Diabetes in Pregnancy1

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.

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 4modified 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.

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 5trimester 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.

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.

6The 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.

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.

7According 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:

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.

8Gestational 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.

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.

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.

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 12same 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.

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 13whether 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).

Patients with GDM are first started on a diet and only when glycaemic control with diet is not satisfactory, insulin is recommended.

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).

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.

In most cases, women with GDM may be managed expectantly unless fasting and postprandial glucose levels are high.

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.

16In 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.

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).

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.

There is also high incidence of chorioamnionitis and endometritis in poorly glycaemia controlled diabetic patients.

19Some 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).

The aims in management are as follows:

Self-monitoring of blood glucose may be expensive but it increases the motivation, decreases the time spent 22in 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.

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 23and 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.

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:

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.

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.

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 26and 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.

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.

The current recommendation that after PNM rates are reduced to the lowest possible levels, the stress is on reducing perinatal morbidity and clinical sequence.

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.

28The 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).

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.

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) 30whereas 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.

The main aims of this surveillance are as follows:

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:

31Johnson 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.

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 32delivered 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.

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 33to 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.

34Hypoglycaemia (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.

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.

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.

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 38continuous 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.

39The programme includes four important elements:

All the four elements combined are important for patients to achieve the level of sustained glycaemic control necessary.

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).

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.