Pregestational Diabetes

Contributor: B. Arkerson, MD; Megan Schellinger, DO

Updated: April 2021

Basics

Types: T1DM (autoimmune process that destroys pancreatic beta cells) and T2DM (peripheral insulin resistance and relative insulin deficiency)

Prevalence: 3.1-6.8% of reproductive-age women, 1-2% of all pregnancies 

The prevalence of both has increased but in different populations: T1DM has increased the most in non-Hispanic white women; T2DM has increased the most in Hispanic women

Diagnosis

Can be diagnosed outside of pregnancy or in the first trimester/early second trimester via early screening

• Failed early GTT at <13w6d = pregestational
  • Obtain an A1c for confirmation and establishment of baseline
• Failed early GTT between 14w0d – 23w6d = suspected pregestational
  • Obtain an A1c and if ≥6.5% = pregestational
• Failed GTT > 24w0d = gestational diabetes 

General approach to diagnosis outside of pregnancy:

• Hgb A1c ≥ 6.5%
• Fasting plasma glucose ≥ 126 mg/dL
• 2-hour glucose ≥ 200 mg/dL on a 75-g oral GTT

Maternal morbidity

Pregnancy has been associated with worsening of diabetes-related complications, including diabetic retinopathy and nephropathy

Renal disease in pregnancy, including diabetic nephropathy, carries significant risks:

Sources: Adapted from Jones DC. Clin Perinatology, 24, 2, 483-96, 1997; Airoldi J, Weinstein L. Obstet Gynecol Surv, 62, 2, 117-24, 2007; Hou SH. Am J Kidney Dis, 23, 1, 60-3, 1994; Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, Phillips LZ, McGrory CH et al. Clin Transpl 97-105, 2001; Luders C, Castro MC, Titan SM, De Castro I, Elias RM, Abensur H et al. Am J Kidney Dis, 56, 1, 77-85, 2010 Crow AV, Rustom R, Gradden C, Sells RA, Bakran A, Bone JM et al. QJM, 92, 11, 631-5, 1999.

Compared to non-diabetics, odds ratios are increased for the following complications in diabetics:

• Hypertension (OR = 14.2)
• Pre-eclampsia (OR 3.4)
• Cesarean delivery (OR = 11.3)
• Preterm birth (OR = 4.4)

For each of the above complications, the relative risk of each is proportional to the duration and severity of the disease

Risks of diabetic ketoacidosis is present in both T1DM and T2DM

Fetal risks

Pregestational diabetes increases the risk of congenital malformations, spontaneous abortion, and IUFD (overall 4-5 times increased risk of stillbirth) and risk is directly related to degree of glycemic control 

Most common anomalies: complex cardiac defects, CNS anomalies, and skeletal malformations, including sacral agenesis

Neonatal risks

Pregestational diabetes increases the risk of the following in the neonate: Birth injury, delayed lung maturity, respiratory distress syndrome, jaundice, hypoglycemia, hypocalcemia, and polycythemia

Long term, there is an association with pregestational diabetes in the mother and obesity, T2DM, and lower IQ in the offspring

Preconception and antepartum considerations

Preconception counseling rarely occurs but is crucial – normalization of blood glucose levels prior to pregnancy prevents most of the complications associated with pregestational diabetes in pregnancy

Preconception visit should include:

• Counseling about pregnancy complications as discussed above
• Counseling on lifestyle modifications
• Evaluation for baseline complications including
  • Hypertension – diagnosed with systolic BP >130 and/or diastolic BP > 80 in pregestational diabetes 
  • Nephropathy – acquire 24-hour urine collection for protein excretion and creatinine clearance
  • Retinopathy – ensure recent eye exam and refer to ophthalmologist if not up to date
  • Cardiovascular disease – consider an EKG in patients who meet the following criteria
    • T1DM and >30 years old
    • DM ≥ 10 years duration
    • Chronic hypertension diagnosis
  • Thyroid dysfunction, especially in T1DM – TSH
• Review all medications and modify or discontinue ones that have evidence of fetal risk including but not limited to: ACE-inhibitors, ARBs, statins, diuretics, beta blockers, GLP-1, SGLT2-I, DPP4-I, TZDs
• Plan to optimize Hgb A1c < 7% (<6% if achievable without hypoglycemia) with contraception plan until this is achieved
• Discuss plan to start increased folic acid (at least 400 mcg but up to 1-4 mg)
• The following should be discussed as contraindications to pregnancy
  • Hgb A1c > 10%
  • Baseline creatinine >2.26 mgl/dL due to increased risk of requiring dialysis during pregnancy

Diabetes-specific care by trimester

• First trimester or initial visit
  • Perform the above baseline workup and counseling on the impact of poor glycemic control on miscarriage, congenital anomalies, and fetal growth if no preconception visit occurred
  • Obtain a detailed diabetes history including: type of DM, age of onset, complications (examples: DKA, hypoglycemia, gastroparesis, nephropathy, neuropathy, retinopathy, hypertension, CAD, PAD)
  • Physical exam should include examination of the lower extremities to look for signs of abnormal perfusion and sensation
  • Evaluation by specialists as needed in the setting of pregnancy (may include endocrinology, cardiology, ophthalmology, nephrology, etc.)
• Second trimester
  • 162 mg aspirin for preeclampsia prevention at 12-28 weeks (optimally before 16 weeks)
  • AFP 16-18 weeks recommended due to increased risk of neural tube defects
  • Detailed anatomic survey at 20 weeks
  • Fetal echocardiography at 24 weeks
• Third trimester
  • Serial growth assessments starting at 28 weeks
  • Fetal monitoring
    • Antenatal testing (twice weekly testing with once-weekly NST, once-weekly BPP) generally starts at 34 weeks in the setting of good glycemic control and no additional comorbidities but can start as early as 28 weeks in the setting of hypertension, IUGR, or significant vascular disease
  • Referral to PCP and/or endocrinology for postpartum care if not already established

SMFM also has a PDF checklist with recommended action items during the first visit, by trimester, and delivery planning at the following link: https://s3.amazonaws.com/cdn.smfm.org/media/805/FINAL-3.15.16_Checklist_DM_antepartum_Clean_v6.pdf

Glucose Monitoring and Treatment

All women diagnosed with diabetes should receive lifestyle modification counseling, specifically nutrition and activity counseling

The actual dietary composition that maximizes perinatal outcomes is unknown, but the following breakdown of macronutrients is recommended:

• Carbohydrates: 33-40%, preferably complex carbohydrates, avoid sugar-sweetened beverages
• Protein: 20%
• Fat: 40%

Women should eat 3 meals a day and 2 snacks in order to maintain stable plasma glucose levels, with one snack at or close to bedtime

• Breakfast 15-30 grams carbohydrates
• Lunch 30-60 grams carbohydrates
• Dinner 30-60 grams carbohydrates
• Snacks 15-30 grams carbohydrates

Daily glucose monitoring should occur based on diagnosis

• T2DM: once fasting and again 2 hours after the first bite of each meal
• T1DM: before meals and at bedtime. Optional to check 2 hours after meals.

Target levels: Fasting and pre-meal < 95 AND 2-hr post-prandial <120

In selected patients (especially those on insulin pumps), glucose checks at 2-3 AM can help detect nocturnal hypoglycemia 

Due to the risk of ketoacidosis in the setting of pregestational diabetes, patients should check urine ketones when their glucose level exceeds 200 mg/dL

Personal continuous glucose monitors can be used in addition to fingerstick self-monitoring to reduce risk of macrosomia and neonatal hypoglycemia in T1DM

Can consider continuous glucose monitor for patients who are noncompliant with checking or for whom false logs are suspected

Patients should be seen in the office every 2-3 weeks to review logs. All patients requiring medication should have a weekly review of logs remotely or in the office. Logs should be reviewed more frequently in the office if glucose is poorly controlled

Insulin therapy is first-line pharmacologic treatment of T2DM and is required for T1DM

Utilize the Diabetes in Pregnancy Smartset for prescribing

Long acting insulins: Detemir (Levemir) and Glargine (Lantus, Basaglar, or Semglee) will impact fasting and pre-prandial values (if checked)

• Lower risk of hypoglycemia than NPH, which used to be preferred

Rapid acting insulins: Aspart (Novolog) and Lispro (Humalog or Admelog) will impact post-prandial values

Dosing: Weight-based dosing based on gestational age using actual body weight

• 0-12 weeks: TDI 0.7 units/kg/day
• 13-28 weeks: TDI 0.8 units/kg/day
• 29-34 weeks: TDI 0.9 units/kg/day
• 35-40 weeks: TDI 1 unit/kg/day

Divide the TDI dose into 50% long acting insulin and 50% rapid acting insulin

• Long-acting insulin should be divided into dosing every 12 hours
• Rapid-acting insulin should be divided into TID with meals

Individualize the patient’s regimen based on need; adjustments, if necessary, should occur in 10-20% increments every 3-7 days

Oral hypoglycemic agents are not preferred over insulin in T2DM, but there is a use for them in women who decline insulin, who cannot afford insulin, or who cannot safely administer insulin. Insulin administration is required in T1DM.

In these situations, patients must be counseled on the lack of safety data, particularly the lack of long-term neonatal follow-up, as well as high treatment failure requiring insulin administration

Metformin (preferred to glyburide)

• Dosing:
  • Starting: Metformin 500 mg BID with breakfast and dinner OR Metformin XR 1000 mg daily with a meal (NOTE: There is a current recall of certain Metformin XR products due to increased nitrosamine (NMDA) impurities – take caution when prescribing)
  • Titrate slowly to minimize GI side effects
  • Maximum dose: 2550 mg per day

Glyburide 

• Dosing
  • Starting: 2.5 mg PO BID with breakfast and dinner
  • Major risk is hypoglycemia, especially if not taken with a meal
  • Maximum dose: 20 mg per day

Notably, two recent meta-analyses have demonstrated worse neonatal outcomes    (RDS, hypoglycemia, macrosomia, birth injury) for glyburide compared to insulin despite no difference in overall glycemic control

Hypoglycemia is defined as a blood glucose ≤ 60 mg/dL. Patients with pregestational diabetes, especially T1DM, should be questioned to determine if they can recognize when they are hypoglycemic

• Treat with 15 g of rapid acting carbs (Dex4, 4 glucose tabs, or 4 oz juice)
• Glucagon prescription is recommended for patients with history or at risk for Level 2 (<54 mg/dL) or Level 3 (hypoglycemia requiring assistance to treat)
  • Glucagon emergency kit, Glucagon prefilled syringe (Gvoke), or nasal spray (Baqsimi)
• Recheck glucose in 15 minutes
• Repeat treatment until glucose > 60 mg/dL
• Once adequately treated, eat meal or protein snack
• Notably, a patient should not drive until her blood glucose is >70 mg/dL, without symptoms of hypoglycemia, and at least 30 minutes after hypoglycemic episode due to delayed recovery of cognitive function

Delivery

Timing (in the absence of other comorbidities)

• In women with good glycemic control and without vascular complications:  39w0d – 39w6d
• In women with poor glycemic control and/or with vascular complications: 36w0d – 38w6d, rarely earlier

Mode

• Generally vaginal
• Recommend cesarean delivery if EFW > 4500 g

Intrapartum management

• Patients with T1DM will require IV insulin infusion. Discontinue home insulin regimen, including pump. Follow IV insulin infusion order sets for safe initiation and discontinuation
• For patients with T2DM: discontinue home regimen, monitor blood sugars every 2 hours and initiate IV insulin infusion if glucose > 120 mg/dL

How to manage T2DM prior to scheduled c-section

• Patients on oral agents should take their last dose of that medication the night before surgery
• Patients on a long-acting basal insulin should take their normal morning dose regardless of surgery time
• Rapid-acting insulin should be held while NPO
• For the rare patient on NPH, she should take her normal nighttime dose and then half of the normal AM dose

Patients with T1DM should not change their regimen prior to scheduled c-section

• If they have a pump in place, they should leave it active on arrival to labor and delivery, at which point they will transition to an insulin drip

Postpartum considerations

If on IV insulin infusion for delivery, follow order set for safe discontinuation and transition to postpartum insulin regimen, either SQ injections or pump

Prescribing a postpartum regimen in T2DM

• Determine if the patient had a pre-pregnancy regimen, and, if so, transition her to that regimen
• Otherwise, transition the patient to a regimen that considers her degree of tolerance and/or compliance. This can include:
  • Long-acting insulin only
  • Long-acting insulin + metformin
  • Metformin only
  • Glyburide only
• Do not prescribe insulin and glyburide together due to risk of hypoglycemia
• Avoid meal-time insulin postpartum, if possible 

A good place to start with a postpartum insulin regimen is generally decreasing total daily insulin dose by half

• Long-acting insulin: Reduce to half total antepartum dose, make once daily dosing
  • Example: Antepartum regimen of Lantus 20 units BID becomes postpartum regimen of Lantus 20 units daily
• Rapid-acting insulin (continue to use postpartum in T1DM): Reduce to half total antepartum dose

Continue to check before meals and at bedtime

• Non-pregnant ADA goals: 
  • 80-130 mg/dL pre-meal
  • <180 mg/dL 1-2 hours post-prandial

Ensure patient had a referral placed to a PCP and/or endocrinology 

• Consider Access Health referral for patients who will not have insurance beyond the immediate postpartum period
• Utilize the Physician Finder referral for those patients who will remain insured beyond the immediate postpartum period

Breastfeeding mothers will need an additional 500 kcal in their diet to prevent hypoglycemia and encourage milk supply

• Insulin, glyburide, and metformin are all compatible with breastfeeding

Order Sets and Smartsets:

• Inpatient Order Sets:

• IP OB Insulin Drip 

• IP OB Insulin Subcutaneous (Diabetes in Pregnancy)

• IP OB Postpartum SQ Insulin

• Outpatient SmartSets

• AMB OB/GYN Diabetes in Pregnancy

---

References

American College of Obstetricians and Gynecologists. “Pregestational Diabetes Mellitus. ACOG Practice Bulletin No. 201.” Obstet Gynecol 2018;132(6):e228-48.

Mackeen, Dhanya, and Michael J Paglia. “Pregestational Diabetes.” Maternal-Fetal Evidence Based Guidelines, by Vincenzo Berghella, Third ed., CRC Press, 2017, pp. 50–58.

Moore, Thomas R, et al. “Diabetes in Pregnancy.” Creasy and Resnik’s Maternal-Fetal Medicine: Principles and Practice, edited by Robert Resnik et al., 8th ed., Elsevier, 2019, pp. 1067–1097.

Riddle, Matthew C, editor. “14. Management of Diabetes in Pregnancy: Standards of Medical Care in Diabetes—2021.” Diabetes Care, vol. 44, no. Supplement 1, 2020, pp. S200–S210., doi:10.2337/dc21-s014.