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Single-Step Test to Diagnose Gestational Diabetes Mellitus

Introduction

OGTT is performed in pregnant women by measuring the plasma glucose in fasting or non-fasting after 2 hours of ingesting 75 grams of Glucose (Monohydrate Dextrose Anhydrous). For diagnosing gestational diabetes (GDM), the Indian Guidelines (DIPSI Test) are simple. They can be done quickly in low-resource settings where many pregnant women visit for ANC check-ups. The severity of GDM increases because the action of Insulin is diminished (insulin resistance) due to raised hormone secretion by the placenta. Other risk factors for GDM are elderly, increased BMI or obesity, weight gain in pregnancy, history of diabetes in the family, stillbirth, or a congenital abnormality in previous deliveries. GDM has previously been considered to be transient during pregnancy and resolved after pregnancy, but pregnant women with hyperglycemia are at higher risk of developing GDM in subsequent pregnancies. About half of the women with a history of GDM will develop type II diabetes within five to ten years after delivery. DIPSI simple testing protocol is endorsed by the [1] National Health Mission (GOI) Guideline on GDM and also supported by the FIGO guideline on the HIP for use in South Asia.

Diabetes in pregnancy and Gestational Diabetes [2], Both together are known as HIP (Hyperglycaemia in Pregnancy).

2. Methodology

OGTT is performed in pregnant women by measuring the plasma glucose in fasting or non-fasting after 2 hours of ingesting 75 grams of Glucose (Monohydrate Dextrose Anhydrous). For diagnosing gestational diabetes (GDM), Indian guidelines are simple and can be done quickly in low-resource settings where many pregnant women visit for ANC check-ups. The severity of GDM increases because the action of Insulin is diminished (insulin resistance) due to raised hormone secretion by the placenta^[1]. Other risk factors for GDM are elderly, increased BMI or obesity, weight gain in pregnancy, history of diabetes in the family, stillbirth, or a congenital abnormality in previous deliveries.

GDM previously used to be transient during pregnancy and decided after pregnancy. Still, pregnant women with hyperglycemia are at higher risk of developing GDM in subsequent pregnancies. About half of women with a history of GDM will develop type II diabetes within five to ten years after delivery.

GDM women have a lifetime risk for type II diabetes and obesity^[2] and adverse outcomes for women and fetuses. The most common shared features among them are hypertension and LGA significant for gestation age (macrosomia). Tight blood sugar control during all trimesters can reduce adverse outcomes for the mother and fetus. All the women who have diabetes before conception need counseling, antenatal care, and good management of hyperglycemia, including. Postpartum care for good results.^[3]

3. Prevalence The global diabetes epidemic is a pandemic, according to IDF Head Professor Andrew Boulton. The global prevalence of diabetes is estimated to rise from 537 million in 2021 to 783 million in 2045, an increase of 46%. Diabetes is common worldwide, and this is a concern; by 2021, there will be 74.1 million diabetics in India^[4].

Type of GDM

GDM & Diabetes in Pregnancy combined is designated as hyperglycemia in pregnancy. Later, one is more fatal than GDM, which may be transient but, if not managed adequately, may lead to diabetes later on in mother and child.

(DIP) diabetes in pregnancy and GDM Gestational Diabetes mellitus(GDM) in HIP Hyperglycemia in pregnancy, including Type 1 & Type II Diabetes.^[5]

=== FIGO Recommendations for Diagnosis of Hyperglycemia in Pregnancy(HIP)

It's a global challenge. Eight low—and middle-income countries, which account for over half the global live births and two-thirds of maternal and perinatal mortality and morbidity, also account for more than half of the worldwide diabetes burden^[6]. This highlights the shared responsibility we all have to address this issue.

In 2016, The Declaration of the High-level Meeting(HLM) of the UNGA Assembly on the Prevention and Control of Non-communicable Diseases(NCDs)^[7]. In this context, while supporting the WHO position on the diagnostic criteria and classification of hyperglycemia first detected in pregnancy^[8], Diabetes Research and Clinical Practice (DRCP), the official journal of the IDF, published an article describing strategies for implementing the WHO recommendations, hinting at the need for a pragmatic approach based on available resources and constraints^[9].

Disadvantages of the IADPSG Test & Advantage of DIPSI Test in Asian Population

Measuring fasting blood sugar levels and waiting 2 hours while fasting is impractical in most settings, especially in South Asia. Therefore, drop-out rates are increased when repetition of testing for OGTT is advised^[10].

In GDM pregnant women, fasting blood sugar is standard in most cases, and postprandial 2-hour blood glucose is abnormal, especially in the Asian context, where GDM prevalence is around 14-16% countrywide. Therefore, a 2-hour OGTT with a 75 gm Glucose load can identify most GDM cases in an Indian context [8]. Asians, especially Indians, are at high risk for a 2-hour postprandial blood sugar increase compared to Caucasians [9].

It is estimated that if the diagnosis is made according to WHO guidelines for fasting FBG> 5.1 mmol/l or 92 mg/dl cut-off with 3.2% sensitivity, around 76% of pregnant women would be missed [11].

NHM Govt of India Guidelines for GDM

NHM, Govt of India, MOHFW released 2014 National Guidelines on diagnosis and management of gestational diabetes to screen all pregnant women during the first visit and a second time at 24 weeks. In addition, the Guidelines were revised in 2018 to include Metformin after 20 weeks of gestation in GDM cases after two weeks of MNT as per the field experience. The tolerance of oral drugs in the public health system, as insulin cold chain maintenance, is often an issue at PHC and sub-center level health care facilities. Tamilnadu Ministery of Health & Family Welfare started GDM Screening by Single Test Procedure to Diagnose Gestational Diabetes mellitus in public health facilities as per a Community GDM study by V Seshiah et al., and later on Govt of India MOHFW adopted GDM Guidelines for all the states in India.

Uttar Pradesh implemented the NHM Guidelines at the Subcentre and PHC, CHCs, and district hospitals in 2016, and more than 1 million screenings of Gestational diabetes in pregnant women have been done, with a prevalence of 13.5%

FIGO/WHO Guidelines for GDM in Low Resource Setting^[11]

In a whole-resource setting, diabetes in pregnancy can be detected by PPG or HbAIc in the First trimester, and FBS is >= 92 as per IADPSG Criteria for GDM diagnosis if negative. Pregnant women are followed for 2 hr—OGTT with 75 gm of Glucose. In situations where women may not be able to come for testing in a fasting state, a single-step 75-g 2-hour non-fasting test (> 140 mg/dl) as used in India may be applied [12].

8. Management of GDM

8.1. NHM Govt of India Guidelines, Management of GDM

National Health Mission, Ministry of Health & Family Welfare, and Govt of India released GDM Guidelines and Management, in which MNT is the mainstay of the treatment once GDM is diagnosed in two weeks. After that, if Blood Sugar post-prandial fails to reach <120 mg/dl, Metformin can be initiated after 20 weeks of pregnancy. Insulin can be added if it cannot achieve the target with or without Metformin [12].

Management of GDM, Guidelines 2018 [12]

Medical Management (Oral Anti-diabetic Drug-Metformin and Insulin Therapy)

1.   Metformin or Insulin therapy is the accepted medical management of pregnant women with GDM not controlled on MNT. Insulin is the first drug of choice, and Metformin can be considered after 20 weeks of gestation for medical management of GDM. 2.   Insulin can be started anytime during Pregnancy for GDM management. If pregnant women with GDM before 20 weeks and Medical Nutrition Therapy (MNT) fails, Insulin should be created. 3.   Metformin can be started at 20 weeks of Pregnancy if MNT has failed to control her blood sugar. Suppose the woman's blood sugar is uncontrolled with the maximum dose of Metformin (2 gm/ day) and MNT, and insulin will be added. Metformin is 500 mg twice daily orally up to a maximum of 2 gm/day. 4.   Hypoglycemia and weight gain with Metformin are less than Insulin. 5. Metformin may be added to the treatment if Insulin is required in high doses. 6.   At PHC, MO should initiate treatment & refer pregnant women with GDM to a higher center if blood sugar levels are not controlled or there is some other complication.

A trained dietician should frame a personalized diet plan that provides the necessary healthy nutrition for the increased demands of the mother and fetus. [16]. Lifestyle modification is the most critical intervention for GDM control and is sufficient to control around 70-80% of all pregnant women with GDM [16].

In Pregnant women, especially those with T1DM and pre-existing type ll diabetes, the ADA advocates for the use of Insulin; however, changing the physiological demand in pregnancy may require more monitoring and titration of Insulin and should frequently be self-monitored by the women [16].

In the 1^st trimester: Insulin generally continues in DIP, but GDM rarely requires Insulin in Type II diabetes. T1DM may experience hypoglycemia. Therefore, insulin titration may be needed more frequently in this group.

In the 2^nd trimester: Insulin requirement increases in the second trimester because of an increase of anti-insulin hormones & Placental lactogen, which is increased bi-weekly or twice a week to achieve glycaemic goals. Generally, 50% insulin is given as a basal dose and 50% as a prandial dose to gain reasonable control.

Insulin treatment is complex and requires referral to higher centers, where a specialized team of obstetricians, endocrinologists, and trained Dieticians is required.

Diabetes in pregnancy is associated with a high risk of preeclampsia; hence, women with type 1 or type 2 should be prescribed a low dose aspirin 81mg/day from the first trimester until the baby is born (16).

During T1DMduring Pregnancy, the risk of hypoglycemia is increased many folds, and unawareness of hypos is also grown as counter-regulatory hormone disturbances occur. Therefore, patient education about hypos is essential throughout pregnancy and afterward. After delivery during the postpartum period, placental hormones decrease, and insulin resistance drops, which may lead to hypos, which, in turn, may lead to diabetic ketoacidosis (DKA). DKA should be treated immediately in order also to prevent diabetic retinopathy [16].

GDM is not at high risk of diabetic retinopathy. Still, DIP or pregnant women who have diabetes before conception are at increased risk of diabetic retinopathy. They should, therefore, be screened for diabetic retinopathy after starting the earliest the1^sttrimester and follow-up three monthly in NPDR and monthly in severe NPDR [17].

Family planning should be addressed to all women with the HIP before conception [20]. Tight blood sugar controls; HBAIc<6.5% reduce the risk of outcomes like anencephaly, congenital heart disease, microcephaly, and caudal regression syndrome in the fetus.

8.2. Preconception Testing

Women with HIP with T1DM and Type II diabetes planning Pregnancy should be screened for diabetic retinopathy and counseled for potential progression.

Other testing and counseling are needed concerning HIV, Hepatitis B, Rubella and Pap smear, blood group, and administration of folic acid 400 mcg daily. Testing HBA1c, TSH, Urine albumin, and creatinine.

Teratogenic drugs in Pregnancy like ACE inhibitors, ARB [18], and statins should be avoided [19], monitoring for diabetic retinopathy before Pregnancy, Use of Anti-hypertensive medication which is indicated in Pregnancy, i.e., methyldopa, Labetalol, Diltiazem, Prazosin, and Clonidine should be followed, use of chronic diuretic should be stopped as it restricts uteroplacental perfusion.

T1DM and Type II Diabetes during Diabetes in Pregnancy (DIP) lead to more risk in mother and fetus compared to GDM; adverse outcomes include abortion, fetal malformations, preeclampsia, macrosomia, raised bilirubin, and neonatal hypoglycemia (21), and in the future, it increases the risk of Type II Diabetes and obesity in mothers and offspring's [21].

All Women & adolescents with diabetes risk during the reproductive period should be educated about the outcomes of unplanned pregnancies [21]; preconception counseling is a very effective method to reduce health costs and the burden of complications associated with hyperglycemia in pregnancy & offspring. Family planning methods should be negotiated until the woman becomes pregnant [21].

8.3. Diabetes in Preeclampsia & use of Aspirin

DIP (Diabetes in Pregnancy) is also linked with a greater risk for preeclampsia [22] due to clinical trials. Therefore US Preventive Taskforce suggests using 81 mg/day aspirin after 12 weeks of gestation for women at high risk for preeclampsia [23].

8.4. Medical Nutrition Therapy

MNT (Medical Nutrition Therapy) is a personalized Diet plan prescribed by a Dietician trained in nutrition & Diet to manage Gestational Diabetes Mellitus [27]. A diet plan should be based on adequate healthy nutrition and calorie intake for the appropriate weight. Although research is lacking on whether GDM has a different calorie intake compared to Non-GDM, a diet plan should be as per Dietary Reference Intake, which recommends at least 175 gm of carbohydrates, a minimum protein of 71 gm, and 28 grams of Fiber. Commonly, carbohydrates will lead to postprandial glucose excursions [27].

|We recommended that the following principles should be adhered to for all pregnant women with diabetes:

1.   Design an appropriate diet concerning Pregnancy BMI, desired body weight, physical activity, habits, and personal and cultural preference.

2.   Provide route follow-up and diet adjustment throughout pregnancy to achieve and maintain treatment goals.

3.   Offer training, education, support, and follow-up by qualified dietician expirees in caring for women with diabetes. issues for discussion include weight control, food records, carbohydrate counting, prevention of hypoglycemia, healthy foods, and physical activity

8.5. Physical Activity for GDM

Physical activity is recommended for all pregnant women with GDM, preferably 30 minutes every day; brisk walking is helpful after meals to lower postprandial glucose excretions. Women with Diabetes in Pregnancy should continue their previous Exercise Plan as before the pregnancy.

|We suggest that appropriate, personally adapted physical activity be recommended for all women with diabetes:

1.   Planed physical activity of 30 min/day

2.   Brisk walking or arm exercises while seated in a chair for 10 min after each meal.

3.   Women's physical activity before pregnancy should be encouraged to continue their previous exercise routine.

9. Pharmacological Management

Pharmacologic treatment in the HIP with significant insulin increase may require the early initiation of oral drugs. In two randomized trials by the US Preventive Task Force Review, such treatment has demonstrated better outcomes in perinatal women. Insulin is the initial drug of choice as per ADA Guidelines. US Preventive Task Force advocates the safety and efficacy of Metformin and Glibenclamide [28, 29] in GDM, but both pass the placenta. Another randomized trial showed that Metformin and Glibenclamide are practical and reduced insulin use, but Metformin was more effective as it causes less hypoglycemia than Glibenclamide [29]. However, more definitive studies are required in this area. Long-term safety data are not available for any oral agent [30].

9.1. Oral Drugs

Suppose Lifestyle Modification alone fails to achieve glucose control. In that case, Metformin is a better option than Glibenclamide and Insulin and should be considered a safe and effective treatment option for GDM. GOI- MOHFW has Introduced Metformin as 1^st line drug for GDM treatment after MNT failed to control Blood sugar <120 mg/dl after two weeks [12].

Table 8. FIGO Recommendations for Oral Drugs in GDM.

Insulin should be considered as the first-line treatment in women with GDM who are at high risk of falling on OAD therapy, including some of the following factors [129]:

1.   Diagnoses of Diabetes 14-16 weeks of gestation. 2.   Need for pharmacologic therapy >20 3.   Fasting plasma glucose levels > 90 mg/dl 4.   hour postprandial glucose >140 mg/dl 5.   Pregnancy weight gain >12 kg

9.1.1. Sulfonylureas

The titer of Glibenclamide in umbilical cord plasma is around 70% of maternal levels and is therefore linked with a higher level of neo-born hypoglycemia and LGA (macrosomia) compared with Metformin or Insulin in review(30, 31).

9.1.2. Metformin

In the systematic meta-analysis (2015) (31), metformin was associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than Insulin. However, Metformin increased the risk of prematurity or birth less than 37 weeks of gestation. Metformin is insufficient to control blood sugar, less than 120 mg/dl in GDM; therefore, additional insulin is needed to control blood sugar and reach the target level [31].

10. Gestational Diabetes Mellitus and Type 2 Diabetes

In Nurse Health Study II, Women with a history of GDM were at increased risk for future Type II diabetes. Still, the risk decreased with women with GDM who followed a healthy diet & lifestyle when normalized for BMI risk was reduced, but the small risk remained [24].

Postpartum weight increases with bad outcomes in future pregnancies [24] and Risk for Type II Diabetes.

11. Postpartum Care & Lactation

Postpartum care should include OGTT (75 gm Glucose Load in fasting state) after six weeks of delivery [12] to determine the status of diabetes. Psychological counseling and breastfeeding are essential for providing long metabolic and immunological advantages for mothers [25] and children [26], which reduces the chances of Type II Diabetes later in life.

12. Pre-conception and Inter-pregnancy Recommendations (FIGO)

FIGO calls for public health measures to increase awareness and acceptance of preconception consulting and increase affordability and access to preconception services for women of productive age. This will likely have immediate and lasting benefits for maternal and child health.

13. Conclusion

There are around 5.5 million cases of HIP hyperglycemia in pregnancy annually in South Asia. It is a great challenge to screen all pregnant women and manage these if needed. Furthermore, it is difficult to screen pregnant women in a fasting state, and the fasting blood sugar in most South Asian women is not abnormal compared to OGTT after 2 hours of 75 gm Glucose load; moreover, using this method of testing can detect most of the pregnant women with the HIP (hyperglycemia in pregnancy). FIGO and IDF, therefore, endorse the DIPSI test, especially in resource-limited settings of South Asia and other countries. In contrast, the IADPSG criteria are not suitable for Asian countries as pregnant women have to go 3 times for testing, which is not practical in a European setting. A large number of pregnant women do not come fasting. In India, two States, Tamil Nadu and Uttar Pradesh, have launched Universal GDM testing. Pregnant women are here detected for GDM and followed up for blood sugar control during the pregnancy. Most women (90%) are managed with MNT (Medical Nutrition Therapy). The remaining group, where the postprandial Blood sugar (2 hours) is > 120 mg/dl after two weeks of MNT, receives Metformin and Insulin for GDM treatment; a large number of ANMs has been recruited to address maternal health issues like hypertension in pregnancy, anemia, malnutrition, over-nutrition, and hyperglycemia of pregnancy. 28,000 ANMs are being trained to cater for estimated6 million pregnant women alone in Uttar Pradesh., Till now, 1 million pregnant women have been screened in UP. UP follows the Tamil Nadu model, where Dr. V Seshiah, father of GDM in India, started a GDM program in 2007 with the Tamil Nadu Government. The Govt of India recently declared Dr. V Seshiahs birthday, the 10^th of March, Indian GDM awareness day.

The support of the maternal health, National Health Mission, MOHFW, and the government of India is well appreciated for providing revised guidelines for GDM, 2018.^[12]