- • Diabetes in Pregnancy MC Gupta, Nidhi Gupta
- • Jaundice in PregnancyMM Singh, UR Raju
- • Pregnancy–induced HypertensionMC Gupta, Nidhi Gupta
- • Chronic Hypertension and PregnancyMC Gupta, Nidhi Gupta
- • Tuberculosis in PregnancyArun Nagrath, Manjula Singh
- • HIV in PregnancyNidhi Gupta
- • Heart Diseases in PregnancyMM Singh, Neeraj Agarwal
Diabetes mellitus is an endocrine disease involving faulty carbohydrate metabolism, probably of genetic origin. Diabetes mellitus in association with pregnancy has become an increasingly common observation during the last decade due to three main reasons. Firstly, more diabetic patients are achieving successful pregnancy outcome due to tight blood sugar control and the discovery of insulin in 1921, by Banting and Best changed the outlook of pregnant patient, reducing the maternal mortality to almost nil and perinatal mortality to 3 to 5 per cent. Even the high incidence of congenital malformation in diabetic pregnancies has been reduced from 12 to 5-6 per cent by prepregnancy counselling and control of diabetes prior to conception.
Secondly, the carbohydrate intolerance is recognised as a common cause of fetal wastage and all patients presenting with bad obstetric history are investigated for abnormal glucose tolerance.
Thirdly, the detection rate of diabetes in pregnancy has increased due to the awareness of the obstetrician, the setting up of special diabetic pregnancy centres and availability of better screening methods.
In order to understand diabetes in pregnancy it is important to review fuel metabolism in normal non-pregnant, non-diabetic pregnant and diabetic pregnant women.
PHYSIOLOGY OF FUEL METABOLISM
Fuel Metabolism in the Normal Non-pregnant
Fuel metabolism will be considered under the fed and fasted states in view of the intermittent eating habits of all human beings.
In the fed state, glucose the end product of carbohydrate metabolism passes through the liver where 45 to 50 per cent is converted into glycogen while the remaining is utilised by the peripheral tissues. Amino acids—the end product of protein metabolism are utilised as energy or stored as proteins and peptides in the muscle.
Dietary fat is transported as chylomicrons in the blood, hydrolysed by the action of lipoprotein lipase and is stored after re-esterification as triacylglycerol in the adipose tissue. All these changes require insulin and are modified by a balance between insulin and contrainsulin hormones.
In the fasted state, blood glucose level falls and in order to spare glucose to the glucose dependent tissues (such as brain, renal medulla and RBC) hepatic glycogenolysis starts followed by gluconeogenesis (glycerol from lipids, glycogenic amino acids from muscles and lactate from hepatic glycolysis all serve as substrates). This is followed by lipolysis releasing fatty acids as additional fuel. When this fasting is further extended, there is excessive delivery of fatty acids which are converted into ketones which serve as additional fuel. Ketones can cross the blood-brain barrier and are utilised by brain to a limited extent.
Thus, the sequence of events that follow fasting are glycogenolysis, gluconeogenesis, lipolysis and ketogenesis. So, in the fed state there is an anabolic metabolism and in the fasted a catabolic metabolism.
Carbohydrate Metabolism in a Non-diabetic Pregnant
The conceptus that has arisen denovo alters the carbohydrate metabolism of the mother because:
- Placental insulinases break down the maternal insulin.
- Placenta, a temporary endocrine organ, releases contrainsulin hormones like human placental lactogen, estrogen and progesterone, blunting the action of insulin.
- Irrespective of the maternal eating habits, the fetus is continuously drawing its nourishment from her.
In the early stages of pregnancy, human chorionic gonadotrophin and progesterone rise, yet insulin sensitivity at this time is normal or enhanced (Catalano et al 1995). In vitro, estradiol increases adipocyte insulin binding (Pyan et al 1988) and this coupled with morning sickness account for a decrease in insulin needs sometimes seen at this stage of pregnancy. In later pregnancy, there is growth of the fetoplacental unit which elaborates estrogen, progesterone, prolactin, cortisol and human placental lactogen which cause insulin resistance as seen in later pregnancy (Buchanan 1990; Catalano et al 1991, Ryan et al 1985). This insulin resistance is maximum in the third trimester and all these hormones except estradiol cause insulin resistance when given in vivo or In vitro HPL is likely the most responsible hormone for the insulin resistance.
This physiologic insulin resistance requires an increase of maternal insulin to maintain glucose homeostasis. In normal pregnancy, the fasting glucose is lower than in the non-pregnant state as a consequence of increase fetal utilization and postprandially normal glucose is maintained at the cost of maternal hyperinsulinaemia. In the last few weeks of pregnancy the diabetogenic hormones tend to plateau and coupled with insulin resistance there is an increase in free fatty acids (Frienkel N, 1980) which may aggravate the insulin resistance further. So in the fed state, the level of insulin as well as glucose following oral glucose load during the third trimester of pregnancy are higher and more prolonged than during the immediate postnatal period. The level of glycogen is suppressed facilitating anabolism.
In the fasted state, due to the diabetogenic placental hormones and constant removal of glucose and amino acids by the fetus there is “accelerated” starvation in the mother (rapid diversion to fat metabolism to save glucose and amino acids for the fetus). It is found that after an overnight starvation of 12 hours, the fasting level of glucose is significantly lowered as compared to non-pregnant state, but there is no alteration in the level of free fatty acids and beta hydroxy-butyric acid. If the fast is extended for a further four hours, glucose level is further lowered in the pregnant women and level of free fatty acids beta hydroxy-butyric acid start rising as well. After 18 hours of starvation a pregnant woman develops a full blown picture of “accelerated starvation: while a non-pregnant woman shows no such change.
So there is “facilitated anabolism” in the fed state and “accelerated starvation” in the fasted state which characterise the maternal fuel adaptive changes during pregnancy.
Fuel Metabolism in Diabetic Pregnancy and Gestational Diabetes
The physiological changes occurring during normal pregnancy reach pathological proportion in the diabetic pregnant and gestational diabetic. The implications of various metabolism changes that occur during pregnancy consist of changes in the placenta and the fetus.
Placental changes in gestational diabetic are identical to those in established overt diabetes. During pregnancy there is blunting of the action of insulin which results in a rise in blood sugar level. This crosses the placenta and stimulates the fetal pancreatic beta cells to produce insulin. The fetal hyperinsulinism is thought to be responsible for the fetal macrosomia in diabetics and gestational diabetics. Maternal insulin does not cross the placenta.
The fetal pancreas develop beta cells by the eleventh gestational week but responds to glucose stimulus only from the 32nd week onwards. So, macrosomia can be prevented if tight glycaemic control can be obtained from the 32nd week. The observation of large sized babies in few euglycaemics has also been seen and this could be due to implications of other metabolic fuels (e.g., amino acids) rather than glucose. Thus, these days we talk of fuel mediated anthropometric changes rather than glucose mediated effects.
The fuel mediated teratogenic effect is dependent on the time of gestation at which the fuel mediated insult occurs. If hyperglycaemia occurs during the period of organogenesis (first trimester), the incidence of congenital malformation is increased. To prevent this we should have prepregnancy counselling and management. Hyperglycaemia commencing during the second trimester causes anthropometric changes in the fetus.
RENAL GLYCOSURIA IN PREGNANCY
The presence of glucose in the urine when blood glucose level is within normal limits is called renal glycosuria and is thought to be due to low renal threshold for elimination of glucose by the kidneys. It occurs frequently in the second and third trimester and the mechanism is uncertain. It is postulated that it could be due to defective tubular reabsorption or due to increased glomerular filtration. Infact, the average renal threshold for glucose is 155+17 mg/dl during pregnancy compared with 197+6.5 mg/dl in the non-pregnant patient. These women with renal glycosuria during pregnancy are at high risk for preterm delivery and for fetal macrosomia (Chen et al 1980).
Glycosuria occurs in 11 to 15 per cent of all pregnant women (Sutherland et al 1970). Most glyosuria in pregnancy is benign, but not so in all cases. The specificity of glycosuria can be increased by defining “significant glycosuria” as that which occurs in the second fasting urine specimen. The patient is instructed to void on waking up. Half an hour later, while still fasting, she voids again and this specimen is tested for glucose. In normal pregnancy the fasting blood glucose is low, so glycosuria at that time cannot be due to low renal threshold and is thus significant.
Management of renal glycosuria consists of frequent urine testing to detect asymptomatic bacteriuria, patient should be instructed to have several small meals in a day and stay alert for early signs and symptoms of preterm labour. Some patients may lose as much as 100 gm glucose in a day in their urine and such large losses leave less glucose for their caloric needs; their lipolysis is activated causing production of ketones and a tendency to ketoacidosis.
CLASSIFICATION OF DIABETES IN PREGNANCY
Pregnant diabetics are now divided into two main categories:
- When the disease exists prior to pregnancy. Pregestational diabetes PGDM.
- When disease is diagnosed during pregnancy for the first time or develops during pregnancy and resolves after delivery : Gestational diabetes mellitus (GDM).
According to the National Diabetes Data Group (NDDG) women with PGDM account for 4 to 15/1000 pregnancies and women with GDM account for 25 to 50/1000 pregnancies diabetes is now classified as follows:
- Insulin dependent—type 1
- Non-insulin dependent—type 2
- Secondary diabetes
- Impaired glucose tolerance
- Gestational Diabetes
- Diet control
- Insulin required.
Ever since White pointed out the age of onset, its duration and the severity of vascular disease influence perinatal outcome her classification has assumed tremendous importance and wide application, but this classification has its drawbacks. Classes A to T are no more used in the management as they do not consider several factors like age of the patient, parity and previous obstetric history, etc. However, it is understood that in PGDM patient, fetal mortality and morbidity are increased in classes, D, F and RF due to vasculopathy. Pregnancy threatens maternal survival in class H with clinically evident arteriosclerotic heart disease. So in 1994, a modified system of classification was recommended by the American College of Obstetricians and Gynaecologist which is given in Table 1.1.
Gestational Diabetes Mellitus (GDM)
Diabetes mellitus complicates 2 to 3 per cent of all pregnancies and 90 per cent of these women have gestational diabetes mellitus.
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy (Metzger et al 1998). The definition applies whether insulin or only diet modification is used for treatment and whether or not the condition persists after pregnancy. It does not exclude the possibility that unrecognised glucose intolerance may have antedated or begun concomitantly with the pregnancy.
Detection and Diagnosis
A four-fold increase in perinatal mortality was seen in untreated GDM and a control group with normal oral glucose tolerance test (6.4% versus 1.5% Olofsson et al 1984). Identification of women with GDM through the use of a universal screening approach is recommended as GDM is associated with significantly elevated perinatal mortality.
Risk factors A few risk factors (both from history and clinical examination) such as listed below were needed to screen pregnant patients for GDM. These are as follows:
- Obesity (> 200 lbs or >15% of non-pregnant ideal body weight)
- Previous stillbirth, unexplained neonatal death birth of a large for gestational age (LGA) infant
- History of prematurity, polyhydramnios, pre-eclampsia in multipara or more than 3 spontaneous abortions in first or second trimester
- History of previous malformed baby
- Family history of diabetes (sibling or parent)
- Patient’s age more than 35 years.
- History of recurrent UTI, moniliasis.
But evidence from various studies shows that if only these women were screened then as many as 50 per cent of the women with GDM would be missed. (O’ Sullivan et al 1973). According to various studies done by O’ Sullivan et al 1973, Coustan et al, 1989 and others it was found that historic and clinical risk factors have a low sensitivity of only 63 per cent and specificity of only 56 per cent. They are therefore insufficient and should no more be used for diagnosis of GDM.
Oral glucose tolerance test for screening GDM Although the oral glucose tolerance test (OGTT) has been the accepted standard for diagnosis of GDM, variations in the methology and interpretation are a source of misunderstanding among clinicians. In North America a 100 gm oral glucose load is used, European centres follow the WHO recommendations of 75 gm glucose load whereas in Australia a 50 gm glucose load is used.
- One hour 50 gm glucose load challenge test (O’ Sulllivan 1973): The best screening test for GDM is the measurement of plasma glucose 1 hour after ingesting 50 gm glucose. It is not necessary to follow a special diet before the test. If the plasma glucose 1 hour after the load is greater than 140 mg/dl (135 mg/dl if patient has been fasting overnight), the patient may have GDM and requires a formal 100 gm GTT.If the plasma glucose is less than 140 mg/dl, the patient is not at risk, but if the patient has risk factors repeat the test between 26 and 30 weeks. The best time to screen patients is between 24-30 weeks, but those with high risk factors the test is done earlier, i.e. 18 to 22 weeks.Patients whose 1 hour screening test produced plasma glucose values more than 200 mg/dl should have a fasting glucose measurement. Any patient whose fasting glucose is 126 mg/dl or greater is diabetic and does not need a 3-hour GTT.
- 3-hour 100 gm glucose load challenge test: To prepare the patient for this test, she is advised to consume daily diets containing approximately 200 gm of carbohydrate for at least 3 days prior to the test and this will minimise false-positive results.The National Diabetes Data Group (NDDG) changed the criteria of O’Sullivan and Mahan in 1979. Presently these criteria have been recommended by the American College of Obstetricians and Gynaecologists and the American Diabetes Association. They have used plasma glucose values and glucose oxidase method for measuring glucose concentration, instead of whole blood by the Somogyi Nelson method of O’Sullivan and Mahan, Carpenter and Coustan also have modified O’Sullivan’s criteria.According to O’Sullivan, NDDG and Carpenter any two values should be greater than these or must meet the range as shown in Table 1.2. According, to WHO, either fasting or 2 hr values must be met, for diagnosis of GDM.
Table 1.2 Oral glucose tolerance test criteriaO’Sullivan and MahanCurrent recommendationsWHO criteriaOriginal dataNDDG adaptationsmg/dlmMmg/dlmMDM (mM)IGT(mM)F905.001055.83≥ 7.8< 7.8601659.1719010.56901437.941659.171201277.061458.06> 11.1> 7.8 & < 11.1Because the identification of all women at risk for adverse fetal outcome is critical, studies show that patients although not meeting the criteria of two abnormal values during an OGTT, appear to have an impaired glucose tolerance by virtue of either high values or presence of one abnormal value during the OGTT.There is also significance of one abnormal OGGT value. Langer et al in 1989 conducted a study of 126 women with one abnormal OGTT value and 146 women in the control group with normal OGTT during the third trimester of pregnancy. The subjects with one abnormal OGTT were randomised into treated (group I-treated by diet and insulin) and untreated (group II).The study showed that the level of glycaemic control before initiation of treatment was similar in both the groups but overall incidences of neonatal complications was 4 per cent in treated and 14 per cent in untreated, with macrosomia present in 7 per cent of treated and 24 per cent in untreated cases. This study shows that women with one abnormal OGTT were similar to women with two abnormal GTTs as regards their glycaemic control prior to therapy and rate of macrosomia (30%). Treatment of such cases will yield better perinatal outcome and it has been shown by prospective studies that a flat OGTT curve is associated with small for gestational age fetuses (SGA).
- Random plasma glucose sampling (RPG): This is an attractive screening method as it is simple, reliable and effective. Levin et al found an incidence of 1.5 per cent of GDM in patients with risk factors, Hatem et al also found a similar incidence of 1.5 per cent by RPG. Mataliya et al found GDM in approximately 1.6 per cent of cases attending OPD.From the various studies we recommended that RPG estimation must be carried out on all patients attending antenatal clinic at their first visit and when RPG level are above 100 mg per cent OGTT should be carried out for early detection of glucose intolerance and GDM cases.
- Glycosylated Blood Proteins: Glycosylated haemoglobin and other proteins have been proposed as screening and diagnostic test for GDM. Higher levels of glycohaemoglobin are found in cases of impaired glucose tolerance and diabetic patients compared to normal (Hall et al 1984). But many studies show that the specificity and sensitivity of this test for screening of GDM is very low. This is not an effective screening tool in pregnancy because glucose intolerance may not have manifested for brief periods before test, in pregnancy there is increased erythropoeisis so decreased glycosylation and lastly fasting blood glucose levels may be normal in GDM and so average daily blood sugar levels may be normal despite significant postprandial elevations.
- Fructosamine assay: Fructosamine is associated with glycaemic control over the previous 1 to 3 weeks possibly making it a more appropriate marker for GDM. Several workers (Roberts et al, Comtois et al) have shown an association between fructosamine assay, haemoglobin AIC, antecedent maternal glycaemia and fetal macrosomia. However its sensitivity is too low for it to be used as a screening test for GDM. Hoffman suggested that it could be used to detect fetal hyperinsulinaemia in women with GDM and so would avoid amniocentesis. Maternal fructosamine more 2.6 MM usually indicates fetal hyperinsulinaemia (Frienkel et al 1980).
Current recommendations for screening for GDM It is recommended that all pregnant patients irrespective of clinical or risk factors and age should be screened at 24 to 28 gestational weeks by a 50 gm glucose 1 hr post-glucose challenge test or using RPG estimation. If the results of screening are within normal range, then the test is repeated at 32 to 34 weeks especially in patients more than 30 years, obese, have risk factors of GDM. If the results of screening are positive then a 3-hour 100 gm OGTT should be carried out at both 24 to 28 weeks for early detection of GDM and if normal repeated at 32 to 34 weeks.
If women have a positive risk criteria like a previous GDM, previous macrosomia or a malformed baby and are obese, they should be screened at the first antenatal visit and if OGTT is negative then repeat it at 24 to 28 weeks of gestation.
- A fasting blood sugar ≥ 126 mg/dl and a random blood sugar ≥ 200 mg/dl (≥ 11.1 n Mol) implies that patient is diabetic.
- As and when clinical evaluation suggests diabetes a 50 gm 1 hr GTT in dose if 1 hr blood sugar is more than 140 mg/dl (7.8 mm/dl) a formal 100 gm OTT is done and interpreted as of today by the NDDG recommendation.
Pathogenesis of GDM
Pregnancy is associated with insulin resistance that necessitates an increase in insulin production to maintain euglycaemia and this insulin resistance has been shown by various studies (Buchaman et al 1990, Catalano et al 1991, Dam et al 1992, Chew et al 1995). Some studies suggests that there is an exaggeration of the pregnancy-induced insulin resistance in GDM, but it appears that the major determinant of whether a woman develops diabetes is likely on her insulin reserve. This reserve is blunted in women with GDM (Kautzky et al 1997), in severe GDM an element of glucose toxicity likely supervenes which may blunt insulin sensitivity further (Sivan et al 1995).
Elevated free fatty acids also found in GDM (Metzger 1980) may be a further cause of insulin resistance or may be a manifestation of the disease process itself. The similarities of GDM to type II DM are insulin resistance and impaired insulin secretion and the persistence of these same abnormalities postpartum contribute to an increase risk of type II DM in the long-term. So, GDM may also be considered as a prodromal form of type II DM being unmasked by pregnancy.
Fetal Complications of GDM
Because GDM is related to insulin resistance induced by placental hormones that rise late in pregnancy, GDM itself is typically found in the late second or early third trimester. It is highly usual for carbohydrate tolerance to be a problem early in pregnancy and so congenital malformations are not a typical feature of GDM (Soler et al 1976, Mills et al 1982). Reports of congenital malformation of GDM are most likely related to the co-existence of type II DM that has been picked up only in pregnancy (Becerra et al 1990, Bower et al 1992).
The significant complications that are associated with GDM are macrosomia and neonatal hypoglycaemia. Hyperbilirubinaemia remains more common but is rarely a major problem. Other major neonatal complications associated with GDM such as respiratory distress syndrome are sufficiently rare so as not to be a concern for most women (Hod et al 1991).
The major determinants of macrosomia are maternal weight, maternal weight gain, parity, gestational age and maternal glucose levels (Spellay 1985, Breschi et al 1993). The only one, of these, that can be altered in pregnant women seen during the second or early third trimester is maternal glucose levels. Thus, although hyperglycaemia may not be the single major determinant of macrosomia it is the one treatable determinant. Macrosomia occurs in 20 per cent of untreated GDM, adiposity is mainly truncal and this leads to increased risks of shoulder dystocia and Erb’s palsy and other fetal trauma plus an increased incidence of postpartum haemorrhage.
Neonatal hypoglycaemia is related to fetal pancreatic hyperplasia found in the setting of increase maternal substrate delivery as proposed by Pederson et al 1954. Although normal glucose levels in the neonate may be as low as 30 mg/dl, 5 to 24 per cent of infants born to GDM mothers glucose drops below these levels and there is concern regarding the long-term neurologic consequences of hypoglycaemia exposure, but a prospective study does not seem to bear this out (Hellmuth et al 1994). Intensive treatment of GDM decreases these complications and reduces the time that the infant spends in the intensive care.
Some have suggested that GDM complications are related to maternal obesity rather than glucose intolerance. Although, there is clearly an overlap and obesity itself is a risk factor of GDM, the improved outcome from the treating the hyperglycaemia in GDM is evidence of its importance (Langer et al 1994). It is clear that GDM exists and that is associated with fetal complications which are decreased with therapy. What remains as a legitimate question is whether the universal screening and detection of 2 per cent to 4 per cent of women with GDM and the associated costs of treating such women to prevent macrosomia and fetal hypoglycaemia cost-effective. An analysis by Kitzmiller in 1997 confirmed that it is cost-effective. Furthermore, even treating women with one abnormal test on OGTT has been demonstrated to lessen macrosomia, neonatal intensive care unit admissions and length of maternal and neonatal hospital stay and to be cost-effective (Jovanoic-Peterson et al 1997, Langer et al 1987).
Management of GDM
Women with GDM are divided into two functional classes A1 and A2 depending on their level of fasting glycaemia (Table 1.3).
Patients with GDM are first started on a diet and only when glycaemic control with diet is not satisfactory, insulin is recommended.
Diet The goals of diet therapy are to provide the necessary nutrients for the mother and the fetus while achieving normal glucose levels and at the same time to prevent starvation and ketosis. Women with GDM generally do not require hospitalisation for dietary instructions and management. Strict caloric restriction 1200 to 1800 kcal/day has been studied in obese pregnant women with GDM but has not been found to be safe and is not recommended (Domhorst et al 1991).
Individualisation of medical nutrition therapy depending on maternal weight and height is recommended by the American Diabetes Association. Simple advice regarding spreading out the calories to divide the total intake among three meals and three snacks, limit simple carbohydrates and avoid high fat food. The extracalories needed for pregnant are about 200 kcal per day.
Continued monitoring of glucose levels is required to determine whether glucose levels are well-controlled by diet. Fasting, postprandial 1 and 2 hr glucose levels are measured weekly and then biweekly.
For obese women (BMI >30 kg/m2); a 30 to 33 per cent calorie restriction has been shown to reduce hyperglycaemia and plasma triglycerides with no increase in ketonuria (Franz et al 1994). Restriction of carbohydrates to 35 to 40 per cent of calories has been shown to decrease maternal glucose levels and improve maternal and fetal outcome (Major et al 1998).
Exercise Women with GDM should be encouraged to have an active lifestyle which should include some exercise. Walking briskly for 35 to 40 min/day will improve glycaemic control.
Insulin It is the pharmacologic therapy that has most consistently been shown to reduce fetal morbidities when added to medical nutrition therapy. Selection of pregnancies for insulin therapy can be based on measures of maternal glycaemia with or without assessment of fetal growth characteristics. When maternal glucose levels are used, insulin therapy is recommended when medical nutrition therapy fails to maintain self-monitored glucose at the following levels:
- Fasting whole blood glucose > 95 mg/dl (5.3 mmol/L).Fasting plasma glucose > 105 mg/dl (5.8 mmol/L)
- 1 hr postprandial whole blood glucose > 140 mg/dl (7.8 mmol/L)1 hr postprandial plasma glucose > 155 mg/dl (8.6 mmol/L)
- 2 hr postprandial whole blood glucose > 120 mg/dl (6.7 mmol/L)2 hr postprandial plasma glucose > 130 mg/dl (7.2 mmol/L)
The GDM women requires hospitalisation to safely titrate the dosage and to educate her on self-administration of insulin and monitoring of blood glucose levels. A combination of a short- and long-acting insulin given once daily before breakfast is commonly used to initiate therapy. Plasma glucose levels are monitored to maintain a fasting level of 95 mg/dl (5.3 mmol/L) or below, a 1 hr postprandial and a 2 hr postprandial level of 120 mg/dl or less (6.7 mmol/L).
Human insulin should be used when insulin is prescribed and daily self-monitoring of blood glucose appears to be superior to intermittent office monitoring of plasma glucose limited evidence also indicates that postprandial monitoring is superior to preprandial monitoring. However, the success of either approach depends on the glycaemic targets that are set and achieved urine glucose monitoring is not useful in GDM. Urine ketone monitoring may be useful in detecting sufficient caloric or carbohydrate intake in women treated with caloric restriction.
Oral glucose lowering agents have generally not been recommended during pregnancy. However, one randomised double blind study compared the use of insulin and glyburide in women with GDM and the results showed similar perinatal outcome (Langer et al 2000). All patients were beyond the first trimester of pregnancy. Glyburide is not FDA approved for treatment of GDM and further studies are needed to establish its safety.
Many studies have shown that oral hypoglycaemic agents may induces severe, prolonged fetal hyperinsulinaemia and neonatal hypoglycaemia. Also, they may aggravate neonatal hyperbilirubinaemia by competing for albumin-binding sites.
Monitoring of fetal well-being Well-controlled GDM has a very low-risk of fetal death. Only those requiring insulin will need to be monitored in the same manner as pregnant women with pre-gestational diabetes. In women with well-controlled non-insulin dependent GDM, no special monitoring is required till 38 week gestation. The three categories of patients who require monitoring for fetal well-being are:
- Those who require insulin.
- Those with hypertension, and
- Those with history of previous stillbirth.
In most cases, women with GDM may be managed expectantly unless fasting and postprandial glucose levels are high.
Obstetrical Management In general, women with GDM, who are not insulin dependant seldom require early delivery or intervention (ACOG, 1994). Antepartum fetal testing is not essential since the risk of fetal death is low.
Women who require insulin therapy do require antenatal fetal testing and are managed in the same way as women with pre-gestational diabetes. Early delivery by induction is followed in these cases. The timing and the route of delivery depends on the fetal condition. Macrosomia is not very common in well-controlled GDM. But according to the American Diabetes Association, prolongation of gestation past 38 weeks increases the risk of fetal macrosomia without reducing caesarean rates, so that delivery during the 38th week is recommended unless obstetric considerations dictate otherwise (Diabetes Care Vol 25, 2002). In presence of a clinically and sonographically diagnosed fetal macrosomia, a caesarean section may be electively recommended to avoid fetal and maternal trauma.
Follow-up testing Because women with GDM have a 50 per cent chance of developing overt diabetes within 20 years of delivery. Reclassification of the maternal glycaemia status should be done according to the following table and guidelines of the “Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus” (Table 1.4).
In clinical settings, the fasting plasma glucose test is greatly preferred because of ease of administration, convenience, acceptability to patients and lower cost. Fasting is defined as no calorie intake for at least 8 hours.
If the glucose levels are normal postpartum, reassessment of glycaemia should be undertaken at a minimum of 3 years intervals.
Women with impaired fasting glucose or impaired glucose tolerance should be tested for diabetes annually. These patients should receive medical nutrition therapy and placed on a individualised exercise programme because of their very high-risk for development of diabetes mellitus.
All patients with prior GDM should be educated regarding lifestyle modifications that lessen insulin resistance, including maintenance of normal body weight, of medical nutrition therapy and physical activity. Medications that worsen insulin resistance, i.e. glucocorticoids, nicotinic acid should be avoided. Patients should be advised to seek medical attention if they develop symptoms suggestive of hyperglycaemia. Recurrence of GDM in subsequent pregnancies has been documental in two-thirds of patients with GDM.
Breast-feeding, as always, should be encouraged in women with GDM.
Contraception Education to patients of GDM must always include need for family planning to assure optimal glycaemic regulation from the start of any subsequent pregnancy.
Low-dose estrogen-progestogen oral contraceptives may safely be used in women who had GDM but do not have any other risk factor. The rate of subsequent diabetes is not increased by the use of oral contraceptives (Kjos et al 1990).
About 1 to 3 per 1000 women of reproductive age have diabetes but 15 per 1000 show evidence of chemical diabetes in pregnancy.
Pedersons’ hypothesis has shown that fetal hyperglycaemia and hyperinsulinaemia secondary to maternal hyperglycaemia can lead to fetal macrosomia and fetal death as well as a delayed pulmonary maturation. Therefore it is essential that a diabetic woman should be encouraged to achieve and maintain euglycaemia throughout pregnancy.
Effect of Hyperglycaemia on Pregnancy
A diabetic pregnancy is more prone to certain complications. Cousin in 1987 showed in his study that incidence of pre-eclampsia, infection, postpartum bleeding and caesarean sections is greater than in normal pregnancy.
Spontaneous abortions The incidence of spontaneous abortion in well-controlled diabetic pregnancy is not higher than in non-diabetic pregnancy; but when glucose levels are high, the abortion rate increases and is probably due to increased incidence of fetal malformations. Insulin-dependant women with initial Hb AIC above 12 per cent or persistent plasma glucose level more than 120 mg/dl have increased risk of abortion (Rosson et al 1994).
Polyhydramnios The amount of liquor ammii is more in diabetic pregnancy specially before 36 weeks of gestation (as seen in about 20% of cases). There is no satisfactory explanation for this, but, it may contain more glucose depending on maternal hyperglycaemia. It is usually associated with a large placenta and macrosomia. One of the theories state that it is due to fetal polyuria due to fetal hyperglycaemia.
Pre-eclamptic toxaemia and hypertension Ten to twenty per cent of pregnant diabetic women have toxaemia or hypertension as compared to fit 5 per cent in non-diabetic women. This contributes to increased perinatal morbidity and mortality, more so as preterm delivery may be required in a number of cases. Diabetic nephropathy may be responsible for hypertension and toxaemia in some of them, but since the presenting signs and symptoms are same, it is difficult to distinguish the cases. The perinatal mortality rate has been reported to be 20 times higher for pre-eclamptic diabetic women compared to those who are normotensive (Garner et al 1995).
Infections Urinary tract infections and monilial vulvo-vaginitis are more likely to occur in diabetic pregnancy. It is advisable to screen such women for asymptomatic bacteriuria and treat them early. Similarly, early diagnosis of monilial vaginitis, enthusiastic treatment and good diabetic control are essential to prevent recurrences of vaginal candidiasis.
There is also high incidence of chorioamnionitis and endometritis in poorly glycaemia controlled diabetic patients.
Postpartum bleeding It may be due to overdistended uterus due to associated polyhydramnios or macrosomic baby. It may also be due to infection and associated pregnancy-induced hypertension or due to increased operative delivery.
Caesarean section Elective caesarean section rate is higher in diabetes pregnants due to increased perinatal loss after 38 weeks of gestation.
Ketoacidosis Though ketoacidosis affects only 1 per cent of diabetic pregnancies, it is one of the most serious complications. The fetal loss can be as high as 20 per cent with ketoacidosis.
Effect of hyperglycaemia on the fetus It is now accepted that the perinatal mortality is inversely correlated with the mean maternal blood glucose level during the third trimester (Karlsson and Kjellmer 1972). The common causes of fetal wastage are congenital malformation, respiratory distress syndrome, prematurity, macrosomia, birth trauma, hypoglycaemia and others.
Congenital malformations The rate of occurrence of congenital malformations is nearly double in a diabetic pregnancy (incidence of major malformations being as high as 5 to 10 per cent in insulin dependent diabetes). The exact cause of fetal anomalies in the diabetic mother is not known. It may be due to hyperglycaemia, ketosis, fetal hyperinsulinaemia or the presence of glycosylated haemoglobin and thus decreased oxygenation of blastocyst (only shown by animal experiments). Uncontrolled diabetes has shown to influence both the preimplantation and implantation stages (Rossen et al 1994). This results in abnormal cell division thus emphasising the optimum blood glucose levels with insulin during organogenesis. The common malformations are skeletal like caudal agenesis or dysgenesis, cardiovascular and cerebral defects.
Respiratory distress syndrome (RDS) It has long been believed that the neonate of the diabetic had delayed lung maturity and therefore was at an increased risk of respiratory distress syndrome (Pederson 1977). No convincing explanation is available for this and several recent studies have challenged the concept of diabetes-altered fetal lung function. The primary reason for RDS may be partly due to prematurity as there is early induction of labour for uncontrolled diabetes, hypertension, retinopathy, etc. (Berkowitz et al 1996).
Fetal deaths Unexplained intrauterine fetal demise is a phenomenon unique to pregnancies complicated with pre-gestational diabetes. No obvious factors such as placental insufficiency, abruption, fetal growth restriction or oligohydramnios are present. These infants are typically large for age and die before labour, usually at about 35th week or later (Garner et al 1995). Hyperglycaemia-mediated abnormalities in the transport of oxygen and fetal metabolites may account for these unexplained fetal death. This hypothesis has been proven with fetal blood sampling which has shown decreased fetal pH and increased fetal pCO2 in diabetic pregnancies.
Macrosomia and birth trauma Excessive growth may predispose the fetus of the diabetic mother to shoulder dystocia, traumatic birth injury and asphyxia. Newborn adiposity also may be associated with significant risk of obesity in later life (Pettit et al 1983). For these reasons, the pathogenesis, diagnosis and prevention of macrosomia in the IDM have become areas of great importance in perinatal medicine.
Some have defined macrosomia as a birth weight in excess of 4000 to 5000 gm but others prefer categorising infants as large for gestational age (a birth weight above 90th percentile using population specific growth curves). According to these definitions, macrosomia has been observed in as many as 50 per cent of pregnancies complicated with GDM (Langer et al 1987, Sepe et al 1985) and 40 per cent of IDDM pregnancies. Delivery of an infant weighing greater than 4500 gm occurs 10 times more often in diabetic than non-diabetic population (Spellacy et al 1985).
Fetal macrosomia in IDM is reflected by increased adiposity, muscle mass and organomegaly. The disproportionate increase in the size of the trunk and shoulders compared with the head may contribute to the likelihood of the difficult vaginal delivery (Modanlau et al 1982). An increase in total body fat in the IDM has been supported by direct measurements as well as assessment of subcutaneous stores using skin fold thickness measurements (Enzi et al 1985). The amount of subcutaneous fat present in the IDM may be an indication of the quality of diabetic control achieved during gestation (Whitelaw et al 1977).
Enzi reported that maternal blood glucose level, as well as neonatal immunoreactive insulin levels measured in cord blood were significantly correlated with fat cell weight.
The concept that maternal hyperglycaemia, leading to fetal hyperglycaemia and hyperinsulinaemia, results in excessive fetal growth and adipose deposition first was advanced by the Danish internist Pederson. Several autopsy studies have confirmed the existence of pancreatic cell and hyperplasia in the IDM (Driscoll et al 1960, Naye et al 1965). Increased beta cell max may be identified as early as second trimester (Reiher et al 1983). Evidence supporting the Pederson hypothesis has also come from studies of amniotic fluid and cord blood which show an increased level of insulin and C-peptide in insulin treated diabetic women at term. Elevated amniotic fluid insulin levels are observed in large for gestational age infants of IDDM mothers as well as those with GDM (Falluca et al 1985).
Persson and colleagues have confirmed a positive relationship between maternal blood glucose and amniotic fluid C-peptide in pregnancies complicated by IDDM and GDM. Cord blood levels of C-peptide are also increased in IDM. In addition to glucose other substrates can also modify the fetal insulin secretory response especially amino acids are important regulators of fetal insulin secretion (Milner et al 1984).
Hyberbilirubinaemia Jaundice occurs in 20 per cent of the infants, that is, four time more frequently than in controls. Prematurity and polycythaemia with haemolysis have been implicated in the pathogenesis of hyperbilirubinaemia in infants born to diabetic mothers.
Hypoglycaemia If maternal diabetes is not controlled, the fetus is exposed to hypoglycaemia which stimulates the fetal beta cells of the pancreas causing hyperinsulinaemia. This leads to excessive glycogen and fat deposition. After delivery the excess insulin in fetal blood continues and favour glycogen storage while inhibiting gluconeogenesis and lipolyses. Hypoglycaemia in the fetus is defined as a blood-glucose level of less than 1.7 mmol/L or 30 mg per cent. The symptoms include hypotonia, hypothermia, apnoea, convulsions, etc. The treatment is infusion of 5 per cent glucose intravenously at the rate of 0.24/kg/hour.
Hypocalcaemia Serum levels of calcium of 1.65 mmol/L or less are found in 50 per cent of the infants. Clinical manifestations include apnoea, neuromuscular irritability and convulsions.
Predisposition to diabetes Children born to diabetic mothers have a 1 to 3 per cent risk of developing insulin dependent diabetes. If only the father is affected the risk for the offspring is 6 per cent. The risk of developing type 1 diabetes is as high as 20 per cent if both parents are affected.
Effect of Pregnancy on Diabetes
Pregnancy causes a diabetogenic influence on the normal and existing carbohydrate metabolism. These patients have a tendency towards metabolic instability and will need frequent monitoring, strict therapy and a highly regulated lifestyle. The effects are as follows:
- More insulin is necessary to achieve metabolic control.
- Progression of diabetic retinopathy.
- Worsening diabetic nephropathy.
- Increased risk of death for patients with diabetic cardiomyopathy.
PROGNOSIS AND PREVENTION IN DIABETES COMPLICATING PREGNANCY
- Maternal mortality: Even after allowing for higher incidence of operative delivery, the risks to a diabetic mother are probably marginally higher than a non-diabetic. Of course morbidity is increased due to sepsis specially in an inadequately controlled diabetic mother.
- Perinatal mortality: The perinatal mortality in diabetes complicating pregnancy varies from 5 to 8 per cent (Gun et al 1978, Molsted-Pederson 1980). Karlsson and Kjellmer 1972 found that perinatal mortality rate is inversely related to the mean maternal blood glucose level during the third trimester. When the level was over 150 mg/dl, 24 per cent babies were lost, but PNM was 12 per cent when glucose levels were between 100 to 150 mg/dl and only 3.8 per cent when it was below 100 mg/dl. Most centres where a maximum tolerated dose of insulin was given as recommended by Roversi et al 1977 the perinatal loss was less than 3 per cent. As diabetic pregnant women are considered high-risk a continuous supervision should be done throughout the prenatal period.
The aims in management are as follows:
- Normalisation of maternal glucose levels.
- Prevention of obstetric complications by good perinatal care.
- Early detection and prompt treatment of medical problems.
- Careful timing and appropriate mode of delivery.
- Intensive neonatal care.
For all types of diabetes in pregnancy, current approaches call for managing glucose levels to achieve and maintain near normal glucose levels throughout pregnancy, diet and administration of short and intermediate acting insulin when required.
Recommended Plasma Glucose Levels
In normal pregnancies, the maternal plasma glucose levels rarely exceeds an average of 100 mg/dl. The fasting is usually between 60 to 90 mg/dl with a 1 hour postprandial of 140 mg/dl and 2 hours postprandial of 120 mg/dl (ACOG 1994). A pregestational diabetic should aim to maintain plasma glucose levels in the same range to achieve a favourable outcome.
Blood Glucose Monitoring
The standard care for pregnant women with diabetes is daily self-monitoring of blood glucose levels at various intervals throughout the day to achieve a tight glycaemic control and which decreases the probability of serious complications like ketoacidosis, etc. In most of the advanced countries, self-monitoring of glucose in blood and urine by patient is encouraged. This is possible now with the availability of the Dextrostix/Eyetone system with a glucometer. These methods are generally accurate to 10 per cent. It should be remembered that these monitor the whole blood glucose and these levels must be increased by 14 per cent to compare with plasma or serum values. In our country this self-monitoring may not be feasible mainly due to illiterate and poor population. For them the best is to get a fasting, 1 hour and 2 hours postprandial glucose levels done weekly.
Self-monitoring of blood glucose may be expensive but it increases the motivation, decreases the time spent in the hospital and improves glycaemic control. Self-monitoring of blood glucose presents a dilemma in actual compliance and reliability of reporting. Therefore, currently patients are asked to use memory reflectance meters, which allows collection of significant amount of glucose data (with a storing of 2 weeks to 3 months). The data can be rapidly analysed by a computer to measure control by hour, day, week and a month.
Dietary therapy for a pregnant diabetic patient includes nutrient meals and meal planning and control of maternal weight gain (current recommendations call for a 10 to 12 kg weight gain or 350 to 400 gm per week).
To plan, a diet first it is important to know the woman’s ideal weight in kilogram according to her height. The number of calories required to maintain 1 kg of body weight (usually 35 calories) is multiplied by ideal body weight in kilograms to obtain the total calories that the patient should consume during a 24-hour period. Some clinicians add 300 calories to cover the additional needs for pregnancy. This is not absolutely necessary and it should be limited to the third trimester when the caloric needs are increased.
The daily caloric requirement should be distributed among different food groups in such a way that 40 to 50 per cent come from complex carbohydrates, 20 to 30 per cent come from high quality proteins and 25 to 40 per cent from fat. Large amounts of concentrated and refined sugars should be avoided. The goal of meal planning is to individualise the meal to the patients eating habits, thus maximizing compliance and limiting the extent of hyperglycaemia.
Because pregnancy is characterised by accelerated starvation, multiple meals are recommended like three meals and two snacks with a preferable break-up: breakfast 25 per cent, lunch 30 per cent and dinner 35 per cent. The last snack at bedtime minimises overnight hypoglycaemia and starvation ketosis.
Some patients specially obese diabetics may find that the amount of food provided by their new diet exceeds what they were ingesting before its institution. In these cases, the calorie intake can be reduced to between 25 and 30 kcal/kg if ideal weight with daily checks for acetone in the urine. If she starts to show marked acetonuria, then she must increase her caloric intake. If the ketonuria disappears only when the caloric intake is increased to a point that precipitates postprandial hyperglycaemia, the patient will need insulin therapy.
There is controversy about how much weight should be gained during a diabetic pregnancy. The classic teaching was that patient should gain approximately 25 lb and should not persistently spill large amounts of acetone in urine. But recent information, shows (Coetz et al 1980, Maresh et al 1985) that obese diabetic women may not gain weight or may even lose weight without adverse consequences. Continuous weight gain in these patients mean that they are eating more that their allowance or retaining large amounts of water. Also, elimination of small to moderate amount of acetone in the urine is not necessarily a bad prognostic sign. Usually, it suggests that they are using their own fat rather than dietary carbohydrates for their caloric needs. Dietary intervention is more effective in preventing fetal macrosomia if the mother is maintained just above the ketonuric threshold (Javanoic-Peterson et al 1990).
The latest weight gain guidelines as suggested by Kitzmiller et al 1998 are given in Table 1.5.
First 135 cm 45 kg plus 900 gm for early centimetre height above 135 cm. Small frame women may have a 10 per cent lower and large frame women a 10 per cent higher values.
Insulin therapy may be required if glycaemic control is not achieved with diet only in gestational diabetes, history of insulin dependent diabetes antepartum and to all patients who show fasting and postprandial hyperglycaemia in pregnancy.
Observations from several trials and workshops propose the following blood glucose values that justify the need for insulin therapy to commence (Javanic L 1998). The two important clinical convention for insulin therapy in pregnancy are as follows:
- Use of appropriate dose and frequency to achieve euglycaemia and
- To regularly monitor blood glucose to enable dosage adjustment.
Most investigators now recommend initiation of insulin therapy at a fasting blood glucose level of 95 mg/dl or more (Carr et al 1998) (Table 1.6).
During the first trimester, fluctuations in glucose values occur frequently. Consequently, overnight hypoglycaemia may develop. Insulin requirement decreases at the end of the first trimester.
The onset of insulin resistance by the 18th to 24th gestation week indicates the need for a gradual increase in insulin requirement. Consequently, insulin requirement may increase up to two or three times the prepregnancy dose. Placenta growth ceases around the 36th week and therefore, insulin demand increases very little thereafter. In view of the above and variables like sickness, stress and dietary indiscretions, it is possible to work within a broad dosage guidelines (as given in Table 1.7) and plan the insulin dose schedule for each individual patient accordingly.
Primarily because of better tolerance and few reactions the current recommendation is for using human insulin in pregnany (American Diabetes Association 2000).
The schedule of insulin therapy given in Table 1.8 envisages a combination of rapid acting and intermediate acting (NPH) insulin given in two or four doses a day. Higher doses of insulin usually result in acceptable rather than adverse outcomes (Langer et al 1994).
The peak effect of NPH insulin occurs about eight hours after dosing. An evening dose of NPH insulin may cause overnight hypoglycaemia in spite of a bedtime snack, particularly when the patients receives a higher evening dose to control the next morning fasting value. Moving the evening dose of NPH insulin to bedtime shifts the peak effect time closer to breakfast. This minimises the prospect of overnight hypoglycaemia. Increasing the morning dose of NPH insulin may interfere with exercise and meal patterns.
Kitzmiller and Davidson, 1998 prefer three injections of regular or rapid insulin before each meal because the schedule offers flexibility concerning meal and exercise and any anticipated modifications in insulin demand. Rapid acting insulin reduces postprandial glucose excursions by providing a more physiologic insulin response to meals. Recent data indicate that greater control on blood sugar values and haemoglobin AIC is possible if patients take insulin four times a day (Nachum et al 1999) instead of usual twice a day. The four times a day schedule has a significant benefit of fewer caesarean section.
The most widely used twice a day schedule provides two-thirds of the total insulin dose in the morning and one-third in the night.
- Evaluate noctural hypoglycaemia and check 3 AM blood glucose
- Adjust diet by increasing/decreasing portions/composition at each meal
- Consider giving insulin 45 minutes before meal
The morning dose usually comprises one-third regular or rapid insulin and two-third intermediate or NPH insulin, whereas the evening dose comprises equal amounts of regular and intermediate NPH insulin. The chief disadvantages of this twice a day schedule is the large diurnal swings in blood glucose levels that occur and the risk of overnight hypoglycaemia.
Progressively, insulin requirement increases in later weeks of pregnancy. In addition, to adjusting the dose of insulin preparations, one could consider altering the timing of the rapid insulin injection relative to meal times. Sometimes, dose adjustments mitigate one problem while creating unacceptable blood glucose values at other times. Solution to such issues lies in making combined changes affecting dose, timing of injection and mealtimes.
Newer rapid acting insulin analogs with peak hypoglycaemic action one to two hours after injections offer the potential for improved control of postprandial excursions. However, clinical data establishing the superiority and safety of these preparations over the other short-acting insulin preparations in improving perinatal outcome is inadequate. Though continuous subcutaneous infusions have been used effectively in pregnancy, they are expensive sometimes cause profound nocturnal hypoglycaemia, pump failure and local abscess.
Role of Oral Hypoglycaemic Agents in Pregnant Diabetics
In clinical practice we have often seen type II diabetics on oral agents, reporting to us with gestations that cannot be terminated medico-legally. The fetuses do not appear obviously abnormal on sonography and the neonates are macrosomic, but have no major congenital anomaly. White in 1965 observed that both tolbutamide and phenformin had been used without adverse effects in 1 per cent of her diabetic patients.
In USA, oral hypoglycaemic agents (OHA) are contraindicated in pregnancy because of their possible teratogenic effects and prolonged neonatal hypoglycaemia. Piacquado et al followed older Mexican NIDDM pregnant women who were on oral hypoglycaemia agents from 3 to 28 weeks of pregnancy and found the rate of congenital malformations was greater in the group exposed to OHA as compared to age, race, glycaemia and parity matched controls (50% vs 15%). Twenty-five per cent of these babies had ear malformations which are not described in diabetic embryopathy. Exposure to sulphonylureas has been associated with ear malformations (Schieff et al 1970). Fetuses exposed to OHA manifested prolonged neonatal hypoglycaemia. OHA’s also have a more prolonged half-life in neonates and some clinicians suggest an exchange transfusion to eliminate them. Sulphonylureas cross the placenta and may exacerbate fetal hyperinsulinaemia. OHA have also known to aggravate neonatal hyperbilirubinaemia by competing for albumin binding sites. So, OHA are not recommended in pregnant diabetics.
Treatment Aimed at Reducing Perinatal Mortality (PNM)
A direct relationship has been demonstrated between the degree of maternal hyperglycaemia and PNM rate. Karlson and Kjellmar 1972, found when the average whole blood glucose of diabetic pregnant in last trimester was 100 mg/dl. The PNM rate was 4 per cent as compared to 15 per cent in those with an average whole blood glucose between 100 to 150 mg/dl. Similarly, Roversi et al kept their patients in relative hypoglycaemia and achieved the lowest PNM rates where Adashi et al had no perinatal mortality in his 113 patients where the glucose levels were kept below 100 mg/dl. Looking at those data the ACOG and American Diabetes Association in 1986 recommended that the fasting plasma glucose be maintained below 105 mg/dl and 2 hours postprandial below 120 mg/dl in gestational diabetic patient and also in pregnant women with pre-existing diabetes.
The current recommendation that after PNM rates are reduced to the lowest possible levels, the stress is on reducing perinatal morbidity and clinical sequence.
Prevention of Macrosomia
Macrosomia is associated with an increase incidence of operative and traumatic delivery and also with childhood and adult obesity (Vohr et al 1980). Its prevention is therefore desirable.
The Pederson hypothesis states that maternal hyperglycaemia is transmitted to fetal circulation as a result of free transfer of glucose through the placenta. Fetal hyperglycaemia causes stimulation of fetal pancreatic cells leading to fetal hyperinsulinaemia. As fetal insulin cannot cross the placenta, it persists in the fetal circulation and causes excess deposition of fat and glycogen in the fetal tissues leading to macrosomia. Therefore, currently, most of the treatment aims at prevention of fetal hyperinsulinaemia, by preventing maternal hyperglycaemia by frequent sampling of circulating glucose levels, using reflectance meters at home and administering insulin at lower threshold levels, to approximate glucose levels as closely as the non-diabetic metabolic milieu (Cousten et al 1991).
Early detection of the macrosomia is also an important aspect of management. If the patient is not obese, periodic fundal measurements are normal then all pregnant diabetic women should have ultrasound examination of the fetus every 4 weeks starting from the 20th week of gestation to monitor fetal growth. Macrosomia is defined as fetal weight of more than 4000 gm or 4500 gm. The birth weight above the 90th percentile or that gestational age is more meaningful practical definition of macrosomia than the absolute birth weight. Macorsomia can be diagnosed by serial BPD and abdominal circumference measurements.
The management of macrosomia is controversial. Most authorities agree that primary caesarean section is justified if the estimated fetal weight at the end of pregnancy is 4500 gm or more. The controversy arises when weight is between 4000 and 4500 gm.
Some investigators (Benedetti et al 1978) argue that in a macrosomic fetus the shoulder and trunk fat pads are relatively larger than head and so may cause shoulder dystocia and so advise caesarean delivery for infants weighing 4000 gm or more. Others argue that there may be as much as 25 per cent error in sonographic weight assessment at term (Benson et al 1987) and the incidence of fetal injuries is approximately in 500 deliveries when the fetus is between 4000 and 4500 gm so does not justify caesarean delivery.
The best approach would be to let them develop spontaneous labour and deliver vaginally. However, any abnormality of labour such as prolongation, failure to descend, secondary arrest of cervical dilation or persistant occipitoposterior position of fetal head which fails to rotate warrants a caesarean delivery.
Another rationale of this management is that some clinicians induce labour 2 to 3 weeks prior to estimated date of delivery in order to avoid caesarean delivery as they believe that a smaller size before term would deliver easily. But for this it is important to document two things, firstly lung maturity (before 39 weeks of gestation) and secondly the cervical ripening (Bishop score of 6 or more).
Prevention of Congenital Malformations among Infants of Overt Diabetic Women
In normal pregnancies the incidence of congenital malformations in newborns is 2 to 3 per cent but in diabetic pregnancies it increases to 7.5 to 12 per cent. Congenital anomalies are the most common causes of perinatal mortality among these infants.
Various aetiological factors have been blamed including hyperglycaemia, hypoglycaemia, hyperketonaemia, somatomedin inhibitors, yolk sac failure, reduced intracellular myoinositol, arachidonic acid deficiency and maternal vasculopathy. Currently, it is believed that the higher incidence of congenital anomalies in overt diabetic pregnancies is due to overplay of multiple factors. The crucial period when the embryo is at the greatest risk for dysmorphogenesis is before 7th week postconception or 9th week of ammenorrhoea.
Prevention can be done, as shown by various studies by an effective preconception normalisation or near normalisation of glycaemia control. A few studies shown in (Table 1.9).
These studies given in Table 1.9 indicate that even mild to moderate increases in the glycaemic levels in first trimester are associated with a significant increase in the risk of major structural defects. Therefore, efforts directed at preconception glycaemic control are rewarding. The current recommendation is preconception counselling of overt diabetics regarding glycaemic control and to explain the preconception glycaemia control before planning a pregnancy.
Efforts to detect diabetic embryopathy should start soonafter conception by measuring the patients glycosylated haemoglobin (Hb AIC). There is a good evidence indicating that levels of Hb AIC greater than 8.5 per cent are associated with a 20 to 25 per cent probability of fetal developmental abnormalities. When concentration of glycosylated haemoglobin is normal the probability of major malformation is less than 2 per cent. Women with high Hb AIC levels should undergo a transvaginal ultrasound at 8 to 10 weeks. Some defects like anencephaly, holoprosencephaly and blighted ova may be detected early.
The search for diabetic embryopathy should also include measurement of maternal serum alpha-fetoprotein at 16 weeks. Normally, serum alpha-fetoprotein is lower in diabetic patients and if abnormal values are found then genetic amniocentesis is indicated.
At 18 to 20 weeks of gestation, a detailed anatomic survey by the fetus, level II examination using high resolution ultrasound should be performed and the final step is to search for fetal cardiac abnormalities by performing a fetal echocardiogram at 24 to 26 weeks of gestation.
Prevention of Intrauterine Death
Sudden unexplained fetal deaths occurred in 10 to 30 per cent of gestation complicated by insulin dependent diabetes in the past (Gabbe, 1980).
Although such losses are uncommon in well-controlled patients, but even today stillbirths are seen in patients who do not receive optimal care. Fetal death most often occurs after the 36th week of pregnancy in patients with poor glycaemic control, hydramnios, fetal macrosomia, pre-eclampsia or women with vascular disease.
The precise cause of excessive stillbirth rate in pregnant diabetics is not known but experimental results link derangement in maternal and fetal carbohydrate metabolism with fetal death. Chronic intrauterine hypoxia is a likely cause. Maternal diabetes may produce alteration in red blood cells oxygen release and placental blood flow (Madsen 1986) whereas Nyland et al in 1982 suggested that reduced uterine blood flow may be the factor involved with IUGR and fetal death. They also suggested that there is a relationship between maternal hyperglycaemia and reduced uteroplacental blood flow. This is seen in cases of ketoacidosis and pre-eclampsia, two conditions associated with IUD. Alteration in fetal carbohydrate metabolism and fetal hyperinsulinaemia leading to hypoxia and fetal death was suggested by Phillips et al in 1982.
Antepartum Fetal Surveillance And Its Significance
Over the past few years techniques of antepartum fetal surveillance have been developed and they should be employed in the third trimester, the period of greatest risk for fetal death.
The main aims of this surveillance are as follows:
- Avoidance of intrauterine death.
- Early detection of fetal compromise.
- Prevention of unnecessary premature delivery.
Initially, biochemical tests (urinary and plasma oestriol, pregnendiol, HPL assays) were used to monitor fetal well-being but they had high false-positive results. Now, biophysical methods are used to monitor pregnancy. These are as follows:
Contraction stress test (CST) This was the first biophysical test to monitor diabetic pregnant women. From 1977 to 1983 various workers like Gabbe, Kitzmiller, Coustan and Lavin have used CST on a large number of pregnant diabetics. Their results show that a positive CST (late decelerations that are consistent and present with most uterine contractions) was associated with abnormal fetal outcome such as fetal distress, low Apgar score, IUGR and fetal death. The incidence of positive CST reported was 1 to 10 per cent. Negative CST predicts fetal well-being in a metabolically stable patient for 1 week. False-positive CST in diabetic pregnancies range from 40 to 60 per cent and elective interventions should be undertaken only when several tests suggest fetal compromise.
Non-stress test (NST) NST’s are easier to perform and have almost the same predictive value as CST, so NST’s are preferred over CST and are used to screen fetal condition in diabetic pregnancies (Landon et al 1990). NSTs are done twice a week from 32 weeks onwards in diabetic pregnant.
Fetal biophysical profile (FBP) FBP is generally done in those diabetic pregnancies when NSTs are non-reactive or when there is severe IUGR as seen in cases of diabetic pregnancies with vasculopathies and pre-eclampsia.
Johnson et al did twice weekly FBP in 50 insulin dependent diabetic pregnants and weekly FBP in 188 gestational diabetic patients and reported no stillbirths. The incidence of abnormal FBP score was only 3.3 per cent in fetus as with normal score, whereas in 8 patients with abnormal FBP score 37.5 per cent fetuses had significant neonatal morbidity.
Maternal assessment of fetal activity (Kick count) It is a simple and inexpensive monitoring technique with a very low false-negative rate (˜ 1%); but false-positive rate is high and may reach 60 per cent, as maternal hypoglycaemia may stimulate fetal activity (Holden et al 1984).
Doppler studies Doppler umbilical artery velocimetry has been recommended especially in diabetic pregnancies complicated by vasculopathy, IUGR and pre-eclampsia. Brascero et al 1986 provided the first description of umbilical waveforms in diabetic pregnancies and found a good correlation between S/D ratio of umbilical artery and serum glucose levels. Landon et al found abnormal umbilical artery waveform in 50 per cent of fetus of diabetic women with vascular disease compared to 12 per cent of those without hypertension or nephropathy. In women vascular disease elevated umbilical with artery S/D ratio which was correlated with fetal growth retardation. Doppler studies are expensive and can be used in selected cases.
Prevention of respiratory distress syndrome(RDS) RDS in newborn was the most common cause of the neonatal mortality in diabetic pregnancies as induction of labour at 36 to 37 weeks was often resorted to in the past. It has been seen that in diabetic pregnancies even with mature L/S ratio of more than 2 some babies develop RDS. It has been found that in diabetic pregnancies there is delayed production of surfactant and lung maturity and pregnancies must be terminated only when the L/S ratio more than 2.5 to 3, sophisticated tests such as phosphatidylglycerol and phosphatidylcholine estimations appear to be reliable, but are expensive and need amniocentesis.
Timing of Delivery in Diabetic Pregnancies
There is no need to terminate the pregnancy before term in stable insulin dependent pregnant diabetic women and in whom fetus is not at risk per se for diabetes only. They can reach term and spontaneous labour is awaited, though pregnancy should not be prolonged beyond the expected date of delivery (Eden et al 1988).
The unstable insulin dependent pregnant diabetic are better served by delivering them as soon as fetal lung maturity is achieved, i.e. L/S ratio more than 2.4 and phosphatidylglycerol is positive. Fetal and maternal complications in unstable diabetes are more and there is no need to prolong pregnancy once lung maturity is achieved. Patients with hypertension, vascular disease and IUGR are delivered early. Induction is carried out if the cervix is favourable or after making it ripe with prostaglandin gel.
The maternal factors which influence the timing of delivery in diabetic pregnancy are vascular disease complications, control of diabetes, condition of cervix, previous obstetric history and an elderly patient.
The fetal factors are the estimated fetal weight and suspected fetal distress. However, fetal health can suddenly deteriorate in a diabetic pregnancy and obstetric management should not have any set rules but each case must be assessed individually and managed.
Route of Delivery
Brundell, 1978 stated “ the ideal way to deliver the baby of diabetic mother, would be for her to go into labour spontaneously at term and be delivered normally by the vaginal route”. The mode of delivery should be based on obstetric consideration and diabetes per se is not an indication for caesarean. However, diabetic deliveries must be conducted in a well-equipped centre under a skilled obstetrician. A neonatologist must be present at the time of delievery. The indications of caesarean are as follows:
- Pregnancy complicated by PIH.
- Previous caesarean.
- Proliferative retinopathy.
- Fetal distress prior to or during labour.
Women are generally not allowed to eat during labour. A traditional compromise is to give one-fourth or one-half of the usual dose as short-acting insulin, then to follow blood glucose levels and adjust the dose of plain insulin accordingly. It has been seen by various studies that maternal glucose levels just before delivery are extremely important in determining whether hypoglycaemia will develop in newborn infant. Oral feeding is resumed soon after delivery and insulin regulated accordingly. The requirement of insulin starts decreasing soon after delivery and many a times a gestational diabetic women may not require any insulin after the 48 hr of puerperium.
If labour is to be induced, the patient eats no breakfast and takes no insulin on the morning of induction. An intravenous saline is placed with 500 ml of 5 per cent dextrose in half normal saline to which 10 units of regular insulin is added. This is given at the rate of 125 ml per hour. In this way the patients gets 1.25 units of insulin and 6.25 gm of dextrose each hour. Whole blood sugar remains as near to 100 mg/dl as possible. According to Javanouic and Pederson 1980, labour has to be viewed as an intensive exercise rather than a major stress situation.
For a patient undergoing elective caesarean, the patient takes her usual meal and dose of insulin on the evening prior to surgery so that her plasma glucose value next day early morning are normal. On the morning of the caesarean an intravenous drip of normal saline is started. After the delivery an infusion of glucose and insulin is used to maintain relative euglycaemia in the mother till she is ready to start subcutaneous insulin and oral intake of feeds.
Postpartum Management of Diabetic Mother
There is a rapid fall in insulin requirement after pregnancy is terminated, probably due to low levels of insulin antagonising hormones. Postpartum assessment of carbohydrate metabolism is essential. The patient should be followed up to six months. A repeat GTT is done after six weeks and she is reclassified. In gestational diabetes the GTT returns to normal. All infections must be treated rigorously. The babies should be followed up to five years.
Earlier, it was believed that combined oral contraceptives carried a potential risk of exacerbating the metabolic disorder. But, the American College of Obstetrician and Gynaecologists have recommended that low -dose oral contraceptives be safely used in diabetic women without vasculopathy or additional risk factors such as strong history of ischaemic heart disease. Injectable progestogen contraception is safe but progesterone only pills are associated with high failure rate. A recently study concluded that diabetic women are often ideal candidates for intrauterine devices (Kjos et al 1994). Barrier method of contraception is good as it protects against sexually transmitted disease. Puerperal sterilisation can be offered as a permanent method of contraception.
Care of the Infant
Infants of diabetic mothers require special nursing care. A paediatrician should be present at the time of delivery. The problems seen are as follows:
- Congenital malformation
- Neonatal hypoglycaemia
- Neonatal hyperbilirubinaemia
- Neonatal respiratory distress syndrome
- Hyperviscosity syndrome
- Feeding problems.
Hypoglycaemia (defined as a neonatal blood glucose value below 30 mg/dl) occurs in 15 to 50 per cent of the infants, being some what less frequent when the mother has an excellent metabolic control up to delivery. If the low blood glucose persists despite the 10 per cent glucose given orally, an intravenous infusion of glucose may be necessary. A word of caution must be added at this point. A bolus intravenous dose of glucose is inappropriate for the hypoglycaemic infant of diabetic mother. Although, the blood sugar will instantaneously come to normal or more; it will stimulate the fetal pancreas to release more insulin, thus causing reactive hypoglycaemia.
Hyperbilirubinaemia also occurs more commonly in these infants probably due to immature liver function or by the bilirubin catabolic system, i.e. glucuronyl transferase. Hypocalcaemia is also reported to be more frequent in such infants. Respiratory distress syndrome is another problem for which the neonatologist should be well-prepared.
Hyperviscosity is diagnosed when the neonatal haemotocrit is 65 per cent or more. This may be asymptomatic or others may have RDS, necrotising enterocolitis, renal vein thrombosis or cerebral infarcts. The cause of this may not clear but may be due to excessive production of erythropoietin in response to chronic fetal hypoxia.
Poor feeding is a common problem too and is often associated with other neonatal complications and may be one of the reasons for prolonged stay of such infants in the nursery.
There is also increased incidence of congenital anomalies and it is advisable that the baby is seen by a paediatric surgeon when necessary.
Management of Unstable Insulin Dependent Diabetic Patients
The care of unstable insulin dependent diabetic pregnant presents a significant challenge to the obstetrician because these patients are difficult to control, need frequent visit to the doctor and frequent hospital admission for metabolic regulation.
These patient should preferably be under a specialist in the field of maternal fetal medicine rather than in for “split” management between a general obstetrician and an internist or diabetologist. Some of the common problems that these women develop are described below.
- Somogyi phenomenon Some patients have high fasting blood sugar levels and complain of sleep disturbance such as nightmares and nocturnal sweating. Nocturnal hypoglycaemia followed by an exaggerated counter-regulatory response produces the elevated fasting blood sugar low blood sugar level between 1 AM and 5 AM diagnoses such cases. The treatment is to decrease the amount of intermediate or long-acting insulin that the patient takes before the dinner or at bedtime.
- Dawn phenomenon Some patients have high fasting blood sugar levels but no nocturnal hypoglycaemia and this is called “dawn phenomenon”. The cause for this is not known and the treatment is to increase the amount of intermediate acting insulin given before dinner or to administer it at bedtime rather than before dinner. There should be small increments in doses as severity of dawn phenomenon may be irregular and variable.
- Hypoglycaemic episodes Severe hypoglycaemic episodes requiring assistance is a common emergency seen in such cases especially in patients with type 1 diabetic mellitus. The cause of this is probably an impairment in the counter-regulatory mechanism (counter-regulatory hormones are epinephrine, growth hormone, cortisol). It seems that when large amounts of insulin are required; the blood glucose threshold for the release of counter-regulatory hormone is lowered. Therefore, these patients may have marked hypoglycaemia without eliciting a compensatory response.In mild-moderate episodes, treatment consists of giving some liquid containing carbohydrates . For severe reactions especially if patient is unconscious, 1 mg of glucagon is given subcutaneously or intramuscularly. As soon as the patient awakens, oral carbohydrate is given. If the patient remain unconscious even after glucagon injection patient should be shifted to intensive care and 20 ml of 50 per cent dextrose is given immediately. Treatment with 5 to 10 per cent dextrose may be continued for several hours until blood sugar levels become normal. Hypoglycaemic attacks may also occur due to hypoglycaemia unawareness, insulin dose errors and excess alcohol intake.
- Change in insulin pharmacokinetics Unstable diabetics especially with long-standing diabetes may have marked variations in the time of onset, time of peak action and total duration of action of the insulin preparation they are using. The most likely cause for this is development of insulin antibodies and secondly due to irregular absorption from the injection site. This problem should be suspected in long-standing diabetic patients with large fluctuations in blood sugar levels, that do not respond predictably to dosage changes.In such cases hourly measurement of blood sugar levels should be done for 24 hours and graphically plot the values, the time of meals and time of insulin administration. If such a problem is strongly suspected then patient should switch to human insulin if she is previously on pork or beef insulin. When switching to human insulin it is best to start with dose half to two-thirds of what they were previously receiving as these patients may develop hypoglycaemia with equivalent doses of human insulin.Secondly, it is well-known that absorption of insulin is more rapid when given in extremities as activity increases the blood flow and is more steady when given as subcutaneous injection in the abdomen. Absorption is also erratic if the same area is used repeatedly and patients should be advised to rotate the sites of injection repeatedly.
- Insulin pumps Patients on continuous subcutaneous insulin pumps constitute a special group. The most common problem found in these patients is hypoglycaemia of varied severity. Because of long-standing diabetes the efficacy of their counter-regulatory mechanism is limited and they can have prolonged severe hypoglycaemia. Such episode, mandate a reduction in the preprandial boluses or in the day-time nocturnal basal rate depending on the timing of the hypoglycaemic events. A second problem is infection at the injection site. This can be minimised by emphasis on aseptic technique and frequent changing of injection site.
Management of Insulin Dependent Diabetic Patient with End-organ Damage
These patients are at high-risk both for maternal and fetal complications. Although twenty years ago such patients were advised against conceiving underwent a therapeutic abortion or surgical sterilisation, today most of these patients can have a successful pregnancy outcome.
- Diabetic nephropathy These patients presents with proteinuria and hypertension in the first and second trimesters. These signs are mild in early pregnancy but by 20 to 24 weeks of gestation most of these patients have showed increases in proteinuria, blood pressure and serum creatinine. Hypertension and oedema are almost always present and in the third trimester it is difficult to determine whether symptoms are caused solely by diabetic nephropathy or by superimposed pre-eclampsia .The main fetal disorders in these patients are prematurity (due to preterm labour or early induction) and fetal growth retardation. Prematurity is seen in almost 45 per cent of cases and growth retardation in 20 per cent .Another problem with these patients is the potential for proliferative retinopathy. It has been seen that out of all patients with diabetic nephropathy, 90 per cent have retinopathy but only 20 per cent proliferative type.Lastly these patients are also at a risk of reduced longevity as it has been seen that end-stage renal disease occurs in 2 to 4 years and the best hope for them is through renal transplantation.
- Diabetic retinopathy The condition affects approximately 40 per cent of all insulin dependent diabetic patients. Pregnancy also seems to accelerate the progression of diabetic retinopathy (Klein et al 1990). In approximately 80 per cent of the cases, the lesion is not severe and have only background retinopathy but another 20 per cent have neovascularisation along the retinal surface named proliferative retinopathy. It is important to diagnose proliferative retinopathy as in them the new vessels are very fragile and bleed easily with increase in intraocular pressure that occurs during labour, thereby leading to sudden vision loss. Such patients are not allowed labour as Valsalva efforts may increase intraocular pressure and cause vitreal haemorrhage and retinal detachment.
- Diabetic cardiomyopathy The maternal and fetal prognosis for this condition is very bad and there is a high rate of maternal and fetal mortality (Silun et al 1980) . These patients need to be identified early in pregnancy and will require intensive care to achieve a good outcome. Successful pregnancies have been undertaken after coronary revascularisation but exercise tolerance should be normal in them to tolerate the increased demands of gestation.
Management of Diabetic Ketoacidosis
Fortunately ketoacidosis affects only 1 per cent of all diabetic pregnancies. This is a serious complication and requires adequate treatment to save both mother and fetus.
It results from a deficit in insulin and the response to that deficit by counter-regulatory hormones. As a result of decreased cellular glucose consumption and increased gluconeogenesis, the blood glucose levels rise. This severe glucose hyperglycaemia, causes osmotic diuresis, is with depletion of intravascular volume and electrolyte changes. Simultaneously, increased lipolysis causes excessive ketone bodies that titrate the body buffers leading to metabolic acidosis. The diagnosis is made on the following criteria.
- Blood sugar concentration > 250 mg/dl.
- Ketone bodies in urine and plasma.
- Arterial pH < 7.3.
- Serum bicarbonate < 15 mEq/L.
Such patients should be immediately hospitalised and investigated—blood glucose, serum and urine ketones, blood gases, electrolytes, complete blood count, electrocardiogram and chest X-ray.
They should be well-hydrated and started on intravenous saline with 1000 ml of normal saline infused in the first hour. If the patient is in shock, plasma expansion with colloid solutions is indicated. If the serum potassium is low, 40 mEq of potassium is given in drip in the first hour. If the arterial pH is below 6.9; 88 mg of sodium bicarbonate should be given every 24 hours till pH rises to 7.0.
Insulin therapy should be started after blood is sent for investigation. Typically initial intravenous bolus of 0.2 U/kg is given followed by continuous infusion @ 0.10/kg/hr. By this treatment blood glucose level decreases by 30 per cent in 2 to 3 hr. If it do not then increase the dose of insulin to twice the initial dose. Once the blood glucose is between 150 and 200 mg/dl the IV fluid should be changed from normal saline to 5 per cent dextrose in half normal saline and the insulin dosage should be adjusted to avoid hypoglycaemia.
The most important aspect in the management of ketoacidosis is identification of the precipitating cause which is frequently viral or bacterial infection which should be adequately treated with antibiotics.
Management of Preterm Labour in Diabetics
It has been seen that intravenous beta–adrenergic drugs to stop preterm labour increase glycogenolysis and lipolysis, so increase a tendency towards metabolic acidosis, so should be avoided. In such cases (that is patients receiving beta-adrenergics) the insulin dose has to be increased. The drug of choice for initial tocolysis is magnesium sulphate. Once tocolysis is achieved patient can be shifted to oral calcium channel blockers (nifedipine) oral terbutaline (2.5 mg 6 hrly) and even indomethacin can be given after 32 weeks of gestation. Usually, about 40 per cent of such patients have intrauterine infection and antibiotics may also be helpful in such cases.
Management of Premature Rupture of Membranes in Pregnant Diabetics
It has been shown that every time a pregnant diabetic has premature rupture of membranes there is a strong possibility that she has intrauterine infection. Obstetric infections occur more easily in diabetic patients and they may be more severe than non-diabetics. Thus, expectant management of diabetics patients with premature rupture should be the exception rather than a rule.
PRECONCEPTION CARE PROGRAMME OF WOMEN WITH DIABETES
(Based on American Diabetes Association Recommendations)
To prevent excess spontaneous abortions and congenital malformations infants of diabetic mothers, diabetic care and education must begin before conception. This is best accomplished by a multidisciplinary team that includes a diabetologist, internist or family physician skilled in diabetes management; an obstetrician familiar with high-risk pregnancy, diabetes educators including nurses and social workers. Ultimately, the diabetic women must become the most active of the team, calling upon the other members for specific guidance and expertise to help her achieve her goal of a healthy pregnancy and newborn.
- Patient education about the interaction of diabetes.
- Pregnancy and family planning.
- Education in diabetes self management skills, physician directed medical care and laboratory testing.
- Counselling by a mental health professional when indicated to the diabetes treatment plan.
All the four elements combined are important for patients to achieve the level of sustained glycaemic control necessary.
Specific Goals of Treatment
The desired outcome of the preconception phase of care is to lower Hb AIC test values to a level associated with optimal development during organogenesis. Epidemiological studies indicate that Hb AIC test values up to 1 per cent of normal are associated with rates of congenital malformation and spontaneous abortions that are not greater than rates in non-diabetic pregnancies. However, rates of each complication continue to decrease with even lower Hb AIC levels. Thus, the general goal for glycaemic management in the preconception period and first trimester should be to achieve the lowest Hb AIC levels (that is less than 1 per cent of the normal range). The practical self management skills to achieve this level of glycaemic control are as follows:
- Use of an appropriate meal plan.
- Self monitoring of blood glucose.
- Self administration of insulin and self adjustments of insulin doses.
- Treatment of hypoglycaemia.
- Incorporation of physical activity.
- Development of techniques to reduce stress and cope with denial.
It is desirable to achieve and maintain blood sugar control for at least three months before the woman plans to get pregnant and thereafter to maintain a very tight control on blood sugar during pregnancy and postpartum period (Table 1.10).
Medical and Obstetrical History
A complete history is imperative before planning for pregnancy. This should include the following:
- Acute complications, including history of infections, ketoacidosis and hypoglycaemia.
- Chronic complications including retinopathy, nephropathy, hypertension, arteriosclerotic vascular disease and autonomic and peripheral neuropathy.
- Diabetes management, including insulin regimen, prior or current use of oral glucose lowering agents, self monitoring blood glucose regimen and results, medical nutrition therapy and physical activity.
- Concomitant medical conditions and medications, thyroid disease in particular for patients with type 1 disease.
- Menstrual/pregnancy history, contraceptive use.
- Support system, including family and work environment.
An initial individual educational evaluation session with a diabetes educator, a registered dietitian and when needed a psychosocial expert is valuable. Patient’s immediate family member should participate in this session. In conjuction with the primary physician, these professionals will review the patients current management plan and develop a comprehensive treatment plan.
Diabetic retinopathy, nephropathy, autonomic neuropathy (especially gastroparesis) and coronary artery disease (CAD) can be affected by or can affect the outcome of pregnancy. Thus, physical examination should give particular attention to the following:
- Blood pressure measurement including testing for orthostatic changes.
- Detailed retinal examination by a ophthalmologist.
- Cardiovascular examination for evidence of cardiac or peripheral vascular disease. If found, patients, should have screening tests for CA before attempting pregnancy to assure that they can be tolerate the increased cardiac demands.
- Neurological examination including examination for signs of autonomic neuropathy.
The evaluation should focus on assessment of metabolic control and detection of diabetic complications that may affect or be affected by pregnancy.
- Hb AIC test.
- Serum creatinine and urinary excretion of total protein and/or albumin. Patients with a protein excretion of more than 190 mg/24 hr have been shown to be at increased risk for hypertensive disorders during pregnancy and those patients with protein excretion more than 100 mg/24 hr also are at risk for intrauterine growth retardation during later pregnancy (patients on ACE inhibitors should stop these drugs).
- Measurement of thyroid-stimulating hormone and/or free thyroxine level in women with type 1 diabetes because of the 5 to 10 per cent coincidence of hyper- or hypothyroidism.
- Other tests as indicated by physical examination or history.
The initial management plan must include the following components:
- Counselling about the risk and prevention of congenital anomalies, fetal and neonatal complications of maternal diabetes, effects of pregnancy on maternal diabetic complications, risks of obstetrical complications, the need of effective contraception until glycaemia is well-controlled and the cost-benefit relationship between preconception care and prevention of malformations.
- Selection of insulin as the best antihyperglycaemic agent and stop oral antidiabetic agents.
- Establishment of plan to achieve low-risk glycaemia that is of Hb AIC less than 1 per cent of the normal range. This can be achieved by the following:
- Set goals for self monitored glucose. Successful pre- and postprandial goals.
- Before meals.
- Capillary whole blood glucose 70 to 100 mg/dl (3.9-5.6 mmol/L) or capillary plasma glucose 80 to 110 mg/dl (4.4-6.1 mmol/L)
- 2 hr after meals.Capillary whole blood glucose more than 140 mg/dl (7.8 mmol/hr) at 2 hr.or capillary plasma glucose more than 115 mg/dl (<8.6 mmol/l) at 2 hr.There is no data to suggest that postmeal glucose monitoring has a role in preconception diabetes care beyond what is needed to achieve the target for Hb AIC. Thus, a focus on preprandial monitoring is recommended initially to assist patients in self selection of insulin doses.
- Implement the treatment plan and monitor Hb AIC levels at 1 to 2 months intervals until stable. Then, counsel patient about the risk associated with her level. If she does not achieve a low-risk level of less than 1 per cent above the upper limit of normal, consider modifications of the treatment regimen, including addition of postprandial glucose monitoring. It is important to note that glycaemic goals may need to be modified according to the patients recognition of hypoglycaemia and risk of severe neuroglycaemia.
After the initial visit patients should be seen at 1 to 2 months interval depending on their mastery of the management programme and the presence or absence of coexisting medical conditions. Once the patient has achieved stable glycaemic control (assessed by Hb AIC list) that is as good as she can achieve, and then she should be counselled about the risk of malformations and spontaneous abortions. If the risk as well as the status of maternal diabetic complications and any coexisting medical conditions are acceptable, then contraception can be discontinued. If conception does not occur within 1 year, the patients’ fertility should be assessed.
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