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PREGNANCY

fetal and renal prognoses are excellent in women with normal


creatinine (< 120 mol/litre) and no hypertension, though creatinine of 120 mol/litre may reflect more severe renal impairment
in a small, vegetarian woman. Obstetric and renal outlook are
poorer in women with moderate renal impairment (creatinine
> 125< 250 mol/litre), with or without hypertension, and
severe renal impairment is associated with a poor prognosis for
both mother and fetus. Pregnancy in dialysis patients is usually
unexpected and is therefore diagnosed late, and is associated with
major problems for mother and baby; such pregnancies should
always be managed in tertiary centres specializing in difficult
dialysis and high-risk pregnancies. Renal transplant patients are
advised to postpone pregnancy until graft function is stable and
has been good for at least 1 year, and immunosuppression is at a
relatively low level.
Patients with renal disease that is likely to progress should be
advised to become pregnant early in the course of their disease.
However, the following points must be considered.
Patients with relapsing/remitting diseases (e.g. renal lupus,
systemic vasculitis) must not become pregnant while taking
cytotoxic agents such as cyclophosphamide. Generally, they are
advised to wait until the disease has been in remission for at least
6 months.
Patients with severe hypertension (even those with ostensibly
normal function)must be aware that some drugs are contraindicated in pregnancy (e.g. angiotensin-converting enzyme (ACE)
inhibitors, angiotensin II receptor (ATIIR) blockers) and must be
discontinued in early pregnancy (by 7 weeks).
Severely proteinuric patients are likely to become frankly nephrotic early in pregnancy, with an increased risk of intravascular
depletion and thromboses.
Patients with reflux nephropathy are likely to develop significant urinary tract infections (UTIs) during pregnancy and should
be advised to take prophylactic antibiotics throughout.
Patients commencing therapy with cytotoxic agents must be
warned of the risk of infertility. Cyclophosphamide causes infertility in a dose-dependent and age-related manner; a total dose
of 10 g seldom causes prolonged amenorrhoea in women under
20 years old, but the risk is high in women over 32 years.
Many renal diseases have an indolent, protracted course,
and once end-stage renal failure occurs, it may be several years

Renal Disease and


Pregnancy
Liz Lightstone

Physicians must be able to advise women with renal disease


about the risks of pregnancy to their long-term well-being and
renal function, and the risks of the disease and its treatment to
their fetus. This advice should include information on the limitations on fertility imposed by the disease and its treatment, and
the risks of ongoing treatment and how it may need to be modified
pre-conception. Ideally, these issues should be discussed before
pregnancy is contemplated, so that appropriate advice can be
given. Occasionally, this is impossible because the renal disease
manifests for the first time during pregnancy; more commonly,
however, physicians overlook the fact that a patient is a woman
of child-bearing age.
Ultimately, physicians can only advise women on the risks
of becoming pregnant, and some women will risk losing renal function in exchange for what may be their only chance of pregnancy.
The author advises renal patients that they are at increased risk of
pre-eclampsia, chaotic hypertension, intrauterine growth retardation (IUGR) and premature delivery. However, meticulous antenatal care reduces the risks for both mother and baby and, because
these women are usually highly motivated, it is often possible to
counsel about problems but expect a successful outcome.

Pre-conception advice for women with renal disease


When to become pregnant: the main influence on the course
of a pregnancy is the degree of renal impairment (Figure 1) and
whether this is associated with hypertension. In general, obstetric,

Liz Lightstone is Senior Lecturer and Consultant Physician at Imperial


College School of Medicine, Hammersmith Hospital, London, UK.

Obstetric and renal outcome and renal function


Creatinine
(mol/litre)
< 120
125250
> 250

Problems
during
pregnancy (%)
26
47
86

Successful
obstetric
outcome (%)
96 (85)
90 (69)
75 (61)

Long-term
renal
problems (%)
< 3 (8)
25 (70)
53 (92)

Based on data collected in 197397 from 2477 women with


3602 pregnancies; does not include collagen diseases. Numbers in
parentheses refer to complications developing before 28 weeks gestation.
Source: Professor John Davison, Directorate of Womens Services, Royal Victoria Infirmary
and Associated Hospitals NHS Trust, Newcastle upon Tyne, UK.

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before a renal transplant becomes available a young woman


who does not become pregnant early in her disease may have to
try to conceive later in life, when her natural fertility is failing.

Preconception counselling and preparation for


pregnancy
Assess renal function
Estimate glomerular filtration rate (CockcroftGault or MDRD
formula, isotopic)
Ultrasonography (renal size, scars, obstruction) micturating
cystography
Assess anaemia
Correct iron or other deficiencies
Assess whether patient is likely to need erythropoietin during
pregnancy (aim to avoid transfusions)
Treat hypertension effectively
Good control is important for renal and pregnancy prognosis
If ACE inhibition or ATIIR blockade not indicated, use
pregnancy-friendly antihypertensives (e.g.methyldopa,
labetolol, nifedipine)
If ACE inhibition or ATIIR blockade required for renal protection,
warn patient of necessity to stop/change no later than 7 weeks
(otherwise risk of ACE fetopathy)
Assess activity of renal disease or underlying systemic disease
Urinary sediment
Systemic lupus erythematosus patients clinical assessment
including screening for pulmonary hypertension, serology to
assess disease activity, stabilize immunosuppression
General advice for all women contemplating pregnancy
Stop smoking (independent risk factor for renal progression),
take folic acid, reduce alcohol intake
Advise use of contraception until patient is ready to try to
conceive

Pre-conception investigations and management: in women with


renal disease who are contemplating pregnancy, pre-conception
counselling requires assessment of renal function and any accompanying anaemia, and effective management of hypertension and
any associated systemic disease. The key areas to address are
listed in Figure 2.

Renal disease presenting in pregnancy


Commonly, women are found to have proteinuria at their first
clinic visit or early in pregnancy. It is important to make a diagnosis, and renal biopsy is safe during pregnancy. In later pregnancy, it is vital to differentiate primary renal causes of proteinuria and pregnancy-induced renal disease. Recurrent UTIs are also
common, associated with underlying structural abnormalities (e.g.
chronic pyelonephritis, reflux nephropathy).
Essential investigations
The level of renal function is determined; Figure 3 gives normal
values in pregnancy. Because of the 50% increase in glomerular
filtration rate seen in pregnant women with normal renal function, creatinine of more than 75 mol/litre after 6 weeks gestation
should raise the suspicion of renal impairment. In patients with
impaired function, a decrease in creatinine during early pregnancy
suggests significant renal reserve. Proteinuria of 80 mg/day is
normal in early pregnancy, and can increase to 300 mg/day (at
the limit of detection with dipsticks) by 38 weeks.
Proteinuria is quantified.
Renal size, perfusion and symmetry are defined using ultrasonography.
A full blood count and film are obtained to exclude haemolysis.
The patient is screened for immunological causes such as systemic lupus erythematosus (SLE) (relatively common) and vasculitis (relatively rare), using serum complements, autoantibody
screen (including dsDNA and antineutrophil cytoplasm antibodies,
anticardiolipin antibodies, lupus anticoagulant).
Immunoglobulin levels are determined.
Serology is performed for hepatitis B and C, and when appropriate, for HIV.

ACE, angiotensin-converting enzyme; ATIIR, angiotensin II receptor

Management of underlying renal disease during pregnancy


Pregnant women with underlying renal disease must be referred
to a centre with combined expertise and facilities for regular monitoring of maternal and fetal well-being.
Renal function and proteinuria are measured at least monthly
throughout pregnancy and more frequently if indicated.
Urine is screened for bacteriuria and frank infections; these
are treated as appropriate, and antibiotic prophylaxis should
be considered.
Patients with reflux nephropathy, particularly, may need monitoring for renal obstruction with regular renal ultrasonography.
Renal tract dilatation is normal in pregnancy and is commonly
worse on the right if there is doubt whether functional obstruc-

Management: when proteinuria is less than 1 g/24 hours, renal


function is normal and there is no hypertension, it is reasonable
to advise the patient that she may have underlying renal disease,
that her prognosis is excellent (Figure 1), that her proteinuria
may increase during pregnancy, and that she may need further
investigations post-partum.
When the patient is nephrotic, or has renal impairment without an evident cause (e.g. ultrasonography suggests chronic
pyelonephritis with scarring), renal biopsy should be perormed.
With an experienced operator, this procedure carries no excess
risk in pregnancy, and is preferable to blind therapy with corticosteroids. In women who are more than 30 weeks pregnant,
expediting delivery before making a renal diagnosis may be
considered.

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Normal serum creatinine and urea (mean values)


Non-pregnant
women
Pregnant women

Serum creatinine
73 mol/litre
(0.82 mg/dl)

Serum urea
4.3 mmol/litre
(25 mg/dl)

51 mol/litre
(0.5 mg/dl)

3.3 mmol/litre
(20 mg/dl)

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tion is present, it is safe to perform a DTPA scan with furosemide


to assess outflow. If there is maternal kidney obstruction, the baby
should be delivered; if it is not sufficiently mature, nephrostomies
should be inserted to drain the kidneys. Unrelieved obstruction
leads to sepsis and irreversible loss of function.
Anaemia is monitored and treated with erythropoietin if
necessary.
Hypertension is treated to maintain a blood pressure of less
than 140/90 mm Hg. Methyldopa and/or labetolol are first-line and
second-line treatments and nifedipine the third line. Hydralazine
often induces unacceptable tachycardia. Unopposed -blockade is
to be avoided because it is associated with IUGR. ACE inhibitors
and ATIIR blockers are stopped no later than 7 weeks, unless the
patient has renal scleroderma.
In chronic disease, relapses during pregnancy should be
avoided. The author continues immunosuppression at stable levels
throughout and does not try to withdraw it; there are extensive
and encouraging worldwide data on the use of prednisolone, azathioprine and hydroxychloroquine during pregnancy. Ciclosporin
A is safe, though it may be associated with an increased risk of
hypertension. Newer immunosuppressants such as mycophenolate mofetil and rapamycin are contraindicated in pregnancy.
Patients with anticardiolipin antibodies and those with
nephrotic-range proteinuria are usually advised to undergo anticoagulant prophylaxis with low molecular weight heparin, which
they learn to self-inject.
If renal function deteriorates rapidly, if there is evidence of
a proliferative renal lesion or if hypertension or nephrotic state is
severe, advice varies according to the stage of pregnancy. In early
pregnancy, therapeutic abortion might be advised; once the fetus is
viable, delivery should be expedited. Superimposed pre-eclampsia
and IUGR are major risks, and the uterine enviroment may be more
hostile than neonatal intensive care.
High-risk patients are given low-dose aspirin from early pregnancy to protect against pre-eclampsia.
Pre-eclampsia is difficult to diagnose in women with significant proteinuria and hypertension. Regular fetal monitoring is
essential to detect decreases in fetal growth rate and to screen for
uterine artery notching on Doppler ultrasonography (a predictor of
pre-eclampsia); many centres also monitor mean platelet volume
as a marker of increased platelet consumption and production.
The outlook for most babies of 30 weeks gestation or more
is so good that it is not justified to risk the well-being of the mother
by undue protraction of the pregnancy.

Does she require specific therapy?


Will delivery make a difference?
To answer these questions, it is important to ascertain whether
there is evidence of pre-existing renal disease (though this also
predisposes to pre-eclampsia). Pre-eclampsia may present as a pure
nephrotic syndrome that may take up to 6 months post-partum to
resolve.
Acute renal dysfunction associated with pre-eclampsia or
HELLP syndrome has an excellent prognosis. However, a significant proportion of patients with pre-existing renal disease
or hypertension suffer irreversible decline or even loss of renal
function. HUS generally has a much worse prognosis.
Timing of renal impairment the later renal impairment
occurs, the more likely it is to reflect pregnancy-induced renal
disease. Pre-eclampsia and HELLP sydrome usually occur
ante-partum (though renal function may decline post-partum),
whereas HUS classically occurs unexpectedly within days to weeks
post-partum.
Parity of patient pre-eclampsia and acute fatty liver of pregnancy (AFLP) are more common in nulliparous women. HELLP
syndrome is more common in multiparous women the group
most likely to develop acute renal failure (8%).
Hypertension new-onset hypertension with or without
proteinuria in the third trimester strongly suggests pregnancyinduced renal dysfunction. However, up to 20% of women who
develop pre-eclampsia and/or HELLP syndrome may never be
frankly hypertensive.
Management of pregnancy-induced renal disease
When pre-eclampsia or its related syndromes are the cause,
the only effective treatment is delivery. Occasionally, expectant
management with close and invasive maternal and fetal monitoring can be used to gain time to accelerate fetal lung maturation
with corticosteroids; however, declining renal function is almost
invariably an urgent indication to deliver.
Women with pre-eclampsia are intravascularly deplete and
peripherally vasoconstricted. Diuresis to treat oedema or oliguria
is inappropriate and likely to further compromise maternal renal
function and the fetus.
Fluid replacement must be monitored with at least a central
venous pressure line and meticulous fluid balance charts. Despite
being intravascularly deplete, patients with pre-eclampsia are

Acute renal failure in pregnancy


Renal disease caused by pregnancy

Secondary to
Hyperemesis
Sepsis
Haemorrhage
Pre-eclamptic toxaemia/HELLP syndrome/ acute fatty liver of
pregnancy/haemolytic uraemic syndrome
Obstruction

The most common cause of pregnancy-induced renal disease


is acute tubular necrosis associated with acute volume depletion (Figure 4). However, pre-eclampsia (particularly the HELLP
variant haemolysis, elevated liver enzymes and low platelet
count) can cause specific renal lesions that may mimic primary
renal disease. Furthermore, pregnant patients appear to be particularly at risk from the devastating complication of cortical necrosis, which results in irreversible renal failure. Less commonly,
patients present early post-partum with haemolytic uraemic syndrome (HUS). Physicians must consider the following.
Is the patients condition a primary renal disease or a
pregnancy-associated syndrome?

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Acute renal failure in pregnancy is much rarer than in the past


(< 1/20,000 pregnancies). Early diagnosis and resuscitation
(e.g. fluids, clotting) often prevents onset of acute tubular necrosis.

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then undergoes diuresis and is at risk of dehydration and electrolyte disturbances. Close post-natal monitoring is required. The high
serum urea may improve the immature kidneys concentrating
ability earlier than normal; thus, abnormalities may be corrected
quickly.
Prednisolone is largely metabolized by the placenta, but fetal
hypo-adrenalism is possible and should be considered.
Advice about breast-feeding is changing. The author advises
that the benefits of breast-feeding probably outweigh any risks with
ciclosporin or azathioprine. Tacrolimus is present in higher levels
in breast milk and therefore breast-feeding is contraindicated. In
the UK, advice about specific drug effects can be obtained from the
national breast-feeding drug information centre in Leicester.

Further information
In the UK, practical advice about the risks of drugs in pregnancy can
be obtained from:
National Teratology Information Service
NHS Northern and Yorkshire Regional Drug and Therapeutics Centre
Wolfson Unit
Claremont Place
Newcastle upon Tyne, NE2 4HI
Fax: 0191 261 5733

susceptible to life-threatening pulmonary oedema caused by leakage via damaged pulmonary capillary endothelium.
Hypertension should be controlled vigorously and magnesium
sulphate should be given as prophylaxis against eclampsia.
Blood loss is replaced and clotting abnormalities are corrected
(disseminated intravascular coagulation is common in preeclampsia and rare in pure HUS).
Renal function often deteriorates post-partum; dialysis may be
required. Eclampsia can also occur post-partum.
There is little evidence that delivery alters the outcome of pure
HUS (i.e. not associated with pre-eclampsia), but this is seldom an
antenatal problem. It should be treated conventionally with plasma
exchange and fresh frozen plasma or cryo-poor supernatant.
Proteinuria may take months to resolve after pre-eclampsia.
Patients should be re-evaluated at 6 weeks. If significant proteinuria or renal impairment remains, renal biopsy should be
considered.
The prognosis is good in women with pure pre-eclampsia
who wish to contemplate another pregnancy. In those with
impaired renal function and/or hypertension, there is a high
risk of recurrence and worsening renal function; 20% of women
with HELLP syndrome in one pregnancy develop pre-eclampsia
(but seldom HELLP syndrome) in subsequent pregnancies.

FURTHER READING
Hou S, ed. Pregnancy in Endstage Renal Disease. Adv Renal Replace Ther
1998; 5(1).
(Covers all aspects of pregnancy in women on dialysis and with
transplants; includes an overview of medical management of
pregnant transplant recipients and a guide to the effects of
immunosuppressive drugs in pregnancy.)
Nelson-Piercy C. Renal Disease. In: Nelson-Piercy C. Obstetric Medicine.
2nd ed. Oxford: Isis Medical Media, 2002.
(Clear and concise, with good management guidelines.)
Sibai B M, Kustermann L, Velasco J. Current Understanding of Severe
Pre-eclampsia, Pregnancy-associated Hemolytic Uremic Syndrome,
Thrombotic Thrombocytopenic Purpura, Hemolysis, Elevated Liver
Enzymes, and Low Platelet Syndrome, and Post-partum Acute Renal
Failure: Different Clinical Syndromes or Just Different Names? Curr
Opin Nephrol Hypertens 1994; 3: 43645.
(A thorough and interesting review of the similarities and differences
between all these syndromes from the group that has undertaken the
most detailed analyses of patients with HELLP.)
Williams D J, de Swiet M. The Pathophysiology of Preeclampsia. Intensive
Care Med 1997; 23: 6209.
(A clear overview of current understanding of the mechanisms
underlying predisposition to and the clinical features of
pre-eclampsia.)

The effect of renal disease on the fetus


The worse the maternal renal function or hypertension, the greater
the likelihood of IUGR and premature labour (Figure 1), with
attendant risks to the baby.
Certain renal diseases have a clear genetic basis; the most
common is adult polycystic kidney disease (autosomal dominant). It is occasionally possible to screen a fetus antenatally
if the parents genotypes are known; specific genetic counselling should be available locally if required. Reflux nephropathy
also can run in families, and parents must be informed about the
need to screen babies for UTIs and renal abnormalities in early
childhood.
Antibodies can cross the placenta, and hence babies can develop
neonatal lupus (a self-limiting disorder). However, antibodies to
the extractable nuclear antigens Ro and La are associated with
development of cardiac abnormalities and congenital heart block,
which can be life-threatening if overlooked. All pregnant women
with SLE-like syndromes should be screened for the presence of
these antibodies, and if they are present should be referred for
expert fetal cardiac ultrasonography by 24 weeks.
In a baby born to a mother with abnormal renal function, serum
urea and creatinine are similar to the mothers at birth; the baby

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Practice points
The normal range for creatinine in pregnant women is
significantly lower than in non-pregnant women beware
creatinine > 75 mol/litre
Do not overlook the fact that a patient is a woman of
child-bearing age discuss issues of fertility and pregnancy
early in the course of her disease and modify treatment if she is
planning a pregnancy
In pre-existing renal disease, the outlook for mother and baby
is better in the presence of normal renal function and blood
pressure; therefore, in chronic diseases recommend the patient
becomes pregnant sooner rather than later
Renal disease caused by pregnancy may mimic underlying
renal disease, may lead to irreversible renal decline and is
more common in women with pre-existing renal disease and
hypertension, in whom it has a worse prognosis

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