Pregnancy in type 1 DM

Pregnancy complicated by type 1 diabetes, is a major risk factor for neonatal morbidity and mortality. Appropriate intensive monitoring to guide therapy and maintenance of glucose control, as close to the normal range, as possible without significant hypoglycemia before and throughout pregnancy, results in reduction of fetal and maternal complications to a similar rate to that observed among non-diabetic pregnancies. Glycemic control is a critical part of the optimal medical management of diabetes during pregnancy, along with screening and optimization of diabetes complications: blood pressure control, retinopathy, nephropathy and neuropathy. The aim of this review is to provide a brief, comprehensive summary on the criteria, monitoring tools and treatment methods to achieve optimal glucose control in type 1 diabetes during pregnancy.

Preconception Care

Optimal control of diabetes in pregnancy starts during the preconception period. Plans and counseling about the importance of achieving normoglycemia before attempting pregnancy should be routinely discussed with women with type 1 diabetes (T1DM) in reproductive age. Counseling women about fetal organogenesis occurring during the first 7 weeks of intrauterine life, will underline that this critical period occurs before missing the first menstrual period, emphasizing the importance of a planned pregnancy. Patients should be encouraged to achieve a hemoglobin A1C (A1C) of <6.5% or lower, as long as the risk of hypoglycemia does not outweigh the benefits. Self-monitoring of blood glucose (SMBG) targets during pregnancy should be discussed and efforts should be made to attain them before conception [1][2][3].

Nutrition and Exercise

Intrauterine growth and development are dependent upon adequate nutrition throughout pregnancy. Extremes of birth weight have long-term detrimental consequences: low birth weight infants are at risk for cardiovascular and metabolic disease as adults and large for gestational age babies (LGA) are also at risk of future obesity and chronic comorbidities [4][5][6]. LGA, the most common neonatal complication in infants of diabetic mothers, are at risk of birth injuries during labor and other serious neonatal complications [7]. Counseling on healthy diet, limitation of carbohydrates, appropriate weight gain, and exercise, should be individualized, and based on pre-pregnancy BMI, weight gain during gestation, glucose control and comorbidities. Supplementation of minerals and vitamins apply to women with T1DM seeking pregnancy, with special attention to folic acid [8].

Insulin Therapy

Insulin requirements in pregnancy complicated by T1DM change as the pregnancy progresses and frequent modifications are needed to maintain euglycemia; this is recommended to be achieved by weekly visits and as needed, with the goal of promptly and proactively adjust insulin doses as the pregnancy progresses. Glucose control is better achieved when using insulin regimens that mimic normal physiology. A combination of long-acting and rapid-acting insulin is the preferred regimen. Premixed insulin regimens are unlikely to achieve the targets recommended during pregnancy, mainly secondary to the inability to titrate only one of them when needed, increasing the risk of hypoglycemia and glycemic variability. Women on a regimen of pre-mixed insulin (insulin 70/30, 75/25, etc.) should be switched to a basal bolus regimen, ideally in the pre-conception period, and glucose control on the new regimen achieved before pregnancy is attempted. Basal bolus regimens allow for flexibility with regards to dosing time, size of meals, facilitation achievement of specific glucose targets, less hypoglycemia, and less basal “overinsulinization”, potentially limiting excessive weight gain [3].

In women with T1DM, a decline in the insulin requirements during the end of the first gestational trimester has been described, increasing the risk of hypoglycemia. Provider and patient knowledge and vigilance about this phenomenon will reduce the potential risk of hypoglycemia. As gestation advances, the diabetogenic hormonal milieu of pregnancy will result in increased insulin resistance and insulin requirements.

Long and intermediate acting insulins approved for their use in pregnancy as basal insulins include detemir insulin and neutral protamine Hagedorn (NPH) insulin [9]. Insulin glargine has recently been accepted by The American Endocrine Society guidelines only in women who pre-conceptionally have achieved optimal glucose control [3], however as data on its use is limited, this regimen is not to be recommended to be initiated during pregnancy, instead other long or intermediate acting insulins are preferred (detemir and NPH insulin).

Rapid acting insulin analogs lispro and aspart are recommended to use before meals, to prevent postprandial hyperglycemia, as opposed to intermediate acting insulins such as regular insulin, as physiologically, intermediate acting insulins will not prevent the one-hour postprandial hyperglycemia in women with T1DM (see glycemic targets). Glulisine insulin has not been approved to its use in pregnancy [3][10][11][12]. The types of insulin demonstrated to be safe and effective in pregnancy are listed in Table 1.

Table 1. Insulins shown to be safe in pregnancy

Basal Intermediate Acting Insulins
Name Onset Peak Effect Pregnancy Class
NPH 2h 2-6 h B
Levemir 2 h - B

Prandial rapid-intermediate Acting Insulins
Name Onset Peak Effect Pregnancy Class
Aspart 15 min 60 min B
Lispro 15 min 60 min B
Regular 60 min 2h-4h B

Subcutaneous continuous insulin infusion (SCII)

SCII in patients with T1DM is safe and non-inferior to multiple daily injections (MDI). Recommendations for CSII cannot be generalized and well-designed randomized trials are needed to assess glycemic control and outcomes for women with diabetes and their infants [13]. The ongoing use of SCII during pregnancy in women with diabetes when this has been initiated before pregnancy is recommended to be continued, however this insulin delivery modality is not recommended to be initiated during pregnancy unless other insulin strategies have been unsuccessful [3]. The initiation of an insulin pump is a process, appropriate only for patients who possess the knowledge on the operation of the pump, troubleshooting technical difficulties and matching carbohydrates with insulin doses [14]. Training is needed prior to its initiation, and awareness on its limitations and risks acknowledged, particularly the risk of ketosis, heightened during pregnancy secondary to metabolic changes inherent to gestation. The use of urine ketone strips and the rationale for their use should be taught [14]. Women who are experienced pump users need additional education and surveillance during pregnancy to ensure optimal insulin absorption and glucose control [3]. Insulin aspart and lispro are considered the standard of care insulins recommended for pumps. Glulisine is not approved for use in insulin pumps and/or pregnancy. Regular insulin is not the preferred insulin for pump therapy, secondary to its longer onset and peak effect when compared to aspart and lispro insulins.

Glycemic Monitoring and Glycemic Targets

Self-Monitoring of Blood Glucose.

The incidence of maternal and neonatal complications has been observed to be a continuum as glucose levels increase, even in the range of previously considered normal values [15]. SMBG is the cornerstone tool to guide treatment decisions in pregnancy complicated by diabetes, therefore its use for metabolic regulation during pregnancy should be monitored carefully: the glucose meter should be checked against standard values periodically and target glucose levels discussed with the patient (see table 2). Intensive SMBG during pregnancy is recommended, at fasting, before and after meals, at bedtime and PRN. Identification of the most appropriate timing for glucose monitoring in the diabetic pregnancy, particularly for postprandial monitoring, is controversial. Interval from meal to peak postprandial levels varies from 45 to 120 minutes depending on meal composition [16][17][18]. Based on these observations, testing either 1 or 2 hours after the start of a meal is recommended, and the interval to be chosen should depend on when it is estimated that peak postprandial blood glucose is most likely to occur [3]. It is therefore reasonable to advise patients at the beginning of their pregnancy, to test at 1 hour and 2 hours after the beginning of a meal and discuss with their providers the best time to test subsequently based on the individual results, targeting the highest point encountered.

Additional times include as needed for symptoms of hypo or hyperglycemia and/or at 2 or 3 in the morning, particularly when a “Dawn phenomenon” is suspected as a potential cause of fasting hyperglycemia or morning hyperglycemia of unclear etiology.

Table 2. Glycemic Targets During Pregnancy Complicated by Diabetes

Capillary Glucose targets*
Fasting ≤90 mg/dL (≤5.0 mmol/L)
Pre-meal ≤90 mg/dL (≤5.0 mmol/L)
Postprandial:
1-hour ≤140 mg/dL (≤7.8 mmol/L)
2-hour ≤120 mg/dL (≤6.7 mmol/L)
3 am ≤ 90 mg/dL (≤5.0 mmol/L)
A1C (%) <6.5%

*Lower targets are recommended when they can be safely achieved without undue hypoglycemia

Glycemic markers

A1C, in combination with SMBG, is considered an important tool to guide treatment. Pregnant women with diabetes should strive to achieve an A1C <6.5%, when this can be achieved without undue hypoglycemia, as the risk of a LGA infant significantly increases with an A1c ≥ 6% during the third trimester of gestation and the risk of other adverse maternal and neonatal outcomes increases further with an A1c ≥ 6.5% [2][19]. Other glycemic markers such as glycated proteins: glycated albumin (GA) and fructosamine have not been studied as extensively as A1C in this population. A1C levels had been described to be elevated in late pregnancy secondary to iron deficiency, but GA appeared to be unaffected, underscoring the importance of iron status on the correct interpretation of A1C, particularly in the pregnant population at risk for iron deficiency. Recently, a new glycemic biomarker has caught the attention of the medical community interested in the care of women with pregnancy complicated by diabetes: 1, 5-anhydroglucytol (1, 5-AG) [20]. The literature on this marker is however, still quite limited. Further studies are needed with regards to alternative glucose markers before they can be routinely recommended in clinical practice.

Continuous Glucose Monitoring (CGM)

A barrier to optimal glucose control is that of the unpracticality to perform SMBG frequently enough to identify every single glucose excursion accurately. SMBG may underestimate the number of hyperglycemic and/or hypoglycemic events, as such CGM can facilitate the detection of otherwise undetected dysglycemic values. CMG has helped providers educate patients about behavior and compliance to treatment. There is evidence of improved A1C in women with overt diabetes using this technology during pregnancy. Real-time CGM systems however, are not available to all women, and when used intermittently, did not improve glycemic control or macrosomia rates [21]. At the present time and because the cost-effectiveness of this technology has not been established, this monitoring modality is recommended when SMBG is not sufficient to accurately assess glycemic control.

Other Resources

Pregnant with diabetes app

This free app is intended for pregnant women with type 1 diabetes and type 2 diabetes, and for women that develop gestational diabetes during their pregnancy. The app is also intended for diabetic women who wish to become pregnant.

References

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