Gestational Diabetes Mellitus (GDM) – What A Physician Must Know?

CME INDIA Presentation by Dr. Shalini Jaggi, Dip Diab (UK), Dip Endo (UK), F Diab, FRSSDI, FRCP (London, Edin, Glas) FACE (USA), Sr. Consultant Diabetologist & Director, New Delhi.

Fetus is a continually feeding boarder in an intermittently eating host – mother – Norman Frienkel.

Maternal Metabolism in Pregnancy changes physiologically to provide an Uninterrupted nutrient supply to fetus for its growth & energy needs!

GDM Impacts Two Lives

• Diagnosis of GDM identifies women at high risk of future diabetes & associated metabolic problems.
• Foetal Origin of Adult Disease: Maternal hyperglycaemia is associated with development of metabolic problems in offspring (Gestational Programming)
• Hyperglycaemia during pregnancy is associated with high risk of maternal and perinatal morbidity and mortality.
• An opportunity for primary prevention of NCDs including Diabetes in Two Generations!

Pre-gestational and Gestational Diabetes Mellitus

Conventional:

• GDM: Any degree of glucose intolerance with onset or first recognition during pregnancy regardless of gestational weeks, whether insulin is used or if the condition persists after pregnancy.
• Pre-GDM: pregnant women known to have pre-existing diabetes mellitus (T1DM/T2DM)

Current ADA 2021:

• Women with diabetes diagnosed in 1st trimester: classified as having pre-gestational DM (T2DM, rarely T1DM or MODY).
• GDM: DM diagnosed in the 2nd/3rd trimester of pregnancy that is not clearly pre-existing diabetes (T1DM/T2DM/MODYetc.).

DIPSI 2020-21:

Manifestation of hyperglycemia in pregnancy i.e., GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. GDM represents detection of chronic β cell dysfunction and is considered to be a stage in the evolution of Type 2 DM.

Risk factors for GDM:

• Overweight/Obese BMI ≥ 30 kg/m2
• Previous macrosomic baby weighing 4.5 kg or above
• Previous GDM/ Deranged OGTT
• Family history of diabetes (first-degree relative)
• Pregnancy at Age≥ 25yrs
• Ethnicity:
  • South Asian (India, Pakistan or Bangladesh)
  • Black Caribbean
  • Middle Eastern (Saudi Arabia, UAE, Iraq, Jordan, Syria, Oman, Qatar,      
  • Kuwait, Lebanon or Egypt).
• Bad Obstetric History
• PCOS

Pregnancy in pre-existing diabetes

• Progressively increasing insulin resistance.
• Diabetogenic stress of placental hormones.

Worsening of Glycemia  

• Maternal & fetal consequences.
• Increasing insulin requirement.
  • Worsening of complications:
  • Retinopathy,
  • Nephropathy,
  • Autonomic neuropathy.
• Nocturnal hypoglycemia.
• Diabetic ketoacidosis.
• Increased risk of childhood obesity & diabetes in the offspring.

“Diabesity Begets Diabesity”

Lifetime Risk for Type 2 Diabetes Increased in Women with Gestational Diabetes (1)

• Up to 50% of GDM women develop IGT/T2DM within 5-10 years of the pregnancy.
• May 26, 2009 – Women with GDM have a 7.5-fold increased risk for the development of type 2 diabetes after delivery, which persists for their lifetime.
• 2021 ADA:
  • Women with GDM have a 10-fold increased risk for the development of T2DM than women with no GDM.
  • The absolute risk increases linearly through a woman’s lifetime:
  • 20% at 10 yrs; 30% at 20 yrs.; 40% at 30 yrs.;
  • 50% at 40 yrs.; 60% at 50 yrs.!

GDM is a public health emergency with grave implications – Trans generation Transmission occurs

Complications (Pre-GDM) Hyperglycemia in Early Pregnancy

Fetal Complications:

• Congenital malformations – cardiac & neural tube defects.
• Anencephaly, microcephaly, congenital heart disease, caudal regression (<10wks).
• Sacral agenesis is the most pathognomonic.
• Higher incidence of stillbirths.
• Polyhydramnios.
• Fetal Macrosomia.
• Shoulder dystocia.
• Prolonged labor.
• Birth trauma and Erb’s palsy.
• Neonatal asphyxia.
• Neonatal hypoglycemia.
• Neonatal hyperbilirubinemia.

Maternal complications:

• Miscarriages in early pregnancy.
• Higher incidence of infections.
• Pre-eclampsia.
• Pre-term labor.
• Birth trauma.
• Assisted delivery and caesarean sections.
• Hypoglycemia.
• Acute metabolic complications such as DKA.
• Worsening of pre-existing microvascular complications.

Gestational Diabetes Mellitus (GDM): Hyperglycemia in Late Pregnancy

Fetal Risks

• No increase in congenital anomalies
• Spontaneous abortion; Intra-uterine Fetal Death
• Macrosomia – LGA, birth injuries, shoulder dystocia
• Infant Respiratory Distress Syndrome; Jaundice
• Neonatal Hypoglycemia
• LGA children or those born to obese mother have a 7% risk of developing IGT at 7-11 yrs. age

Maternal Risks

• Polyhydramnios/ C-section/ Prolonged labor/ Preterm delivery
• Abortion/ Uterine Atony
• Pre-eclampsia/ Postpartum Hemorrhage
• Infection
• Recurrence risk of GDM is 30-50% & 20-60% lifetime risk in developing IFG, IGT or type 2 diabetes

GDM effect on mother and baby

Courtsey: Medscape

Screening for GDM

INDIA: Universal Approach for Screening! (DIPSI)

• Asian Indians are a high-risk ethnic group for development of diabetes.
• Indian women have 11-fold increased risk of developing glucose intolerance during pregnancy compared to Caucasian women.
• In India alone, GDM complicates nearly 4 million pregnancies annually, representing a large subset of population at high risk for adverse perinatal morbidity and mortality if not diagnosed and managed well.
• Hence all pregnant Indian women need to be screened for GDM*!

Screening For GDM – Indian Perspective

When to screen?

• GDM usually develops during mid to late pregnancy (After the first trimester).
• However, if screening is delayed till that time, there is a chance that pre-existing diabetes/ early dysglycemia may be missed in high-risk ethnic population like us Indians.
• Therefore, it is ideal to perform the first screening as early as possible (during the first antenatal checkup in the 1st trimester itself).

How to Screen?

Recommendations for screening for GDM:

Depends on who you ask!

• ADA/EASD
• ACOG
• WHO
• NICE-UK
• National Diabetes Data Group
• IADPSG -International Association of Diabetes and Pregnancy Study Group 
• 5th International Workshop-Conference on GDM
• DIPSI
• FOGSI

DIPSI Guidelines

Approved by Ministry of Health, Government of India, WHO, IDF and International Federation of Gynecologists & Obstetricians Society (FIGO)

• Universal screening during pregnancy has become important in our country & we need a simple single test procedure which is both economical and feasible.
• In the antenatal clinic, a pregnant woman after undergoing preliminary clinical examination, has to be given a 75-gm oral glucose dissolved in about 300ml water over 5-10 minutes without regard to the time of the last meal.
• GDM is diagnosed if 2hr plasma glucose is ≥140 mg/dl.
• The first testing should be done during the first trimester as almost one third of GDM positive women are detected during this period or first antenatal contact as early as possible in pregnancy.
• If found negative at this time, the second screening test is to be performed again around 24th – 28th week.
• In high risk /suspicious cases repeat testing at 32-34 weeks may be indicated.

Rationale behind DIPSI Cut-off of 140 mg/dl:

• GDM is representative of early beta cell dysfunction, and is considered a step in the evolution of T2DM.
• After a meal, a normal glucose tolerant woman would be able to maintain euglycemia despite a glucose challenge due to brisk and adequate insulin response as a result of normal beta cell functioning.
• But a woman with GDM who has impaired insulin secretion-glycemic level increases with a meal & hence an exaggerated glycemic excursion is seen post a glucose challenge.
• It stands to reason that if in the non-pregnant state 2hr PG > 140mg/dl is considered abnormal (Impaired glucose tolerance – IGT) and given attention, then why can’t it be considered abnormal during pregnancy?

Knowing Targets

Glycosylated Hb in Pregnancy (10)

• Although A1C may be useful, it should be used as a secondary measure of glycaemic control in pregnancy, after SMBG.
• HbA1c is useful in pre-existing DM to know retrospective blood glucose control.
• Recommended A1C target*:
  • Preconception ≤ 6.5%
  • Ideally Aim for A1c target of <6 % (42 mmol/mol) in Pregnancy: has lowest risk for LGA, pre-eclampsia, pre-term delivery (especially in 2nd/3rd trimester) if this can be achieved without significant hypoglycaemia, but the target may be relaxed to <7 % (53 mmol/mol) if necessary to prevent hypoglycaemia.
• Limitations:
  • Due to increased red blood cell turnover, A1C is slightly lower in normal pregnancy than in normal non pregnant women.
  • A1C represents an integrated measure of glucose, it may not fully capture postprandial hyperglycaemia, which drives macrosomia.
  • Given the alteration in red blood cell kinetics during pregnancy and physiological changes in glycaemic parameters, A1C levels may need to be monitored more frequently than usual (e.g., monthly).
  • Monitoring the control but not for daily management.

CGM in Pregnancy (Ambulatory Glucose Profiling) (11)

• CGM time in range (TIR) can be used for assessment of glycaemic control in patients with T1DM, but it does not provide actionable data to address fasting and postprandial hypoglycaemia or hyperglycaemia.
• CONCEPTT (CGM in Pregnant Women with T1DM Trial):
  • RCT of CGM in addition to standard care- showed a mild improvement in A1C   without an increase in hypoglycaemias and reductions in large-for-gestational-age births, length of stay, and neonatal hypoglycaemias.
• Use of the CGM-reported mean glucose is superior to the use of estimated A1C, glucose management indicator, and other calculations to estimate A1C given the changes to A1C that occur in pregnancy.
• There are no data to support the use of TIR in women with T2DM or GDM.

Management

• Goal: “Not only to improve peri-natal outcome but also to prevent long term maternal & foetal effects”

“If glycemic control can be maximized to the extent that the fetus no longer recognizes that its mother has diabetes, then the treatment of mother during pregnancy may become the first step in prevention of Obesity and Diabetes in the Offspring.” Diabetes care Aug 1998; Vol.21, Supp.2, B138-B141

Psychological Support

* Explain * Reassure * Educate

LSM – Physical Activity

• Planned physical activity of 30 min/day is recommended
• Can improve metabolic control in cases not responding to MNT alone
• Upper body exercises are preferred 
• Simple exercise – e.g., walking. Start slow, gradually increasing the time& intensity.
• Individualize programs – start with 20 minutes/day→ increase to 45-60 minutes/day.
• Important to maintain balance and avoid falls.
• Avoid Contact sports/activities with risks of falling or trauma (snow & water skiing, horseback riding, etc.)
• Exercise that increases blood pressure should be avoided.
• Cornerstone of GDM Management
• MNT and lifestyle changes: effectively manage 70% – 85% of mild GDM cases¹
• Primary approach is to normalize blood glucose levels through MNT, physical activity and weight management along with glucose monitoring.
• Because glycaemic targets in pregnancy are stricter than in nonpregnant individuals, it is important that women with diabetes eat consistent amounts of carbohydrates to match with insulin dosage and to avoid hyperglycaemia or hypoglycaemia.
• Severe caloric restriction is not recommended as it may result in ketonemia and ketonuria and impair physical and mental development in offspring Medical Nutrition Therapy & Lifestyle Modification

MNT Principles

• The food plan should provide adequate calorie intake to promote fetal/neonatal and maternal health, achieve glycaemic goals, and promote weight gain according to 2009 Institute of Medicine recommendations*.
• As per Indian ICMR guidelines, for an average weight gain of 10-12 Kg, an addition of 350 kcal/ day above the adult requirement is recommended during second and third trimester.
• Individualisation is important when determining energy requirement, and adjustments should be made based on weight change patterns.
• Energy requirement during pregnancy includes the normal requirement of adult and an additional requirement for fetal growth plus the increase in the body weight of pregnant woman
• Dietary Reference Intakes (DRI) for all pregnant women recommends a minimum of 175 g of carbohydrate, a minimum of 71 g of protein, and 28 g of fibre*.
• The diet should emphasize monounsaturated and polyunsaturated fats while limiting saturated fats and avoiding trans fats.
  • Choose healthy low-carbohydrate, high-fibre sources of nutrition, with fresh vegetables as the preferred carbohydrate sources⁴
  • Count carbohydrates. Adjust intake based on fasting, premeal, and postprandial SMBG measurements^4,6
  • Avoid sugars, simple carbohydrates, highly processed foods, dairy, juices & most high glycaemic index fruits^4,5
  • Eat frequent small meals to reduce risk of postprandial hyperglycaemia and pre-prandial starvation ketosis⁵
• As pregnancy progresses, glucose intolerance typically worsens; patients may ultimately require pharmacotherapy^1,3

Pharmacotherapy

• As pregnancy progresses, glucose intolerance typically worsens; patients may ultimately require Pharmacotherapy.
• Insulin is the preferred First –line medication for treating hyperglycaemia in GDM
• None of the currently available human insulin preparations have been demonstrated to cross the placenta.
• While individual RCTs support limited efficacy of metformin and glyburide in reducing glucose levels for the treatment of GDM, these agents are not recommended as first-line treatment for GDM because they are known to cross the placenta and data on long-term safety for offspring is of some concern.
• Randomized, double-blind, controlled trials comparing metformin with other therapies for ovulation induction in women with polycystic ovary syndrome have not demonstrated benefit in preventing spontaneous abortion or GDM, and there is no evidence-based need to continue metformin in such patients.

ADA 2022:

Metformin Recommendation: Restricted use

• There are some women with GDM requiring medical therapy who, due to cost, language barriers, comprehension, or cultural influences, may not be able to use insulin safely or effectively in pregnancy.
• Oral agents may be an alternative in these women after a discussion of the known risks and the need for more long-term safety data in offspring.
• However, due to the potential for growth restriction or acidosis in the setting of placental insufficiency, metformin should not be used in women with hypertension, preeclampsia, or at risk for intrauterine growth restriction.
• DIPSI:  If pregnant women is not willing for insulin, metformin can be recommended provided gestational week is more than 12 weeks. The starting dose of metformin is 500 mg twice daily orally up to a maximum of 2 gm/day. If the woman’s blood sugar is not controlled with the maximum dose of metformin (2 gm/ day) and MNT, there is no other option but to advise Insulin.

Insulin Is the Gold Standard and Has to Be Preferred In All Cases Needing Pharmacotherapeutic Agents!

Factors which predict need for insulin in GDM

• Higher FBG >110, PPBG >140mg%
• Early detection of GDM <20 weeks
• Past history of GDM
• Older age at diagnosis
• Higher baseline A1C or Fructosamine
• Elevated BMI. Pregnancy weight gain of >20kg
• Need for pharmacotherapy <30 weeks
• Renal /Hepatic dysfunction
• GI intolerance, previous adverse reactions or allergy to metformin
• h/o major congenital anomaly in previous pregnancy
• Hydramnios
• Maternal and fetal distress
• Presence of HT, pre-eclampsia, IUGR

Insulin

• Preferred agent for management of diabetes in pregnancy. Does not cross placenta.
• Insulin therapy has to be individualized.
• Both multiple daily insulin injections and continuous subcutaneous insulin infusion are reasonable delivery strategies, and neither has been shown to be superior to the other during pregnancy.
• No convincing evidence for the superiority of one insulin regimen over another even in MDI.
• E.g.: Many women with GDM have isolated elevation of post breakfast glucose levels; in such cases, a single dose of short/rapid acting insulin before breakfast may suffice.
• PreGDM – Basal Bolus Regime recommended.
• All human insulins – regular/NPH are safe in pregnancy.
• Analogues: Insulin as part and lispro are approved for use in pregnancy; insufficient data on glulisine.
• Insulin detemir has been approved for use in pregnancy; glargine and degludec are still not approved, though glargine use has been found safe in pregnancy.
• Analogues: faster, predictable, less hypos!

Mode & Timing of Delivery – When & How?

• GDM -not a sole indicator for Caesarean delivery or delivery before 38-39 weeks’ gestation in well controlled patients.
• If Normal Estimated Fetal Weight, good metabolic control, good biophysical profile & normal amount of amniotic fluid                                    

PLAN FTND

• Elective Caesarean section should be strongly considered if the EFW is more than 4000-4250 g (macrosomia).
• Prolongation of gestation past 38 weeks- Increases risk of fetal macrosomia without reducing Caesarean rates→ delivery during the 38-39th week is recommended unlessobstetric considerations dictate otherwise.
• Well-controlled DM with normal Antenatal testing – allowed to progress to their EDD, not recommended to go beyond 40 weeks though.
• In poorly controlled DM pregnant patients- early delivery indicated.

Immediately After Delivery* & Later Follow-Up

• Sharp decline in insulin requirement – stop insulin & continue monitoring to see if the sugars normal in the postpartum period. FPG next 3 days. 
• Immediate postpartum T2DM: uncommon in GDM.
• 15% of GDM remain glucose intolerant or develop T2DM in the postpartum period and 10-50% of the women develop diabetes within 5 years of delivery**.
• Importance of weight control, diet and exercise- both mother & baby.   
• W/O for Symptoms of hyperglycemia.
• Explain: Risk of GDM in subsequent pregnancies and screening for diabetes when planning next pregnancy. Highlight importance of Preconception Counselling
• Explain: Risk of childhood obesity/ diabetes to the baby.
• Women with GDM should be tested for persistent diabetes or prediabetes at 4–12 weeks postpartum with a 75-g OGTT using non-pregnancy criteria & thereafter every 1–3 years thereafter if the 4–12 weeks postpartum 75-g OGTT is normal.
• Ongoing evaluation may be performed with any recommended glycaemic test (e.g., annual A1C, annual fasting plasma glucose, or triennial 75-g OGTT using nonpregnant thresholds).
• Both metformin and intensive lifestyle intervention prevent or delay progression to diabetes in women with prediabetes and a history of GDM. 

Take Aways:

• Hyperglycaemia in Pregnancy/GDM is associated with an increased risk of maternal and fetal complications.
• Guidelines recommend early screening and diagnosis of GDM followed by optimum glycemic control to prevent the risk of maternofetal complications and improve outcomes.
• MNT & LSM form the cornerstone of GDM Management.
• Insulin is the preferred agent for management of diabetes in pregnancy. Insulin therapy has to be individualized.
• Oral agents like metformin may be an alternative where insulin is not acceptable or possible after a discussion of the known risks and the need for more long-term safety data in offspring.
• Women with GDM should be tested for persistent diabetes or prediabetes at 4–12 weeks postpartum and every 1-3 years thereafter lifelong.

References:

1. Laurie Barclay, MD;Charles Vega, MD, Lancet. 2009
2. DIPSI Guidelines, J Assoc Physicians India, 2006
3. Alberti K, Zimmett P. WHO Consultation, Definition, diagnosis and Classification of diabetes mellitus and its complications, 1: Diabetes Med 1998; 15 :539-53.
4. Coustan, Donald R. MD, “Making the diagnosis of Gestational Diabetes Mellitus (Diabetes and Pregnancy)” Clin Obstet Gynecol. 2000 Mar;43(1):99-105.
5. ADA 2018. Diabetes Care 2018Jan; 41 (Supplement 1);
6. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus Obstetrics & Gynecology: February 2018 – Volume 131 – Issue 2 – p e49–e64,
7. AACE/ACE Diabetes Guidelines, Endocr Pract. 2015;21(Suppl 1)
8. NICE GUIDELINES
9. Diabetes in pregnancy: management from preconception to the postnatal period (NG3), V Sehiah et al. DIPSI guidelines, JAPI 2006.
10. K K Gangopadhyay et al. JAPI. 2017.
11. ADA STANDARDS OF Med Care 2021.Frequent Hypo- increases risk of LBW
12. Diabetes Care 2021; S44(Suppl. 1):S 200-S210
13. Chitayat, L, et al. Diabetes Technology & Therapeutics. 2009;11:S105-111. 2. ADA. Diabetes Care. 2013;36(suppl 1):S11-66.
14. Jovanovic L, et al. Mt Sinai J Med. 2009;76(3):269-80. 6. Mathiesen ER, et al. Endocrinol Metab Clin N Am. 2011;40:727-738
15. Kalra P, Anakal M. Peripartum management of diabetes. Indian Journal of Endocrinology and Metabolism. 2013;17(Suppl1):S72-S76.
16. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: A systematic review. Diabetes Care. 2002;25:1862–8

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