PRE-EXISTING DIABETES MELLITUS

Metabolic changes in the pregnant mother also affect her child – in utero and thereafter, in infancy, childhood and even adulthood. Many researchers are attempting to define and describe the known obstetric risks and complications associated with maternal diabetes, the underlying pathophysiology of the disease, and the manner in which hyperglycaemia affects these processes. Some of the recent improvement noted in the health of infants of diabetic women derives from the advances made in our understanding of the disease, in monitoring techniques, and in neonatal and paediatric medicine. However, for the most part it is due to prevention by means of good maternal metabolic regulation. Careful control of glucose levels for several months before conception can usually lower the risk of complications during pregnancy and delivery, in some cases to within the range of the normal population. Today, glucose analyzers are available for home use to enable self-regulation by women at risk. Clinicians can then combine these daily measures with monthly measurement of glycosylated haemoglobin (HbA1c) levels for precise and continuous surveillance. Together, the physician-patient team can achieve maximum balance and lower fetal and neonatal morbidity and mortality rates. It is essential to bring these issues to the awareness of all physicians so that diabetic women of reproductive age will be referred to the appropriate clinics before pregnancy. There, they will learn about the importance of glucose regulation already before conception, and during pregnancy and delivery.

4.1 Definition:

PreDM is a metabolic disturbance characterized by hyperglycaemia due to a disruption in the production or function of insulin, which is first detected before pregnancy. The diabetes may be type 1 or 2 or MODY or IGT.

4.2 Incidence:

About 10% of all diabetic women have PreDM, that is, about 0.3 to 0.5% of all pregnant women, or 15,000-25,000 women in Europe annually.

4.3 Preparation for Pregnancy:

Metabolic balance at the time of conception and even before is mandatory to prevent congenital anomalies. Therefore, careful, precise pre-pregnancy planning is necessary. Cumulative data indicate a target HbA1c level lower than 6SD of the laboratory mean at the medical centre.

Despite the advances in the clinical treatment of PreDM, the incidence of congenital malformations is still three times higher in women with diabetes than in healthy women (in whom the rate is 2-3% in the general population). Congenital malformations are currently the major cause of perinatal mortality in this population. Much of the clinical research of the last 20 years indicates that close clinical surveillance and proper treatment to maintain glucose within pre-pregnancy physiological levels (with family planning and metabolic preparation) can drastically decrease congenital anomalies, to rates almost equal to those in the general population, i.e., about 3%. According to prospective studies, the rate of anomalies in offspring of diabetic mothers who were properly treated before conception in specialised clinics is 2.2%, compared to 8.7% in offspring of mothers who started treatment after conception (in most cases, after organogenesis). Clinicians must counsel all women of reproductive age who have diabetes to use contraceptive means and not to get pregnant without proper planning ^(47-53).

Evaluation of diabetic risk and treatment - Preparation should begin 3-6 months before the desired time of pregnancy, as outlined below.

1.           Dilated retinal examination. Patients should be seen by an ophthalmologist. All laser treatments should be completed before onset of pregnancy.

2.           Kidney function tests. Measurement of electrolyte levels is required in addition to blood kidney function tests and 24-hour urine collection for creatinine clearance test (CCT) and microalbumin levels. When microalbumin measures more than 300 m/day, quantitative urine collection for protein should be performed. A recent study determined the influence of microalbuminuria on pregnancy outcome in women with type 1 diabetes. They found that the prevalence of preterm delivery is considerably increased in women with microalbuminuria, mainly caused by preeclampsia. Accordingly they suggested that classification according to urinary albumin excretion and metabolic control around the time of conception are superior to the White classification in predicting preterm delivery in women with type 1 diabetes.

3.           Thyroid function test- due to high rate of co-morbidity, screening for thyroid dysfunction is recommended.  

4.           Blood pressure. Blood pressure should be controlled with medications that are not indicated in pregnancy.

5.           Cardiac evaluation. Women with adverse findings on anamnesis or physical examination should undergo electrocardiography and, according to these findings, echocardiography, an exercise test, and further work-up as needed with nuclear and angiographic imaging. Women over 40 years old or who have had diabetes for more than 10 years should undergo echocardiography regularly.

6.           Neurologic evaluation/electromyography.  These should be done in women with suspicious neuropathic findings.

7.           All oral antidiabetic medications should be stopped and balance achieved with insulin.

8.           Intensive treatment with insulin is necessary to balance glucose levels and achieve an optimal HbA1c. There is evidence that maintaining an HbA1c level at less than 6 SD of the average laboratory level will prevent an increased incidence of congenital anomalies.

9.           Insulin analogues - Rapid-acting insulin analogues can improve glycemic levels, Although available data does not clearly find insulin lispro or insulin aspart to be superior to regular insulin in pregnant women in terms of glycemic control and risk of hypoglycemia, it appears they are as safe and as efficacious as regular insulin for the management of GDM. Recently, a large randomized controlled trial comparing insulin detemir with long-acting human insulin has been published, and was found to be safe and effective as long acting insulin during pregnancy. Paucity of data exists on insulin glargine during pregnancy, and although it appears to be safe and well tolerated, data is of low quality and fear of terategonicity has not been clearly removed.

10.       Blood tests.  Routine blood tests should be conducted before pregnancy, as for the general population of pregnant women. Thyroid function should also be assessed.

11.       Hospitalization. In general, glucose regulation before pregnancy can probably be done in outpatient clinics. Sometimes patients need to be hospitalised to start intensive treatment because of technical limitations or complications of diabetes, such as ketoacidosis or severe hyperglycaemia.

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Diet - Consultation with a dietitian with expertise in the field of diabetes is an integral part of the preparatory program. Patients are given personal diets formulated according to their BMI. Usually, blood glucose can be better controlled by establishing the correct amount of carbohydrates for every meal (see Table 8). The effects of the diet should be followed by postprandial self-monitoring, with changes made accordingly. Sometimes, the amount of carbohydrates needs to be increased at breakfast and reduced at dinner.

Treatment of hypoglycaemia - At every intensive intervention before and during pregnancy, an increased prevalence of hypoglycaemic events may be expected (especially in the first weeks of pregnancy as a result of oestrogen release). Clinicians should educate their patients to recognise the early signs of hypoglycaemia, which can be different from the pre-pregnancy period, and apply proper treatment, such as two teaspoons sugar, rapidly absorbed tablets (dextro-pur), appropriate liquids, and one portion of bread. Patients should be equipped with a glucagon injection for emergencies, and family members, too, should be taught to use it.

Treatment of high blood pressure - All ACE inhibitors should be stopped near to the expected onset of pregnancy, as early as possible. The accepted treatment for high blood pressure in pregnancy includes several class C drugs:

·         Beta blockers (propranolol) – Beta blockers have been linked to retarded growth in utero and to neonatal hypoglycaemia and bradycardia. However, in general, they are considered safe in pregnancy. As beta blockers may mask signs of hypoglycaemia, they should be used with care in patients with PreDM.

·         Calcium channel blockers (mainly nifedipine) – Calcium blockers do not affect glucose metabolism and are effective in lowering blood pressure. They are considered relatively safe for use in pregnancy.

·         Apresoline (hyralazine) – This drug, too, does not affect glucose metabolism and is relatively safe for use in pregnancy. It is very effective in lowering blood pressure and is the preferred drug in moderate and severe cases.

·         Aldomin (methyldopa) – Aldomin does not affect glucose metabolism and is relatively safe for use in pregnancy. As much experience with this drug has been gained over the years, it is preferred in cases of chronic high blood pressure.

Aspirin - Recent Cochrane analysis has shown that aspirin may be prescribed, in low doses (75-100 mg), in selected high risk groups - such as type 1 and 2 diabetes – for the prevention of preeclampsia

Vitamins - As in normal pregnancy, women with PreDM should be prescribed folic acid at a dose of 400 mcg/day. In women with a previous child with a central nervous system anomaly (neural tube defect), the dose should be raised to 5 mg/day. Folic acid should be added starting about three months before pregnancy.

Smoking - Patients should be counselled to stop smoking already at their first visit.

Physical activity - Moderate physical activity is recommended both before and during pregnancy. Adding carbohydrates before physical activity to prevent hypoglycaemia might be considered.

4.4 Treatment and Follow-Up in Pregnancy:

The ultimate goal for the management of pregnancies complicated by diabetes should be a normal outcome for both mother and baby. Since maternal survival has been nearly uniform for several decades, fetal and neonatal survival has, until recently, been the primary therapeutic goal. With the advent of reliable techniques for outpatient assessment of fetal well-being and for control of maternal diabetes, perinatal survival approaching that of the non-diabetic population may now be achieved in many cases with a minimum of in-hospital care. Fetal and maternal outcome is directly correlated with the degree of maternal metabolic derangement.

1.       Frequency of visits - The physician should be seen at least once monthly and the dietician as necessary.

2.       Weight, blood pressure, and urine protein. These should be measured every two weeks in the second and third trimesters, and once a week starting from the 36th week of pregnancy.

3.       Kidney function. Twenty-four-hour urine collection for protein analysis and CCT is recommended once each trimester.

4.       Ophthalmologic complications. Retinal examination should be performed every trimester and treatment initiated as necessary. Pregnancy is not a contraindication for laser treatment of diabetic retinopathy.

Glucose Monitoring - Blood glucose level can be measured in one of three ways - Glycosylated haemoglobin concentration (Hemoglobin A1C), Self Monitoring of Blood Glucose (SMBG) and continuous glucose monitoring (CGM).

1.       Continuous glucose monitoring (CGM) during pregnancy is recomeded for women with pre-gestational diabetes, and data suggest an improved glycemic control with reduced dosage of insulin.

2.       Self-monitoring of blood glucose (SMBG) - Glucometer readings should be taken before meals, 2 hours after meals, and at bedtime. In the middle of the night, measurements should be made as necessary.

5.       HbA1c - HbA1c levels should be measured every 4-6 weeks during pregnancy.

Nutritional treatment - In women with PreDM, the guiding principle is 1g protein/1 kg ideal body weight. In women with early signs of nephropathy, the clinician may consider lowering the protein dose to 0.6-0.8 g/kg ideal body weight. As before pregnancy, artificial sweeteners are allowed, but only in moderation.

Recommended weight gain - The recommended weight gain in pregnancy is 11-13 kg. Sometimes women who were overweight before pregnancy do not gain weight, and they need to be carefully followed for urine ketone levels and fetal development.

Diabetologic follow-up - The patient with PreDM should be seen by a diabetologist and nurse once every week to three weeks, as necessary, and a dietician as necessary. At each visit, the number of hypoglycaemic events should be documented and the patient’s glucose-measuring technique, physical activity (including time, duration, level), and understanding of the insulin treatment regimen should be checked.

Obstetric follow-up - Very close and careful obstetric follow-up is required after conception in a woman with PreDM. Examinations should be performed in a multidisciplinary clinic with professional expertise in high-risk pregnancy. Considered use should be made of the following tools:

1.       Ultrasonography - early estimation of gestational age, detection of congenital anomalies, follow-up of fetal growth; and evaluation of biophysical profile and umbilical cord blood flow see  above in detail.

2.       Biochemical - Triple test adapted for diabetes (MSAFP, HCG, E2).

3.       Fetal heart monitoring.

4.       Follow-up of fetal movements.

5.       Hospitalization - In most cases, hospitalization is required only for emergencies or extreme events that require follow-up and treatment every 24 hours (toxaemia, premature labour etc.).

4.5 Contraindications For Pregnancy

§  Severe nephropathy manifested as CCT<40 or creatinine above 2.5  

§  Uncontrolled hypertension

§  Unmanageable proliferative retinopathy

§  Active coronary disease warranting in-depth evaluation