Diabetes Mellitus in Pregnancy

Definition and Natural HistoryTop

Diabetes mellitus in a pregnant woman is any type of diabetes that has been diagnosed before pregnancy or early in pregnancy on the basis of standard diabetes diagnostic criteria for nonpregnant patients (see Diabetes Mellitus).

1. The effect of pregnancy on the course of diabetes: In pregnancy, mainly due to placental secretion, the levels of insulin antagonist hormones (placental lactogen, placental growth hormone [growth hormone isoform V], insulin-like growth factor 1 [IGF-1], estrogen, progesterone, prolactin, and cortisol), as well as binding proteins (IGF-binding proteins, cortisol-binding globulin) are significantly increased, which results in insulin resistance and increased beta-cell activity demand. In patients with diabetes this leads to hyperglycemia, increased insulin requirements, as well as difficult-to-control diabetes and accelerated development of diabetes-specific microvascular complications (retinopathy, nephropathy).

2. The effect of diabetes on the course of pregnancy: Unlike insulin, glucose crosses the placental barrier—facilitated by glucose transporter proteins, predominantly glucose transporter 1, independently from insulin—and thus hyperglycemia in the mother results in elevated fetal blood glucose levels, stimulation and hypertrophy of fetal pancreatic islets, and insulin hypersecretion. This leads to anabolic effects, causing fetal macrosomia, and to fetal immaturity, which together increase the risk of obstetric complications associated with more frequent deliveries by cesarean sections, birth weight ≥4000 g, shoulder dystocia, perinatal injury, polyhydramnios, preeclampsia, and low Apgar scores. Significant hyperglycemia may also result in miscarriage, growth restriction, preterm delivery, intrauterine death, or congenital malformations, most commonly neural tube defects and congenital heart malformations.

TreatmentTop

1. When planning pregnancy/preconception management:

1) Preconception management and counseling is important for good pregnancy outcomes. Counseling is mandatory to start in patients with diabetes at puberty. Contraception should be offered and encouraged until a woman is planning to become pregnant. Counseling should address the importance of maintaining glycemic control close to normal along with the specific risks for obesity in pregnancy. Referrals to registered dieticians and diabetes educators are recommended as indicated.

2) Try to maintain a fasting blood glucose level ≤5.5 mmol/L (100 mg/dL) and glycated hemoglobin level (HbA1c) <6.5%, if safely achieved.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias (observational studies) and indirectness of outcomes measured. Jensen DM, Korsholm L, Ovesen P, et al. Peri-conceptional A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care. 2009 Jun;32(6):1046-8. doi: 10.2337/dc08-2061. Epub 2009 Mar 5. PMID: 19265024; PMCID: PMC2681038. Nielsen GL, Møller M, Sørensen HT. HbA1c in early diabetic pregnancy and pregnancy outcomes: a Danish population-based cohort study of 573 pregnancies in women with type 1 diabetes. Diabetes Care. 2006 Dec;29(12):2612-6. doi: 10.2337/dc06-0914. PMID: 17130193. Oral glucose-lowering agents, including glucagon-like peptide-1 (GLP-1) receptor agonist, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinediones (TZDs), or sodium-glucose cotransporter-2 (SGLT-2) inhibitor, lack long-term safety data during pregnancy and should not be continued. Patients should be transitioned to either oral agents that are safe during pregnancy, such as metformin and glyburide, or to insulin (see Pharmacologic Therapy, below). Monitor for infections and treat them as required. Diagnose and treat chronic complications and intensify patient education.

3) Fundoscopic eye examination should be performed before pregnancy or in the first trimester of pregnancy and repeated in each trimester until 1 year postpartum (treatment may be provided if needed).

4) Folic acid at a dose of 400 microg daily is recommended ≥3 months before the planned pregnancy.

5) Statins should be withheld during pregnancy as they have been associated with congenital malformations.

6) Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be stopped and beta-blockers (labetalol) or calcium channel blockers (nifedipine) should be considered as needed.

7) Thyroid-stimulating hormone (TSH) is recommended to be checked before pregnancy, particularly in patients with type 1 diabetes. Subclinical hypothyroidism has been associated with preterm delivery, preeclampsia, and pregnancy loss along with fetal consequences such as cognitive dysfunction, lower IQ, and developmental delays in infancy.

2. During pregnancy: Strict control of diabetes is suggested throughout the entire duration of pregnancy (HbA1c <6.0% if achieved without hypoglycemia; otherwise <7.0%). This is especially important during the first trimester of pregnancy,Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias (observational studies) and indirectness of outcomes measured. Jensen DM, Korsholm L, Ovesen P, et al. Peri-conceptional A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care. 2009 Jun;32(6):1046-8. doi: 10.2337/dc08-2061. Epub 2009 Mar 5. PMID: 19265024; PMCID: PMC2681038. Nielsen GL, Møller M, Sørensen HT. HbA1c in early diabetic pregnancy and pregnancy outcomes: a Danish population-based cohort study of 573 pregnancies in women with type 1 diabetes. Diabetes Care. 2006 Dec;29(12):2612-6. doi: 10.2337/dc06-0914. PMID: 17130193. because the risk of congenital malformations is higher in this period. The goals of treatment are to maintain normoglycemia with the minimum risk of hypoglycemia and to maintain fetal well-being and maternal health during pregnancy. This can be achieved through nutritional and pharmacologic therapy. Low-dose acetylsalicylic acid (60-120 mg) should be prescribed to women with preexisting diabetes from the end of the first trimester until delivery in order to lower the risk of preeclampsia (see Preeclampsia). In patients with preexisting hypertension, a blood pressure target of <135/85 mm Hg is recommended. Blood pressure <120/80 mm Hg may be associated with impaired fetal growth.

3. Postpartum care: Insulin sensitivity increases dramatically after delivery of the placenta. Insulin requirements are usually 1/2 lower than during pregnancy and return to their prepregnancy baseline within 6 to 8 weeks. Attention should be paid to avoid hypoglycemia in the setting of breastfeeding and erratic sleep schedules with further insulin dose reduction if required. In the immediate postpartum period it is suggested to review contraception options to prevent unplanned pregnancy.

Monitoring and Target Blood Glucose Values

As indicated above, the suggested HbA1c target level is <6.0% if it can be safely achieved or otherwise <7.0% to prevent hypoglycemia during pregnancy; we suggest measuring the level every 6 to 12 weeks.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due the risk of bias, imprecision, and inconsistency in outcomes measured. American Diabetes Association. 12. Management of Diabetes in Pregnancy. Diabetes Care. 2016 Jan;39 Suppl 1:S94-8. doi: 10.2337/dc16-S015. Review. PMID: 26696688. Target blood glucose levels (based on glucometer measurements) may slightly differ from the values specified below as long as they allow the target HbA1c levels to be maintained.

Fasting blood glucose and glucose levels:

1) Fasting or before meals: <5.3 mmol/L (95 mg/dL).

2) 1 hour after meals: <7.8 mmol/L (140 mg/dL).

3) 2 hours after meals: <6.7 mmol/L (120 mg/dL).

4) At night between 2:00 and 4:00: >3.3 mmol/L (60 mg/dL).

It is important to avoid hypoglycemic episodes, as they have been closely associated with an increased maternal and fetal morbidity. The most accurate assessment of 24-hour blood glucose levels is obtained using continuous glucose monitoring (CGM) systems. The target mean 24-hour glucose level is ≤5.3 mmol/L (95 mg/dL). Pregnant women can self-monitor glucose levels 8 to 10 times a day (to meet all the goals), although this is often not needed. In our experience, measurements performed 3 to 4 times a day, including fasting and postprandial, are sufficient in most cases. CGM can help identify periods of hyper- or hypoglycemia and reduce glycemic variability, especially in patients with type 1 diabetes, as shown by the CONCEPTT (Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes) trial. Data on the use of CGM in patients with type 2 diabetes and gestational diabetes and on the use of flash glucose monitoring are lacking.

Nutritional Therapy

No specific diet regimen is recommended to improve maternal or fetal outcomes.Evidence 4Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due the risk of bias, imprecision, and indirectness to patient-important outcomes. Han S, Crowther CA, Middleton P, Heatley E. Different types of dietary advice for women with gestational diabetes mellitus. Cochrane Database Syst Rev. 2013 Mar 28;(3):CD009275. doi: 10.1002/14651858.CD009275.pub2. Review. Update in: Cochrane Database Syst Rev. 2017 Feb 25;2:CD009275. PMID: 23543574. The goals of nutritional therapy are to prevent ketone formation and promote adequate maternal weight gain and fetal growth. The suggested caloric intake is per current weight and prepregnancy body mass index (BMI) calculation:

1) Underweight: 40 kcal/kg/d.

2) Normal weight: 30 kcal/kg/d.

3) Overweight: 20 to 25 kcal/kg/d.

4) Morbid obesity (BMI ≥40): 12 to 14 kcal/kg/d.

The Dietary Reference Intakes (DRI) recommend a minimum of 175 g of carbohydrate, 71 g of protein, and 28 g of dietary fiber intake for all pregnant women.

Physical activity in women with diabetes should be encouraged unless obstetrical contraindications exist, as physical activity may be an important component of diabetes management.

Pharmacologic Therapy

1. Before delivery: In most cases, if insulin therapy has not been used before, it is suggested to start it immediately and continue throughout pregnancy (using a basal-bolus regimen or an insulin pump). The use of an insulin pump during pregnancy in patients with type 1 diabetes has not shown any increase in harm in maternal or fetal outcomes, with possible improvement in glycemic control as compared with the basal-bolus regimen; however, more studies are needed in this area. Intermediate-acting human insulin (insulin isophane [NPH]) and rapid-acting insulin are the preferred choices. However, in patients using long-acting insulin (glargine or detemir) who were well controlled before pregnancy, these agents can be continued. Consider the possibility of increased (as much as 2-fold) insulin requirements particularly during the second and third trimesters.

Systematic reviews have found that oral medications could be safely used in pregnancy.Evidence 5Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the lack of blinding and concealment of some studies. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008 May 8;358(19):2003-15. doi: 10.1056/NEJMoa0707193. Erratum in: N Engl J Med. 2008 Jul 3;359(1):106. PMID: 18463376. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000 Oct 19;343(16):1134-8. doi: 10.1056/NEJM200010193431601. PMID: 11036118. Balsells M, García-Patterson A, Solà; I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ. 2015 Jan 21;350:h102. doi: 10.1136/bmj.h102. Review. PMID: 25609400; PMCID: PMC4301599. Feig DS, Donovan LE, Zinman B, et al. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2020 Oct 1;8(10): P834-844. doi: 10.1016/S2213-8587(20)30310-7. PMID: 32946820. Accordingly, oral medications such as metformin and glyburide may be used in type 2 diabetes and other types of diabetes, such as maturity-onset diabetes of the youth (MODY), during pregnancy (Table 1). Although metformin crosses the placenta, its use during pregnancy has been tested and is considered to be safe. A recently published randomized controlled trial investigated addition of metformin to standard insulin therapy in pregnant women with type 2 diabetes and found reduced maternal weight gain, reduced insulin dosage, improved glycemic control, and lower rates of caesarean sections. The infants had reduced adiposity measures; however, higher rates of small for gestational age infants were noted, the implications of which are yet to be determined. Glyburide also crosses the placental barrier, and some studies have shown an increased rate of neonatal hypoglycemia and birth weight ≥4000 g. Therefore a pragmatic approach is to use metformin if the patients are reluctant to immediately initiate insulin therapy, especially if they were already on metformin before pregnancy. If glycemic targets are not met, insulin therapy may be added to the oral medication; in most cases, during the second and third trimesters some insulin will be required to achieve glycemic targets (Table 1).

2. During delivery (either vaginal or cesarean): Administer continuous IV insulin infusion (continuous subcutaneous infusion using an insulin pump is acceptable) at doses corresponding to daily requirements and ensure appropriate caloric intake (800-1200 kcal) by IV glucose (dextrose) infusion. Blood glucose levels should be within the range of 4.0 to 7.0 mmol/L. Insulin administration should not be discontinued at this point, especially in type 1 diabetes, since there is an increased risk of developing diabetic ketoacidosis.

3. After delivery: Insulin requirements may decrease to 50% or even as little as 30% of the predelivery levels. In patients with type 1 diabetes, hypoglycemia is very common during the first 24 to 48 hours. After delivery our pattern of practice for patients with type 2 diabetes is to stop insulin infusion, monitor glucose levels every 4 to 6 hours, and prescribe sliding-scale insulin therapy. Standard diabetes therapy can be restarted by reducing the total insulin dose used before delivery by 50%. In patients who have been treated with oral antidiabetic drugs, these agents may be restarted. Metformin has been usually considered the first-line therapy. The evidence regarding oral glucose-lowering agents is scarce but, in general, those agents are considered safe (entering milk in minimal amounts), particularly metformin and glyburide. The risk of infant hypoglycemia is minimal with these drugs. As there are no human studies for other glucose-lowering agents, including GLP-1 receptor agonists, SGLT-2 inhibitors, DPP-4 inhibitors, and TZDs, these agents should not be taken during breastfeeding.

TablesTop