidated. It was found that, the GDM status (2-h PG ≥ 7.8 mmol/L) of the pregnant women after intervention was not associated with macrosomia (adjusted OR = 0.752; 95% CI (0.406-1.390); P=0.363). There are publications confirming that treatment of GDM women as defined by WHO criterion was associated with a reduced risk of pregnancy outcome (Crowther et al., 2005; Gayle et al., 2010). In pregnancy, the decision to perform a placebo controlled trial requires clinical equipoise (Gifford et al., 2001). Hence, in this study, the authors did not have a control group of untreated pregnant women with 2-h PG ≥ 7.8 mmol/L, as there are evidences confirming that the treatment of GDM women as defined by WHO criterion was associated with a reduced risk of pregnancy outcome (Crowther et al., 2005; Gayle et al., 2010)**.** The policy of not treating women with 2-h PG ≥ 7.8 mmol/L amounts to deliberately exposing the pregnant mothers to unphysiological glycemic level despite our extensive knowledge of the benefits of treatment of mild hyperglycemia during pregnancy (Seshiah et al., 2008a; Landon et al., 2009; Bevier et al.,

Gestational Diabetes Mellitus - A Perspective 29

pregnancy are likely to have delayed diagnosis and may not receive appropriate medical care. Further, early screening for glucose intolerance and care could avoid some diabetes related complications in women with gestational diabetes (Bartha et al., 2003). To substantiate the above observation the present author's group screened 207 pregnant women attending their referral centre for diabetes and pregnancy with a 75g OGTT (Seshiah et al., 2006). Among them, 87 (42.03%) were diagnosed with GDM. Women in whom GDM was detected between 0 - 23 weeks of gestation were classified as Group 1 [54 (62.7%)] and beyond 24 weeks of gestation as Group 2 [33 (37.93%)]. All of them were treated and followed till confinement. There was no statistically significant difference (P < 0.05) between the birth weight of the neonates born to Normal Glucose Tolerance (NGT) women (3.28 0.50 kg) and GDM women in group 1 (3.13 ± 0.55 kg). In group 2, the neonatal birth weight was 3.42 ± 0.58 kg which is the upper limit of the normal range in Indian new born babies. In India, the normal birth weight varies between 2.5 to 3.5 kg (Paul et al., 2002). The observation of this study was that, by early detection of glucose intolerance during pregnancy and by giving adequate care to the antenatal women, a good fetal outcome can be achieved similar to that of

The goal in the management is to avoid both low birth weight and macrosomic babies, as they are prone to develop diabetes in their adolescent and adult life (Jovanovic, 1998). In India, both under nutrition and over nutrition exists during pregnancy. There are two reported studies in India that relates size at birth to future risk of type 2 DM. In Mysore, low birth weight did not increase the risk of diabetes but babies who were short and fat at birth (higher BMI) were at increased risk (Fall et al., 1998). Fall et al speculate that the rise in type 2 DM in Indian urban populations would have been triggered by mild obesity in mothers, leading to glucose intolerance during pregnancy, macrosomic changes in the fetus and insulin deficiency in adult life (Fall et al., 1998). Yet another study attributes high prevalence of type 2 DM and IGT in Indian people linked to poor fetal growth (Yajnik et al., 1995)

The meal pattern should provide adequate calories and nutrients to meet the needs of pregnancy metabolism. The meal plan advised has to be simple and easy to practice. The MNT recommended is based on their routine diet habit and glycemic excursions that occur with the meal. In a normal person, the peaking of the plasma glucose is high after breakfast (due to 'Dawn phenomenon') than after lunch and dinner, and the insulin secretion also matches the glycemic excursions that occur with these three meals (Polonsky et al., 1988). Since GDM mothers have deficiency in first phase insulin secretion, the quantity of food at one time should also be less, to overcome this insulin deficiency, particularly after breakfast. To avoid the post prandial plasma glucose peaking with breakfast, the authors guide their women with GDM to distribute calorie consumption especially the breakfast into two portions 'Split Breakfast'. This implies splitting the usual breakfast into two halves and consuming these portions with a two-hour gap in between. By this, the undue peak in plasma glucose levels after ingestion of the total quantity of breakfast at one time is avoided.

NGT pregnant women (Seshiah et al., 2006, 2008b).

which is at variant to Fall *et al* observation (Fall et al., 1998).

**7.1 Medical Nutrition Therapy (MNT)**

**7. Management**

1999; Negrato et al., 2008). Wahi et al observed in their prospective study, the advantage of adhering to a cut-off level of 2-h PG ≥ 7.8 mmol/L in diagnosis and management of GDM for a significantly positive effect on pregnancy outcomes (Wahi et al., 2011). Fetal exposure to high maternal glucose (1-h PG > 7.2 mmol/L with 50g GCT) in the absence of preexisting diabetes/GDM may contribute to the development of overweight/obesity in the offspring, independent of maternal pre-pregnancy BMI (Deierlein et al., 2011). All these studies validate WHO/DIPSI criterion for the diagnosis of GDM

Fig. 2. Neonate Birth weight distribution of women with NGT and GDM

#### **6. Gestational weeks for screening**

The current recommendation is to perform screening test between 24 - 28 weeks of gestation, though there are reports that claim, about 40% to 66% of women with GDM can be detected early during pregnancy (Super et al., 1991; Nahum et al., 2002). Nahum et al also suggest that the ideal period to screen for GDM is around 16 weeks of gestation and even earlier in high-risk groups with a history of fetal wastage (Nahum et al., 2002). This is due to the embryological development of fetal β cells. Each islet cell functions as an endocrine organ and differentiates between 10th and 12th weeks of gestation. They recognize and respond to maternal glycemia before 15 weeks of gestation, suggesting that metabolic perturbations are underway before diagnosis and that earlier screening and intervention may be warranted (Tisi et al., 2011). The study performed by the present authors group in the DIPAP project revealed that, 16.3% had glucose intolerance within 16 weeks, 22.4% between 17 - 23 weeks and remaining 61.3% more than 24 weeks of gestation (Seshiah et., 2007). If a pregnant woman has an A1c level > 6%, she is more likely to be an overt diabetic (Balaji et al., 2007). These studies stress the need for screening for GDM during the early weeks of gestation. If the test is normal in the first visit, the test has to be repeated in the subsequent visits. GDM diagnosis may not be missed by screening around 24 -28 weeks of gestation, but a substantial number of pregnant women who develop GDM in the earlier weeks of

1999; Negrato et al., 2008). Wahi et al observed in their prospective study, the advantage of adhering to a cut-off level of 2-h PG ≥ 7.8 mmol/L in diagnosis and management of GDM for a significantly positive effect on pregnancy outcomes (Wahi et al., 2011). Fetal exposure to high maternal glucose (1-h PG > 7.2 mmol/L with 50g GCT) in the absence of preexisting diabetes/GDM may contribute to the development of overweight/obesity in the offspring, independent of maternal pre-pregnancy BMI (Deierlein et al., 2011). All these studies validate

WHO/DIPSI criterion for the diagnosis of GDM

**6. Gestational weeks for screening**

Fig. 2. Neonate Birth weight distribution of women with NGT and GDM

The current recommendation is to perform screening test between 24 - 28 weeks of gestation, though there are reports that claim, about 40% to 66% of women with GDM can be detected early during pregnancy (Super et al., 1991; Nahum et al., 2002). Nahum et al also suggest that the ideal period to screen for GDM is around 16 weeks of gestation and even earlier in high-risk groups with a history of fetal wastage (Nahum et al., 2002). This is due to the embryological development of fetal β cells. Each islet cell functions as an endocrine organ and differentiates between 10th and 12th weeks of gestation. They recognize and respond to maternal glycemia before 15 weeks of gestation, suggesting that metabolic perturbations are underway before diagnosis and that earlier screening and intervention may be warranted (Tisi et al., 2011). The study performed by the present authors group in the DIPAP project revealed that, 16.3% had glucose intolerance within 16 weeks, 22.4% between 17 - 23 weeks and remaining 61.3% more than 24 weeks of gestation (Seshiah et., 2007). If a pregnant woman has an A1c level > 6%, she is more likely to be an overt diabetic (Balaji et al., 2007). These studies stress the need for screening for GDM during the early weeks of gestation. If the test is normal in the first visit, the test has to be repeated in the subsequent visits. GDM diagnosis may not be missed by screening around 24 -28 weeks of gestation, but a substantial number of pregnant women who develop GDM in the earlier weeks of pregnancy are likely to have delayed diagnosis and may not receive appropriate medical care. Further, early screening for glucose intolerance and care could avoid some diabetes related complications in women with gestational diabetes (Bartha et al., 2003). To substantiate the above observation the present author's group screened 207 pregnant women attending their referral centre for diabetes and pregnancy with a 75g OGTT (Seshiah et al., 2006). Among them, 87 (42.03%) were diagnosed with GDM. Women in whom GDM was detected between 0 - 23 weeks of gestation were classified as Group 1 [54 (62.7%)] and beyond 24 weeks of gestation as Group 2 [33 (37.93%)]. All of them were treated and followed till confinement. There was no statistically significant difference (P < 0.05) between the birth weight of the neonates born to Normal Glucose Tolerance (NGT) women (3.28 0.50 kg) and GDM women in group 1 (3.13 ± 0.55 kg). In group 2, the neonatal birth weight was 3.42 ± 0.58 kg which is the upper limit of the normal range in Indian new born babies. In India, the normal birth weight varies between 2.5 to 3.5 kg (Paul et al., 2002). The observation of this study was that, by early detection of glucose intolerance during pregnancy and by giving adequate care to the antenatal women, a good fetal outcome can be achieved similar to that of NGT pregnant women (Seshiah et al., 2006, 2008b).

#### **7. Management**

The goal in the management is to avoid both low birth weight and macrosomic babies, as they are prone to develop diabetes in their adolescent and adult life (Jovanovic, 1998). In India, both under nutrition and over nutrition exists during pregnancy. There are two reported studies in India that relates size at birth to future risk of type 2 DM. In Mysore, low birth weight did not increase the risk of diabetes but babies who were short and fat at birth (higher BMI) were at increased risk (Fall et al., 1998). Fall et al speculate that the rise in type 2 DM in Indian urban populations would have been triggered by mild obesity in mothers, leading to glucose intolerance during pregnancy, macrosomic changes in the fetus and insulin deficiency in adult life (Fall et al., 1998). Yet another study attributes high prevalence of type 2 DM and IGT in Indian people linked to poor fetal growth (Yajnik et al., 1995) which is at variant to Fall *et al* observation (Fall et al., 1998).

#### **7.1 Medical Nutrition Therapy (MNT)**

The meal pattern should provide adequate calories and nutrients to meet the needs of pregnancy metabolism. The meal plan advised has to be simple and easy to practice. The MNT recommended is based on their routine diet habit and glycemic excursions that occur with the meal. In a normal person, the peaking of the plasma glucose is high after breakfast (due to 'Dawn phenomenon') than after lunch and dinner, and the insulin secretion also matches the glycemic excursions that occur with these three meals (Polonsky et al., 1988). Since GDM mothers have deficiency in first phase insulin secretion, the quantity of food at one time should also be less, to overcome this insulin deficiency, particularly after breakfast. To avoid the post prandial plasma glucose peaking with breakfast, the authors guide their women with GDM to distribute calorie consumption especially the breakfast into two portions 'Split Breakfast'. This implies splitting the usual breakfast into two halves and consuming these portions with a two-hour gap in between. By this, the undue peak in plasma glucose levels after ingestion of the total quantity of breakfast at one time is avoided.

Gestational Diabetes Mellitus - A Perspective 31

1991; Rossetti et al., 1990). Another advantage is that, the human placental transfer of glibenclamide is negligible. Maternally administered glibenclamide in pharmacologic doses, and even doses greatly exceeding therapeutic levels, may not reach the fetus (Elliott et al., 1991). The landmark study of Langer et al concluded that glyburide was as effective as insulin in maintaining the desired glycemic levels and resulted in a comparable outcome (Langer et al., 2000). The author's group undertook a prospective study comparing insulin and glibenclamide in GDM. In this study, both Glibenclamide and insulin treatment achieved equally good glycemic control and the perinatal outcome was not different (Anjalakshi et al., 2007). The observation of this study was that the mean dose of glibenclamide required at term was 1.45 ± 0.57 mg/day and mean insulin requirement at term was 21.7 ± 13.55 units/day to achieve the same glycemic level (Anjalakshi et al., 2007). It is noteworthy that Glibenclamide is very much economical and cost effective compared to insulin, which is not only expensive but also inconvenient as it has to be taken parenterally. Yet an another observation was that in Indian population, the dose of glibenclamide required is very much less compared to the other published studies (Langer et al., 2005).

Women with polycystic ovary syndrome (PCOS) are advised metformin to induce ovulation. The drug is not withdrawn if a woman conceives while on metformin therapy and the maximum dose prescribed in the author's clinical practice is 1500 mg. If the plasma glucose is not under control with metformin, insulin is always added. No adverse pregnancy outcome with metformin therapy was observed. A preliminary study showed that metformin was safe in pregnant, glucose intolerant women either as an adjunct to insulin treatment or even as a monotherapy (Ramachandran et al., 2005). A prospective study found no adverse influence on the pregnancy outcome in PCOS women treated

Metformin in gestational diabetes (MiG) trial found that in women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) was not associated with increased

The success of the treatment for a woman with GDM depends on the glycemic control maintained with meal plan or pharmacological intervention. To know the effectiveness of

 Once diagnosis is made, medical nutritional therapy (MNT) is advised initially for two weeks. If MNT fails to achieve control i.e., FPG ≥ 5.0 mmol/L and/or 2-h PG ≥ 6.7

 Once target blood glucose is achieved, woman with GDM till the 28th week of gestation require laboratory monitoring of both fasting and 2-h post breakfast once a month and

After the 28th week of gestation, the laboratory monitoring should be more frequent

After 32 weeks of gestation, laboratory monitoring should be done once a week till

In high risk pregnancies, frequency of monitoring may be intensified with self

throughout pregnancy with Metformin (Glueck et al., 2004).

treatment, monitoring of glycemic control is essential.

at other time of the day as the clinician decides.

atleast once in 2 weeks, if need be more frequently.

**8. Monitoring glycemic control**

mmol/L, insulin may be initiated.

monitoring of blood glucose (SMBG).

perinatal complications as compared with insulin (Rowan et al., 2008).

**7.3.2 Metformin**

delivery

#### **7.2 Insulin therapy 7.2.1 Human insulin**

The policy followed in India is to advise human insulin in women with GDM who failed to achieve FPG of ≤ 5.0 mmol/L and 2-h post meal plasma glucose level of ≤ 6.7 mmol/L with MNT. The aim is to maintain post meal peak plasma glucose level of ≤ 6.7 mmol/L. This time point is suggested as the diagnosis of GDM is made with 2-h PG and it is easy to remember the same timing. A number of studies have established the benefits of maintaining the plasma glucose at this level (Franks et al., 2006; de Sereday et al., 2003; Ben-Haroush et al., 2004). However whichever time is targeted for monitoring glycemic control and adjusting the insulin dose, the blood tests have to be done at the same time at each visit. GDM women usually have high post breakfast plasma glucose level compared to post lunch and post dinner. The period between breakfast and lunch are often problematical because of the physiological tendency to hyperglycemia at this time and may necessitate substantial increases in the morning dose of short acting insulin, together with careful adjustment of meal timing and snacks to avoid pre-lunch hypoglycemia (Langer et al., 2000).

#### **7.2.2 Insulin analogues**

Due to the pharmacokinetic action of human regular insulin, a considerable segment of pregnant women with GDM, fail to achieve optimum glycemic control, mostly the post prandial plasma glucose. In them, the best option is to administer ultra short acting analogues, insulin lispro (Humalog) or insulin aspart (Novo rapid). These analogues improve the post prandial glucose control in pregnant women with type 1, type 2 DM and GDM, and are also safe and effective (Hermansen et al., 2002; Jovanovic et al., 1999).

The authors group conducted an open label trial using a large independent cohort of GDM patients to evaluate the efficacy, safety and foetal outcome for Biphasic Insulin aspart (BIAsp 30) compared with biphasic human insulin (BHI 30) in the management of GDM (Balaji et al., 2010). GDM women (N = 323) who remained unable to maintain a FPG ≤ 5.0 mmol/L and 2-h PG ≤ 6.7 mmol/L with MNT were randomly allocated in a 1:1 ratio to receive either BIAsp 30 (Group A) or BHI 30 (Group B). There was no statistical significance in the levels of glycaemic control achieved by the groups by labour onset. However, the mean total insulin dose administered by the last visit was significantly lower for Group A [19.83±15.75 U compared with 26.34±23.15 U for Group B (*p*=0.006)], implying that those receiving BHI 30 required a higher dose to achieve a similar degree of glycaemic control. The frequency of macrosomia was 6.3% in Group A and 6.9% in Group B. Although the proportion of macrosomia was numerically higher for Group B than Group A, the difference was not statistically significant (*p*=0.819). It was found that BIAsp 30 was non-inferior to BHI 30 and was well tolerated during pregnancy. Yet in another study, the authors observed that pregnant women found BIAsp convenient as this preparation allows flexibility in the meal time insulin dosing and did not disturb their routine life pattern. Most importantly, BIAsp was found to be safe during pregnancy (Balaji et al., 2010).

#### **7.3 Oral hypoglycemic agents 7.3.1 Glibenclamide**

Glibenclamide (Glyburide) may be an alternative safe therapy for many GDM women who are hesitant to take insulin. This drug decreases the insulin resistance and improves insulin secretion, the pathogenic factors in the causation of hyperglycemia in GDM (Groop et al., 1991; Rossetti et al., 1990). Another advantage is that, the human placental transfer of glibenclamide is negligible. Maternally administered glibenclamide in pharmacologic doses, and even doses greatly exceeding therapeutic levels, may not reach the fetus (Elliott et al., 1991). The landmark study of Langer et al concluded that glyburide was as effective as insulin in maintaining the desired glycemic levels and resulted in a comparable outcome (Langer et al., 2000). The author's group undertook a prospective study comparing insulin and glibenclamide in GDM. In this study, both Glibenclamide and insulin treatment achieved equally good glycemic control and the perinatal outcome was not different (Anjalakshi et al., 2007). The observation of this study was that the mean dose of glibenclamide required at term was 1.45 ± 0.57 mg/day and mean insulin requirement at term was 21.7 ± 13.55 units/day to achieve the same glycemic level (Anjalakshi et al., 2007). It is noteworthy that Glibenclamide is very much economical and cost effective compared to insulin, which is not only expensive but also inconvenient as it has to be taken parenterally. Yet an another observation was that in Indian population, the dose of glibenclamide required is very much less compared to the other published studies (Langer et al., 2005).

#### **7.3.2 Metformin**

30 Gestational Diabetes

The policy followed in India is to advise human insulin in women with GDM who failed to achieve FPG of ≤ 5.0 mmol/L and 2-h post meal plasma glucose level of ≤ 6.7 mmol/L with MNT. The aim is to maintain post meal peak plasma glucose level of ≤ 6.7 mmol/L. This time point is suggested as the diagnosis of GDM is made with 2-h PG and it is easy to remember the same timing. A number of studies have established the benefits of maintaining the plasma glucose at this level (Franks et al., 2006; de Sereday et al., 2003; Ben-Haroush et al., 2004). However whichever time is targeted for monitoring glycemic control and adjusting the insulin dose, the blood tests have to be done at the same time at each visit. GDM women usually have high post breakfast plasma glucose level compared to post lunch and post dinner. The period between breakfast and lunch are often problematical because of the physiological tendency to hyperglycemia at this time and may necessitate substantial increases in the morning dose of short acting insulin, together with careful adjustment of

Due to the pharmacokinetic action of human regular insulin, a considerable segment of pregnant women with GDM, fail to achieve optimum glycemic control, mostly the post prandial plasma glucose. In them, the best option is to administer ultra short acting analogues, insulin lispro (Humalog) or insulin aspart (Novo rapid). These analogues improve the post prandial glucose control in pregnant women with type 1, type 2 DM and

The authors group conducted an open label trial using a large independent cohort of GDM patients to evaluate the efficacy, safety and foetal outcome for Biphasic Insulin aspart (BIAsp 30) compared with biphasic human insulin (BHI 30) in the management of GDM (Balaji et al., 2010). GDM women (N = 323) who remained unable to maintain a FPG ≤ 5.0 mmol/L and 2-h PG ≤ 6.7 mmol/L with MNT were randomly allocated in a 1:1 ratio to receive either BIAsp 30 (Group A) or BHI 30 (Group B). There was no statistical significance in the levels of glycaemic control achieved by the groups by labour onset. However, the mean total insulin dose administered by the last visit was significantly lower for Group A [19.83±15.75 U compared with 26.34±23.15 U for Group B (*p*=0.006)], implying that those receiving BHI 30 required a higher dose to achieve a similar degree of glycaemic control. The frequency of macrosomia was 6.3% in Group A and 6.9% in Group B. Although the proportion of macrosomia was numerically higher for Group B than Group A, the difference was not statistically significant (*p*=0.819). It was found that BIAsp 30 was non-inferior to BHI 30 and was well tolerated during pregnancy. Yet in another study, the authors observed that pregnant women found BIAsp convenient as this preparation allows flexibility in the meal time insulin dosing and did not disturb their routine life pattern. Most importantly, BIAsp was found to be safe during

Glibenclamide (Glyburide) may be an alternative safe therapy for many GDM women who are hesitant to take insulin. This drug decreases the insulin resistance and improves insulin secretion, the pathogenic factors in the causation of hyperglycemia in GDM (Groop et al.,

GDM, and are also safe and effective (Hermansen et al., 2002; Jovanovic et al., 1999).

meal timing and snacks to avoid pre-lunch hypoglycemia (Langer et al., 2000).

**7.2 Insulin therapy 7.2.1 Human insulin**

**7.2.2 Insulin analogues**

pregnancy (Balaji et al., 2010).

**7.3.1 Glibenclamide**

**7.3 Oral hypoglycemic agents**

Women with polycystic ovary syndrome (PCOS) are advised metformin to induce ovulation. The drug is not withdrawn if a woman conceives while on metformin therapy and the maximum dose prescribed in the author's clinical practice is 1500 mg. If the plasma glucose is not under control with metformin, insulin is always added. No adverse pregnancy outcome with metformin therapy was observed. A preliminary study showed that metformin was safe in pregnant, glucose intolerant women either as an adjunct to insulin treatment or even as a monotherapy (Ramachandran et al., 2005). A prospective study found no adverse influence on the pregnancy outcome in PCOS women treated throughout pregnancy with Metformin (Glueck et al., 2004).

Metformin in gestational diabetes (MiG) trial found that in women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) was not associated with increased perinatal complications as compared with insulin (Rowan et al., 2008).

#### **8. Monitoring glycemic control**

The success of the treatment for a woman with GDM depends on the glycemic control maintained with meal plan or pharmacological intervention. To know the effectiveness of treatment, monitoring of glycemic control is essential.

Gestational Diabetes Mellitus - A Perspective 33

increased prevalence of diabetes in India. This is likely to be true as GDM has a far reaching consequence in predisposing their offsprings to glucose intolerance. This observation was substantiated and documented in Pima Indians (Dabelea et al., 2000). The children born in 1965 to women with GDM were followed up till 2000. By the time they reached 35 years, more than half of the group had diabetes (Dabelea et al., 2000). Hence as a policy to identify GDM and its consequences on the infant, a 75 g OGTT has been recommended to all women in the population during the third trimester of pregnancy (Dabelea et al., 2000). Now it is obvious that taking care of women with GDM is the first step in the primary prevention of

The important aspect of diabetes and pregnancy is that, the intrauterine millieu interieur, whether one of nutritional deprivation or one of nutritional plenty, results in changes in fetal pancreatic development and peripheral response to insulin that may lead to adultonset GDM and type 2 DM (Savona-Ventura & Chircop, 2003). Thus, the timely action taken now in screening all pregnant women for glucose intolerance, achieving euglycemia in them and ensuring adequate nutrition may prevent in all probability, the vicious cycle of transmitting glucose intolerance from one generation to another (Aerts, 2004)*.* GDM offers an important opportunity for the development, testing and implementation of clinical

'No single period in human development provides a greater potential than pregnancy for a long range pay off via relatively short range period of enlightened metabolic manipulation' -

GDM women are at increased risk of future diabetes as are their children and following

Asian women are ethnically more prone to develop glucose intolerance compared to

GDM based on 2-h 75g OGTT defined by WHO predicts adverse pregnancy outcome

 A 2-h 75g post plasma glucose ≥ 7.8 mmol/L serves both as screening and diagnostic criteria which is a technically simple economical and evidence based one step

IADPSG recommendations are suitable in clinical settings where technical and financial

Early screening for glucose intolerance and care could avoid some diabetes related

Women with NGT in the first visit are advised to undergo glucose tolerance test in the

Occurrence of macrosomia was continuum as the FPG increased from 5.0 mmol/L and

The meal pattern advised has to be simple, and easy to understand and follow.

The goal is to maintain mean plasma glucose of 5.8 to 6.1 mmol/L

 Prevalence of GDM varies from one region to another region in the same country. Compared with selective screening, Universal screening for GDM detects more cases

strategies for diabetes prevention (Buchanan et al., 2007).

and improves maternal and offspring prognosis.

complications in women with gestational diabetes

diabetes.

Norbert Frienkel.

**11. Summary**

generations.

procedure.

other ethnic groups.

and warrants treatment.

supports are available.

subsequent trimesters.

2-h PG increased from 6.7 mmol/L.

 Continuous glucose monitoring devices are available but these equipments need special training and are expensive. These devices may be useful in high risk pregnancies to know the glycemic fluctuations and to plan proper insulin dosage.

#### **8.1 Glycosylated haemoglobin – A1c levels**

If the glucose intolerance is detected in the early pregnancy, A1c level will be helpful to differentiate between a pre gestational diabetic and GDM. If A1c level is more than 6% (Balaji et al., 2007), the chances are that she may be a pre GDM or GDM, in whom the glucose intolerance was detected in the early weeks of pregnancy; all the more validating that the screening needs to be performed in the early weeks of gestation. The estimation of A1c may help in distinguishing a pre GDM from an early onset GDM, but not essential, as this differentiation is of no consequence in clinical practice, as the treatment approach is going to be the same (Seshiah et al., 2007). Further, A1c is not estimated in the community health centres, barring a few tertiary care hospitals due to the difficulty in standardization, inadequate technical support and the cost.

#### **8.2 Measuring other parameters**

The blood pressure has to be monitored during every visit. Examination of the fundus and estimation of microalbuminuria, every trimester is recommended.

#### **8.3 Ultrasound fetal measurement**

The management of gestational diabetes, based on the foetal growth by ultrasonogram demands that the fetus at risk must first manifest overgrowth before treatment decisions are made. Further, the cost of performing a number of ultrasonograms to monitor the foetal growth and recommending therapy has to be kept in mind. Until there is evidence to absolutely prove that ignoring maternal hyperglycemia when the fetal growth patterns appear normal on the ultrasonogram, it is prudent to achieve and maintain normoglycemia in every pregnancy complicated by gestational diabetes.

#### **9. Target glycemic level**

Increased birth weight of neonates occurred even when the mother's glucose tolerance was less than the glycemic criteria recommended by WHO (2-h PG > 7.8 mmol/L) for diagnosis of GDM. Increasing carbohydrate intolerance in women without overt GDM was associated with graded increase in the incidence of macrosomia (Sermer et al., 1998). The author's group documented that the occurrence of macrosomia was continuum as the FPG increased > 5.0 mmol/L (Seshiah et al., 2008c) and the 2-h PG > 6.7 mmol/L (Balaji et al., 2006). Thus maintenance of mean plasma glucose level ~ 5.8 to 6.1 mmol/L is desirable for a good fetal outcome (Langer et al., 1989)*.* This is possible if FPG and peak postprandial glucose levels are maintained ~ 5.0 mmol/L (4.4-5.0 mmol/L) and ~ 6.7 mmol/L (6.1 – 6.7 mmol/L, respectively)

#### **10. Prevention of type 2 dm**

The screening for glucose intolerance during pregnancy is not done routinely and probably the undiagnosed glucose intolerance that has been occurring in the past has resulted in the

 Continuous glucose monitoring devices are available but these equipments need special training and are expensive. These devices may be useful in high risk pregnancies to

If the glucose intolerance is detected in the early pregnancy, A1c level will be helpful to differentiate between a pre gestational diabetic and GDM. If A1c level is more than 6% (Balaji et al., 2007), the chances are that she may be a pre GDM or GDM, in whom the glucose intolerance was detected in the early weeks of pregnancy; all the more validating that the screening needs to be performed in the early weeks of gestation. The estimation of A1c may help in distinguishing a pre GDM from an early onset GDM, but not essential, as this differentiation is of no consequence in clinical practice, as the treatment approach is going to be the same (Seshiah et al., 2007). Further, A1c is not estimated in the community health centres, barring a few tertiary care hospitals due to the difficulty in standardization,

The blood pressure has to be monitored during every visit. Examination of the fundus and

The management of gestational diabetes, based on the foetal growth by ultrasonogram demands that the fetus at risk must first manifest overgrowth before treatment decisions are made. Further, the cost of performing a number of ultrasonograms to monitor the foetal growth and recommending therapy has to be kept in mind. Until there is evidence to absolutely prove that ignoring maternal hyperglycemia when the fetal growth patterns appear normal on the ultrasonogram, it is prudent to achieve and maintain normoglycemia

Increased birth weight of neonates occurred even when the mother's glucose tolerance was less than the glycemic criteria recommended by WHO (2-h PG > 7.8 mmol/L) for diagnosis of GDM. Increasing carbohydrate intolerance in women without overt GDM was associated with graded increase in the incidence of macrosomia (Sermer et al., 1998). The author's group documented that the occurrence of macrosomia was continuum as the FPG increased > 5.0 mmol/L (Seshiah et al., 2008c) and the 2-h PG > 6.7 mmol/L (Balaji et al., 2006). Thus maintenance of mean plasma glucose level ~ 5.8 to 6.1 mmol/L is desirable for a good fetal outcome (Langer et al., 1989)*.* This is possible if FPG and peak postprandial glucose levels are maintained ~ 5.0 mmol/L (4.4-5.0 mmol/L) and ~ 6.7 mmol/L (6.1 – 6.7 mmol/L,

The screening for glucose intolerance during pregnancy is not done routinely and probably the undiagnosed glucose intolerance that has been occurring in the past has resulted in the

estimation of microalbuminuria, every trimester is recommended.

in every pregnancy complicated by gestational diabetes.

know the glycemic fluctuations and to plan proper insulin dosage.

**8.1 Glycosylated haemoglobin – A1c levels**

inadequate technical support and the cost.

**8.2 Measuring other parameters**

**8.3 Ultrasound fetal measurement**

**9. Target glycemic level**

**10. Prevention of type 2 dm**

respectively)

increased prevalence of diabetes in India. This is likely to be true as GDM has a far reaching consequence in predisposing their offsprings to glucose intolerance. This observation was substantiated and documented in Pima Indians (Dabelea et al., 2000). The children born in 1965 to women with GDM were followed up till 2000. By the time they reached 35 years, more than half of the group had diabetes (Dabelea et al., 2000). Hence as a policy to identify GDM and its consequences on the infant, a 75 g OGTT has been recommended to all women in the population during the third trimester of pregnancy (Dabelea et al., 2000). Now it is obvious that taking care of women with GDM is the first step in the primary prevention of diabetes.

The important aspect of diabetes and pregnancy is that, the intrauterine millieu interieur, whether one of nutritional deprivation or one of nutritional plenty, results in changes in fetal pancreatic development and peripheral response to insulin that may lead to adultonset GDM and type 2 DM (Savona-Ventura & Chircop, 2003). Thus, the timely action taken now in screening all pregnant women for glucose intolerance, achieving euglycemia in them and ensuring adequate nutrition may prevent in all probability, the vicious cycle of transmitting glucose intolerance from one generation to another (Aerts, 2004)*.* GDM offers an important opportunity for the development, testing and implementation of clinical strategies for diabetes prevention (Buchanan et al., 2007).

'No single period in human development provides a greater potential than pregnancy for a long range pay off via relatively short range period of enlightened metabolic manipulation' - Norbert Frienkel.

#### **11. Summary**

Gestational Diabetes Mellitus - A Perspective 35

Ben-Haroush, A.; Yogev, Y.; Chen R.; et al (2004). The post prandial glucose profile in the

Bevier, WC.; Fischer, R.; Jovanovic, L. (1999). Treatment of women with an abnormal

Buchanan, TA.; Xiang, A.; Kjos, SL.; et al. (2007). What is Gestational Diabetes.*Diabetes Care.*

Cosson, E.; Benthimol, M.; Carbilon, L.; et al. (2004). Universal screening for gestational

Cosson, E. (2004). Screening and insulin sensitivity in gestational diabetes. Abstract volume

Crowther, CA.; Hiller, JE.; Moss, JR.; et al. (2005). Effect of treatment of gestational diabetes

Dabelea, D.; Knowler, WC.; Pettitt, DJ. (2000). Effect of diabetes in pregnancy and offspring:

Das, S.; Behera, MK.; Misra, S.; et al. (2010). Β-cell function and insulin resistance in

de Sereday, MS.; Damiano, MM.; Gonzalez, CD.; et al. (2003). Diagnostic criteria for

Deierlein, AL.; Siega-Riz, AM.; Chantala, K.; et al. (2011). The association between maternal

Dornhorst, A & Rossi, M. (1998). Risk and Prevention of Type 2 Diabetes in women with

Dornhost, A.; Paterson, CM. ; Nicholls, JS. ; et al. (1992) High prevalence of GDM in women

Elliott, BD.; Langer, O.; Schenker, S.; et al. (1991). Insignificant transfer of glyburide occurs

Fall, CH.; Stein, CE.; Kumaran, K.; et al. (1998). Size at birth, maternal weight, and type 2

Forsbach, G.; Vazquez-Lara, J.; Alvarez-y-Garcia, C.; et al. (1998). Diabetes and pregnancy in

1,(January – February 2000); 83–8, ISSN 1057-0802.

No. 1, (February 2010), pp. 25-32. ISSN 1540-4196.

(February 2011), pp. 480-4, ISSN 0149-5992.

Vol. 17, No. 3, (May-June 2003), pp. 115-119, ISSN 1056-8727.

Vol. 30, Suppl No. 2, (July 2007), pp. S 105–11, ISSN: 0149-5992.

81, ISSN 0002-9378.

0735-1631.

2004; A61.

4793.

September 2004: A 350.

ISSN 0149-5992.

2, ISSN 0742-3071.

0742-3071.

pp. 807 – 12, ISSN 0002-9378.

diabetic pregnancy. *Am J Obstet Gynecol*. Vol. 191, No. 2, (August 2004), pp. 576 –

glucose challenge test (but a normal oral glucose tolerance test) decreases the prevalence of macrosomia. Am J Perinatol. Vol. 16, No. 6, (1999), pp. 269-75, ISSN

diabetes mellitus improves maternal and fetal outcomes compared with selective screening. In : Mateclinsky FM (ed). Abstract book of the 64th Scientific Sessions of the American Diabetes Association (ADA). Florida. American Diabetes Association

of the 40th Annual Meeting of the European Association for the Study of Diabetes,

mellitus. *N Engl J Med* 2005; Vol. 352, No. 24, (June 2005), pp. 2477-86, ISSN 0028-

follow up research in the Pima Indians. *J Matern Fetal Medicine*. Vol. 9, No.

pregnancy and their relation to fetal development. *Metab Syndr Relat disorder*. Vol. 8,

gestational diabetes in relation to pregnancy outcome. *J Diabetes and complications*.

glucose concentration and child BMI at age 3 years. *Diabetes Care.* Vol. 34, No. 2,

Gestational Diabetes. *Diabetes Care.* Vol. 21, Suppl No. 2, (August 1998), pp. B43-9,

from ethnic minority groups. *Diabetic Med*. Vol. 9, No. 9, (November 1992), pp. 820-

across the human placenta. *Am J Obstet Gynecol*. Vol. 165, No. 4 pt 1, (October 1991),

diabetes in South India. *Diabet Med*. Vol. 15, No. 3, (March 1998), pp. 220-7, ISSN

Mexico. *Rev Invest Clin*. Vol. 50, No. 3, (May-June 1998), pp. 227-31, ISSN 0034-8376.

#### **12. References**

 At least one point testing in the third trimester of measuring haemoglobin, blood pressure and plasma glucose in pregnant women will go a long way in achieving safe

Taking care of women with gestational diabetes is envisaged as the first step in the

Aerts, L. (2004). Intergenerative transmission of DM. Abstract volume of the 36th Annual

Agarwal, S.; & Gupta, AN. (1982). Gestational Diabetes. *J Assoc Physicians India* Vol. 30, No.4,

Al Mahroos, S.; Nagalla, DS.; Yousif, W.; et al (2005). A population – based screening for

Anjalakshi, C.; Balaji, V.; Balaji, MS.; et al (2007). A Prospective Study Comparing Insulin

Ardawi, MS.; Nasrat, HA.; Jamal, HS.; et al (2000). Screening for gestational diabetes

Balaji, V.; Balaji, MS.; Seshiah, V.; et al (2006). Maternal glycemia and neonates birth weight

Balaji, V.; Madhuri, BS.; Ashalatha, S.; et al (2007). A1C in gestational diabetes mellitus in

Balaji, V.; Balaji, MS.; Alexander, C.; et al (2010). Premixed insulin aspart 30 (Biasp 30) vs.

*Assoc Physicians India*. Vol. 58, (February 2010), pp. 99-101, ISSN 0004-5772. Balaji, V.; Madhuri, Balaji.; Anjalakshi, C.; et al. (2011). Inadequacy of fasting plasma glucose

Balaji, V.; Madhuri, Balaji.; Anjalakshi, C.; et al. (2011). Diagnosis of gestational diabetes

Barker, DJ (1995). Fetal origins of coronary heart disease. *BMJ*. Vol. 311, No. 6998, (July

Bartha, JL.; Martinez-Del-Fresno, P.; Comino-Delgado, R.; (2003). Early diagnosis of

*Diabetes*. Vol. 40, Suppl. No. 2, (December 1991), pp. 35 – 8, ISSN 0012-1797.

*Res Clin Pract*, Vol. 76, No. 3, (June 2007), pp. 474-5, ISSN 0168-8227. Anjalakshi, C.; Balaji, V.; Balaji, MS.; et al (2009). A single test procedure to diagnose

gestational diabetes mellitus in non-diabetic women in Bahrain. *Ann Saudi Med,*

and Glibenclamide In Gestational Diabetes Mellitus In Asian Indian Women. *Dia*

gestational diabetes mellitus. *Acta Diabetol*, Vol. 46, No.1, (March 2009), pp. 51-4,

mellitus in pregnant females. *Saudi Med J*. Vol. 21, No. 2, (February 2000), pp. 155–

in Asian Indian women. *Diabetes Res Clin Pract*. Vol. 73, No. 2, (August 2006), pp.

Asian Indian women. *Diabetes Care*. Vol. 30, No. 7, (July 2007), pp. 1865-7, ISSN

premixed human insulin 30 (BHI 30) in gestational diabetes mellitus-a pilot study. *J*

to diagnose gestational diabetes mellitus in Asian Indian women. *Dia Res Clin Pract.*

mellitus in Asian-Indian women. *Indian J Endocrinol Metab.* In Press. ISSN 2230-

gestational diabetes mellitus and prevention of diabetes related complications. *Eur J Obstet Gynecol Reprod Biol*. Vol. 109, No. 1, (July 2003), pp. 41 – 4, ISSN 0301-2115. Beischer, NA.; Oats, JN.; Henry, OA.; et al. (1991). Incidence and severity of gestational

diabetes mellitus according to country of birth in women living in Australia*.*

Meeting of the DPSG, Luso – Portugal, September 2004.

Vol. 25, No.2, (March-April 2005),129 – 33, ISSN 0256-4947.

(April 1982): pp. 203 – 5, ISSN 0004-5772.

maternal and fetal outcome.

ISSN 0940-5429.

60, ISSN 0379-5284.

223-4, ISSN 0168-8227.

In Press. ISSN 0168-8227.

1995), pp. 171–4, ISSN 0959-8138.

0149-5992.

8210.

**12. References**

primary prevention of diabetes.

Gestational Diabetes Mellitus - A Perspective 37

Kuhl, C. (1991). Insulin Secretion and insulin resistance in pregnancy and GDM.

Landon, MB.; Spong, CY.; Thom, E.; et al. (2009). A multicenter, randomized trial of

Langer, O.; Levy, J.; Brustman, L.; et al. (1989). Glycemic control in gestational diabetes

Langer, O.; Cornway, DL.; Berkus, MD.; et al. (2000). A comparison of glyburide and insulin

Langer, O.; Yogev, Y.; Xenakis, EM.; et al. (2005). Insulin and glyburide therapy: dosage,

Lucas, A. (1991). Programming by early nutrition in man. In: *The childhood environment and*

Magee, S.; Walden, CE.; Benedetti, TJ.; et al. (1993). Influence of diagnostic criteria on the

Mazze, R.; (2006). Epidemiology of Diabetes in Pregnancy. In: *The Diabetes In Pregnancy*

Press of America, ISBN 0-7618-3270X, Maryland, United States of America. Metzger, BE.; (1991). Summary and recommendations of the Third International Workshop

Metzger, BE.; Gabbe, SG.; Persson, B.; et al. International Association of Diabetes and

Mohan, V.; Sandeep, S.; Deepa, R.; et al. (2007). Epidemiology of Type 2 diabetes: Indian

Nahum, GG.; Wilson, SB.; Stanislaw, H.; (2002). Early pregnancy glucose screening for

Narendra, J.; Munichoodappa, C.; Gurudas, A., et al. (1991). Prevalence of glucose

Negrato, CA.; Jovanovic, L.; Tambascia, MA.; et al. (2008). Mild gestational hyperglycemia

Vol. 192, No. 1, (January 2005), pp. 134-9. ISSN 0002-9378.

1991), pp. 18-24. ISSN 0012-1797.

2009), pp. 1339-48. ISSN 0028-4793.

471 92957 3, Chichester, UK.

197–201, ISSN 0012-1797.

5916.

62. ISSN 0024-7758.

ISSN 1520-7552.

2010), pp. 676-82. ISSN 0149-5992.

1991), pp. 2-4. ISSN 0973-3930.

(February 1993), pp. 609-15. ISSN 0098-7484.

ISSN 0002-9378.

Implications for diagnosis and management. *Diabetes.* Vol. 40, Suppl. 2, (December

treatment for mild gestational diabetes. N Engl J Med. Vol. 361, No. 14, (October

mellitus-how tight is tight enough: small for gestational age versus large for gestational age? *Am J Obstet Gynecol*. Vol. 161, No. 3, (September 1989), pp. 646-53.

in GDM. *N Engl J Med*. Vol. 343, No. 16, (October 2000), pp. 1134-8. ISSN 0028-4793.

severity level of gestational diabetes, and pregnancy outcome. *Am J Obstet Gynecol*.

*adult disease.* Bock GR, Whelan J, editors. pp. 38-55. John Wiley and Sons, ISBN 0

incidence of gestational diabetes and perinatal morbidity. *JAMA.* Vol. 269, No. 5,

*Dilemma, Leading change with Proven Solutions.* Langer, O.; pp. 13-22, University

Conference on Gestational Diabetes Mellitus. *Diabetes.* Vol. 40, Suppl No. 2, pp.

Pregnancy Study Groups Consensus Panel (2010). International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. *Diabetes Care.* Vol. 33, No. 3, (March

Scenario. *Indian J Med Res.* Vol. 125, No. 3, (March 2007), pp. 217-30. ISSN 0971-

gestational diabetes mellitus. *J Reprod Med.* Vol. 47, No. 8, (August 2002), pp. 656-

intolerance during pregnancy. *Int J Diab Dev Countries*. Vol. 11, No. 2, (April – June

as a risk factor for metabolic syndrome in pregnancy and adverse perinatal outcomes. Diabetes Metab Res Rev. Vol. 24, No. 4, (May-June 2008), pp. 324-30.

Franks, PW.; Looker, HC.; Kobes, S.; et al. (2006). Gestational Glucose tolerance and risk of

Gayle, C.; Germain, S.; Marsh, MS.; et al. (2010). Comparing pregnancy outcomes for

Gifford F. (2001). Uncertainty about clinical equipoise. Clinical equipoise and the

Girling, J. & Dornhorst, A. (2003). Pregnancy and diabetes mellitus. In: *Textbook of Diabetes 2,*

Glueck, CJ.; Goldenberg, N.; Pranikoff, J.; et al. (2004). Height, weight and motor- social

Gough, WW.; Shack, MJ.; Bennett, PH.; et al. (1970). Evaluation of glucose in the Pima

Groop, LC.; Barzilai, N.; Ratheiser, K.; et al. (1991). Dose-dependent effects of Glyburide on

Hermansen, K.; Colombo, M.; Storgaard, H.; et al. (2002). Improved postprandial glycemic

Hunt, KJ. & Schuller, KL. (2007). The increasing prevalence of diabetes in pregnancy. *Obstet Gynecol Clin North Am.* Vol 34, No. 2, (June 2007), pp. 173-99. ISSN 0889-8545. Jovanovic, L. (1998). American Diabetes Association's Fourth International Workshop –

Jovanovic, L. (2001). What is so bad about a big baby? *Diabetes Care*. Vol. 24, No. 8, (August

Jovanovic, L.; Ilic, S.; Pettitt, DJ.; et al. (1999). Metabolic and immunologic effects of insulin

King, H. (1998). Epidemiology of glucose intolerance and gestational diabetes in women of

Kuhl, C.; Hornnes, PJ.; Andersen, O. (1985). Etiology and pathophysiology of gestational

2006), pp. 460 – 5. ISSN 0012-1797.

(March 2001), pp. 795. ISSN 0959-8138.

(August 1991), pp. 724-7. ISSN 0149-5992.

Vol. 25, No. 5, (May 2002), pp. 883-88. ISSN 0149-5992.

company, ISBN 0-632-05915-X, United Kingdom.

pp. S435, ISSN 0012-186X.

ISSN 0268-1161.

B137. ISSN 0149-5992.

1422-27. ISSN 0149-5992.

ISSN 0149-5992.

1797.

2001), pp. 1317-8. ISSN 0149-5992.

0012-1797.

type 2 diabetes in Young Pima Indian Offspring. *Diabetes*. Vol. 55, No. 2, (February

intensive versus routine antenatal treatment of GDM based on a 75 gm OGTT 2- h blood glucose (>140 mg/dl). *Diabetologia.* Vol. 53, Suppl. No. 1, (September 2010),

uncertainty principles both require further scrutiny. *BMJ.* Vol. 322, No. 7289,

John C Pick Up, Gareth Williams, editors. 3rd ed, pp. 65-66, Blackwell publishing

development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued Metformin throughout pregnancy. *Hum Reprod*. Vol. 19, No. 6, (June 2004), pp. 1323-30.

Indians by longitudinal studies. *Diabetes.* Vol. 19, Suppl No. 1, (1970). pp. 388. ISSN

insulin secretion and glucose uptake in humans. *Diabetes Care*. Vol. 14, No. 8,

control with biphasic human insulin in patients with Type 2 diabetes. *Diabetes Care*.

Conference on Gestational Diabetes Mellitus: Summary and Discussion. Therapeutic interventions. *Diabetes Care*. Vol 21, Suppl No. 2, (August 1998), B131 -

lispro in gestational diabetes. *Diabetes Care*. Vol. 22, No. 9, (September 1999), pp.

childbearing age. *Diabetes Care.* Vol. 21, Suppl No. 2, (August 1998), pp. B9 - B13.

diabetes mellitus. *Diabetes*. Vol. 34, Suppl No. 2, (June 1985), pp. 66–70. ISSN 0012-

Gestational Diabetes Mellitus - A Perspective 39

Savona - Ventura C.; & Chircop, M.; (2003). Birth weight influence on the subsequent

Schmidt, MI.; Duncan, BB.; Reichelt, AJ.; et al. (2001). Gestational diabetes mellitus

Seshiah, V.; Balaji, V.; Balaji MS.; et al. (2004). Gestational diabetes mellitus in India.*J Assoc Physicians India.* Vol. 52, No. 9, (September 2004), pp. 707-11. ISSN 0004-5772. Seshiah, V.; Balaji, V.; Balaji, MS.; et al. (2005). One step procedure for screening and

Seshiah, V.; Alexander, C.; Balaji, V.; et al. (2006). Glycemic control from early weeks of

manifests in all trimesters of pregnancy. *Dia Res Clin Pract.* Vol. 77, No. 3, (September 2007),

Seshiah, V.; Balaji, V.; Balaji, MS.; et al. (2008). Prevalence of gestational diabetes mellitus in

Seshiah, V.; Cynthia, A.; Balaji, V.; et al. (2008). Detection and care of women with

Seshiah, V.; Balaji, V.; Panneerselvam, A.; et al. (2008). "Abnormal" fasting plasma glucose

Seshiah, V.; Sahay, BK.; Das, AK.; et al. (2009). Gestational diabetes mellitus-

Seshiah, V.; Balaji, V.; Siddharth, Shah,; et al. (2011). Diagnosis of Gestational Diabetes Mellitus in the Community. *J Assoc Physicians India.* In Press. ISSN 0004-5772. Shamsuddin, K.; Mahdy, ZA.; Siti Rafiaah, I.; et al. (2001). Risk factor screening for abnormal

Simmons, D.; Devers, MC.; Wolmarans, L.; et al. (2009). Difficulties in the use of risk factors

Snehalatha C, Mary S, Selvam S, Sathish Kumar CK, Shetty SB, Nanditha A et al. (2009).

(November/December 2005), pp. 525-29. ISSN*:* 0971-9202.

Seshiah, V.; Balaji, V.; Balaji, MS,; et al. (2007). Gestational Diabetes Mellitus

56, No. 5, (May 2008), pp. 329-33. ISSN 0004-5772.

(May 2008), pp. 199-202. ISSN 0168-8227.

2003), pp. 101-4. ISSN 0940-5429.

1998), pp. B33 – B42. ISSN 0149-5992.

604, ISSN 0012-1797.

pp. 482-4. ISSN 0168-8227.

1935-5548 (Electronic).

pp. 27-32. ISSN 0020-7292.

2009), e8. ISSN 0149-5992.

pp. 1796-1801. ISSN 0149-5992.

6. ISSN 0019-5847.

development of gestational diabetes mellitus. *Acta Diabetol*. Vol. 40, No. 2, (June

diagnosed with a 2-h 75-g oral glucose tolerance test and adverse pregnancy outcomes. *Diabetes Care.* Vol. 24, No. 7, (July 2001), pp. 1151–5. ISSN 0149-5992. Sermer, M.; Naylor, CD.; Farine, D.; et al. (1998). The Toronto Tri Hospital Gestational

diabetes project-A preliminary review. *Diabetes Care*. Vol. 21, Suppl. No. 2, (August

diagnosis of gestational diabetes mellitus. *J Obstet Gynecol Ind.* Vol. 55, No. 6,

gestation and pregnancy outcome. *Diabetes*. Vol. 55, Suppl. No. 1, (June 2006), pp. A

South India (Tamil Nadu)-a community based study. *J Assoc Physicians India*. Vol.

gestational diabetes mellitus from early weeks of pregnancy results in birth weight of newborn babies appropriate for gestational age. *Dia Res Clin Pract*. Vol. 80, No. 2,

during pregnancy. *Diabetes Care*. Vol. 31, No. 12, (December 2008), pp. e92. ISSN.

Indianguidelines. *J Indian Med Assoc*. Vol. 107, No. 11, (Nov 2009), pp. 799-802, 804-

glucose tolerance in pregnancy. *Int J Gynecol Obstet.* Vol. 75, No. 1, (October 2001),

to screen for gestational diabetes mellitus. *Diabetes Care.* Vol. 32, No. 1, (January

Changes in insulin secretion and insulin sensitivity in relation to the glycemic outcomes in subjects with impaired glucose tolerance in the Indian Diabetes Prevention Programme – (IDPP- 1). *Diabetes Care.* Vol. 32, No. 10, (October 2009),

Paul, VK.; Deorari, AK.; Singh, M.;. (2002). Management of Low Birth Weight Babies. In: *IAP*

Perucchini, D.; Fischer, U.; Spinas, GA.; et al. (1999). Using fasting plasma glucose

Pettitt, DJ.; Bennett, PH.; Saad, MF.; et al. (1991). Abnormal glucose tolerance during

Pettitt, DJ.; Bennett, PH.; Hanson, RL.; et al. (1994). Comparison of World Health

Philips, LS.; Ziemer, DC.; Kolm, P.; et al. (2009). Glucose challenge test screening for

Polonsky, KS.; Given, BD.; Van Cauter, E.; (1988). Twenty four hour profiles and pulsatile

Ramachandran, A.; Jali, MV.; Mohan, V.; et al. (1988). High prevalence of diabetes in an

Ramachandran, A.; Snehalatha, C.; Dharmaraj, D.; et al. (1992). Prevalence of glucose

Ramachandran, A.; Snehalatha, C.; Kapur, A.; et al. For the Diabetes Epidemiology Study

Ramachandran, A.; Snehalatha, C.; Vijayalakshmi, S.; et al. (2005). Use of metformin in

of obesity on insulin resistance in pregnancy: a comparison of Asian, South Asian and

Rossetti, L.; Giaccari, A.; De Fronzo, RA.; (1990). Glucose toxicity. *Diabetes Care.* Vol. 13, No.

Rowan, JA.; Hague, WM.; Gao, W.; et al. MiG Trial Investigators. (2008). Metformin versus

Sacks, DA.; (2010). Screening for hyperglycemia in pregnancy. In: *A practical Manual of*

Retnakaran, R.; Hanley, AJ.; Connelly, PW.; et al. (2006). Ethnicity modifies the effect

40, Suppl. No. 2, (December 1991), pp. 126–130. ISSN 0012-1797.

(November 1994), pp. 1264-68. ISSN: 0149-5992.

2, (February 1988), pp. 442 – 8. ISSN 0021-9738.

(September 2001), pp. 1094-101. ISSN 0012-186X.

6, (June 1990), pp. 610-30. ISSN 0149-5992.

(May 2008), pp. 2003-15. ISSN 0028-4793.

53, No. 2, (February 2005), pp. 157 – 58. ISSN 0004-5772.

Publishing Ltd, ISBN 978-1-4051-7904-1, United Kingdom.

pp. 1798 -1807. ISSN 0012-186X.

–90. ISSN 0959-8138.

55. ISSN 0149-5992.

ISSN 0021-972X.

Delhi.

*Textbook of Pediatrics*. Parthasarathy, A.; Menon, PSN.; Nair, MKC.; Lokeshwar, MR.; Srivastava, RN.; Bhave, SY.; editors., 2nd edition, pp. 60, Jaypee Brothers, New

concentrations to screen for gestational diabetes mellitus: prospective population based study. BMJ. Vol. 319, No. 7213, (September 1999), pp. 812-15. ISSN 0959-8138.

pregnancy in Pima Indian women: Long term effects on the offspring. *Diabetes*. Vol.

Organization and National Diabetes Data Group procedures to detect abnormalities of glucose tolerance during pregnancy. *Diabetes Care.* Vol. 17, No. 11,

prediabetes & undiagnosed diabetes. *Diabetologia.* Vol. 52, No. 9, (September 2009),

patterns of insulin secretion in normal and obese subjects. *J Clin Invest*. Vol. 81, No.

urban population in south India. *BMJ*. Vol. 297, No. 6648, (September 1988), pp. 587

intolerance in Asian Indians. *Diabetes Care*. Vol. 15, No. 10, (October 1992), pp. 1348-

Group in India (DESI). (2001). High prevalence of diabetes and impaired glucose tolerance in India: National Urban Diabetes Survey. *Diabetologia*. Vol. 44, No. 9,

pregnancies with diabetes: A Case series from India. *J Assoc Physicians India.* Vol.

Caucasian women. *J Clin Endocrinol Metab* Vol. 91, No. 1, (January 2006), pp. 93-97.

insulin for the treatment of gestational diabetes. *N Engl J Med.* Vol. 358, No. 19,

*Diabetes in Pregnancy*. Mc Cance DR, Maresh M, Sacks DA,. pp. 45-55, Blackwell

**3**

*Brazil*

**Gestational Diabetes: Evidence-Based**

*Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) – Recife, Pernambuco,*

Gestational diabetes (GD) is defined as carbohydrate intolerance that begins or is first diagnosed during pregnancy. Hyperglycemia is found only during pregnancy and diagnosis is confirmed when glucose tolerance test results return to normal levels in the postpartum (Metzger et al., 2007). GD occurs in around 4-10% of pregnancies; however, its incidence varies as a function of nutritional habits and differences in genetic patterns

The importance of GD was first described around forty years ago when it was noticed that women with this disorder were more likely to develop diabetes mellitus later on in their lives. The original diagnostic criteria proposed by O'Sullivan and Mahan were in fact never validated for the development of gestational complications or adverse perinatal outcomes (O'Sullivan and Mahan, 1964). Throughout all this time, the importance of this diagnosis for the prognosis of the pregnancy has been the subject of debate (Holt et al., 2011). Whereas some specialists feared that even mild levels of hyperglycemia would negatively affect pregnancy outcome, others have questioned the very existence of GD as a disease

Recently, however, the harmful effects of hyperglycemia during pregnancy have been demonstrated (HAPO, 2008) and evidence is mounting on the risks of hyperglycemia during pregnancy, not only in terms of adverse perinatal outcome, but also for the future of the infant

In this chapter, the rationale and current recommendations for the diagnosis and treatment of gestational diabetes will be evaluated based on the best scientific evidence currently available. The MEDLINE, EMBASE, SCOPUS and SciELO databases and the systematic reviews of the Cochrane Library were reassessed using the key words: gestational diabetes, screening, diagnosis and therapy. Preference was given to randomized clinical trials and meta-analyses, with observational studies and review articles being included only when studies with a better level of evidence were unavailable. Guidelines and recommendations established by medical societies for the screening, diagnosis and treatment of gestational diabetes were also consulted.

As any carbohydrate metabolism disorder, GD is characterized by insufficient insulin levels for insulin demand (Metzger et al., 2007). The cause of this insulin insufficiency in

in adult life (Catalano, 2010; Chandler-Laney et al., 2011; Fall, 2010; Lawlor et al., 2011).

**1. Introduction**

between populations (Metzger et al., 2007).

(Buchanan and Kjos, 1999).

**2. Physiopathology**

**Screening, Diagnosis and Treatment**

Melania Maria Ramos Amorim and Leila Katz

## **Gestational Diabetes: Evidence-Based Screening, Diagnosis and Treatment**

Melania Maria Ramos Amorim and Leila Katz *Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) – Recife, Pernambuco, Brazil*

#### **1. Introduction**

40 Gestational Diabetes

Super, DM.; Edelberg, SC.; Philipson, EH.; et al. (1991). Diagnosis of gestational diabetes in

Tisi, DK.; Burns, DH.; Luskey, GW.; et al. (2011). Fetal exposure to altered amniotic fluid

Tuomilehto, J.; (2005). A paradigm shift is needed in the primary prevention of type 2

Valensi, P.; Benroubi, M.; Borzi, V.; et al. (2009). Initiating insulin therapy with, or switching

Voto, LS.; Uranga Imaz, M.; Margulies, M. (2003). Gestational diabetes in developing

Mellitus (GDM) and its Outcomes in Jammu Region. *J Assoc Physicians India.* Vol. 59, No. 4,

Weiss, PA.; Haeusler, M.; Tamussino, K.; et al. (2000). Can glucose tolerance test predict fetal

Wild, S.; Roglic, G.; Green, A.; et al. (2004). Global prevalence of diabetes: estimates for the

Wojcikowski, C.; Krolikowska, B.; Konarzewska, J.; et al. (2002). The prevalence of

Yajnik, CS.; Fall, CH.; Vaidya, U.; et al. (1995). Fetal growth and glucose and insulin

Yogev, Y.; Avi Ben-Haroush, Moshe Hod: Pathogenesis of gestational diabetes mellitus; In:

Zargar, AH.; Sheikh, MI.; Bashir, MI.; et al. (2004). Prevalence of gestational diabetes

66, No. 2, (November 2004), pp. 139-45. ISSN 0168-8227.

Wahi, P.; Dogra, V.; Jandial, K.; et al. (2011). Prevalence of Gestational Diabetes

5992.

1368-5031.

0328.

2011), pp. 139-44. ISSN 0149-5992.

Ltd, England, ISBN: 978-0-470-85734-2.

Group plc, ISBN 1 84184 110 2, London.

(April 2011), pp. 227-30. ISSN 0004-5772.

(October 2002), pp. 811-6. ISSN 0017-0011.

1995), pp. 330-6. ISSN 0742-3071.

1047-53. ISSN 0149-5992.

84184 110 2, London.

early pregnancy. *Diabetes Care.* Vol. 14, No. 4, (April 1991), pp. 288-94. ISSN 0149-

glucose, insulin, and insulin-like growth factor-binding protein 1 occurs before screening for gestational diabetes mellitus. *Diabetes Care*. Vol. 34, No. 1, (January

diabetes. In: *Prevention of type 2 diabetes*. Ganz M, pp. 153-65, John Willey & Sons

existing insulin therapy to, biphasic insulin aspart 30/70 (NovoMix 30) in routine care: safety and effectiveness in patients with type 2 diabetes in the IMPROVE observational study. *Int J Clin Pract.* Vol. 63, No. 3, (March 2009), pp. 522–31. ISSN

countries. In: *Textbook of Diabetes and Pregnancy.* Hod, M.; Jovanovic, L.; Di Renzo, GC.; de Leiva, A.; Langer, O.; 1st ed. pp. 183- 90. Martin Dunitz, Taylor & Francis

hyperinsulinism?. *BJOG*. Vol. 107, No. 12, (December 2000), pp. 1480-5. ISSN 1470-

year 2000 and projections for 2030. *Diabetes Care.* Vol. 27, No. 5, (May 2004), pp.

gestational diabetes mellitus in Polish population. *Ginekol Pol.* Vol. 73, No. 10,

metabolism in four year old Indian children. *Diabetic Medicine*. Vol. 12, No. 4, (April

*Textbook of Diabetes and Pregnancy.* Hod, M.; Jovanovic, L.; Di Renzo, GC.; de Leiva, A.; Langer, O.; 1st ed. pp. 46. Martin Dunitz, Taylor & Francis Group plc, ISBN 1

mellitus in Kashmiri women from the Indian subcontinent. *Dia Res Clin Pract*. Vol.

Gestational diabetes (GD) is defined as carbohydrate intolerance that begins or is first diagnosed during pregnancy. Hyperglycemia is found only during pregnancy and diagnosis is confirmed when glucose tolerance test results return to normal levels in the postpartum (Metzger et al., 2007). GD occurs in around 4-10% of pregnancies; however, its incidence varies as a function of nutritional habits and differences in genetic patterns between populations (Metzger et al., 2007).

The importance of GD was first described around forty years ago when it was noticed that women with this disorder were more likely to develop diabetes mellitus later on in their lives. The original diagnostic criteria proposed by O'Sullivan and Mahan were in fact never validated for the development of gestational complications or adverse perinatal outcomes (O'Sullivan and Mahan, 1964). Throughout all this time, the importance of this diagnosis for the prognosis of the pregnancy has been the subject of debate (Holt et al., 2011). Whereas some specialists feared that even mild levels of hyperglycemia would negatively affect pregnancy outcome, others have questioned the very existence of GD as a disease (Buchanan and Kjos, 1999).

Recently, however, the harmful effects of hyperglycemia during pregnancy have been demonstrated (HAPO, 2008) and evidence is mounting on the risks of hyperglycemia during pregnancy, not only in terms of adverse perinatal outcome, but also for the future of the infant in adult life (Catalano, 2010; Chandler-Laney et al., 2011; Fall, 2010; Lawlor et al., 2011).

In this chapter, the rationale and current recommendations for the diagnosis and treatment of gestational diabetes will be evaluated based on the best scientific evidence currently available. The MEDLINE, EMBASE, SCOPUS and SciELO databases and the systematic reviews of the Cochrane Library were reassessed using the key words: gestational diabetes, screening, diagnosis and therapy. Preference was given to randomized clinical trials and meta-analyses, with observational studies and review articles being included only when studies with a better level of evidence were unavailable. Guidelines and recommendations established by medical societies for the screening, diagnosis and treatment of gestational diabetes were also consulted.

#### **2. Physiopathology**

As any carbohydrate metabolism disorder, GD is characterized by insufficient insulin levels for insulin demand (Metzger et al., 2007). The cause of this insulin insufficiency in

Gestational Diabetes: Evidence-Based Screening, Diagnosis and Treatment 43

The screening and diagnosis of GD is the subject of intense debate and controversy worldwide (Holt et al., 2011; Leary et al., 2010). All aspects of diagnosis (who should be investigated, using which tests and what values are considered diagnostic) have been widely discussed over the past two decades (Holt et al., 2011). Consequently, the guidelines published by the major societies differ with respect to these aspects with the result that the

The World Health Organization (WHO) recommends screening high-risk women with a 75 gram oral glucose tolerance test in the first trimester of pregnancy and all other women at 24-28 weeks, with fasting glucose measurements of 126 mg/dl and two-hour glucose levels of 140 mg/dl being considered abnormal (WHO, 1999). However, until recently (up to autumn 2010), the American Diabetes Association (ADA) recommended screening only women with risk factors and advocated an oral load of 100 grams of anhydrous glucose

Recently, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) assembled the evidence accumulated over recent years and published new criteria for the

Screening is performed to select individuals to be investigated. Since 1999, the World Health Organization (WHO) has recommended the screening of all women or all women except

In 2003, a US taskforce was formed to evaluate screening for gestational diabetes. The authors' conclusion was that better-quality evidence was required to determine whether the benefits of screening are greater than the risks. They recommended that until such evidence was available, to screen or not to screen should be left to the discretion of each individual physician according to his/her own clinical judgment and that both options are reasonable

The same taskforce evaluated the risk factors for gestational diabetes and found a strong association with: maternal obesity (body mass index > 25), age > 25 years, personal or family history of a carbohydrate metabolism disorder or a history of gestational diabetes in a previous pregnancy. Some ethnic groups such as Hispanics, Blacks, native American Indians and Asians are also at an increased risk of developing gestational diabetes. If all these criteria are taken into consideration, 90% of all women at risk of developing

A systematic review was conducted of observational studies published in the past thirty years to evaluate the presence and strength of the association between pre-gestational body mass index (BMI) and the presence of gestational diabetes. Seventy studies were included involving 671,945 women (59 cohort studies and 11 case-control studies). Compared to women with normal pregestational BMI, in accordance with the odds ratio (OR) the estimated risk of developing gestational diabetes was 1.97 [95% confidence interval (95%CI) 1.77 – 2.19], 3.01 [95%CI: 2.34 – 3.87] and 5.55 [95%CI: 4.27 – 7.21] for overweight, moderate

In addition to the principal risk factors, Table 2 provides a detailed list of risk factors from previous pregnancies as well as risk factors that may appear during the course of pregnancy

practices of physicians worldwide differ to the same extent (Leary et al., 2010).

(ADA, 2004). The values adopted in each one of the guidelines also differed greatly.

**4. Screening and diagnosis of gestational diabetes**

screening and diagnosis of GD (IADPSG, Metzger et al., 2010).

(The US Preventive Services Task-Force – USPSTF, Brody et al., 2003-A).

gestational diabetes will be identified (Brody et al., 2003-A).

obesity and severe obesity, respectively (Torloni et al., 2009).

and may merit investigation.

those considered low-risk (WHO, 1999).

**4.1 Screening**

pregnancy remains to be fully established; however, it is believed that the occurrence of this event during pregnancy reveals underlying maternal pancreatic disorders that would otherwise only become apparent later on in the woman's life (Metzger et al., 2007).

In a normal pregnancy, fetal and placental growth increases cortisol, growth hormone, human placental lactogen, progesterone, estrogen and prolactin levels. The presence of these stimuli triggers hyperinsulinemia, insulin resistance, fasting hypoglycemia and postprandial hyperglycemia. Consequently, there is a reduction in peripheral sensitivity to insulin and an increase in demand. As a compensatory mechanism, an increase occurs in pancreatic function at the cost of both hypertrophy and hyperplasia. Furthermore, in response to the high insulin levels, peripheral utilization of glucose by the muscles and peripheral glycogen storage increase in an attempt to maintain balance (Metzger et al., 2007; Pridjian and Benjamin, 2010).

As pregnancy advances, these compensatory mechanisms may be insufficient in susceptible women, resulting in an imbalance between insulin production and insulin requirements in pregnancy. Compared to a normal pregnant woman, a woman with GD has pancreatic βcell dysfunction and a reduction in adaptive β-cell capacity. This results in insufficient insulin secretion and consequent hyperglycemia (Metzger et al., 2007; Pridjian and Benjamin, 2010).

#### **3. Consequences for the mother and child**

The consequences of gestational diabetes for the mother and child are summarized in Table 1.

Modified from Pridjian and Benjamin, 2010

Table 1. Risks of Gestational Diabetes

#### **4. Screening and diagnosis of gestational diabetes**

The screening and diagnosis of GD is the subject of intense debate and controversy worldwide (Holt et al., 2011; Leary et al., 2010). All aspects of diagnosis (who should be investigated, using which tests and what values are considered diagnostic) have been widely discussed over the past two decades (Holt et al., 2011). Consequently, the guidelines published by the major societies differ with respect to these aspects with the result that the practices of physicians worldwide differ to the same extent (Leary et al., 2010).

The World Health Organization (WHO) recommends screening high-risk women with a 75 gram oral glucose tolerance test in the first trimester of pregnancy and all other women at 24-28 weeks, with fasting glucose measurements of 126 mg/dl and two-hour glucose levels of 140 mg/dl being considered abnormal (WHO, 1999). However, until recently (up to autumn 2010), the American Diabetes Association (ADA) recommended screening only women with risk factors and advocated an oral load of 100 grams of anhydrous glucose (ADA, 2004). The values adopted in each one of the guidelines also differed greatly.

Recently, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) assembled the evidence accumulated over recent years and published new criteria for the screening and diagnosis of GD (IADPSG, Metzger et al., 2010).

#### **4.1 Screening**

42 Gestational Diabetes

pregnancy remains to be fully established; however, it is believed that the occurrence of this event during pregnancy reveals underlying maternal pancreatic disorders that would

In a normal pregnancy, fetal and placental growth increases cortisol, growth hormone, human placental lactogen, progesterone, estrogen and prolactin levels. The presence of these stimuli triggers hyperinsulinemia, insulin resistance, fasting hypoglycemia and postprandial hyperglycemia. Consequently, there is a reduction in peripheral sensitivity to insulin and an increase in demand. As a compensatory mechanism, an increase occurs in pancreatic function at the cost of both hypertrophy and hyperplasia. Furthermore, in response to the high insulin levels, peripheral utilization of glucose by the muscles and peripheral glycogen storage increase in an attempt to maintain balance (Metzger et al., 2007; Pridjian and

As pregnancy advances, these compensatory mechanisms may be insufficient in susceptible women, resulting in an imbalance between insulin production and insulin requirements in pregnancy. Compared to a normal pregnant woman, a woman with GD has pancreatic βcell dysfunction and a reduction in adaptive β-cell capacity. This results in insufficient insulin secretion and consequent hyperglycemia (Metzger et al., 2007; Pridjian and

The consequences of gestational diabetes for the mother and child are summarized in Table 1.

**Risks of Gestational Diabetes Mother Fetus Newborn infant Child/Adult**

Respiratory distress

Hypocalcemia Metabolic

Obesity

Mellitus

syndrome

syndrome

Cardiomyopathy Hypoglycemia Type 2 Diabetes

Polycythemia: • Hyperviscosity • Hyperbilirubinemia Cardiomyopathy

otherwise only become apparent later on in the woman's life (Metzger et al., 2007).

Benjamin, 2010).

Benjamin, 2010).

Obstetric trauma

Higher rate of Cesarean sections

Preeclampsia/ gestational hypertension

Type 2 Diabetes

mellitus

Metabolic syndrome

**3. Consequences for the mother and child**

Hyperinsulinemia:

• Macrosomia

Obstetric trauma: • Shoulder dystocia

• Brachial plexus lesion

Stillbirth Hypomagnesemia

• Fractures

Modified from Pridjian and Benjamin, 2010 Table 1. Risks of Gestational Diabetes

• Large for gestational age

Screening is performed to select individuals to be investigated. Since 1999, the World Health Organization (WHO) has recommended the screening of all women or all women except those considered low-risk (WHO, 1999).

In 2003, a US taskforce was formed to evaluate screening for gestational diabetes. The authors' conclusion was that better-quality evidence was required to determine whether the benefits of screening are greater than the risks. They recommended that until such evidence was available, to screen or not to screen should be left to the discretion of each individual physician according to his/her own clinical judgment and that both options are reasonable (The US Preventive Services Task-Force – USPSTF, Brody et al., 2003-A).

The same taskforce evaluated the risk factors for gestational diabetes and found a strong association with: maternal obesity (body mass index > 25), age > 25 years, personal or family history of a carbohydrate metabolism disorder or a history of gestational diabetes in a previous pregnancy. Some ethnic groups such as Hispanics, Blacks, native American Indians and Asians are also at an increased risk of developing gestational diabetes. If all these criteria are taken into consideration, 90% of all women at risk of developing gestational diabetes will be identified (Brody et al., 2003-A).

A systematic review was conducted of observational studies published in the past thirty years to evaluate the presence and strength of the association between pre-gestational body mass index (BMI) and the presence of gestational diabetes. Seventy studies were included involving 671,945 women (59 cohort studies and 11 case-control studies). Compared to women with normal pregestational BMI, in accordance with the odds ratio (OR) the estimated risk of developing gestational diabetes was 1.97 [95% confidence interval (95%CI) 1.77 – 2.19], 3.01 [95%CI: 2.34 – 3.87] and 5.55 [95%CI: 4.27 – 7.21] for overweight, moderate obesity and severe obesity, respectively (Torloni et al., 2009).

In addition to the principal risk factors, Table 2 provides a detailed list of risk factors from previous pregnancies as well as risk factors that may appear during the course of pregnancy and may merit investigation.

Gestational Diabetes: Evidence-Based Screening, Diagnosis and Treatment 45

2010) and in the risk factors for the occurrence of GD such as, for example, obesity (Catalano, 2010). In addition, it ensures that cases of early-onset GD will be identified (Leary

In addition, IADPSG recommends **universal** investigation at 24-28 weeks of all women not

The argument used by those who support universal screening is based on the randomized clinical trial entitled the *Australian Carbohydrate Intolerance Study in Pregnant Women*  (ACHOIS) trial group (Crowther et al., 2005), which showed a reduction in healthcare costs with universal screening. Nevertheless, criticism to the use of these results for recommending IADPSG's proposal is based on the fact that the ACHOIS study used an oral glucose tolerance test of 75 grams, measuring fasting glucose levels and two-hour glucose levels alone, whereas the IADPSG recommendations also include measurement of glucose levels one hour after overload (Leary et al., 2010). Further studies should be conducted to

The origin of all this controversy surrounding the diagnosis of GD lies in the form in which testing was initially developed. The first authors to develop a diagnostic test for GD were John O'Sullivan and Clare Mahan in 1964 (O'Sullivan and Mahan, 1964). The test was developed to predict the risk of developing diabetes mellitus years after the pregnancy

Although it constituted a watershed in the diagnosis of GD, faults were found in the study conducted by O'Sullivan and Mahan when analyzed from a methodological point of view, particularly with respect to the conclusions drawn and the validation of the test as a diagnostic technique, which was clearly demonstrated by Naylor in a study published in 1989 (Naylor, 1989). One of the questions raised was that gestational diabetes is more important as a predictor of a pregnancy with a higher maternal-fetal risk, whereas the endpoint initially evaluated was the presence of carbohydrate intolerance after the end of pregnancy. Since the investigators' objective was to predict the development of diabetes mellitus over the long-term, this characteristic was taken into consideration to select the cutoff points. It was later shown that when pregnant women considered to be diabetic in accordance with the values selected were treated with insulin, the rate of macrosomia decreased when glucose levels returned to normal (O'Sullivan, 1996 and 1973). This is an indirect way of reaching conclusions that is, nonetheless, far from ideal and does not allow the diagnostic technique to be adequately validated. According to Naylor, it would have been more appropriate to try to record the immediate and long-term neonatal complications

In the following years, changes were made to the diagnostic techniques used and glucose levels were no longer measured in full blood but rather in venous plasma. Furthermore, enzymatic methods began to be used to measure plasma glucose levels instead of the Somogyi-Nelson technique. These technical modifications led to the mathematical correction of the values initially proposed by O'Sullivan and Mahan with the appearance of different sets of values adopted by different organizations involved in the study of GD (National

Later, an intense debate ensued among investigators regarding the best form of diagnosing GD. Many investigators suggested the adoption of more rigid diagnostic criteria, including a

previously diagnosed as having clinical or gestational diabetes (IADPSG et al., 2010).

et al., 2010). Early screening reflects the preference for universal investigation.

evaluate the costs and benefits associated with this form of management.

rather than the risk of an adverse perinatal outcome.

and test their association using an oral glucose tolerance test.

Diabetes Data Group [NDDG], 1979; Carpenter and Coustan, 1982).

**4.2 Diagnosis**

#### **Personal characteristics:**

Age > 35 years Obesity (BMI > 25) Arterial hypertension Family history of diabetes **Obstetric history:**  Diabetes in previous pregnancy Multiparity Recurrent miscarriage Prematurity Recurrent preeclampsia Fetal death, principally in the final weeks of pregnancy **Neonatal morbidity and mortality:**  - Hypoglycemia - Respiratory distress syndrome - Hyperbilirubinemia - Hypocalcemia - Malformations **Complications in current pregnancy:**  Excessive weight gain Excessive growth of uterine fundal height Polyhydramnios Fetal macrosomia Glycosuria Use of hyperglycemic drugs (betamimetics, corticoids)

Amorim and Katz, 2011

Table 2. Risk factors for gestational diabetes

More recently, another systematic review evaluated the available literature, searching for further evidence on screening for gestational diabetes (Tieu et al.,2011). The authors searched for articles which evaluated any individual screening tool or screening program, protocol or guideline for gestational diabetes compared with the absence of screening; or any individual screening tool or screening program, protocol or guideline for gestational diabetes with another. Thirty-one trials were considered for inclusion into the review but after application of eligibility criteria, only four of these trials were included. After analysis the authors found that there was insufficient evidence to determine the effects of screening for gestational diabetes and its subsequent management, or the comparative effects of different protocols for screening. Although women who were routinely screened by 50 g glucose challenge testing were more likely to be diagnosed with gestational diabetes than those screened by their risk factors, effects of subsequent management on health outcome are unclear.

IADPSG recommends investigating "all women or all high-risk women" at their first prenatal consultation (IADPSG, Metzger et al., 2010). Universal investigation is justified by the increase in the prevalence of undiagnosed type 2 diabetes in young women (Leary et al., 2010) and in the risk factors for the occurrence of GD such as, for example, obesity (Catalano, 2010). In addition, it ensures that cases of early-onset GD will be identified (Leary et al., 2010). Early screening reflects the preference for universal investigation.

In addition, IADPSG recommends **universal** investigation at 24-28 weeks of all women not previously diagnosed as having clinical or gestational diabetes (IADPSG et al., 2010).

The argument used by those who support universal screening is based on the randomized clinical trial entitled the *Australian Carbohydrate Intolerance Study in Pregnant Women*  (ACHOIS) trial group (Crowther et al., 2005), which showed a reduction in healthcare costs with universal screening. Nevertheless, criticism to the use of these results for recommending IADPSG's proposal is based on the fact that the ACHOIS study used an oral glucose tolerance test of 75 grams, measuring fasting glucose levels and two-hour glucose levels alone, whereas the IADPSG recommendations also include measurement of glucose levels one hour after overload (Leary et al., 2010). Further studies should be conducted to evaluate the costs and benefits associated with this form of management.

#### **4.2 Diagnosis**

44 Gestational Diabetes

**Personal characteristics:**

Diabetes in previous pregnancy

**Neonatal morbidity and mortality:**

**Complications in current pregnancy:**

Excessive growth of uterine fundal height

Fetal death, principally in the final weeks of pregnancy

Use of hyperglycemic drugs (betamimetics, corticoids)

factors, effects of subsequent management on health outcome are unclear.

More recently, another systematic review evaluated the available literature, searching for further evidence on screening for gestational diabetes (Tieu et al.,2011). The authors searched for articles which evaluated any individual screening tool or screening program, protocol or guideline for gestational diabetes compared with the absence of screening; or any individual screening tool or screening program, protocol or guideline for gestational diabetes with another. Thirty-one trials were considered for inclusion into the review but after application of eligibility criteria, only four of these trials were included. After analysis the authors found that there was insufficient evidence to determine the effects of screening for gestational diabetes and its subsequent management, or the comparative effects of different protocols for screening. Although women who were routinely screened by 50 g glucose challenge testing were more likely to be diagnosed with gestational diabetes than those screened by their risk

IADPSG recommends investigating "all women or all high-risk women" at their first prenatal consultation (IADPSG, Metzger et al., 2010). Universal investigation is justified by the increase in the prevalence of undiagnosed type 2 diabetes in young women (Leary et al.,

Age > 35 years Obesity (BMI > 25) Arterial hypertension Family history of diabetes

**Obstetric history:**

Recurrent miscarriage

Recurrent preeclampsia

Excessive weight gain

Polyhydramnios Fetal macrosomia

Table 2. Risk factors for gestational diabetes

Glycosuria

Amorim and Katz, 2011

Multiparity

Prematurity

The origin of all this controversy surrounding the diagnosis of GD lies in the form in which testing was initially developed. The first authors to develop a diagnostic test for GD were John O'Sullivan and Clare Mahan in 1964 (O'Sullivan and Mahan, 1964). The test was developed to predict the risk of developing diabetes mellitus years after the pregnancy rather than the risk of an adverse perinatal outcome.

Although it constituted a watershed in the diagnosis of GD, faults were found in the study conducted by O'Sullivan and Mahan when analyzed from a methodological point of view, particularly with respect to the conclusions drawn and the validation of the test as a diagnostic technique, which was clearly demonstrated by Naylor in a study published in 1989 (Naylor, 1989). One of the questions raised was that gestational diabetes is more important as a predictor of a pregnancy with a higher maternal-fetal risk, whereas the endpoint initially evaluated was the presence of carbohydrate intolerance after the end of pregnancy. Since the investigators' objective was to predict the development of diabetes mellitus over the long-term, this characteristic was taken into consideration to select the cutoff points. It was later shown that when pregnant women considered to be diabetic in accordance with the values selected were treated with insulin, the rate of macrosomia decreased when glucose levels returned to normal (O'Sullivan, 1996 and 1973). This is an indirect way of reaching conclusions that is, nonetheless, far from ideal and does not allow the diagnostic technique to be adequately validated. According to Naylor, it would have been more appropriate to try to record the immediate and long-term neonatal complications and test their association using an oral glucose tolerance test.

In the following years, changes were made to the diagnostic techniques used and glucose levels were no longer measured in full blood but rather in venous plasma. Furthermore, enzymatic methods began to be used to measure plasma glucose levels instead of the Somogyi-Nelson technique. These technical modifications led to the mathematical correction of the values initially proposed by O'Sullivan and Mahan with the appearance of different sets of values adopted by different organizations involved in the study of GD (National Diabetes Data Group [NDDG], 1979; Carpenter and Coustan, 1982).

Later, an intense debate ensued among investigators regarding the best form of diagnosing GD. Many investigators suggested the adoption of more rigid diagnostic criteria, including a

Gestational Diabetes: Evidence-Based Screening, Diagnosis and Treatment 47

100 grams of anhydrous glucose (O'Sullivan and Mahan, 1964), a procedure that was also recommended by the American Diabetes Association in 2004 (ADA, 2004). Nonetheless, since the WHO proposal in 1980 to use a 75-gram overload, as used in non-pregnant women, this practice became more and more common and even the HAPO study used the 75-gram glucose overload. With the power obtained in the HAPO study showing the adverse perinatal effects of hyperglycemia associated with the levels obtained following a 75-gram overload of anhydrous glucose, this test will probably increase in popularity

Another interesting outcome of the HAPO study was the recommendation that a finding of only one abnormal value on the glucose curve should also be considered abnormal and diagnostic. This recommendation was made with the aim of increasing the likelihood of identifying milder degrees of hyperglycemia that had been associated with poorer maternal

The cut-off points recommended by IADPSG are arbitrarily defined based on an odds ratio of 1.75 relative to the mean glucose levels at each time-point, i.e. those measurements that result in a 75% greater likelihood of adverse perinatal outcomes. The selection had to be made in this way, since, as previously mentioned, the association between glucose levels and adverse outcome is continuous. These values, however, are subject to criticism and the occurrence of adverse outcomes with glucose levels below the proposed values is to be expected. Nevertheless, use of a lower cut-off point would certainly result in a greater percentage of diagnosed cases and the impact of this excess number of diagnoses on

The absence of any IADPSG recommendations regarding a category referred to as "carbohydrate intolerance" is noteworthy. According to current criteria, either a woman has normal glucose levels or she has gestational diabetes. However, cases need to be taken into consideration in which women have glucose levels outside the limits considered normal yet without reaching levels that would be considered diagnostic. The adoption of the term

The findings of the HAPO study appear to indicate that only normal glucose levels would eliminate the risk of adverse perinatal outcome; therefore, it could be argued that any deviation above normal levels should be considered abnormal (Leary et al., 2010). However, the economic and even the psychological impact of so many diagnoses of an "abnormal

To determine the ideal cut-off point, a cost-benefit analysis has to be performed of different cut-off points. In addition to the cost of the diagnostic test itself, the financial burden caused by the additional cases diagnosed in terms of follow-up and treatment has to be taken into consideration. In addition, it has to be confirmed that treating these diagnosed cases will indeed lead to a reduction in the number of adverse outcomes (Leary et al., 2010) and, furthermore, that this reduction will cause a positive impact that will compensate for the

The change in the diagnostic criteria defined by IADPSG will certainly have significant clinical implications for women and for the healthcare system. The number of women diagnosed as having gestational diabetes will rise. This increase in the prevalence of GD may cause a significant impact on all the additional women who will be diagnosed (Holt et al., 2011). In addition to the greater volume of resources required to follow-up and treat these women, the

compared to the 100-gram overload (Leary et al., 2010).

perinatal outcomes has yet to be established (Leary et al., 2010).

"carbohydrate intolerance" is suggested for such cases (Leary et al., 2010).

pregnancy" needs to be taken into consideration and may be immense.

effect on patients of the very existence of a diagnosis should be kept in mind.

and perinatal prognosis in previous studies.

costs of diagnosis and follow-up.

reduction in blood glucose levels or the adoption of fewer points on the curve as being sufficient for diagnosis. It was even proposed that the presence of hyperglycemia below the levels established for diagnosis could be sufficient to lead to adverse maternal and perinatal outcomes, or that the hyperglycemia occurring irrespective of an overload should be taken into consideration (Aberg et al., 2001; Jensen et al., 2001; Langer et al., 1987; Rudge et al., 1990; Sermer et al., 1995).

If on the one hand evidence was accumulating to the effect that milder degrees of hyperglycemia, albeit below the levels established for a diagnosis of GD, could lead to unfavorable perinatal outcomes, on the other hand some authors questioned the very existence of this diagnosis as a valid entity and called attention to the possible negative effects of this diagnosis (Buchanan, 1999; Lucas et al., 1993). A diagnosis of GD may result in excessive medicalization of pregnancy, which in itself would be negative. Furthermore, this diagnosis may result in an increase in the number of interventions performed, including even Cesarean sections, in situations in which the need for this type of delivery is questionable, due to the mere presence of a diagnosis of diabetes. In addition, it is important to remember the psychological burden caused by a label of diabetes.

In 2005, an Australian group (ACHOIS) published the findings of a randomized clinical trial in which mild hyperglycemia was treated in women who did not fulfill the diagnostic criteria for GD, but who had measurements of 140 to 199 mg/dl in a 75-gram oral glucose tolerance test (OGTT) and were consequently considered to be carbohydrate intolerant (Crowther et al., 2005). These investigators found a reduction in composite final outcome (perinatal death, shoulder dystocia, fractures and brachial plexus palsy) compared with women managed in the usual manner.

In 2009, a clinical trial was conducted to treat women who were found not to fulfill the diagnostic criteria for GD after being submitted to an oral glucose tolerance test with 100 grams of carbohydrate, but whose glucose levels were not completely normal. Likewise, when this group was treated, a reduction was found in macrosomia, shoulder dystocia, Cesarean section and hypertensive diseases (Landon et al., 2009).

Finally, the HAPO (Hyperglycemia and Adverse Pregnancy Outcome) study was conducted to evaluate the risks of hyperglycemia during pregnancy for the mother, the fetus and the newborn infant (HAPO, 2008). A total of 25,505 women were included and followed up prospectively to evaluate a possible association between glucose levels and maternal and perinatal outcome. The women were submitted to an OGTT using 75 grams of anhydrous glucose.

The HAPO results were conclusive with respect to the existence of a linear association between elevated glucose levels in the pregnant woman and the rates of large-forgestational-age infants, preeclampsia and Cesarean sections. Moreover, an association was found between maternal hyperglycemia and neonatal hypoglycemia, C-peptide in umbilical cord blood, premature delivery, admission to the neonatal intensive care unit (ICU) and hyperbilirubinemia. No association was found between maternal hyperglycemia and neonatal death; however, the sample size may have been insufficient to evaluate this particular outcome.

One of the most important findings of HAPO was the demonstration of an association that is continuous; hence no clear cut-off point can be defined above which adverse events occur (Leary et al., 2010).

The choice of the 75-gram curve to investigate these women has never been validated scientifically. The first glucose overload to be described in pregnancy was performed using

reduction in blood glucose levels or the adoption of fewer points on the curve as being sufficient for diagnosis. It was even proposed that the presence of hyperglycemia below the levels established for diagnosis could be sufficient to lead to adverse maternal and perinatal outcomes, or that the hyperglycemia occurring irrespective of an overload should be taken into consideration (Aberg et al., 2001; Jensen et al., 2001; Langer et al., 1987; Rudge et al.,

If on the one hand evidence was accumulating to the effect that milder degrees of hyperglycemia, albeit below the levels established for a diagnosis of GD, could lead to unfavorable perinatal outcomes, on the other hand some authors questioned the very existence of this diagnosis as a valid entity and called attention to the possible negative effects of this diagnosis (Buchanan, 1999; Lucas et al., 1993). A diagnosis of GD may result in excessive medicalization of pregnancy, which in itself would be negative. Furthermore, this diagnosis may result in an increase in the number of interventions performed, including even Cesarean sections, in situations in which the need for this type of delivery is questionable, due to the mere presence of a diagnosis of diabetes. In addition, it is important

In 2005, an Australian group (ACHOIS) published the findings of a randomized clinical trial in which mild hyperglycemia was treated in women who did not fulfill the diagnostic criteria for GD, but who had measurements of 140 to 199 mg/dl in a 75-gram oral glucose tolerance test (OGTT) and were consequently considered to be carbohydrate intolerant (Crowther et al., 2005). These investigators found a reduction in composite final outcome (perinatal death, shoulder dystocia, fractures and brachial plexus palsy) compared with

In 2009, a clinical trial was conducted to treat women who were found not to fulfill the diagnostic criteria for GD after being submitted to an oral glucose tolerance test with 100 grams of carbohydrate, but whose glucose levels were not completely normal. Likewise, when this group was treated, a reduction was found in macrosomia, shoulder dystocia,

Finally, the HAPO (Hyperglycemia and Adverse Pregnancy Outcome) study was conducted to evaluate the risks of hyperglycemia during pregnancy for the mother, the fetus and the newborn infant (HAPO, 2008). A total of 25,505 women were included and followed up prospectively to evaluate a possible association between glucose levels and maternal and perinatal outcome. The women were submitted to an OGTT using 75 grams of anhydrous

The HAPO results were conclusive with respect to the existence of a linear association between elevated glucose levels in the pregnant woman and the rates of large-forgestational-age infants, preeclampsia and Cesarean sections. Moreover, an association was found between maternal hyperglycemia and neonatal hypoglycemia, C-peptide in umbilical cord blood, premature delivery, admission to the neonatal intensive care unit (ICU) and hyperbilirubinemia. No association was found between maternal hyperglycemia and neonatal death; however, the sample size may have been insufficient to evaluate this

One of the most important findings of HAPO was the demonstration of an association that is continuous; hence no clear cut-off point can be defined above which adverse events occur

The choice of the 75-gram curve to investigate these women has never been validated scientifically. The first glucose overload to be described in pregnancy was performed using

to remember the psychological burden caused by a label of diabetes.

Cesarean section and hypertensive diseases (Landon et al., 2009).

1990; Sermer et al., 1995).

women managed in the usual manner.

glucose.

particular outcome.

(Leary et al., 2010).

100 grams of anhydrous glucose (O'Sullivan and Mahan, 1964), a procedure that was also recommended by the American Diabetes Association in 2004 (ADA, 2004). Nonetheless, since the WHO proposal in 1980 to use a 75-gram overload, as used in non-pregnant women, this practice became more and more common and even the HAPO study used the 75-gram glucose overload. With the power obtained in the HAPO study showing the adverse perinatal effects of hyperglycemia associated with the levels obtained following a 75-gram overload of anhydrous glucose, this test will probably increase in popularity compared to the 100-gram overload (Leary et al., 2010).

Another interesting outcome of the HAPO study was the recommendation that a finding of only one abnormal value on the glucose curve should also be considered abnormal and diagnostic. This recommendation was made with the aim of increasing the likelihood of identifying milder degrees of hyperglycemia that had been associated with poorer maternal and perinatal prognosis in previous studies.

The cut-off points recommended by IADPSG are arbitrarily defined based on an odds ratio of 1.75 relative to the mean glucose levels at each time-point, i.e. those measurements that result in a 75% greater likelihood of adverse perinatal outcomes. The selection had to be made in this way, since, as previously mentioned, the association between glucose levels and adverse outcome is continuous. These values, however, are subject to criticism and the occurrence of adverse outcomes with glucose levels below the proposed values is to be expected. Nevertheless, use of a lower cut-off point would certainly result in a greater percentage of diagnosed cases and the impact of this excess number of diagnoses on perinatal outcomes has yet to be established (Leary et al., 2010).

The absence of any IADPSG recommendations regarding a category referred to as "carbohydrate intolerance" is noteworthy. According to current criteria, either a woman has normal glucose levels or she has gestational diabetes. However, cases need to be taken into consideration in which women have glucose levels outside the limits considered normal yet without reaching levels that would be considered diagnostic. The adoption of the term "carbohydrate intolerance" is suggested for such cases (Leary et al., 2010).

The findings of the HAPO study appear to indicate that only normal glucose levels would eliminate the risk of adverse perinatal outcome; therefore, it could be argued that any deviation above normal levels should be considered abnormal (Leary et al., 2010). However, the economic and even the psychological impact of so many diagnoses of an "abnormal pregnancy" needs to be taken into consideration and may be immense.

To determine the ideal cut-off point, a cost-benefit analysis has to be performed of different cut-off points. In addition to the cost of the diagnostic test itself, the financial burden caused by the additional cases diagnosed in terms of follow-up and treatment has to be taken into consideration. In addition, it has to be confirmed that treating these diagnosed cases will indeed lead to a reduction in the number of adverse outcomes (Leary et al., 2010) and, furthermore, that this reduction will cause a positive impact that will compensate for the costs of diagnosis and follow-up.

The change in the diagnostic criteria defined by IADPSG will certainly have significant clinical implications for women and for the healthcare system. The number of women diagnosed as having gestational diabetes will rise. This increase in the prevalence of GD may cause a significant impact on all the additional women who will be diagnosed (Holt et al., 2011). In addition to the greater volume of resources required to follow-up and treat these women, the effect on patients of the very existence of a diagnosis should be kept in mind.

Gestational Diabetes: Evidence-Based Screening, Diagnosis and Treatment 49

the different organizations, it is clear that there is no consensus with respect to the quantity of glucose that should be used in the oral glucose tolerance test (OGTT), to the glucose levels that should be considered abnormal, or to the number of abnormal measurements on the

Table 4 shows the different criteria currently adopted for a diagnosis of gestational diabetes.

Fasting glucose levels

92mg/dl

126mg/dl

95mg/dl

100mg/dl

95mg/dl

108mg/dl

100mg/dl

ADA: American Diabetes Association (until autumn 2010); ADIPS: Australasian Diabetes in Pregnancy Society; CDA: Canadian Diabetes Association; EASD: European Association for the Study of Diabetes; IADPSG: International Association of Diabetes and Pregnancy Study Groups; NZSSD: New Zealand Society for the Study of Diabetes; WHO: World Health Organization. \*The ADA adopted the IAPDSG criteria in the autumn of 2010.

Until randomized clinical trials are conducted to compare the different strategies for screening and diagnosis and to define possible differences in maternal and perinatal outcome, the ideal test and the ideal criteria remain to be defined. The characteristics of each population should be evaluated, principally with respect to the frequency of gestational diabetes and macrosomia. In populations with a high risk for diabetes, we suggest that the IADPSG criteria be used; however, in low-risk populations in which there is no significant association between macrosomia and gestational diabetes, these criteria may not be

Normally, the proposal of any strategy for screening and diagnosis of gestational diabetes is aimed at establishing a therapeutic plan for diagnosed cases, since available evidence

Glucose levels after 1 hour

10.0mmol/l 180mg/dl

10.0mmol/l 180mg/dl

10.6mmol/l 190mg/dl

Glucose levels after 2 hours

8.5mmol/l 153mg/dl

7.8mmol/l 140mg/dl

8.6mmol/l 155mg/dl

8.0mmol/l 144mg/dl

8.9mmol/l 160mg/dl

9.0mmol/l 162mg/dl

9.0mmol/l 162mg/dl

curve that would permit a diagnosis of GD to be made (Holt et al., 2011).

Number of abnormal values required

Organization Glucose

Holt et al, 2011

applicable (Leary et al., 2010).

**5.1 Rationale for treatment**

**5. Treatment of gestational diabetes**

overload

IADPSG 75g > 1 5.1mmol/l

WHO 75g > 1 7.0mmol/l

ADA 100g > 2 5.3mmol/l

ADIPS 75g > 1 5.5mmol/l

CDA 75g > 2 5.3mmol/l

EASD 75g > 1 6.0mmol/l

NZSSD 75g > 1 5.5mmol/l

Table 4. Comparison of diagnostic criteria for gestational diabetes

Therefore, this change needs to be supported with convincing data showing beyond doubt that its adoption will improve pregnancy outcome. Since the HAPO study was merely observational, it is limited to associating adverse perinatal outcomes with higher glucose levels; however, it does not prove that normalizing glucose levels will necessarily result in any improvement in prognosis (Holt et al., 2011).

Two studies evaluated the benefits of treating milder degrees of hyperglycemia in pregnancy: the ACHOIS study (Crowther, 2005) and the US Multicenter Randomized Trial for Treatment of Mild GMD (Landon, 2009). Despite promising results, it should be remembered that these studies differed in relation to the glucose levels considered treatable and in the number of glucose measurements performed for diagnosis. This hampers extrapolation of these results to the findings of the IADPSG study (Holt et al., 2011).

#### **4.3 Investigation**

The IADPSG proposal for the screening and diagnosis of GD is shown in Table 3:

*First prenatal consultation*

Fasting glucose level or hemoglobin A1 (HgA1) or random measurement in women

	- and fasting glucose level is > 92 and < 126 => diagnosis of GD
	- and fasting glucose level is < 92 => test at 24-28 weeks with OGTT, 75 grams.

*24 - 28 weeks of pregnancy*

OGTT, 75 grams: fasting glucose measurement/1 hour/2 hours

#### **For a diagnosis of GD (OGTT, 75g)**

Table 3. **S**creening and diagnosis of GD according to the IADPSG

It is important, however, to call attention to the fact that controversies persist, despite the enormous number of studies conducted in this field. Analyzing the guidelines drawn up by the different organizations, it is clear that there is no consensus with respect to the quantity of glucose that should be used in the oral glucose tolerance test (OGTT), to the glucose levels that should be considered abnormal, or to the number of abnormal measurements on the curve that would permit a diagnosis of GD to be made (Holt et al., 2011).

Table 4 shows the different criteria currently adopted for a diagnosis of gestational diabetes.

ADA: American Diabetes Association (until autumn 2010); ADIPS: Australasian Diabetes in Pregnancy Society; CDA: Canadian Diabetes Association; EASD: European Association for the Study of Diabetes; IADPSG: International Association of Diabetes and Pregnancy Study Groups; NZSSD: New Zealand Society for the Study of Diabetes; WHO: World Health Organization. \*The ADA adopted the IAPDSG criteria in the autumn of 2010.

Holt et al, 2011

48 Gestational Diabetes

Therefore, this change needs to be supported with convincing data showing beyond doubt that its adoption will improve pregnancy outcome. Since the HAPO study was merely observational, it is limited to associating adverse perinatal outcomes with higher glucose levels; however, it does not prove that normalizing glucose levels will necessarily result in

Two studies evaluated the benefits of treating milder degrees of hyperglycemia in pregnancy: the ACHOIS study (Crowther, 2005) and the US Multicenter Randomized Trial for Treatment of Mild GMD (Landon, 2009). Despite promising results, it should be remembered that these studies differed in relation to the glucose levels considered treatable and in the number of glucose measurements performed for diagnosis. This hampers

extrapolation of these results to the findings of the IADPSG study (Holt et al., 2011).

The IADPSG proposal for the screening and diagnosis of GD is shown in Table 3:

• If clinical diabetes => treatment and follow-up for preexisting diabetes.

• and fasting glucose level is > 92 and < 126 => diagnosis of GD

• Consider GD if ONE or more measurements are above the cut-off points.

**For a diagnosis of clinical diabetes during pregnancy (any one of these tests)**

It is important, however, to call attention to the fact that controversies persist, despite the enormous number of studies conducted in this field. Analyzing the guidelines drawn up by

OGTT, 75 grams: fasting glucose measurement/1 hour/2 hours

• Consider normal if all the values are below the cut-off points.

Fasting glucose > 92 mg/dl

Fasting glucose > 126 mg/dl Hemoglobin A1 > 6.5%

Table 3. **S**creening and diagnosis of GD according to the IADPSG

Fasting glucose level or hemoglobin A1 (HgA1) or random measurement in women

• and fasting glucose level is < 92 => test at 24-28 weeks with OGTT, 75 grams.

>180 mg/dl

>153 mg/dl

> 200 mg/dl

any improvement in prognosis (Holt et al., 2011).