Review of FIGO & ADA, WHO, IADPSG Guidelines for GDM for Low Resource Setting and Integration of DIPSI with MOHFW Govt of India, Guidelines

OGTT is performed in pregnant women by measuring the plasma glucose in fasting or non-fasting after 2-hour ingesting 75 grams of glucose (Monohydrate Dextrose Anhydrous). For diagnosing gestational diabetes (GDM) Indian Guidelines (DIPSI Test) are simple and can be done easily in low resource setting where large number of pregnant women visit for ANC check-up. The severity of GDM increases because of the action of insulin is diminished (insulin resistance) due to raised hormone secretion by the placenta. Other risk factors for GDM are being elderly, increased BMI, or obesity, weight gain in pregnancy, history of diabetes in family, stillbirth or a congenital abnormality in previous deliveries. GDM has previously been considered to be transient during pregnancy and resolve after pregnancy but, pregnant women with hyperglycaemia are at higher risk of developing GDM in subsequent pregnancies and 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 National Health Mission (GOI) Guideline on GDM, and also endorsed by the FIGO guideline on HIP for use in South Asia. This testing protocol has been followed by Sri Lanka, Pakistan and Bangladesh in the region. Tamil-Nadu state and Uttar Pradesh states in India launched a Universal GDM Program in 2007 and 2016 respectively, covering all pregnancies by testing and managing GDM with MNT, Metformin and Insulin in most of health care facilities. Around 28,000 ANM have been given glucometers, strips, glucose 75 gm packets for implementation of the largest GDM program in Uttar Pradesh, India to date.


Introduction
Hyperglycaemia Elevated Blood Sugar that is newly found in pregnancy is named as either gestational diabetes mellitus (GDM) or hyperglycaemia in pregnancy. Pregnant women with slightly elevated blood glucose levels is called as having GDM. Pregnant women with substantially elevated blood glucose levels are named as women with diabetes in pregnancy with previously known diabetes [1], both together is known as HIP (Hyperglycaemia in pregnancy).
It has been roughly estimated that most (75-90%) of the cases of elevated blood glucose in pregnancy are defined gestational diabetes mellitus [2]. GDM is a type of diabetes that can present in pregnant women during the first, second or third trimester of pregnancy. If it is diagnosed in the first trimester of pregnancy most likely diabetes existed before pregnancy but was undiagnosed.
GDM and diabetes in pregnancy is mostly an asymptomatic disease and may overlap with normal pregnancy symptoms.
An oral glucose tolerance test (OGTT) is therefore recommended for screening of GDM between 12-16 weeks or during 1 st ANC visit and a second test at the 24 th -28 th week of pregnancy [12] as universal GDM testing in all pregnant women. National guideline (NHM, GOI) fordiagnosisandmanagementofGestationalDiabetesendorsesth esinglesteptestrecommendedbyWHOfordiagnosisofGDMusin ga75gmglucose, through Oral Glucose Tolerance Test (OGTT) irrespective of the last meal with a threshold value of 2-hour BS >140 mg/dl. Guidelines advocate for universal screening of all pregnant women at first antenatal contact. If the first test is negative, second test should be done at 24-28 weeks of gestation [4,12]. However, as per ADA guidelines high risk pregnant women are selectively screened in pregnancy in second trimester [3].

Methodology
OGTT is performed in pregnant women by measuring the plasma glucose in fasting or non-fasting after 2-hour ingesting 75 grams of glucose (Monohydrate Dextrose Anhydrous). For diagnosing gestational diabetes (GDM) Indian guidelines are simple and can be done easily in low resource setting where large number of pregnant women visit for ANC check-up. The severity of GDM increases because the action of insulin is diminished (insulin resistance) due to raised hormone secretion by the placenta [4]. Other risk factors for GDM are being elderly, increased BMI, or obesity, weight gain in pregnancy, history of diabetes in family, stillbirth or a congenital abnormality in previous deliveries.
GDM previously used to be transient during pregnancy and resolve after pregnancy but pregnant women with hyperglycaemia are at higher risk of developing GDM in subsequent pregnancies and about half of women with a history of GDM will develop type II diabetes within five to ten years after delivery.
GDM women have lifetime risk for type II diabetes and obesity [5], and adverse outcomes both for women and foetus. The most common shared features among them are hypertension and LGA large for gestation age (macrosomia). Tight control of the blood sugar during all the trimesters can reduce adverse outcomes in mother and foetus. All the women who have diabetes prior to conception need counselling, antenatal care and good management of hyperglycaemia incl. post-partum care for good outcomes.

Prevalence
As per IDF Atlas 2017, 21.3 million or 16.2% (Figure 1) of births to pregnant women had some form of hyperglycemia in pregnancy; HIP before and during pregnancy [6]. An estimated 86.4% of HIP were due to gestational diabetes mellitus (GDM), 6.2% due to (DIP) diabetes detected prior to pregnancy (6), and 7.4% due to other types of DM (type 1 (T1DM) and type 2 diabetes) first detected in pregnancy ( Table 1). The prevalence of hyperglycemia in pregnancy (HIP) increases with the age of women and is highest at the age 45 year (around 45%), Due to higher birth rates in early age, half of all the HIP, 49% cases occur in women under 30 years of age ( Figure 2).
The prevalence of GDM in India is 27.9 as per IDF 2017 estimated in the age group of 20-49 Years [6].  The prevalence of hyperglycaemia in pregnancy (HIP) varies widely around the world, with the South-East Asia Region WHO region with the highest prevalence at 24.2% compared to 10.4% in the Africa Region (Table 1). The highest number of (88%) of cases of hyperglycaemia in pregnancy are in low-and middle-income countries (LMIC), with low access to health care facility. Integration of DIPSI with MOHFW Govt of India, Guidelines

FIGO Recommendations & Review of Guidelines on Hyperglycaemia in Pregnancy [4]
1. FIGO adopts and support the IADPSG/WHO/IDF position that all pregnant women should be tested for hyperglycaemia during pregnancy using a one-step procedure. 2. FIGO encourages all countries and its member associations to adapt and promote strategies to ensure universal testing of all pregnant women of forhyperglycaemia during pregnancy 3. Universal testing:All pregnant women should be tested for hyperglycemia during pregnancy using a one-step procedure and FIGO encourages all countries and its member associations to adapt and promote strategies to ensure this. HIP Hyperglycaemia in Pregnancy Guidelines Differ Ethnicity wise and regional wise around the world, below is the table for various important organizations Guidelines for HIP.

Disadvantages of the IADPSG Test & Advantage of DIPSI Test in Asian Population
Measuring fasting blood sugar levels and waiting while fasting for 2hours is impractical in most settings especially in South Asia and therefore drop-out rates are increased when repetition of testing for OGTT [7] is advised.
In GDM pregnant women fasting blood sugar is normal in most cases and post prandial 2-hour blood glucose is abnormal especially in the Asian context where GDM prevalence is around 14-16% countrywide. Therefore 2-hour OGTT with 75 gm Glucose load is able to identify most GDM cases in an Indian context [8]. Asians and especially Indians are high risk for 2-hour post prandial blood sugar increase compared to Caucasians [9].
It is estimated that fasting FBG> 5.1 mmol/l or 92 mg/dl cut-off with 3.2% sensitivity, around 76% of pregnant women would be missed if the diagnosis is made by WHO guidelines [11].

NHM Govt of India Guidelines for GDM
NHM, Govt of India, MOHFW released in 2014, National Guidelines on diagnosis and management of gestational diabetes to screen all the pregnant women during the first visit and a second time at 24 weeks onwards. In addition, the Guidelines were revised in 2018 to include Metformin after 20 weeks of gestation in GDM cases after 2 weeks of MNT [12] as per the field experience and tolerability of oral drugs in the public health system as insulin cold chain maintenance is often an issue at PHC and sub-centre level health care facilities [12].

FIGO/WHO Guidelines for GDM in Low Resource Setting
In fully resource setting Diabetes in pregnancy can be detected by PPG or HbAIc in First trimester, and FBS is >= 92 as per IADPSG Criteria for GDM diagnosis, if negative Pregnant women is followed for 2 hr-OGTT with 75 gm of Glucose. In the 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].

FIGO Recommendation for Foetal Monitoring
FIGO Recommends at least one USG for Growth every 2-4 Weeks in GDM Diagnosed cases, as it will help in Labelling of Macrosomia and Small of Gestational Age (SGA). Table 5. Recommendation for growth assessment in women with gestational diabetes mellitus.

Recommendation
Resource setting Strength of recommendation and quality of evidence Clinical and songraphic growth assessment every 2-4 weeks from diagnosis until time.
High 1| 000 Periodic clinical and sonographic growth assessment from until time.
Mid and Low 2| 000  A personalised diet plan should be framed by a trained dietician, which should provide necessary healthy nutrition for the increased demand of the mother and foetus. [13]. Lifestyle modification is the most important intervention for GDM control and is sufficient to control around 70-80% of all pregnant women with GDM [13].

NHM Govt of India Guidelines, Management of GDM
In Pregnant women especially those with T1DM and preexisting type ll diabetes, ADA advocates for the use of Insulin however, changing the physiological demand in pregnancy may require more monitoring and titration of Insulin and should be frequently self-monitored by the women [13].
In the 1 st trimester: Generally, insulin continues in DIP but GDM rarely requires the use of insulin in Type II diabetes. T1DM may experience hypoglycaemia, therefore Insulin titration may be needed more frequently for this group.
In the 2 nd trimester: Insulin requirement increases in second trimester because of increase of anti-insulin hormones & Placental lactogen which is increased bi-weekly or twice a week to achieve glycaemic goals. Generally, 50% insulin given as basal dose and 50% as prandial dose to achieve good control.
Late in 3 rd trimester: Treatment with Insulin is complex and need referral to higher centres where specialised team of Obstetrician, endocrinologist and trained Dietician is needed.
Diabetes in pregnancy is associated with high risk of preeclampsia hence women with type 1 or type 2 should be prescribed a low dose aspirin 81mg/day from the end of the first trimester until the baby is born (13).
In T1DMduring pregnancy the risk of hypoglycaemia is increased many folds and unawareness of hypos is also increased as counter regulatory hormone disturbances occur. Therefore patient education toward hypos are very important through pregnancy and afterwards. After delivery during the post-partumperiod placental hormones decreases and insulin resistance drops which may lead to hypos and which in turn may lead to diabetic keto-acidosis (DKA). DKA should be treated immediately in order to also prevent diabetic retinopathy [13].
GDM is not at high risk of diabetic retinopathy but DIP or pregnant women who have diabetes before conception are at increased risk of diabetic retinopathy and should thereforebe screened for diabetic retinopathy after conception earliest during the1 st trimester and follow-up 3 monthly in NPDR and monthly in severe NPDR [14].
Family planning should be addressed to all women with HIP before conception [13]. Tight blood sugar controls; HBAIc<6.5% for reduction of risk of outcomes like anencephaly, congenital heart disease, microcephaly and caudal regression syndrome in foetus.

Preconception Testing
Women with HIP with T1DM and Type II diabetes, who are planning pregnancy should be screened for diabetes retinopathy and counselled for potential progression.
Other testing and counselling is needed concerning HIV, Hepatitis B, Rubella and Pap smear, blood group, administration of folic acid 400 mcg daily. Testing HBA1c, TSH, Urine albumin and creatinine.
Teratogenic drugs in pregnancy like ACE inhibitors, ARB [15], statin should be avoided [16], monitoring for diabetic retinopathy before the pregnancy, Use of Anti-hypertensive medication which is indicated in pregnancy i.e methyl dopa, Labetalol, Diltiazem, Prazosin and Clonidine should be followed, use of chronic diuretic should be stopped as it restricts utero-placental perfusion.
T1DM and Type II Diabetes during diabetes in pregnancy (DIP) leads to more risk in mother and foetus compare to GDM, adverse outcomes includes abortion, foetal malformations, preeclampsia, macrosomia, raised bilirubin and neonatal hypoglycaemia (18) and in futures it increases risk of Type II Diabetes and obesity in mothers and offspring's [18].
All the Women & adolescent with diabetes risk during the reproductive period should be educated about outcomes of unplanned pregnancies [18], Preconception counselling is very effective method to reduce health cost and burden of complication associated with hyperglycaemia in pregnancy & offspring, family planning methods should be negotiated until the women become pregnant [18].

DIP (Diabetes in Pregnancy)
is also linked with greater risk for preeclampsia [19] as a results of clinical trial and therefore US Preventive Task force suggest use of 81 mg/day aspirin after 12 weeks of gestation for women high risk for preeclampsia [20].
Recommendation: Level of evidence A Type I or Type II diabetes Women should be given aspirin 60-150 mg/daily or usually 81 mg/dl to lower risk of preeclampsia since first trimester onwards.

Medical Nutrition Therapy
MNT (Medical Nutrition therapy) is personalised Diet plan prescribed by Dietician trained in nutrition & Diet for the management of Gestational Diabetes Mellitus [24]. Diet plan should be based on adequate healthy nutrition and calories intake for appropriate weight. Although research is lacking whether GDM have different calories intake compare to Non-GDM therefore diet plan should be as per Dietary Reference Intake which recommend at least 175 gm of carbohydrate, minimum protein of 71 gm and 28 gram of Fibers. It's is common that amount of carbohydrates will leads to post prandial glucose excursions [24]. Table 6. Nutritional Therapy Recommendations, FIGO.

Recommendation
Resource setting Strength of recommendation and quality of evidence We recommended that the following principals should be adhered for all pregnant women with diabetes: 1. Design an appropriate diet with respect to pregnancy BMI, desired body weight, physical activity, habits, and personal and cultural preference. 2. Provide route follow-up and diet adjustment throughout pregnancy to archive and maintain All 1| 00

Recommendation Resource setting
Strength of recommendation and quality of evidence treatment goals. 3. Offer training, education, support and follow-up by a qualified dietician expirees in care of women with diabetes. issues for discussion include: weight control, food records, carbohydrate counting, prevention of hypoglycemia, healthy foods, and physical activity We suggest that caloric intake be calculated based on pregnancy BMI and desirable weight gain as follows: 1. 35-40 kcal/kg desirable body weight for underweight women 2. 30-35 kcal/kg desirable body weight for normal weight women 3. 25-30 kcal/kg desirable body weight for overweight women All 2| 00 We recommended limiting carbohydrate in take to total calories, with a minimum of 175 carbohydrate per day, distribiuted in three small-to-moderate size meals and 2-4 snacks. All 1| 0 For obese women, caloric intake may be reduced by 30%, but not below 1600-1800 kcal/d All 2| 00 For women with diabetic nephropathy, protein me be lowered to 0.6-0.8 g/kg ideal body weight All 2| 000 1. FIGO recognized that nutrition counseling and physical activity are the primary tools in the management of GDM. 2. FIGO recommend that women GDM receive practical to nutrition education and counseling that empowers them to choose the right quality and quality of food . 3. Women with GDM must be repeatedly advised to continue the same healthy eating habits after delivery to reduce the risk for future T2DM

Physical Activity for GDM
Physical activity is recommended to all the Pregnant Women with GDM preferably 30 minutes every day, brisk walking is helpful after meal to lower Post Prandial Glucose Excursions. Women with Diabetes in Pregnancy should continue their previous Exercise Plan as before the Pregnancy.

Recommendation
Resource setting Strength of recommendation and quality of evidence 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 white seated in a chair for 10 min after each meal. 3. Women physical activity prior to pregnancy should be encouraged to continue their previous exercise routine.

Pharmacological Management
Pharmacologic treatment in HIP with large insulin increase may need early initiation of oral drugs. Such treatment has demonstrated better outcome in perinatal women in two randomised trials by the US Preventive Task Force Review. Insulin is the initial drug of choice as per ADA Guidelines and US Preventive Task Force advocate safety and efficacy of Metformin and Glibenclamide [25,26] in GDM, but both pass the placenta. Another randomised trial showed that Metformin and Glibenclamide are both effective and reduced insulin use but Metformin was more effective as it causes less hypoglycaemia compared to Glibenclamide [26]. However, more definitive studies are required in this area. Long-term safety data are not available for any oral agent [27].
If Lifestyle Modification alone fails to achieve glucose control, Metformin is a better option compared to Glibenclamide and insulin and should be considered as safe and effective treatment options 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].

Sulfonylureas
Titre of Glibenclamide in umbilical cord plasma is around 70% of maternal levels and is therefore linked with the higher level of neo-born hypoglycaemia and LGA (macrosomia) if we compare with Metformin or Insulin in review (28).

Metformin
Metformin was associated with a lower risk of neonatal hypoglycaemia and less maternal weight gain compare to insulin in systematic meta-analysis (2015) (28); although, Metformin increased the risk of prematurity or birth less than 37 weeks of gestation. Metformin is however not sufficient to control blood sugar less than 120 mg/dl in GDM and therefore additional insulin is neededto control blood sugar to reach target level [25].

Gestational Diabetes Mellitus and Type 2 Diabetes
In Nurse health study II Women with history of GDM was found to be at increased risk for future Type II diabetes but risk decreased with women with GDM who followed healthy diet & lifestyle when normalised for BMI risk was reduced but small risk still remained [21].
Postpartum weight increased was associated with bad outcomes in future pregnancies [21] and Risk for Type II Diabetes.

Postpartum Care & Lactation
Postpartum care should include OGTT (75 gm Glucose Load in fasting state) after 6 weeks of delivery [12], to know the status of Diabetes. Psychological counselling and breastfeeding are very important for provide long metabolic & Immunological advantage for mother [22] and children [22] which reduces the chances of Type II Diabetes later in life.

Pre-conception and Inter-pregnancy Recommendations (FIGO)
FIGO calls for public health measures to increase awareness and acceptance of preconception consulting and to increase affordability and access to preconception service to women of productiveage, as this is likely to have both immediate and lasting benefits for material and child health.

Conclusion
There are around 5.5 million cases of HIP hyperglycaemia 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 fasting state and the fasting blood sugar in most of South Asian women is not abnormal compared to OGTT after 2hour of 75 gm Glucose load, Moreover, using this method of Testing is able to detect most of pregnant women with HIP (hyperglycaemia in pregnancy). FIGO and IDF therefore endorses the DIPSI test especially in resource limited settings of South Asia and other countries, whereas the IADPSG criteria is not suitable for Asian countries as pregnant Women has to go 3 times for testing which is even not practical in a European setting and large number of pregnant women do also not come in fasting state. In India two States; Tamil Nadu and Uttar Pradesh have launched Universal GDM testing and pregnant women are here detected GDM and followed-up for blood sugar control during the pregnancy and most women (90%) are managed with MNT (Medical Nutrition Therapy). The remaining group where the post prandial Blood sugar (2hour) is > 120 mg/dl after 2 weeks of MNT, receive Metformin and Insulin for GDM treatment, A large number of ANMs has been recruited to address maternal health issues like hypertension in pregnancy, anaemia, malnutrition, over-nutrition and hyperglycaemia of pregnancy. 28,000 ANMs are being trained to cater for an estimated6 million pregnant women alone in the Uttar Pradesh., Till now, 1 million pregnant women have been screened in UP. UP is following the Tamil Nadu model, where Dr. V Seshiah; father of GDM in India started a GDM program in 2007 with the Tamil Nadu Government., Recently the Govt of India declared Dr. V Seshiahs birthday, the 10 th of March as Indian GDM awareness day.

Conflict of Interest
No conflict of interest in Preparation of Manuscript involved.