Gestational diabetes mellitus

Background

The incidence of GDM will vary according to the definition used (see ‘Definition') and the population being studied but would usually be within the range 5-20%. The higher levels mostly are in centres using the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria with an ethnically predisposed population.

What impairs glucose tolerance in pregnancy?

The hormonal environment in pregnancy impairs glucose tolerance. In a predisposed patient, the insulin secretion will not be able to keep up with insulin demand and the plasma glucose concentration will rise—hence the condition of GDM.

The principal hormone responsible is probably human placental lactogen which is structurally analogous to human growth hormone and carries the same property of impairing glucose tolerance. The increased levels of progesterone and corticosteroid may also contribute to hyperglycaemia in pregnancy. Given that all these hormones do not reach high levels until the latter half of pregnancy, GDM is most often a third-trimester condition and diagnosed by a glucose tolerance test at 24-28 weeks' gestation.

Why is there a clinical impact of raised plasma glucose in pregnancy?

Medical colleagues have sometimes thought it strange that obstetricians are concerned about lower levels of plasma glucose than would raise concern in the non-pregnant population. This comes about for two reasons. Firstly, the fetus appears particularly sensitive to increased plasma glucose levels in terms of the impact on fetal growth. The clinical consequences of excessive fetal size will be discussed in a later section. The second issue is that, like non-pregnant diabetes mellitus, the increased plasma glucose may lead to inadequate placental blood flow. This may create a critical mismatch of poor maternal placental perfusion but increased fetal demands on the placenta for oxygenation.

Definition

Historically, GDM has been defined as the diagnosis of clinically significant impaired glucose tolerance in pregnancy in a woman not previously known to be diabetic. This has recently been complicated by recognizing that some diabetes mellitus will present for the first time in pregnancy and lack of clarity as to where the lower threshold for diagnosis should best be placed.

Upper threshold for diagnosis

Where the impairment of glucose tolerance is severe such that the criteria for diagnosing diabetes mellitus outside pregnancy would be met, the condition is better termed ‘diabetes mellitus in pregnancy' (rather than GDM). This would apply to a fasting level of at least 7.0 mmol/L or a 2-hour level of at least 11.1 mmol/L on a 75 g glucose tolerance test.

Lower threshold for diagnosis

It has proved difficult to set a lower threshold for diagnosis, given a remarkably linear relationship of glucose tolerance with such outcomes as birthweight, caesarean section rate, neonatal hypoglycaemia, and cord blood C-peptide levels (1). This is discussed in the following section.

Screening for GDM

Early pregnancy diagnosis

As alluded to previously, impaired glucose tolerance in the first half of pregnancy is unlikely to be the consequence of pregnancy but rather a pre-existing tendency to diabetes mellitus. There is remarkably little research that explores the consequences of minor impairments of glucose tolerance in early pregnancy. Most centres will undertake testing in early pregnancy only where there are significant predisposing factors (Box 13.1) and then treat if GDM criteria are met. Interestingly, the New Zealand health system has

Box 13.1 Predisposing factors for gestational diabetes mellitus

• Ethnicity: Asian, Melanesian, Polynesian, Middle Eastern, non-white African

• Overweight and obese

• Family history of type 2 diabetes mellitus

• Previous macrosomia (baby with birth weight >4500 g or >90th centile)

• Previous GDM

• Advanced maternal age (≥40 years)

• Polycystic ovarian syndrome

• Medications: corticosteroids, antipsychotics

chosen to screen all women using glycated haemoglobin (HbAlc) in early pregnancy and treat if the HbA1c level is 6.5% or greater.

This may reflect a high incidence of impaired glucose tolerance in the Polynesian population in that country.

Late second-trimester diagnosis

The IADPSG recommend the performance of a 75 g fasting glucose tolerance test on all women not previously diagnosed with diabetes at 24-28 weeks' gestation. Their criteria for diagnosis (Table 13.1) have been endorsed by the World Health Organization and numerous national organizations (2).

The introduction of the IADPSG criteria created significant controversy—largely in relation to the subsequent increase in incidence of GDM in most populations. The thresholds were set at the plasma glucose levels associated with a 1.75-fold increase in the risk of complications based on the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study (1). It is true that this threshold is somewhat arbitrary but more logical than having fasting and 2-hour thresholds at different levels of clinical risk as was the case with previous definitions.

Given that there is a linear correlation of glucose tolerance with measurable clinical outcomes, the benefits of treating GDM will be less with levels closer to the threshold values. At least one study (3) investigated as to whether there is any benefit to treating mild GDM. Although using different diagnostic criteria to those subsequently

Table 13.1 IADPSG threshold values for diagnosis of gestational diabetes mellitus or overt diabetes in pregnancy

	Glucose concentration (mmol/L)	Glucose concentration (mg/dL)
Gestational diabetes mellitus diagnosis⁹
Fasting plasma glucose	5.1	92
1-hour plasma glucose	10.0	180
2-hour plasma glucose	8.5	153
Overt diabetes in pregnancy diagnosis^b
Fasting plasma glucose	7.0	126
Random plasma glucose	11.1	200

^a One or more of these values from a 75 g oral glucose tolerance test must be equalled or exceeded for the diagnosis of GDM.

^b One or more of these values must be equalled or exceeded for the diagnosis of overt diabetes in pregnancy. Also diagnosed if the HbA1c level is at least 6.5% (Diabetes Control and Complications Trial/United Kingdom Prospective Diabetes Study standardized).

Source data from IADPSG Consensus Panel, 2010.

suggested by the IADPSG, the study found that treating mild GDM resulted in reduced rates of macrosomia, shoulder dystocia, caesarean birth, and pre-eclampsia. A benefit in treating mild GDM therefore appears likely but the magnitude of that benefit and the cost-effectiveness of treating marginal GDM is uncertain. The issue is likely to be long debated as an effective randomized controlled trial of sufficient magnitude would not be feasible if it is recognized that even a small clinical benefit is likely to be of significance to most women (4). Additionally, such a study would not be the best use of limited research resources when so little is known about other aspects of GDM such as the impact of minor impairments of glucose tolerance through the second trimester of pregnancy.

Clinical consequences of GDM

The clinical consequences of GDM are listed in Box 13.2. Many are a direct impact of increased fetal and placental size which in turn correlates with blood glucose control as well as maternal body weight and pregnancy weight gain. Shoulder dystocia is particularly noteworthy as it occurs at a lower fetal weight than in the absence of diabetes—presumably due to the disproportionately large shoulders.

Most controversial is the increase in perinatal mortality. While an important feature in the early report of O'Sullivan et al. (5), some subsequent observational studies have not shown an increase in perinatal death. This may be explained by the current management of GDM: effecting birth in most centres at or prior to 40 weeks' gestation appears to result in an overall perinatal mortality no worse than the non-GDM population. This is at least in part attributable to avoiding perinatal deaths after 40 weeks that are relatively common in all pregnancies and avoided in the GDM group if birth is recommended before 40 weeks (6)

Antenatal management of GDM

Crowther et al.

(7) in the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) study established that treatment of GDM improved a composite perinatal outcome. Given that the rationale for therapy is in part due to that study, the therapeutic regimen used underpins the treatment protocols of many units today. In broad terms, antenatal management comprises maternal and fetal surveillance, diet and exercise, and insulin or an oral hypo- glycaemic drug. Further important care includes the timing and mode of birth, intrapartum care, postnatal and neonatal care, and long-term follow-up.

Box 13.2 Clinical consequences of gestational diabetes mellitus

Maternal

• Pre-eclampsia

• Caesarean section

Fetal

• Birthweight greater than the 90th percentile

• Preterm birth (of Medicine recommendations are listed in Table 13.2 but in the presence of morbid obesity (body mass index ≥40 kg/m²), no weight gain or even weight loss may be recommended. Regular exercise also is important in the control of blood sugar but should be limited to mild to moderate levels of exertion only. A common recommendation is a 30-minute walk during the day or after the evening meal.

Medications to control hyperglycaemia

When diet and exercise are unable to maintain satisfactory glucose levels, medical therapy should be initiated. There are many thresholds used but the ACHOIS study recommended that insulin be initiated if there were more than two capillary blood glucose measurements above target (fasting 5.5 mmol/L; 2-hour postprandial 7.0 mmol/L) in a week of testing. In the study by Landon et al. (3), insulin was prescribed if the majority of fasting values or postprandial values

Table 13.2 Institute of Medicine recommendations for total and average rate of weight gain during pregnancy

Pre-pregnancy body mass index (kg/m²)

Total weight gain range (kg)

Underweight (are unexplained.

Management of type 1 or 2 diabetes at the prepregnancy visit

Prepregnancy management for women with underlying diabetes provides a very important chance to change the outcome for the women and her baby. At a preconception visit, all the usual aspects of prepregnancy care (see Chapter 6) should be discussed, but in addition, special attention should be paid to a number of specific issues.

Assessment

Diabetes assessment

The therapeutic regimen for the diabetes should be assessed along with the glucose control being achieved. The incidences of both miscarriage and congenital abnormalities are directly related to diabetic control in the periconceptual period. The HbA1c level is an accepted marker of glucose control and women should aim for an HbA1c level less than 6.5%. Where the HbA1c level is greater than 10%, the woman should be advised to delay pregnancy until improved control is achieved (11).

The prepregnancy visit is also an opportunity to assess and stabilize complications of diabetes including nephropathy and retinopathy. Renal function should be evaluated with a serum creatinine and urinary albumin:creatinine ratio. Retinopathy should be assessed by an ophthalmologist.

Assessment of comorbidities

Type 1 diabetes may be associated with other autoimmune disorders including thyroid disease and coeliac disease.

Common comorbidities in type 2 diabetes include obesity and hypertension. Weight loss prior to pregnancy may enable some women to return to normal glucose tolerance. Bariatric surgery may be appropriate for some markedly obese diabetic women, but pregnancy should be delayed until the weight loss has stabilized after surgery. Smoking is of particular concern in women with diabetes, and a planned pregnancy may provide motivation to quit.

Treatment

Optimizing control of blood glucose

Oral hypoglycaemic agents will be changed to insulin in some centres, but in others, women will continue on metformin throughout pregnancy. Other oral hypoglycaemic agents are usually not recommended in pregnancy.

For those with relatively poor control, obtaining good blood glucose control may take a number of months. For some women, this will involve changing the insulin regimen to a more intensive method with insulin administered three or four times daily. For women with type 1 diabetes, an insulin pump may provide better control, but this has not been shown to unequivocally improve obstetric outcomes.

Folic acid-5 mg daily

Women with diabetes are at increased risk of having a baby with a neural tube defect, (anencephaly or spina bifida), and should take 5 mg of folate from 1 month prior to conception until 3 months of gestation to reduce this risk. This is in contrast to the usual 0.5 mg of folate recommended for other women.

Other medications

Many women with diabetes will be on angiotensin-converting enzyme (ACE) inhibitors, statins, diuretics, or oral hypoglycaemic agents. These should be changed to safer alternatives, in the preconception period if possible, or as soon as pregnancy is confirmed. Statins can usually be ceased. ACE inhibitors should be ceased. If an antihypertensive is required, control should be achieved with those documented to be safe in pregnancy such as methyldopa or labetalol.

Advice regarding a pregnancy with diabetes

The woman and her family should be informed of what to expect during pregnancy and possible outcomes. They should be made aware of the increased numbers of antenatal visits and the need for strict adherence to glucose control. They should also be informed of the increased rates of congenital abnormality, miscarriage, preeclampsia, preterm birth, and obstetric intervention and that these risks will relate to the degree of diabetic control.

Most women can be reassured that they are likely to successfully navigate pregnancy without long-t erm harm to their own health or that of their child. For the small number of women with significant renal impairment from diabetic nephropathy, pregnancy may cause a permanent deterioration in renal function—even to the extent of requiring renal dialysis. Decisions around whether or not to counsel against pregnancy should be undertaken with a multidisciplinary team.

First antenatal visit

Antenatal care should start as early in pregnancy as possible, especially if preconception care has not taken place. All of the aspects discussed earlier in prepregnancy care should be addressed again at the first antenatal visit.

Accurate dating is very important because of the risks of preterm delivery and the need for timed delivery. An ultrasound scan should be performed in the first trimester for accurate estimation of gestational age, and an agreed due date calculated and documented.

Congenital anomalies, especially cardiac abnormalities and neural tube defects, are increased, and the risk is proportional to the degree of maternal glycaemic control in the periconceptual period. Ultrasound assessment of fetal anatomy should be performed by an experienced sonographer at 20-22 weeks' gestation. An additional ultrasound assessment for structural abnormalities may also be performed at 12-16 weeks' gestation in those women who would consider termination of pregnancy in the presence of a serious congenital anomaly.

Women with diabetes, especially those with underlying hypertension or obesity, are at an increased risk of pre-eclampsia. This risk can be reduced by commencing 150 mg daily of aspirin and 1200 mg of calcium supplementation before 16 weeks of pregnancy.

Subsequent antenatal care

Care should be with a multidisciplinary team where possible, including an obstetrician, endocrinologist, diabetes educator, dietician, neonatologist, and midwife. Antenatal visits occur at increased frequency to enable increased maternal and fetal surveillance and careful management of the diabetes in the presence of changing glucose tolerance as the pregnancy advances and hormonal milieu changes.

Fetal surveillance

All women should pay attention to fetal movements and present for review early if there are any concerns that fetal movements have decreased. As women with diabetes are at increased risk of fetal loss, additional fetal surveillance is indicated in the third trimester. A common surveillance regimen includes ultrasound for fetal growth, amniotic fluid, and umbilical artery Doppler at 28, 32, and 36 weeks' gestation. These 4-weekly fetal growth assessments may be supplement with weekly cardiotocography and ultrasound for amniotic fluid and fetal Dopplers from 34 weeks.

Diabetes management

Women with type 1 diabetes will have increased difficulty with blood sugar control in early pregnancy if there is significant nausea or vomiting. Extra care must be taken to avoid hypoglycaemia or ketoacidosis in these situations. In this circumstance, glucose targets may need to be revised and multiple admissions to hospital may prove necessary.

For the reasons specified earlier, insulin requirements will increase during pregnancy. Home blood glucose monitoring should be performed multiple times each day, but the preferred regimen varies in diflerent units. A suggested testing plan is a morning fasting level, and either 1 or 2 hours after each meal. Some women may require more frequent testing, including overnight. A period of continuous glucose monitoring can be helpful if glucose control has been very difficult. Blood glucose targets vary but, as a guide, women should aim for fasting levels of 5.3 mmol/L, and either 1 hour of 7.8 mmol/L or 2 hours of 6.4 mmol/L. Regular HbA1c assessment during the pregnancy will help women and clinicians assess control of blood glucose.

Exercise should be encouraged in most women with diabetes as it improves glucose control, weight management, and feelings of wellbeing. Daily walking is generally recommended. Women with type 1 diabetes undertaking more strenuous exercise should monitor blood glucose more often while exercising to exclude hypoglycaemia.

Dietary management is very similar to women with gestational diabetes, but many women will benefit from additional individualized advice from a dietitian with experience in diabetes and pregnancy.

Assessment of retinopathy should be performed in early pregnancy and repeated later in pregnancy. Treatment of diabetic eye disease can be undertaken safely in pregnancy.

As women with diabetes are at increased risk of pre-eclampsia, frequent antenatal visits with measurement of blood pressure and urinalysis contribute to earlier detection of pre-eclampsia. Women with underlying hypertension and proteinuria are at particularly high risk of developing pre-eclampsia but diagnosis is more difficult. Aspirin commenced in early pregnancy with a view to preventing pre- eclampsia is commonly ceased at 36 weeks' gestation.

Pregnancy in women with diabetes can be very stressful because of the increased focus on risks and the increased workload for the woman in terms of visits and careful control of diabetes. Support and education for the woman and her family may help manage these extra stressors.

Timing and mode of birth

As the gestation advances toward and beyond the due date, the fetus of the woman with diabetes is at increased risk of fetal death in utero and birth trauma. To minimize these risks, birth is usually recommended at 37-38 weeks' gestation in an otherwise uncomplicated diabetic pregnancy.

For many women with pregnancy diabetes, a vaginal delivery can be recommended, subject to the same contraindications as for other women. However, macrosomia is a common complication of diabetes and shoulder dystocia is more likely than with an infant of the infant of a non-diabetic woman with the same birth weight. If the fetus is estimated to weigh more than 4500 g at the time of planned delivery, a caesarean section is usually recommended.

If an elective caesarean section is planned, antenatal corticosteroids may be recommended in the days prior birth to reduce the rate of respiratory distress syndrome in the newborn. Corticosteroids in women with diabetes will result in an increase in blood sugar levels, and this will often require a short-term increase in insulin.

The overall primary caesarean section rate is increased in women with prepregnancy diabetes due to macrosomia and increased rates of fetal compromise in labour. For the woman with a prior caesarean section, vaginal birth rates are low because of the need for timed delivery and a reluctance to induce labour in a diabetic woman with a uterine scar.

Intrapartum care

Delivery should take place in a hospital equipped to manage intrapartum and neonatal complications.

A plan should be made with the woman prior to labour with respect to insulin. Blood glucose levels should be measured every hour during labour. For women with type 2 diabetes, long-acting insulin should be stopped or reduced and short-acting insulin administered as needed according to test results. Women with type 1 diabetes will usually require an insulin and dextrose infusion to maintain stable blood glucose. Women having an elective caesarean section should be first on the elective list in the morning to better manage fasting, and there should be a staff member present at the time of delivery responsible for neonatal resuscitation.

Continuous electronic fetal monitoring should be used during labour because the fetus is at increased risk of intrapartum hypoxia. An experienced obstetrician should be present for delivery, and preparations made in anticipation of shoulder dystocia.

Postpartum care

In the first 24 hours after birth, insulin demand is usually low. Insulin requirements then usually return rapidly to prepregnancy levels. As lactation is established, further modification of the insulin regimen will be required. Tight control of diabetes may be difficult in the postpartum period as the woman adjusts to the needs of the baby and the changes in her own sleeping and food patterns.

Breastfeeding should be encouraged in women with diabetes, both to manage neonatal hypoglycaemia, and because breastfeeding may have a role in reducing the long-term risks to the baby of obesity and cardiovascular disease. In the past, infants of diabetic mothers were often routinely separated from their mothers and cared for in a neonatal special care or intensive care setting. The common consequence was increased difficulty in establishing breastfeeding.

Many women with diabetes choose to limit family size. All pregnancies in women with diabetes should be planned, so discussion and provision of postpartum contraception is very important. All of the available contraceptive options are acceptable for women with diabetes, limited only by the avoidance of oestrogen-based contraception in women who are breastfeeding, as for all other women.

Neonates

Babies of women with diabetes have increased rates of hypoglycaemia, hyperbilirubinaemia, and respiratory distress syndrome. Less commonly, they may have clinical or imaging/laboratory evidence of cardiomyopathy, polycythaemia, hypocalcaemia, or hypo- magnesaemia. The impact of diabetes on the baby is explained by the ‘Pederson' hypothesis. High levels of glucose cross the placenta and result in high blood glucose in the fetus. The fetus responds appropriately by increasing insulin and insulin-like growth factor (IGF) secretion. The IGF encourages fetal growth, and the high levels of insulin are maintained in the first days of life, resulting in neonatal hypoglycaemia.

The baby of a woman with diabetes should not be routinely separated from the mother, but will need regular measurements of blood glucose during the first few hours of life and additional observation for signs of clinical hypoglycaemia. Early feeding is recommended. The baby should have careful clinical examination for congenital abnormalities.

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Source: Arulkumaran S., Ledger W., Denny L., Doumouchtsis S. (eds.). Oxford Textbook of Obstetrics and Gynaecology. Oxford University Press,2020. — 928 p.. 2020

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