maternal complications in diabetic pregnancy

Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 77–90

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Best Practice & Research ClinicalObstetrics and Gynaecology

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7

Maternal complications in diabetic pregnancy

Gillian Hawthorne, PhD, FRCP, Consultant Diabetologist *

Newcastle Diabetes Centre, Newcastle General Hospital, Westgate Road, Newcastle NE4 6BE, UK

Keywords:hypoglycaemiadiabetic ketoacidosisgastropathynephropathyretinopathyvascular disease

* Tel: þ44 191 256 3393; Fax: þ44 191 256 3235E-mail address: Gillian.hawthorne@newcastle-p

1521-6934/$ – see front matter � 2010 Elsevier Ltdoi:10.1016/j.bpobgyn.2010.10.015

Pregnant women with diabetes have to manage both the effect ofpregnancy on glucose control and its effect on pre-existing diabeticcomplications. Most women experience hypoglycaemia as a conse-quence of tightened glycaemic control and this impacts on dailyliving. Less commonly, diabetic ketoacidosis, a serious metabolicdecompensation of diabetic control and a medical emergency, cancause foetal and maternal mortality.Microvascular complications of diabetes include retinopathy andnephropathy. Retinopathy can deteriorate during pregnancy; hence,regular routine examination is required and, if indicated, ophthal-mological input. Diabetic nephropathy significantly increases the riskof obstetric complications and impacts on foetal outcomes. Preg-nancy outcome is closely related to pre-pregnancy renal function.Diabetic pregnancy is contraindicated if the maternal complica-tions of ischaemic heart disease or diabetic gastropathy are knownto be present before pregnancy as there is a significant maternalmortality associated with both of these conditions.

� 2010 Elsevier Ltd. All rights reserved.

Women with diabetes and their health-care professionals have to be mindful of both the impact ofdiabetes 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 preg-nancy outcome (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.3–4.9).1 The complications ofmaternal diabetes that can affect pregnancy may be categorised as those related to glycaemic control,hypoglycaemia and diabetic ketoacidosis (DKA); those related to microvascular complications, gas-tropathy, retinopathy and nephropathy and those related to macrovascular complications of which themost relevant is coronary heart disease.

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G. Hawthorne / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 77–9078

To minimise the risk of poor pregnancy outcome, all diabetic women need the input of a skilledmultidisciplinary team that includes consultant physician, obstetrician, diabetes midwife, diabetesnurse specialist and a dietician, with additional members such as opthalmologists or nephrologist, co-opted as required.2,3

There is a dearth of robust evidence underpinning practice for the management of diabeticcomplications during pregnancy. Evidence in the form of randomised controlled trials (RCTs) hasmostly been obtained from non-pregnant populations, whereas most studies in diabetic preg-nancy have been case-controlled studies, observational cohort studies and reported clinical casestudies.

Hypoglycaemia

There is sound evidence that optimal glucose control periconception reduces the risk of congenitalmalformations in the offspring and the risks of stillbirth, macrosomia and pre-eclampsia duringpregnancy. The target set for optimal glucose control is a fasting glucose of 3.5–5.9 mmol l�1 with 1-hpost prandial blood glucose of 7.8 mmol l�1.2 The target for glycosylated haemoglobin (HbA1c) atpreconception and in the first trimester is recommended as close to 6.1% as can be achieved withoutthe risk of hypoglycaemia.3

Not surprisingly, the most common adverse event for women with diabetes on insulin treatmentis hypoglycaemia, a consequence of optimising glucose control, and this has significant implicationsfor daily living. Reassuringly, poor pregnancy outcome is not associated with recurrent hypo-glycaemia (OR 1.1, 95% CI 0.7–1.7) and severe hypoglycaemia (SH) (OR 1.3, 95% CI 0.7–2.3) duringpregnancy.1

Many women experience SH defined as all episodes, including hypoglycaemic coma, for whichexternal help was needed.4 Women at risk of SH have a history of hypoglycaemia before pregnancyand hypoglycaemic unawareness.5,6 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.7 The Confi-dential Enquiry into Maternal and Child Health (CEMACH) enquiry documented that 61% of womenwith 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 recurrentepisodes of hypoglycaemia.1 Womenwith type 1 diabetes have a three- to fivefold increased risk ofSH during the first trimester.6 Asymptomatic nocturnal hypoglycaemia is also more common.8

Hypoglycaemia is more frequent in the first trimester but can also occur in the third trimester.These episodes are not prevented by preconception care.9 SH has been implicated in maternaldeaths,7 and has been cited as the most common cause of maternal death for pregnant womenwithdiabetes.10

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 ofglycaemic control (tight vs. very tight) in pregnant women with pre-existing type 1 and type 2diabetes.11 A secondary outcome of this review is hypoglycaemia requiring treatment duringpregnancy.

Diagnosis

As all women on insulin therapy are at risk of hypoglycaemia during pregnancy. It is essential thatwomen and their carers are taught to recognise the signs and symptoms of hypoglycaemia and knowhow to treat this effectively.2,3

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 topregnancy 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 timesa day and this will usually include checking fasting blood glucose, 1-h post-prandial breakfast, lunchand tea, and again before bed. Hypoglycaemic unawareness is more common during pregnancy, andmay only be detected by checking glucose levels.

G. Hawthorne / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 77–90 79

Symptoms of hypoglycaemia

Mild hypoglycaemia Moderate hypoglycaemiaSweating HeadacheDizziness Poor concentrationTrembling Poor coordinationTingling hands, feet, lips or tongue Double visionHunger Confusion
Anxiety Palpitations Odd behaviourIrritability Slurred speech
Treatment

It is important for all pregnant women to learn how to manage their diabetes. The diabetes teamshould make sure that women understand how to count carbohydrates and match this to insulindosage, adjust their basal bolus insulin regimen in response to results from home glucose monitoringand balance exercise and insulin. Sometimes, despite intensive education and effort in partnershipwith diabetes nurses, women have problematic, recurrent, severe, disabling hypoglycaemia whiletrying 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, allpregnant 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 touse glucagon as this can be administered by a third party, if hypoglycaemia has rendered the womanunconscious.

Treatment of hypoglycaemia

The treatment for hypoglycaemia depends on its severity and is indicated thus:

� Mild hypoglycaemia may be treated with 12–20 g glucose – this is equivalent to four to six sugarlumps or 200 ml orange juice or other sweet drink or dextrose tablets;

� Moderate hypoglycaemia is treated with a sugary drink or a tablespoon of sugar dissolved inwarmwater; and

� SH is when the woman is unable to swallow or is unconscious; – a third party should inject 1 mgglucagon subcutaneously and call emergency services for help.

To prevent recurrent hypoglycaemia after the initial treatment of hypoglycaemia, a snack such asa sandwich or meal should be eaten.

DKA

This is a serious metabolic complication of diabetes and a medical emergency. Fortunately, theprevalence of DKA in diabetic pregnancy is low at 1–2%.12 It most commonly occurs in the second orthird trimester or in pregnant women with new-onset type 1 diabetes, although it may affect womenwith type 2 diabetes or, more rarely, gestational diabetes.12,13 There is an increased risk of DKAdeveloping in pregnancy, as, in pregnancy, there is a marked increase in insulin resistance andenhanced lipolysis and ketosis.14

The maternal mortality rate secondary to DKA is not well established but foetal mortality haspreviously been reported ranging from 30% to 90%, although this has decreased to 10%.12,13 Foetal loss isrelated 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 gastro-paresis and the use of steroids and b sympathomimetic drugs. Vomiting and the use of betamimeticdrugs accounted for 57% of the episodes of DKA in a case series.15


Euglycaemic DKA in pregnancy is rare and has been reported in type 1 diabetes and gestationaldiabetes. Case reports highlight this as multifactorial in origin and linked to starvation ketoacidosisand/or alcoholic ketoacidosis.16,17

Diagnosis

Diabetic pregnantwomenwithnausea, vomiting andpersistentmoderatehyperglycaemia should beevaluated for DKA.2 The presence of hyperglycaemia, acidosis and ketonaemia are characteristic of DKA.Thediagnosis is confirmedby laboratory testsofplasmaglucose, serumbicarbonate, urea, creatinine andelectrolytes 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 andpyrexia. Hyperventilation and altered mental status occur as a result of the ketoacidosis, and there isa characteristic smell of ketones on the breath. Dehydration may be secondary to vomiting andexacerbated by the osmotic diuresis secondary to hyperglycaemia.

Treatment

Prevention of DKA is key. All diabetic women planning pregnancy or already pregnant should beaware of and educated about DKA.Women should be aware of ‘sick-day rules’ (see box) and check theirurine for ketones at times of illness orwhen their glucose levels are persistently higher than10 mmol l�1

and promptly report positive values. They should knowwhom to contact if they are unwell. This shouldbe formulated in a clear, agreed-upon, management plan for hyperglycaemia with ketonuria.

The treatment of DKA includes fluid replacement, insulin administration and identification andtreatment of the underlying cause. The treatment of DKA in pregnancy is the same as the treatment ofDKA in the non-pregnant population, apart from the requirement of foetal monitoring. It is bestmanaged in a critical care unit in a hospital with experience in monitoring high-risk pregnancies.2

Treatment protocols correct volume depletion, infuse intravenous insulin with careful monitoring tocorrect hyperglycaemia and correct electrolyte disturbances.18

Electronic foetal monitoring is recommended for gestational ages greater than 24weeks. During theacute episode of DKA, foetal-heart-rate abnormalities are likely to be observed. The mother’s conditionmust be stable before induction of labour or emergency caesarean section is carried out because of theincreased risk of maternal mortality.2,3,12

Sick day rules

� 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 ketonesYour blood glucose levels stay highYou are vomiting and unable to keep anything downYou do not improve quicklyYou are worriedYour blood sugars are low

If flushed, persistent vomiting, deep rapid breathing and drowsiness then hospital treatment isneeded quickly


Gastroparesis diabeticorum

Gastroparesis is one of the few complications in which pregnancy is contraindicated. Womenshould be advised at preconception counselling that there is a significant risk of morbidity and a poorperinatal outcome if pregnancy is pursued.3

Gastroparesis occurs in people with long-standing diabetes, who have microvascular complicationsincluding retinopathy, nephropathyandneuropathy. It is thepresence of delayedgastric emptying in theabsence of mechanical obstruction.19,20 Until recently, diabetic gastroparesis was classified asa component of diabetic autonomic neuropathy, a poorly understood complication of long-standingdiabetes. Autonomic neuropathy can affect the cardiovascular, gastrointestinal and genitourinarysystem, and is associated with metabolic dysfunction, disorders of sweating and pupillary abnormali-ties.21 Abnormalities of cardiovascular autonomic function have been used as a marker of more gener-alised autonomic dysfunction, including gastropathy. Emerging evidence suggests that the correlationbetween disordered gastric motility and abnormal cardiovascular autonomic function in diabeticpatients is weak. A recent review has highlighted that gastric motility is influenced by ambient glucoselevels, and that disordered autonomic function is unlikely to be the sole cause of diabetic gastropathy.19

Symptoms

Symptoms of delayed gastric emptying include nausea, bloating, postprandial fullness and vomit-ing. The presence of symptoms correlates poorly with rate of gastric empting. Severe symptoms mayresult 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 beruled out by the use of upper gastrointestinal (GI) endoscopy or by a barium study. Food retained in thestomach after a 12-h fast is suggestive of gastroparesis.

Treatment

Treatment is difficult. The key principles of treatment are correction of exacerbating factors such ashyperglycaemia and electrolyte disturbances, the provision of nutritional support and the use ofprokinetic 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 withsevere gastroparesis are considered for jejunal feeding or gastrostomy tubes.

Pharmacological therapy is with prokinetic agents that tend to improve gastric emptying. Theseinclude erythromycin, metoclopramide and domperidone. Other treatments tried include antiemeticssuch as ondansetron. Physical treatments recently studied for refractory symptoms include gastricelectrical stimulation and intra pyloric injection of botulinum toxin.19,20

Implications for pregnancy

Women known to have gastropathy before pregnancy should be counselled that it will likely worsenduringpregnancy. Theymayexpect difficultieswithnutrition andmight require parenteral nutritionduringpregnancy.Gastroparesisposesanextremerisk tomaternalhealth, secondonly tocoronaryheartdisease.2,22

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 differentialdiagnosis includes hyperemesis gravidarum.


There are no guidelines available on the management of the combination of hyperemesis andgastropathy. One case report found the use of prednisolone is helpful in management.23 In very severecases, termination may be considered.

Effect on glucose control

Delayed gastric emptying has a major impact on glucose control and hyperglycaemia exacerbatesthe delay in gastric emptying. Postprandial hyperglycaemia is difficult tomanagewith consequences ofeither hypo- or hyperglycaemia.

Management of vomiting

There is insufficient data about the safety of antiemetics in pregnancy. Recent UK National Institutefor Health and Clinical Excellence (NICE) guidelines recommend ginger, acupressure and anti-hista-mines for the treatment of vomiting in pregnancy.24 Prokinetic therapies such as erthyromycin andmetoclopramide may be used.

Summary

� Diabetic gastropathy is a contraindication to pregnancy.� Women should be aware of the risks and informed of this at preconception counselling.� Women who become pregnant should make early contact with their diabetes team as vomitingand dehydration are a significant risk throughout pregnancy.

� Treatment is symptomatic, but many therapies are contraindicated in pregnancy.

Diabetic retinopathy

Diabetic retinopathy is the major cause of blindness in those of working age in the UK and USA.25,26

It is characterised as non-proliferative retinopathy and proliferative retinopathy,27,28 and its presencecan only be determined by examining the retina through dilated pupils, preferably using digital retinalphotography. The earliest clinical signs of non-proliferative retinopathy are microaneurysms and dotintra-retinal haemorrhages. These lesions may increase with progression of the condition and cotton-wool spots, a marker for ischaemia of the retina, may develop. Proliferative retinopathy is diagnosedwhen new blood vessels form that develop from the retinal circulation and grow into the vitreouscavity. These new blood vessels can bleed causing vitreous haemorrhage, and may also developcontractile fibrous tissue that causes retinal detachment. Untreated proliferative retinopathy causesloss of vision from vitreous haemorrhage and/or retinal detachment, and later in its course may lead toneovascular glaucoma. In addition, maculopathy due to macular oedema is a cause of severe loss ofcentral vision.

Screening programmes have been developed to detect and treat diabetic eye disease.In England, the English National Screening Programme for Diabetic Retinopathy uses digital retinal

photographs to grade diabetic eyes into levels by defining the presence and severity of diabetic reti-nopathy, presence and severity of referable maculopathy and presence of photocoagulation scars.29

Risk factors

Risk factors for the development of diabetic retinopathy include the duration of diabetes, glycaemiccontrol and blood pressure control and are discussed below:

� The duration of diabetes is the most closely linked to an increasing incidence of retinopathy;� Tight glycaemic control has beendemonstrated toprotect against the development andprogressionof retinopathy4,30; and

� Tightbloodpressure control is protective against thedevelopment andprogressionof retinopathy.31


Diabetic retinopathy in pregnancy

There are no RCTs on the management of diabetic retinopathy in pregnancy. All evidence has beenderived from cohort studies.

Although it is unusual for diabetic retinopathy to develop de novo in the eyes of women withdiabetes during pregnancy,32 those women known to have diabetic retinopathy pre-pregnancy are atan increased risk of progression of this condition.32–36 Factors that increase the risk of progression ofretinopathy include longer duration of diabetes (>10 years) and the presence during pre-pregnancy ofmoderate-to-severe retinopathy.35 During pregnancy, rapid improvement of glycaemic control in thosewith poor glucose control and known retinopathy has been shown to worsen diabetic retinopathy.32

Post-partum, the severity of the retinopathy may regress and complete remission may occur, iftherewas no retinopathy present before the pregnancy.37 Proliferative retinopathymay not regress andshould be followed closely by an ophthalmologist with expertise in diabetic retinopathy.2,3 It has beensuggested that treatment with photocoagulation during pregnancy and in the first months afterdelivery should be delayed, if possible, as it had been considered that development of persistentproliferative retinopathy is exceptional. Laser photocoagulation should be considered in sight-threatening diabetic retinopathy, if retinal neovascularisation, clinically significant macular oedema orvery severe non-proliferative retinopathy is identified.3 Others suggest that intervention with laserphotocoagulation should be even earlier when severe preproliferative change occurs.38 Close follow-uppost-partum is required for up to 1 year.

After the pregnancy is completed, there is no long-term effect of pregnancy on the course of diabeticretinopathy and the development of sight-threatening retinopathy.39

Management and treatment

Glycaemic control

It is well known from the Diabetes Control and Complications Trial (DCCT) trial4 that diabeticretinopathy may progress when glycaemic control is tightened. Despite this, all diabetic women needto have good glycaemic control at and around the time of conception; hence, rapid optimisation ofglucose control is recommended, even in the presence of diabetic retinopathy.

Examination for diabetic retinopathy- NICE Guidance2

� At the first antenatal clinic visit all pregnant women with pre-existing diabetes should havean eye examination using retinal assessment by digital imaging with mydriasis using tropi-camide. If this assessment is normal, it should be repeated again at 28 weeks gestation.

� If any diabetic retinopathy is present, an additional eye examination using digital imagingshould be performed at 16–20 weeks.

� Women with any evidence of macular oedema, severe non proliferative retinopathy or anyproliferative retinopathy on examination should be referred to an ophthalmologist skilled inmanaging diabetic retinopathy. Monitoring with a monthly examination may be required.

Treatment for diabetic retinopathy

High-risk proliferative retinopathy and clinically significant macular oedema are treated by laserphotocoagulation during pregnancy. Some cases of severe non-proliferative retinopathy may alsorequire laser treatment.

Women, who have preproliferative diabetic retinopathy diagnosed during pregnancy, should haveophthalmological follow-up for at least 6 months to 1 year post-partum.


Delivery

Diabetic retinopathy is not a contraindication to vaginal birth. For women with untreated prolif-erative retinopathy, vaginal delivery is best avoided. This is because the Valsalva manoeuvre increasesthe risk of developing retinal and vitreous haemorrhage. Assisted second-stage delivery or caesareansection may be appropriate in this situation.

Diabetic nephropathy

Diabetic nephropathy is a long-term microvascular complication of diabetes.40 It is a progressivedisease that is categorised as:

� Microalbuminuria (incipient nephropathy). This occurs when small amounts of albumin (30–300 mg 24 h) are excreted in the urine, but, at this stage, the glomerular filtration rate (GFR) isnormal. Microalbuminuria may increase over the years. The rate of increase in microalbuminuriaexcretion is linked to blood pressure and glycaemic control.

� Macroalbuminuria or proteinuria (overt nephropathy). This is diagnosed when urinary albuminexcretion rate (UAE)> 300 mg 24 h and total urinary protein> 300 mg 24 h. There is a progressivedecline in GFR.

� End-stage renal disease. It is characterised by decreasing creatinine clearance, increasing serumcreatinine and uraemia.

The presence of diabetic nephropathy has a major influence on pregnancy outcome for both motherand baby. Maternal hazards include possible renal failure and pre-eclampsia, whereas foetal compli-cations include intrauterine growth restriction, prematurity and foetal death.2,40

Preconception counselling

Theoutcomeof pregnancy forwomenwith establisheddiabetic nephropathy is closely linked to theirrenal function asmeasured by serumcreatinine. The chance of a successful pregnancy declines as serumcreatinine increases. In addition, the higher the prepregnancy creatinine concentrations, the higher therisk of permanent loss of renal function.41,42 Womenwith established diabetic nephropathy need to beadvised that diabetic nephropathy is progressive and that renal function will decline over a period ofmonths and years. An important consequence of this is that as diabetic nephropathy deteriorates withtime, and if pregnancy is desired, this should be embarked on sooner rather than delaying till renalfunction has declined further. This needs to be clearly explained at preconception counselling.

Changes to renal function in pregnancy

During normal pregnancy, the GFR increases by 50–100% and proteinuria increases.43 Innephropathy, the GFR may increase slightly or even decrease. Patients with clinical nephropathy mayhave dramatic increases in protein excretion. Post-partum, protein excretion reduces back to pre-pregnancy levels for most women. Proteinuria may develop for the first time in women with diabetesnot recognised as nephropathic, and, in the second half of pregnancy, the presence of proteinuria mayindicate pre-eclampsia.

Outcome related to pre-pregnancy renal function

Symptoms in chronic kidney disease are uncommon until the GFR declines to<25% of normal. Morethan 50% renal function can be lost before serum creatinine rises above 120 mmol l�1.42 Provided pre-pregnancy renal function is normal or near normal with serum creatinine <124 mmol l�1, proteinurialess than the nephrotic range (>3 g 24 h) and hypertension absent or controlled, the obstetric outcome


is usually successful,44,45 and the long-term course of diabetic nephropathy is not affected.46, 47

Aggressive anti-hypertensive therapy may be required.A small study found that the relative risk for pre-eclampsia in women with pre-pregnancy

microalbuminuria is 16 [95%CI 4–69] and suggested that this is used as a predictor of pre-eclampsia.48

A recent, larger, prospective, population-based study of 846 womenwith type 1 diabetes reported thatthe presence ofmicroalbuminuria in early pregnancy is associatedwith a fourfold increase in the risk ofdeveloping pre-eclampsia, and that pre-eclampsia was associated with a threefold higher risk ofdelivery before 34 weeks.49 Pre-term delivery is increased mainly as an outcome of the increase in pre-eclampsia.50 A prospective study of 117 pregnant women with type 1 diabetes treated aggressively tomaintain BP at <135/85 found that none of the women with microalbuminuria developed pre-eclampsia and the frequency of pre-term delivery was equal to those with non albuminuria.51

In women with moderate-to-severe renal compromise, there is a >40% chance of acceleratedprogression of renal damage secondary to pregnancy.52 In 67 women with primary renal disease andmoderate-to-severe renal insufficiency who had 87 pregnancies, the frequency of hypertension rosefrom 28% at baseline to 41%, and there was worsening proteinuria rising from 23% to 41%. Pregnancy-related loss of renal function occurred in 43% and pre-term delivery in 59%. Although foetal growthrestrictionwas present in 37%, foetal survival was high at 93%.53 The worsening of renal function mightbe contributed to by inadequate anti-hypertensive treatment.54

Obstetric outcome

Those with a serum creatinine between 125 and 180 mmol l�1 pre-pregnancy have an 80% chance ofsuccessful outcome. This falls to a 75% chance if serum creatinine is 180–220 mmol l�1 and falls again to60% if serum creatinine is >220 mmol l�1.41,55

Foetal outcomes

Intrauterine growth restriction still occurs at approximately twice the rate of the general pop-ulation, and this is related to the severity of the nephropathy and hypertension. Pre-term delivery isa significant problem attributable to pre-eclampsia, accelerated hypertension or foetal distress.3

Maternal outcomes

The risk of complications for some women with nephropathy are so high that pregnancy is rela-tively contraindicated. Womenwith known ischaemic heart disease and those at borderline end-stagerenal disease creatinine clearance less than 30 mlmin�1 should be considered for dialysis or renaltransplantation before pregnancy. Further, those women with uncontrolled hypertension have a lowchance of a successful pregnancy.

Medical management

Maternal and foetal outcomes for women with diabetic nephropathy can be optimised usinga multidisciplinary team approach.

Pre-pregnancy: at first contact when pregnant

At first contact in pregnancy, womenwith diabetes should have a renal assessment, which includesclinical and biochemical parameters (urea, creatinine, electrolytes, albumin and full blood count,urinalysis and urine culture). Proteinuria is assessed by either using 24-h collection of urine or by a spottest for total urine protein:creatinine ratio. Estimated GFR (eGFR) should not be used during pregnancy.These tests should be checked frequently – at least every 4 weeks or more often, depending on theclinical situation.2

If serum creatinine is abnormal (120 mmol l�1 ormore) or if total protein excretion exceeds 2 g day�1,input from a nephrologist may be helpful.


Blood pressure

Drugs such asmethyldopa, calcium channel blockers, hydalazine and labetalol are safe and effective.Targets for blood pressure (BP) management are controversial. Every 10-mm fall in systolic BP isassociated with a mean 145-g reduction in mean birthweight. There is a consensus that BP should bemaintained no higher than 140/90 mmHg,44 and this is supported by emerging evidence thataggressive management of BP reduces the risks of preeclampsia and pre-term delivery.56

Angiotensin-converting enzyme inhibitors (ACE inhibitors) in diabetic nephropathy

Prior to pregnancy, ACE inhibitors are the treatment of choice for diabetic nephropathy.In pregnancy and prepregnancy, all foetotoxic drugs such as angiotensin-converting enzyme ACE

inhibitors should be stopped.57 In the first trimester, ACE inhibitors are linked to an increased risk ofmajor congenital malformations,58 whilst during the second and third trimester of pregnancy, they areassociated with foetopathy, a group of conditions that include oligohydramnios, intrauterine growthrestriction, hypocalvaria, renal dysplasia, anuria, renal failure and death.

Nephrotic syndrome

Thromboprophylaxis should be considered for women with proteinuria above 5 g day�1 and thisshould be continued for 6 weeks post-partum.2

Coronary artery disease

Coronary artery disease is a macrovascular complication of diabetes. Until recently, this has beenrarely associated with diabetic pregnancy, as it has been unusual to diagnose coronary heart diseasein younger type 1 diabetic women but demographics are changing. The number of pregnant womenwith type 2 diabetes has risen 11-fold in 10 years in northern England, 59 and, within England,women with type 2 diabetes make up 25–30% of the pregnant diabetic population.1 In some areas,this proportion is higher. Womenwith type 2 diabetes are older and more likely to be obese, and thisincreases their risk of developing cardiac disease. Additional cardiovascular risk factors are listed inthe box.

This trend of increasing maternal age and obesity may explain why ischaemic heart disease is anincreasing cause of maternal death in the UK.60 This mirrors the findings of a Californian study thatshowed an increasing incidence of myocardial infarction in pregnancy throughout the 1990s in thenon-diabetic population.61

Risk factors for cardiovascular disease

� Older age and higher parity,� Smoking,� Diabetes,� Pre-existing hypertension, and� Family history.

Maternal outcomes

The most common cause of maternal death is cardiac disease.60 Diabetic women with ischaemicheart disease do poorly in pregnancy. A case series reported 24 pregnancies with 16 survivors. 62 Bagget al. distinguished betweenwomenwho had a myocardial infarction before pregnancy and those who


had an infarct during pregnancy. All the mothers who survived had myocardial ischaemia prior topregnancy, but only 5 of 13 women survived who developed a myocardial infarct during pregnancy.The shorter the interval between myocardial infarction and delivery, the worse the outcome. Foetaloutcome was poor and related to maternal outcome.

Diagnosis

In pregnancy, myocardial infarction and acute coronary syndrome may present with atypicalfeatures such as abdominal or epigastric pain and vomiting. It may be difficult to distinguish thesesymptoms from pregnancy-related symptoms of fatigue, dyspnoea and nausea. Clinicians need to bealert and have a low threshold for further investigation of ischaemic-sounding chest pain in diabeticwomenwith additional cardiovascular risk factors.63 If there is any clinical suspicion of coronary heartdisease, cardiology consultation is recommended.

Myocardial infarction is diagnosed in the sameway as in the non-pregnant population. Troponin I isthe marker of choice for myocardial injury in pregnant women, as the levels are not altered by normalpregnancy and delivery.64

Treatment

Women with diabetes and known ischaemic heart disease should be counselled againstpregnancy.62

During pregnancy, if myocardial infarction is confirmed, management is similar to that in non-pregnant women. There should be a low threshold for emergency coronary intervention, and treat-ment with angioplasty with or without stenting is recommended. Thrombolysis should not be with-held in either pregnancy or post-partum.

Delivery should take place in a centre with adequate facilities and staff to deal with any cardiac orobstetric complication.2 Obstetric factors should determine the mode of delivery, as caesarean sectiondoes not protect women from the immediate post-partum changes in stroke volume and cardiacoutput.

Myocardial infarction is not an indication for immediate delivery, as maternal mortality is increasedin women delivered within 2 weeks of myocardial infarction.62,64

Summary

Maternal diabetes and its complications have implications for the successful outcome of pregnancy.Women with diabetes should be aware of their individual risks prior to pregnancy and, in mostinstances, good preconception care and management of the diabetes and pregnancy by a skilledmultidisciplinary team will ensure a good outcome for mother and baby.

All pregnant diabetic women on insulin therapy should be equipped with the skills and knowledgeto deal with hypoglycaemia and hyperglycaemia and have ready access to professional support.Womenwith diabetic retinopathy should have regular examinations of the dilated eyes to determine ifthe retinopathy has progressed. It is not clear why diabetic retinopathy progresses, although hyper-tension and glycaemic control are likely to have a role. Women with nephropathy need closesurveillance as they are at high risk of pre-eclampsia, pre-term delivery and hypertension. There isemerging evidence that tight blood pressure control during pregnancy may prevent or reduce pre-eclampsia and pre-term delivery in women with pre-existing microalbuminuria.

Diabetic women with the complication of gastropathy, severe nephropathy or ischaemic heartdisease should understand the reasons for advising against pregnancy. The risks should be carefullyexplained to them and their partners during preconception counselling. If pregnancy should occur, it isvery high risk, and outcome may be poor for both mother and baby. It is likely that with the risingprevalence of obesity and type 2 diabetes, more women will be at risk of coronary heart disease inpregnancy. Clinicians should have a high index of suspicion, if women complain of symptoms of chestpain.

Practice points

� Pregnant diabetic women treated with insulin therapy should be aware of the risks ofhypoglycaemia and hypoglycaemia unawareness. They should have a concentrated glucosesolution to treat hypoglycaemia available at all times. In addition, their partners or otherfamily members should be instructed on how to use glucagon.

� All women planning pregnancy or already pregnant should be aware of and educated aboutthe risk of DKA. They should have a clear agreed management plan for ’sick day rules’(hyperglycaemia with ketonuria) and know how to access care early.

� Diabetic gastropathy is a contraindication to pregnancy. Women should be aware of the risksand be informed of this at preconception counselling. Womenwith gastropathy, who becomepregnant, should make early contact with their diabetes team as vomiting and dehydrationare a significant risk throughout pregnancy. Treatment is symptomatic but many therapiesare contraindicated in pregnancy.

� All womenwith pre-existing diabetes should have their eyes dilated and examined at the firstantenatal visit. This examination should be repeated at 28 weeks gestation. If retinopathy isnot present before pregnancy, it is unlikely that clinically significant changes will developduring pregnancy. If moderate background changes are present, over half the women willdevelop proliferative retinopathy and full retinal screening is required at booking, 16–20weeks and at 28 weeks. Ophthalmologists should be closely involved in the management ofwomen with severe non-proliferative and proliferative diabetic retinopathy duringpregnancy.

� Women with diabetic nephropathy should be managed by a multidisciplinary team thatincludes a nephrologist during pregnancy. Pregnancy outcome is optimised by tight gly-caemic control and BP management and is closely related to serum creatinine prepregnancy.ACE inhibition is contraindicated in pregnancy.

� Women with active ischaemic heart disease should be counselled against pregnancy andwarned of the risk of maternal mortality.

Research agenda

� How good does glycaemic control need to be to maximise pregnancy outcome and minimisehypoglycaemia.

� How common is DKA in pregnancy and what impact does it have, if managed in a critical careunit, on foetal outcome and long-term foetal morbidity?

� The underlying pathogenesis of gastropathy is unknown – a better understanding wouldfacilitate treatment.

� There is a case report of hyperemesis with gastropathy in pregnancy successfully treatedwithsteroids. More evidence is required before this can be routinely recommended as a treatment.

� Progression of diabetic retinopathy is associated with improvement of glycaemic control inpregnant diabetic women, who have had previous poor glycaemic control. Is this deterio-ration an outcome of improving glycaemic control or related to pregnancy?

� Observational evidence shows that women with microalbuminuria and poor glycaemiccontrol prior to pregnancy are at high risk of pre-eclampsia. A prospective RCT is required todetermine if aggressive BP management may prevent or reduce the risk of pre-eclampsia.

� There is insufficient evidence to derive evidence-based recommendations for management ofcoronary heart disease in pregnant women with diabetes. Population-based diabetes preg-nancy registers should make provision to capture diabetic pregnancies complicated byischaemic heart disease and cardiovascular risk factors to determine if pregnancy outcome iscompromised.



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