Pregnant women with diabetes have to manage both the effect of pregnancy on glucose control and its effect on pre-existing diabetic complications. Most women experience hypoglycaemia as a consequence of tightened glycaemic control and this impacts on daily living. Less commonly, diabetic ketoacidosis, a serious metabolic decompensation of diabetic control and a medical emergency, can cause foetal and maternal mortality.
Microvascular complications of diabetes include retinopathy and nephropathy. Retinopathy can deteriorate during pregnancy; hence, regular routine examination is required and, if indicated, ophthalmological input. Diabetic nephropathy significantly increases the risk of obstetric complications and impacts on foetal outcomes. Pregnancy outcome is closely related to pre-pregnancy renal function.
Diabetic pregnancy is contraindicated if the maternal complications of ischaemic heart disease or diabetic gastropathy are known to be present before pregnancy as there is a significant maternal mortality associated with both of these conditions.
Women with diabetes and their health-care professionals have to be mindful of both the impact of diabetes on pregnancy and its outcome and the impact of pregnancy on diabetes and its complications.
Diabetic women with pre-existing complications of diabetes are more likely to have a poor pregnancy outcome (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.3–4.9). The complications of maternal diabetes that can affect pregnancy may be categorised as those related to glycaemic control, hypoglycaemia and diabetic ketoacidosis (DKA); those related to microvascular complications, gastropathy, retinopathy and nephropathy and those related to macrovascular complications of which the most relevant is coronary heart disease.
To minimise the risk of poor pregnancy outcome, all diabetic women need the input of a skilled multidisciplinary team that includes consultant physician, obstetrician, diabetes midwife, diabetes nurse specialist and a dietician, with additional members such as opthalmologists or nephrologist, co-opted as required.
There is a dearth of robust evidence underpinning practice for the management of diabetic complications during pregnancy. Evidence in the form of randomised controlled trials (RCTs) has mostly been obtained from non-pregnant populations, whereas most studies in diabetic pregnancy have been case-controlled studies, observational cohort studies and reported clinical case studies.
Hypoglycaemia
There is sound evidence that optimal glucose control periconception reduces the risk of congenital malformations in the offspring and the risks of stillbirth, macrosomia and pre-eclampsia during pregnancy. The target set for optimal glucose control is a fasting glucose of 3.5–5.9 mmol l −1 with 1-h post prandial blood glucose of 7.8 mmol l −1 . The target for glycosylated haemoglobin (HbA1c) at preconception and in the first trimester is recommended as close to 6.1% as can be achieved without the risk of hypoglycaemia.
Not surprisingly, the most common adverse event for women with diabetes on insulin treatment is hypoglycaemia, a consequence of optimising glucose control, and this has significant implications for daily living. Reassuringly, poor pregnancy outcome is not associated with recurrent hypoglycaemia (OR 1.1, 95% CI 0.7–1.7) and severe hypoglycaemia (SH) (OR 1.3, 95% CI 0.7–2.3) during pregnancy.
Many women experience SH defined as all episodes, including hypoglycaemic coma, for which external help was needed. Women at risk of SH have a history of hypoglycaemia before pregnancy and hypoglycaemic unawareness. In a nationwide, prospective cohort study in the Netherlands, 41% of women in the first trimester had SH decreasing to 17% by the third trimester. The Confidential Enquiry into Maternal and Child Health (CEMACH) enquiry documented that 61% of women with type 1 diabetes had recurrent hypoglycaemic episodes during pregnancy and 25% had SH. Although women with type 2 diabetes were less at risk of SH, 21% of these women had recurrent episodes of hypoglycaemia. Women with type 1 diabetes have a three- to fivefold increased risk of SH during the first trimester. Asymptomatic nocturnal hypoglycaemia is also more common. Hypoglycaemia is more frequent in the first trimester but can also occur in the third trimester. These episodes are not prevented by preconception care. SH has been implicated in maternal deaths, and has been cited as the most common cause of maternal death for pregnant women with diabetes.
Although tight glucose control is recommended, it is not clear how tight this should be for benefit. An ongoing Cochrane Systematic review is assessing, from RCTs, the effects of different intensities of glycaemic control (tight vs. very tight) in pregnant women with pre-existing type 1 and type 2 diabetes. A secondary outcome of this review is hypoglycaemia requiring treatment during pregnancy.
Diagnosis
As all women on insulin therapy are at risk of hypoglycaemia during pregnancy. It is essential that women and their carers are taught to recognise the signs and symptoms of hypoglycaemia and know how to treat this effectively.
The signs and symptoms of hypoglycaemia include anxiety, nausea, palpitations, tremor, sweating, warmth and dizziness. During pregnancy, these symptoms can be misinterpreted as being due to pregnancy itself and therefore overlooked; hence, women need to be vigilant.
Frequent home blood glucose testing is recommended. Women are asked to test up to six times a day and this will usually include checking fasting blood glucose, 1-h post-prandial breakfast, lunch and tea, and again before bed. Hypoglycaemic unawareness is more common during pregnancy, and may only be detected by checking glucose levels.
Symptoms of hypoglycaemia
| Mild hypoglycaemia | Moderate hypoglycaemia |
| Sweating | Headache |
| Dizziness | Poor concentration |
| Trembling | Poor coordination |
| Tingling hands, feet, lips or tongue | Double vision |
| Hunger | Confusion |
| Anxiety Palpitations | Odd behaviour |
| Irritability | Slurred speech |
Treatment
It is important for all pregnant women to learn how to manage their diabetes. The diabetes team should make sure that women understand how to count carbohydrates and match this to insulin dosage, adjust their basal bolus insulin regimen in response to results from home glucose monitoring and balance exercise and insulin. Sometimes, despite intensive education and effort in partnership with diabetes nurses, women have problematic, recurrent, severe, disabling hypoglycaemia while trying to achieve the target levels set for glucose control. Continuous subcutaneous insulin infusion (CSII or insulin pump therapy) may be of benefit in this situation.
As the risk of hypoglycaemia is high and increases if activity changes or meals are omitted, all pregnant diabetic women on insulin should have readily available concentrated oral glucose solution. In practice, this means access to sugary drinks such as lucozade. Family members need to know how to use glucagon as this can be administered by a third party, if hypoglycaemia has rendered the woman unconscious.
Treatment of hypoglycaemia
The treatment for hypoglycaemia depends on its severity and is indicated thus:
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Mild hypoglycaemia may be treated with 12–20 g glucose – this is equivalent to four to six sugar lumps or 200 ml orange juice or other sweet drink or dextrose tablets;
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Moderate hypoglycaemia is treated with a sugary drink or a tablespoon of sugar dissolved in warm water; and
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SH is when the woman is unable to swallow or is unconscious; – a third party should inject 1 mg glucagon subcutaneously and call emergency services for help.
To prevent recurrent hypoglycaemia after the initial treatment of hypoglycaemia, a snack such as a sandwich or meal should be eaten.
DKA
This is a serious metabolic complication of diabetes and a medical emergency. Fortunately, the prevalence of DKA in diabetic pregnancy is low at 1–2%. It most commonly occurs in the second or third trimester or in pregnant women with new-onset type 1 diabetes, although it may affect women with type 2 diabetes or, more rarely, gestational diabetes. There is an increased risk of DKA developing in pregnancy, as, in pregnancy, there is a marked increase in insulin resistance and enhanced lipolysis and ketosis.
The maternal mortality rate secondary to DKA is not well established but foetal mortality has previously been reported ranging from 30% to 90%, although this has decreased to 10%. Foetal loss is related to the severity of the maternal illness and the degree of maternal decompensation.
Factors that predispose to the development of DKA include infection, vomiting, diabetic gastroparesis and the use of steroids and β sympathomimetic drugs. Vomiting and the use of betamimetic drugs accounted for 57% of the episodes of DKA in a case series.
Euglycaemic DKA in pregnancy is rare and has been reported in type 1 diabetes and gestational diabetes. Case reports highlight this as multifactorial in origin and linked to starvation ketoacidosis and/or alcoholic ketoacidosis.
Diagnosis
Diabetic pregnant women with nausea, vomiting and persistent moderate hyperglycaemia should be evaluated for DKA. The presence of hyperglycaemia, acidosis and ketonaemia are characteristic of DKA. The diagnosis is confirmed by laboratory tests of plasma glucose, serum bicarbonate, urea, creatinine and electrolytes and pH as determined by arterial blood gases and serum and urinary ketones.
A high level of suspicion is necessary as signs may include hyperventilation, altered mental status, weakness, dehydration and polyuria. Additional warning symptoms include abdominal pain and pyrexia. Hyperventilation and altered mental status occur as a result of the ketoacidosis, and there is a characteristic smell of ketones on the breath. Dehydration may be secondary to vomiting and exacerbated by the osmotic diuresis secondary to hyperglycaemia.
Treatment
Prevention of DKA is key. All diabetic women planning pregnancy or already pregnant should be aware of and educated about DKA. Women should be aware of ‘sick-day rules’ (see box) and check their urine for ketones at times of illness or when their glucose levels are persistently higher than 10 mmol l −1 and promptly report positive values. They should know whom to contact if they are unwell. This should be formulated in a clear, agreed-upon, management plan for hyperglycaemia with ketonuria.
The treatment of DKA includes fluid replacement, insulin administration and identification and treatment of the underlying cause. The treatment of DKA in pregnancy is the same as the treatment of DKA in the non-pregnant population, apart from the requirement of foetal monitoring. It is best managed in a critical care unit in a hospital with experience in monitoring high-risk pregnancies. Treatment protocols correct volume depletion, infuse intravenous insulin with careful monitoring to correct hyperglycaemia and correct electrolyte disturbances.
Electronic foetal monitoring is recommended for gestational ages greater than 24 weeks. During the acute episode of DKA, foetal-heart-rate abnormalities are likely to be observed. The mother’s condition must be stable before induction of labour or emergency caesarean section is carried out because of the increased risk of maternal mortality.
- •
Do not stop insulin injections
- •
If you are unwell act immediately and seek prompt treatment for infections
- •
Try to eat a normal diet – if you cannot manage this replace with fluids such as milk or juice
- •
Drink plenty of water –5-7 pints /day. Sip through the day
- •
Keep testing your blood at least 4 times a day or every 2–4 h if necessary
- •
Test urine for ketones at least 4 times a day
- •
Rest as exercise can make ketoacidosis worse
Seek help if:
You have ketones
Your blood glucose levels stay high
You are vomiting and unable to keep anything down
You do not improve quickly
You are worried
Your blood sugars are low
If flushed, persistent vomiting, deep rapid breathing and drowsiness then hospital treatment is needed quickly
DKA
This is a serious metabolic complication of diabetes and a medical emergency. Fortunately, the prevalence of DKA in diabetic pregnancy is low at 1–2%. It most commonly occurs in the second or third trimester or in pregnant women with new-onset type 1 diabetes, although it may affect women with type 2 diabetes or, more rarely, gestational diabetes. There is an increased risk of DKA developing in pregnancy, as, in pregnancy, there is a marked increase in insulin resistance and enhanced lipolysis and ketosis.
The maternal mortality rate secondary to DKA is not well established but foetal mortality has previously been reported ranging from 30% to 90%, although this has decreased to 10%. Foetal loss is related to the severity of the maternal illness and the degree of maternal decompensation.
Factors that predispose to the development of DKA include infection, vomiting, diabetic gastroparesis and the use of steroids and β sympathomimetic drugs. Vomiting and the use of betamimetic drugs accounted for 57% of the episodes of DKA in a case series.
Euglycaemic DKA in pregnancy is rare and has been reported in type 1 diabetes and gestational diabetes. Case reports highlight this as multifactorial in origin and linked to starvation ketoacidosis and/or alcoholic ketoacidosis.
Diagnosis
Diabetic pregnant women with nausea, vomiting and persistent moderate hyperglycaemia should be evaluated for DKA. The presence of hyperglycaemia, acidosis and ketonaemia are characteristic of DKA. The diagnosis is confirmed by laboratory tests of plasma glucose, serum bicarbonate, urea, creatinine and electrolytes and pH as determined by arterial blood gases and serum and urinary ketones.
A high level of suspicion is necessary as signs may include hyperventilation, altered mental status, weakness, dehydration and polyuria. Additional warning symptoms include abdominal pain and pyrexia. Hyperventilation and altered mental status occur as a result of the ketoacidosis, and there is a characteristic smell of ketones on the breath. Dehydration may be secondary to vomiting and exacerbated by the osmotic diuresis secondary to hyperglycaemia.
Treatment
Prevention of DKA is key. All diabetic women planning pregnancy or already pregnant should be aware of and educated about DKA. Women should be aware of ‘sick-day rules’ (see box) and check their urine for ketones at times of illness or when their glucose levels are persistently higher than 10 mmol l −1 and promptly report positive values. They should know whom to contact if they are unwell. This should be formulated in a clear, agreed-upon, management plan for hyperglycaemia with ketonuria.
The treatment of DKA includes fluid replacement, insulin administration and identification and treatment of the underlying cause. The treatment of DKA in pregnancy is the same as the treatment of DKA in the non-pregnant population, apart from the requirement of foetal monitoring. It is best managed in a critical care unit in a hospital with experience in monitoring high-risk pregnancies. Treatment protocols correct volume depletion, infuse intravenous insulin with careful monitoring to correct hyperglycaemia and correct electrolyte disturbances.
Electronic foetal monitoring is recommended for gestational ages greater than 24 weeks. During the acute episode of DKA, foetal-heart-rate abnormalities are likely to be observed. The mother’s condition must be stable before induction of labour or emergency caesarean section is carried out because of the increased risk of maternal mortality.
- •
Do not stop insulin injections
- •
If you are unwell act immediately and seek prompt treatment for infections
- •
Try to eat a normal diet – if you cannot manage this replace with fluids such as milk or juice
- •
Drink plenty of water –5-7 pints /day. Sip through the day
- •
Keep testing your blood at least 4 times a day or every 2–4 h if necessary
- •
Test urine for ketones at least 4 times a day
- •
Rest as exercise can make ketoacidosis worse
Seek help if:
You have ketones
Your blood glucose levels stay high
You are vomiting and unable to keep anything down
You do not improve quickly
You are worried
Your blood sugars are low
If flushed, persistent vomiting, deep rapid breathing and drowsiness then hospital treatment is needed quickly
Gastroparesis diabeticorum
Gastroparesis is one of the few complications in which pregnancy is contraindicated. Women should be advised at preconception counselling that there is a significant risk of morbidity and a poor perinatal outcome if pregnancy is pursued.
Gastroparesis occurs in people with long-standing diabetes, who have microvascular complications including retinopathy, nephropathy and neuropathy. It is the presence of delayed gastric emptying in the absence of mechanical obstruction. Until recently, diabetic gastroparesis was classified as a component of diabetic autonomic neuropathy, a poorly understood complication of long-standing diabetes. Autonomic neuropathy can affect the cardiovascular, gastrointestinal and genitourinary system, and is associated with metabolic dysfunction, disorders of sweating and pupillary abnormalities. Abnormalities of cardiovascular autonomic function have been used as a marker of more generalised autonomic dysfunction, including gastropathy. Emerging evidence suggests that the correlation between disordered gastric motility and abnormal cardiovascular autonomic function in diabetic patients is weak. A recent review has highlighted that gastric motility is influenced by ambient glucose levels, and that disordered autonomic function is unlikely to be the sole cause of diabetic gastropathy.
Symptoms
Symptoms of delayed gastric emptying include nausea, bloating, postprandial fullness and vomiting. The presence of symptoms correlates poorly with rate of gastric empting. Severe symptoms may result in malnutrition, impaired glucose control, poor quality of life and a high rate of hospitalisation.
Diagnosis
The diagnosis of gastropathy is confirmed by measuring gastric emptying using the ‘gold standard’ of measurement by scintigraphy. But, before proceeding to this, mechanical obstruction should be ruled out by the use of upper gastrointestinal (GI) endoscopy or by a barium study. Food retained in the stomach after a 12-h fast is suggestive of gastroparesis.
Treatment
Treatment is difficult. The key principles of treatment are correction of exacerbating factors such as hyperglycaemia and electrolyte disturbances, the provision of nutritional support and the use of prokinetic therapies.
Mild gastroparesis can be controlled by maintaining weight and nutrition. Severe gastroparesis, when nutrition is compromised, may require nutritional support by enteral feeds. Only people with severe gastroparesis are considered for jejunal feeding or gastrostomy tubes.
Pharmacological therapy is with prokinetic agents that tend to improve gastric emptying. These include erythromycin, metoclopramide and domperidone. Other treatments tried include antiemetics such as ondansetron. Physical treatments recently studied for refractory symptoms include gastric electrical stimulation and intra pyloric injection of botulinum toxin.
Implications for pregnancy
Women known to have gastropathy before pregnancy should be counselled that it will likely worsen during pregnancy. They may expect difficulties with nutrition and might require parenteral nutrition during pregnancy. Gastroparesis poses an extreme risk to maternal health, second only to coronary heart disease.
Diagnosis in pregnancy
If gastropathy is known to be present before pregnancy, the diagnosis is straightforward. However, it may not have been recognised and presents in pregnancy with nausea and vomiting. The differential diagnosis includes hyperemesis gravidarum.
There are no guidelines available on the management of the combination of hyperemesis and gastropathy. One case report found the use of prednisolone is helpful in management. In very severe cases, termination may be considered.
Effect on glucose control
Delayed gastric emptying has a major impact on glucose control and hyperglycaemia exacerbates the delay in gastric emptying. Postprandial hyperglycaemia is difficult to manage with consequences of either hypo- or hyperglycaemia.
Management of vomiting
There is insufficient data about the safety of antiemetics in pregnancy. Recent UK National Institute for Health and Clinical Excellence (NICE) guidelines recommend ginger, acupressure and anti-histamines for the treatment of vomiting in pregnancy. Prokinetic therapies such as erthyromycin and metoclopramide may be used.
Summary
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Diabetic gastropathy is a contraindication to pregnancy.
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Women should be aware of the risks and informed of this at preconception counselling.
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Women who become pregnant should make early contact with their diabetes team as vomiting and dehydration are a significant risk throughout pregnancy.
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Treatment is symptomatic, but many therapies are contraindicated in pregnancy.
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