*Diabetes Mellitus in Pregnancy

Chapter: Diabetes Mellitus in Pregnancy
McMaster Section Editor(s): Victor M. Montori, Juan P. Brito
Section Editor(s) in Interna Szczeklika: Barbara Jarząb, Ewa Płaczkiewicz-Jankowska
McMaster Author(s): René Rodríguez-Gutiérrez, Paola Portillo-Sanchez, José M. Hinojosa-Amaya
Author(s) in Interna Szczeklika: Jacek Sieradzki, Ewa Płaczkiewicz-Jankowska
Additional Information

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 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 (eg, placental lactogen, estrogens, corticotropin-releasing hormone, progesterone, growth hormone, and prolactin) are significantly increased, which results in insulin resistance, hyperglycemia, and increased insulin requirements, as well as difficult-to-control diabetes and an 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:

1) Preconception management and counseling is important for good pregnancy outcomes.

2) Try to maintain a fasting blood glucose level ≤5.5 mmol/L (100 mg/dL) and a glycated hemoglobin level (HbA1c) of around 6.0% to 6.5%,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. PubMed PMID: 19265024; PubMed Central 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. PubMed PMID: 17130193. monitor for and treat infections as required, diagnose and treat chronic complications, and intensify patient education.

3) A fundoscopic eye examination should be performed before pregnancy and then each pregnancy trimester (laser treatment of retinopathy is used if needed).

4) Folic acid in a dose 400 microg daily is recommended at least 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 discontinued and beta-blockers or calcium channel blockers should be considered as needed.

7) Thyroid-stimulating hormone is recommended to be checked before pregnancy, particularly in patients with type 1 diabetes, as subclinical hypothyroidism has been associated with preterm delivery, preeclampsia, and pregnancy loss.

2. During pregnancy: Strict control of diabetes is suggested before and during the first weeks of pregnancy (HbA1c <6.0%-6.5%)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. PubMed PMID: 19265024; PubMed Central 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. PubMed PMID: 17130193. as the risk of congenital malformations is highest 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.

Monitoring and Target Blood Glucose Values

As indicated above, the suggested HbA1c target level is <6.0% to 6.5%; we suggest to measure the level every 6 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. PubMed 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) Before meals: 3.3 to 5.0 mmol/L (60-90 mg/dL).

2) 1 hour after meals: ≤7.2 to 7.8 mmol/L (130-140 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 blood glucose monitoring systems. The target mean 24-hour glucose level is not higher than 5.3 mmol/L (95 mg/dL). It is also important to mention that while pregnant women can self-monitor glucose levels 8 to 10 times a day (to meet all the goals), this is usually not necessary. In our experience, measurements performed 3 to 4 times a day, alternating times between days, are sufficient in most cases; however, this can be different from patient to patient.

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. PubMed 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.

Pharmacologic Therapy

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). 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 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. PubMed 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. PubMed 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. PubMed PMID: 25609400; PubMed Central PMCID: PMC4301599. 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. Some of the advantages of metformin are the low risk of hypoglycemia, reduced maternal weight gain, and a reduction in perinatal morbidity, particularly in obese women or those using concomitantly high doses of insulin. Glyburide also crosses the placental barrier, and some studies have shown an increased rate of neonatal hypoglycemia and birth weight ≥4000 g. Therefore, our pattern is to use metformin or glyburide (especially if such treatment was received before pregnancy), and if the patient remains well controlled, the agents may be continued. 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).

1. During delivery (either vaginal or cesarean): Administer continuous intravenous 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 intravenous glucose (dextrose) infusion. Blood glucose levels should be within the range of 5.6 to 10.0 mmol/L (100-180 mg/dL). Insulin administration should not be discontinued at this point, especially in type 1 diabetes, since there is an increased risk for developing diabetic ketoacidosis.

2. 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, for patients with type 2 diabetes, our pattern of practice is to stop insulin infusion, monitor glucose levels every 4 to 6 hours, and prescribe the insulin sliding scale 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.

TablesTop

Table 1. Medical management of diabetes during pregnancy

 

Duration

Onset

Time to peak

Peak effect

Pregnancy risk factor

Oral agents

Biguanides: Metformin

 

 

 

 

B

Immediate-release

4-9 h

2-3 h

 

Extended-release

 

7 h

 

Sulfonylureas

 

 

 

 

 

Glyburide

<24 h

2-4 h

B/C

Insulin

Short-acting

 

 

 

 

 

Lispro

15-30 min

0.5-3 h

B

Aspart

12-30 min

1-2 h

B

Regular

15-30 min

2.5-5 h

B

Intermediate-acting

 

 

 

 

 

NPH

1-2 h

4-12 h

B

Long-acting

 

 

 

 

 

Detemir

3-4 h

3-9 h

B

Glargine

3-4 h

No peak

C

B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

NPH, insulin isophane (intermediate-acting human insulin).

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