Pregestational Diabetes

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Diagnosis and reasoning

This lady has presented with pregestational diabetes mellitus. Unfortunately, she has not received a preconception evaluation - thus, it is of paramount importance to optimize her glycemic status and medications, screen her for comorbidities, and come up with a clear plan of management. Her HbA1c level indicates excellent glycemic control in the past few months. This is a reassuring finding, as hyperglycemia during the period of organogenesis (< 9 weeks of gestation) is associated with a significant incidence of congenital abnormalities. However, note that she is on glipizide, which is a category C drug in pregnancy (i.e. studies in animals have shown an adverse effect on the fetus) - this should be changed as soon as possible. The physical examination reveals no evidence of the microvascular or macrovascular complications of diabetes. This is supported by the normal urine albumin:creatinine ratio. A lipid profile is important, as these patients are at risk of coexisting dyslipidemia and cardiovascular disease. This reveals elevated levels of LDL and Triglycerides. An echocardiogram is not indicated if the screening ECG is normal and the physical examination shows no signs of cardiac disease or hypertension. In addition, a TSH assay is indicated in only in patients with type 1 diabetes (as 5 to 10% of such patients have thyroid dysfunction), or in those with chronic kidney failure. Note also that GFR estimates are inaccurate in pregnancy, as the glomerular filtration rate (GFR) temporarily increases in the early stages. The first step in her management is to stop glipizide and start her on insulin. Even though she is dyslipidemic, stains are contraindicated in pregnancy. Dietary control and exercise should be attempted instead. While there is evidence that low-dose Aspirin therapy reduces the incidence of preeclampsia and intrauterine growth restriction (IUGR), it is probably best limited to high-risk patients (for example, if the is an obstetric history of these conditions). ACE Inhibitors are contraindicated during pregnancy.


Discussion

The incidence of pregestational diabetes increased from 0.81% of all pregnancies in 1999, to 1.82% in 2005. This trend will very likely continue, given the epidemic of obesity and type 2 diabetes in younger individuals. The treatment of pregestational diabetes poses several unique challenges. First and foremost, hyperglycemia during the period of organogenesis is a significant risk for congenital fetal abnormalities, leading to major birth defects in 5% to 10% of such pregnancies, and spontaneous abortion in 15% to 20%. Unfortunately, these women may not be aware that they are pregnant during the majority of this period (and some of them may not even know that they are diabetic). Secondly, these women are at risk for miscarriage, preeclampsia, preterm labor and stillbirths. Their fetuses are at risk of macrosomia and birth injury, and may experience difficulties in postnatal adaptation (such as neonatal hypoglycemia). Last but not least, pregnancy may worsen certain complications of diabetes - especially diabetic retinopathy and nephropathy. Thus, if at all possible, women with diabetes who wish to become pregnant should be identified, counselled and optimized prior to conception. Important principles in this regard include: - Optimization of glycemic control. The ADA recommends the use of insulin, but the NICE guidelines mention that metformin may be used as an adjunct or alternative. - Identification and treatment of complications - especially retinopathy, nephropathy, autonomic neuropathy, and cardiovascular disease. - Screening for co-morbidities - especially hypertension (which should be tightly controlled if present), dyslipidemia, and thyroid dysfunction (in patients with type 1 diabetes). - Stopping teratogenic drugs - especially ACE Inhibitors. - Many clinicians also initiate folate supplementation, as there is an increased risk of neural tube defects in the fetus. It is important to emphasize the risks of an unplanned pregnancy and offer effective contraception until these patients are fully optimized. Unfortunately, all too many of these women are not optimized preconceptually - if so, this should be performed at the booking visit. Following conception, close follow up with regard to glycemic control is essential, as is monitoring for the acute and chronic complications of diabetes, and fetal surveillance. For optimal control of blood glucose, the patient should be taught the principles of self management - these include self-monitoring of blood glucose levels, self administration and self adjustment of insulin doses, and use of an appropriate dietary plan. Note that the ACOG recommends that mean capillary glucose levels should be maintained at an average of 100 mg/dL, with a HbA1C no higher than 6%. Considering acute complications, these women are at an increased risk of metabolic disturbances such as hypoglycemia and diabetic ketoacidosis (DKA). The risk of hypoglycemia is particularly high in early pregnancy - patients and family members should be educated on recognition of symptoms and proper treatment measures. DKA may occur even with moderately elevated glucose levels - patients with nausea, vomiting, and persistent hyperglycemia (no matter what the measurement) should always be evaluated for DKA. Considering chronic complications, diabetic nephropathy may rapidly progress during pregnancy. Tight glycemic and blood pressure control is essential to prevent this. Note also that patients with nephropathy are at a significantly increased risk of preeclampsia, fetal growth restriction, premature delivery, and stillbirth. Diabetic retinopathy is also prone to rapid progression during pregnancy. As with nephropathy, proper glycemic and blood pressure control is essential. In addition, these patients should be evaluated frequently depending on the degree of retinal involvement. Note that women who do not have retinopathy should also be assessed in the first and third trimesters. If medically indicated laser photocoagulation can be performed during pregnancy. Considering comorbidities, the blood pressure should be kept < 130/80 mmHg, due to its effect on nephropathy, retinopathy and cardiovascular risk. Preferred antihypertensives include methyldopa, long-acting calcium channel blockers, and β-adrenergic blockers. As mentioned earlier, ACE inhibitors and angiotensin receptor blockers are contraindicated in pregnancy. During the course of pregnancy, these patients may need to be seen every 1 to 2 weeks during the first two trimesters, and weekly after 28 to 30 weeks. Note also that a dating scan is important to accurately estimate the gestational age, while an anomaly scan is crucial, considering the increased risk of fetal defects. The timing of delivery relies on balancing the risk of intrauterine fetal death with the risks of preterm birth. In general, early delivery may be considered in patients with poor glycemic control, maternal complications such as vasculopathy or nephropathy, or fetal complications such as macrosomia. If both mother and fetus are well, delivery at the expected date of delivery (EDD), is possible. Expectant management beyond this point is generally not recommended. Pregestational diabetes does not mandate cesarean section. The mode of delivery should be tailored to each individual patient, based on their unique circumstances. Note insulin requirements decrease rapidly after delivery - in many cases, patients can be started on half of the predelivery dose after starting regular food intake. The NICE guidelines additionally mention that women who breastfeed can resume or continue to take metformin or glyburide, although other oral hypoglycemics should be avoided.


Take home messages

  1. Maternal hyperglycemia during the period of organogenesis is a major risk factor for fetal congenital malformations.
  2. Patients with type 2 diabetes who intend to become pregnant should be offered effective contraception until fully optimized.
  3. Pregnancy can rapidly worsen diabetic retinopathy and nephropathy - aggressive management is necessary to prevent this.
  4. Pregnant patients with pregestational diabetes are at an increased risk of hypoglycemia and DKA.

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  1. AFP: Recommendations for Preconception Care (August 2007)
  2. BMC Women’s Health: Preconception Care of Women with Diabetes: A Review of Current Guideline Recommendations (2010)
  3. Diabetes Care: Managing Preexisting Diabetes for Pregnancy: Summary of evidence and consensus recommendation for care (May 2008)
  4. Diabetes Care: Preconception Care for Women with Diabetes (January 2003)
  5. Diabetes Care: Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999-2005. (2008)