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Kidney disease and pregnancy
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Kidney disease and pregnancy
pre-pregnancy planning and antenatal care can reduce the risks for both mother and baby, and because these women are usually highly motivated it is possible to counsel them about problems while expecting a successful outcome.
Liz Lightstone
Preconception advice for women with kidney disease When to become pregnant The main influence on the course of pregnancy in a woman with kidney disease is the degree of kidney impairment (Figure 1a and b) and whether this is associated with hypertension. All published data suggest that, in general, obstetric, fetal and kidney prognoses are excellent in women with serum creatinine lower than 120 micromol/litre and no hypertension.1 The current renal approach in non-pregnant patients is always to consider kidney function in terms of estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease (MDRD) equation.2 This is because serum creatinine is hugely influenced by body size, muscle mass, diet, ethnicity, age and gender, and does not tend to rise above the normal range until about 70% of the GFR has been lost. However, in pregnancy, the MDRD formula does not work well and published data suggest that serum creatinine remains the best marker of kidney function.3 Obstetric and kidney outlook are poorer in women with moderate kidney impairment (creatinine >125e250 micromol/litre), with or without hypertension, and severe kidney impairment is associated with a poor prognosis for both mother and fetus. Pregnancy in patients having dialysis is usually unexpected (and therefore identified late) and commonly associated with major problems for mother and baby, although recent work has demonstrated that intensive haemodialysis can markedly improve prognosis.4 Nevertheless, such pregnancies should always be managed in tertiary centres specializing in difficult dialysis and high-risk pregnancies. Kidney transplant patients are advised to postpone pregnancy for at least 1 year until graft function is stable, and immunosuppression is at a relatively low level.5e7 Patients with kidney disease that is likely to progress should be advised to consider pregnancy early in the course of their disease. Circumstances in which a delay may be necessary are listed in Table 1. Conventional advice to switch from angiotensin-converting enzyme inhibitors (ACEI) use before pregnancy was based on evidence from a survey of children exposed to ACEI only in the first trimester, who demonstrated an excess incidence of congenital (especially cardiac and neurological) malformations. However, a more recent (also retrospective) study found a lower incidence, related to the use of antihypertensives as a whole and not to ACEI in particular.8,9 The risk to the fetus must be balanced against the risk of reduced maternal kidney protection. For example, it is reasonable to advise a woman with mild kidney impairment, minimal proteinuria and easily manageable blood pressure to avoid ACEI before pregnancy, whereas in a woman with diabetic nephropathy, the risk of kidney progression would be significant if treatment with ACEI were stopped for a significant period. As a compromise, it might be reasonable to suggest that women at higher risk continue their ACEI until no later than 5e6 weeks of pregnancy, once they have been apprised of the balance of benefit and harm.
Abstract Women with kidney disease should be counselled about the risks pregnancy may pose to mother and fetus before they conceive. Although impaired baseline function and hypertension are associated with worse outcome, all women with renal disease should be advised that they may suffer irreversible kidney damage, may well need to change their medications in advance of pregnancy and face a higher risk of preeclampsia with its attendant risks to the fetus. They need to consider the implications of having a premature baby. Compared with the probability that pregnancy will exacerbate existing kidney disease, pregnancyinduced kidney disease in women with previously normal renal function is less common and kidney failure rare. The commonest causes are those associated with severe pre-eclampsia and are usually managed by early delivery. Proteinuria can persist for months after pre-eclampsia. Women with kidney disease who present in pregnancy should be assessed and a diagnosis made where possible. If their disease is relatively mild, they can be managed expectantly and monitored post partum. Arrangements for appropriate renal follow-up should be made for all women who present in pregnancy, to ensure that a diagnosis is secured and a proper management plan is in place. Women with kidney disease must generally be considered as having high-risk pregnancies; they need to be aware of this and to be managed in a centre with appropriate obstetric and kidney expertise.
Keywords hypertension; kidney function; post-partum management; pre-eclampsia; preconception advice; pregnancy; systemic lupus erythematosus
Physicians must be able to advise women with kidney disease about the possible effects of pregnancy upon their longterm health and kidney function, and of the disease and its treatment upon the fetus. Advice should include information on the effects of kidney disease and its treatment upon fertility, and the benefits of adjusting treatment before conception wherever possible. Occasionally, this is impossible because kidney disease can manifest for the first time during pregnancy. Ultimately, physicians can only advise women on the risks of becoming pregnant, and some women will risk losing kidney function in exchange for what may be their only chance of pregnancy. It is well recognized that the presence of kidney disease is associated with adverse outcomes for both mother (pre-eclampsia, eclampsia and abruption) and fetus (prematurity, low birth weight or neonatal death).1 However, meticulous
Liz Lightstone PhD FRCP is Professor of Renal Medicine and Honorary Consultant Renal Physician at Imperial College London and the Imperial AHSC Renal and Transplant Centre, Hammersmith Hospital, London, UK. Competing interests: none declared.
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Risks associated with pregnancy in women with pre-existing kidney disease Women with heavy proteinuria are likely to become overtly nephrotic early in pregnancy, with an increased risk of intravascular volume depletion and thromboses. Women with reflux nephropathy are likely to develop significant urinary tract infections during pregnancy and should be advised to take prophylactic antibiotics throughout. A single dose of an oral cephalosporin at night is often suitable. Trimethoprim and quinolones, such as ciprofloxacin, should be avoided during pregnancy.
a. Increasing risks to fetus with worsening renal function 100
Estimate of infants affected (%)
90 80 70 60 50 40
Influence of treatment for kidney disease on future fertility 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 aged over 32 years.
30 20 10 0
FGR
Preterm
Perinatal death
Influence of progression of kidney disease on future fertility Many kidney diseases have an indolent, protracted course, and once end-stage kidney failure occurs it may be several years before a kidney 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.
Estimates of percentage of infants affected by fetal growth retardation (FGR), preterm delivery (Preterm) or perinatal death according to maternal serum creatinine pre pregnancy
b. Risk to the mother of > 25% decline in renal function during and after pregnancy and/or developing pre-eclampsia (PET) according to pre-pregnancy serum creatinine
Preconception investigations and management Preconception counselling in women with kidney disease contemplating pregnancy requires assessment of kidney function and any accompanying anaemia, and effective management of hypertension and any associated systemic disease. The key areas to address are summarized in Table 2 and reviewed elsewhere.10,11
80
Risk to the mother (%)
70 60 50 40
Kidney disease presenting in pregnancy
30
Commonly, women are found to have proteinuria at their first clinic visit or early in pregnancy. It is important to make a diagnosis, and kidney biopsy is safe during early pregnancy. In later pregnancy, it is vital to differentiate primary kidney causes of proteinuria and pregnancy-induced kidney disease. Recurrent urinary tract infections (UTIs) are also common in those with underlying structural abnormalities (e.g. chronic pyelonephritis, reflux nephropathy). The presence of haematuria and proteinuria almost always suggests the presence of glomerular disease. Isolated haematuria is not uncommon in the general population.
20 10 0
During pregnancy
Persists post
ESRF 1 yr
PET
Creatinine pre-pregnancy (micromol/litre) >180 On dialysis <125 125–180 Williams, D. and J. Davison, Chronic kidney disease in pregnancy. Br Med J 2008; 336: 211–5.
Figure 1
Kidney disease caused by pregnancy The most common cause of pregnancy-induced kidney disease is acute tubular necrosis associated with acute volume depletion
Indications for delay in conception C
C C
C
Patients with relapsing/remitting diseases (e.g. kidney lupus, systemic vasculitis) are advised to wait until the disease has been in remission for at least 6 months and they are taking medications ‘safe’ for use in pregnancy Patients taking cytotoxic or teratogenic agents such as cyclophosphamide or mycophenolate mofetil must avoid becoming pregnant Patients with severe hypertension (even those with ostensibly normal function) should be made aware that drugs contraindicated in pregnancy (e.g. angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) may need to be discontinued before pregnancy and definitely in the first trimester Kidney transplant patients are advised to delay pregnancy until 1 year after transplantation when they have more stable renal function
Table 1
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Preconception counselling and preparation for pregnancy Assess level of kidney function C Estimate glomerular filtration rate (MDRD formula) C Ultrasound scan (kidney size, scars, obstruction) micturating cystogram Assess anaemia C Correct iron or other deficiencies C Assess likelihood of need for erythropoietin (EPO) during pregnancy (aim to avoid transfusions) Treat hypertension effectively C Good control important for kidney and pregnancy prognosis but do not overtreat C Switch ACE inhibitors (ACEI) or angiotensin II receptor blockers (ARB) to pregnancy-friendly anti-hypertensives (e.g. methyldopa, labetalol, and nifedipine) C If ACEI or ARB mandated for kidney protection, advise of possible increased risk of congenital abnormalities even with first trimester exposure; must stop/change no later than 5e7 weeks of pregnancy (otherwise risk of ACE fetopathy) if keen not to change before conception. Assess activity of kidney disease or underlying systemic disease C Urinary sediment and urine protein:creatinine ratio to measure proteinuria; consider biopsy to ensure inactive disease/absence of rejection C Women with systemic lupus erythematosus (SLE) e clinical assessment to include screening for pulmonary hypertension, serology to assess disease activity, stabilize immunosuppression and ensure not taking cyclophosphamide, methotrexate or mycophenolate mofetil for at least 3 months before conception. In those with lupus nephritis, consider renal biopsy to evaluate level of disease activity and ensure quiescence before pregnancy. C Women with renal transplants e should have stable function, having withdrawn teratogenic drugs and switched to safe alternatives such as azathioprine instead of mycophenolate mofetil. If any doubts about the presence of rejection or other problems, arrange renal biopsy to ensure stable graft histologically. General advice for all women contemplating pregnancy C Stop smoking (independent kidney progression risk factor); take folic acid, reduce alcohol intake C Until ready to try to conceive, use contraception Advise re post-partum management C Need to use contraception again C Need to re-introduce appropriate BP medications C Need to review renal function early, especially if declining in pregnancy Table 2
Is the patient’s condition a primary kidney disease or a pregnancy-associated syndrome? 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 kidney disease (though this also predisposes to pre-eclampsia which may be severe enough to cause acute kidney injury). Pre-eclampsia may rarely present as a pure nephrotic syndrome that may take more than 6 months post partum to resolve. Acute kidney dysfunction associated with pre-eclampsia or HELLP syndrome has an excellent prognosis. However, a significant proportion of patients with pre-existing kidney disease or hypertension suffer irreversible decline or even loss of kidney function; HUS generally has a much worse prognosis.
(Table 3). However, pre-eclampsia, particularly the HELLP (haemolysis, elevated liver enzymes and low platelet count) variant, can cause specific kidney lesions that may mimic primary kidney disease.12e14 Furthermore, pregnant patients appear particularly at risk from the serious complication of cortical necrosis, which results in irreversible kidney failure. Less commonly, patients present early post partum with haemolytic euraemic syndrome (HUS). Physicians must consider the following questions.
Acute kidney injury (AKI) in pregnancy Secondary to: C Hyperemesis C Sepsis C Haemorrhage C Pre-eclampsia/HELLP (haemolysis, elevated liver enzymes and low platelet count) syndrome/acute fatty liver of pregnancy/haemolytic uraemic syndrome C Obstruction Much rarer than it used to be (<1/20,000 pregnancies) in developed countries. Early diagnosis and appropriate resuscitation (e.g. fluids, clotting) often prevents onset of acute tubular necrosis.
Timing of kidney impairment: the later the appearance of kidney impairment during gestation, the more likely it is to reflect pregnancy-induced kidney disease. Pre-eclampsia and HELLP syndrome usually occur ante partum (though kidney 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 e the group most likely to develop acute kidney failure (8%).
Table 3
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in pregnant patients).18 For comparison, a PCR of 30 mg/mmol is equivalent to 300 mg proteinuria/24 hours, 100 mg/mmol to approximately 1 g/24 hours, and over 300 mg/mmol suggests nephrotic-range proteinuria.
Hypertension: new-onset hypertension with or without proteinuria in the third trimester strongly suggests pregnancyinduced kidney dysfunction. However, up to 20% of women who develop pre-eclampsia and/or HELLP syndrome may never be frankly hypertensive.
Excluding structural abnormalities and other aetiologies for kidney impairment identified in pregnancy Kidney 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 complement and auto-antibody screens (including dsDNA and antineutrophil cytoplasmic antibodies, anticardiolipin antibodies, lupus anticoagulant). Serum immunoglobulins are determined. Serology (hepatitis B and C, and HIV when appropriate) is performed. Urine is sent for microscopy (to quantitate red cells) and culture.
Effect of kidney disease on the fetus The worse the maternal kidney function or hypertension, the greater is the likelihood of intrauterine growth restriction and premature labour (Figure 1a), with attendant risks to the baby. Antibodies can cross the placenta and babies can develop neonatal lupus, a self-limiting disorder. However, antibodies to the extractable nuclear antigens, Ro and La, are associated with the development of cardiac abnormalities and congenital heart block (CHB), which can be life threatening if overlooked. Hydroxychloroquine reduces the risk of developing CHB15 and is recommended in all women with lupus during pregnancy as it also reduces the likelihood of flare. All pregnant women with SLE-like syndromes should be screened for the presence of these antibodies and referred for expert fetal cardiac ultrasonography by 18 weeks if antibodies are detected. In a baby born to a mother with abnormal kidney function, serum urea and creatinine are similar to the mother’s at birth; the baby 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. Breast-feeding should not be discouraged in women taking azathioprine or tacrolimus.16,17
Managing kidney disease in pregnancy Management of kidney disease identified for the first time in pregnancy If proteinuria is less than 1 g/24 hours, kidney function normal, immune screen negative and there is no hypertension, it is reasonable to advise the woman that, although she may have underlying kidney disease, her proteinuria may increase during pregnancy and she may need further investigations post partum, her renal prognosis is excellent (Figure 1a and 1b).19 Similarly, isolated haematuria needs no further investigation during pregnancy once structural abnormalities have been excluded; however, it is worth enquiring about a family history as this could be a manifestation of hereditary nephritis.20 In early pregnancy (<18 weeks generally) if the woman is nephrotic, or has kidney impairment without an evident cause, kidney biopsy should be performed. This procedure carries no excess risk when performed by an experienced operator in early pregnancy,21 and is preferable to blind therapy with corticosteroids. In women who are more than 30 weeks pregnant, expediting delivery before making a kidney diagnosis may be considered.22
Essential investigations Quantifying kidney function GFR rises by 50% in pregnant women with normal kidney function. As a consequence of this, a serum creatinine over 75 micromol/litre after 6 weeks’ gestation should raise the suspicion of kidney impairment. In patients with impaired function, a fall in creatinine during early pregnancy suggests significant kidney reserve. Table 4 gives normal values in pregnancy. Quantifying proteinuria Proteinuria of 80 mg/day is normal in early pregnancy, and can increase to 300 mg/day (at the limit of detection with dipstick) by 38 weeks. Proteinuria is quantified using a spot urine (ideally second of the day) using protein:creatinine ratio (PCR, validated
Management of underlying kidney disease during pregnancy Pregnant women with underlying kidney disease must be referred to a centre with combined expertise and facilities for regular monitoring of maternal and fetal health. Kidney 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 if they have had prior ureteric re-implantation, may need monitoring
Normal levels of serum creatinine and urea
Non-pregnant women Pregnant women
Serum creatinine (mmol/litre) (mean)
Serum urea (mmol/litre) (mean)
73 (0.82 mg/dl) 51 (0.5 mg/dl)
4.3 (25 mg/dl) 3.3 (20 mg/dl)
Table 4
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for renal obstruction with regular kidney ultrasonography. Renal tract dilatation is normal in pregnancy and is commonly worse on the right side e if there is doubt whether functional obstruction is present, it is safe to perform a diethylene triamine penta-acetic acid (DTPA) scan with furosemide to assess outflow. If there is maternal kidney obstruction, the baby should be delivered; if the fetus is not sufficiently mature, nephrostomies, or retrograde stents (if feasible) should be considered to drain the kidneys and are mandated if there is evidence of infection or pain. Unrelieved obstruction can lead to irreversible loss of function. Anaemia is monitored and treated with intravenous iron supplementation and erythropoietin if necessary.23 In women with treated hypertension, treatment should be targeted to maintain a blood pressure reading of 120e139/ 70e85 mmHg (labetalol, nifedipine and methyldopa are all considered safe in pregnancy). Hydralazine often induces unacceptable tachycardia. Unopposed b-adrenoceptor blockade should be avoided as it is associated with intrauterine growth restriction. ACEI and angiotensin II receptor blockers (ARB) should ideally have been stopped antenatally (see earlier), or no later than 5e6 weeks’ gestation, unless patients have renal scleroderma. High-risk patients (i.e. nearly all women with underlying renal disease) should be offered low-dose aspirin from early pregnancy to protect against pre-eclampsia (PET).24 PET is difficult to diagnose in women with significant proteinuria and hypertension. Regular fetal monitoring is essential to detect decreases in fetal growth rate from 24 weeks’ gestation and new biomarkers may be able to predict the onset of PET.25 In chronic diseases such as vasculitis and SLE, relapses during pregnancy should be avoided. The author continues pregnancy-safe immunosuppression at stable levels throughout and does not to try to withdraw it. There is extensive and encouraging worldwide data on the use of prednisolone, azathioprine and hydroxychloroquine during pregnancy. Ciclosporin and tacrolimus are safe, though they may be associated with an increased risk of hypertension. Mycophenolate mofetil, methotrexate and cyclophosphamide are teratogenic and should be avoided during pregnancy. A stable alternative such as azathioprine should be substituted at least 3 months before conception. Patients with anti-cardiolipin antibodies (ACA) would normally be advised to take aspirin. However, in ACApositive patients with a poor obstetric history, and in those women with nephrotic-range proteinuria, it is usual to prescribe anticoagulant prophylaxis with low-molecularweight heparin, which women learn to self-inject. If kidney function deteriorates rapidly, if there is evidence of a proliferative kidney 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 intrauterine growth retardation are major risks and the uterine environment may be more hostile than neonatal intensive care.
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The outlook for most babies of 30 weeks’ gestation or more is so good that risking the well-being of the mother by undue protraction of the pregnancy is not justified. If the mother has advanced chronic kidney disease, and if serum urea is rising to around 18 mmol/litre, the choice is to commence dialysis or consider delivery. Urea at high concentration is fetotoxic. The outcome of a pregnancy in which dialysis has been started during pregnancy are generally better than for those in which the woman is already having dialysis at the time of conception.26 Management of pregnancy-induced kidney disease When pre-eclampsia or its related syndromes are the cause, delivery is the only effective treatment. 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 kidney 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 compromise maternal kidney function further and harm 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 preeclampsia are susceptible to life-threatening pulmonary oedema caused by leakage via damaged pulmonary capillary endothelium. Hypertension should be controlled vigorously and magnesium sulphate given as prophylaxis against eclampsia. Blood loss should be replaced and clotting abnormalities corrected (disseminated intravascular coagulation is common in pre-eclampsia and rare in pure HUS). Kidney function often deteriorates post partum and dialysis may be required. Eclampsia can also occur post partum. Referral to the NICE guidelines on the management of severe gestational hypertension or preeclampsia is recommended.27 There is little evidence that delivery alters the outcome of pure HUS, which is 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 preeclampsia. Patients should be re-evaluated at 6 weeks e if significant proteinuria or kidney impairment remains, kidney biopsy should be considered, though the timing will depend on rate of change of proteinuria and any accompanying renal dysfunction. In some cases a wait and watch approach will be reasonable, in others, early biopsy. The prognosis is good in women with ‘pure’ pre-eclampsia who wish to contemplate another pregnancy. The earlier and the more severe the pre-eclampsia, the greater is the likelihood of recurrence. In those with impaired kidney function and/or hypertension, there is a high risk of recurrence and worsening kidney function; 20% of women with HELLP syndrome in one pregnancy develop preeclampsia (but seldom HELLP syndrome) in subsequent pregnancies.
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Further information
17 Sau A, Clarke S, Bass J, Kaiser A, Marinaki A, Nelson-Piercy C. Azathioprine and breastfeeding: is it safe? Br J Obs Gynaecol 2007; 114: 498e501. 18 Quadri KH, Bernardini J, Greenberg A, Laifer S, Syed A, Holley JL. Assessment of renal function during pregnancy using a random urine protein to creatinine ratio and Cockcroft-Gault formula. Am J Kidney Dis 1994; 24: 416e20. 19 Lightstone L. Post partum follow up of antenatally identified problems. In: Davison J, Nelson-Piercy C, Baker P, eds. RCOG 54th study group consensus on renal disease in pregnancy. London: RCOG, 2008; 53e60. 20 McKnight AJ, Currie D, Maxwell AP. Unravelling the genetic basis of renal diseases; from single gene to multifactorial disorders. J Pathol 2010; 220: 198e216. 21 Day C, Hewins P, Hildebrand S, et al. The role of renal biopsy in women with kidney disease identified in pregnancy. Nephrol Dial Transpl 2008; 23: 201e6. 22 de Swiet M, Lightstone L. Glomerular endotheliosis in normal pregnancy and pre-eclampsia. Br J Obs Gynaecol 2004; 111: 191e2 (author reply 193e5;discussion 195). 23 Krafft A, Bencaiova G, Breymann C. Selective use of recombinant human erythropoietin in pregnant patients with severe anemia or nonresponsive to iron sucrose alone. Fetal Diagn Ther 2009; 25: 239e45. 24 Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan KS. Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Obstet Gynecol 2003; 101: 1319e32. 25 Bramham K, Seed P, Nelson-Piercy C, et al. [42-OR]: Diagnostic accuracy of placental growth factor in women with chronic kidney disease or hypertension and suspected preeclampsia: a prospective cohort study. Pregnancy Hypertens 2015; 5: 21. 26 Jesudason S, Grace BS, McDonald SP. Pregnancy outcomes according to dialysis commencing before or after conception in women with ESRD. Clin J Am Soc Nephrol 2014; 9: 143e9. 27 Redman CW. Hypertension in pregnancy: the NICE guidelines. Heart 2011; 97: 1967e9.
In the UK, practical advice about the risks of drugs in pregnancy can be obtained from the National Teratology Information Service at the NHS Northern and Yorkshire Regional Drug and Therapeutics Centre, Newcastle upon Tyne. http://rdtc.nhs.uk/ services/teratology. A REFERENCES 1 Williams D, Davison J. Chronic kidney disease in pregnancy. Br Med J 2008; 336: 211e5. 2 Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: third national health and nutrition examination survey. Am J Kidney Dis 2003; 41: 1e12. 3 Smith MC. Assessment of glomerular filtration rate during pregnancy using the MDRD formula. Br J Obs Gynaecol 2008; 115: 109e12. 4 Hladunewich MA, Hou S, Odutayo A, et al. Intensive hemodialysis associates with improved pregnancy outcomes: a Canadian and United States cohort comparison. J Am Soc Nephrol 2014; 25: 1103e9. 5 Blume C, Pischke S, von Versen-Hoynck F, Gunter HH, Gross MM. Pregnancies in liver and kidney transplant recipients: a review of the current literature and recommendation. Best Pract Res Clin Obstet Gynaecol 2014; 28: 1123e36. 6 Wyld ML, Clayton PA, Jesudason S, Chadban SJ, Alexander SI. Pregnancy outcomes for kidney transplant recipients. Am J Transpl 2013; 13: 3173e82. 7 Josephson MA, McKay DB. Women and transplantation: fertility, sexuality, pregnancy, contraception. Adv Chron Kidney Dis 2013; 20: 433e40. 8 Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. Br Med J 2011; 343: 5931. 9 Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443e51. 10 Lightstone L. Preconception counselling and risk assessment: general overview. In: Davison J, Nelson-Piercy C, Baker P, eds. RCOG 54th study group consensus on renal disease in pregnancy. London: RCOG, 2008; 21e30. 11 Wiles KS, Bramham K, Vais A, et al. Pre-pregnancy counselling for women with chronic kidney disease: a retrospective analysis of nine years’ experience. BMC Nephrol 2015; 16: 28. 12 Van Hook JW. Acute kidney injury during pregnancy. Clin Obstet Gynecol 2014; 57: 851e61. 13 Acharya A, Santos J, Linde B, Anis K. Acute kidney injury in pregnancy-current status. Adv Chron Kidney Dis 2013; 20: 215e22. 14 Machado S, Figueiredo N, Borges A, et al. Acute kidney injury in pregnancy: a clinical challenge. J Nephrol 2012; 25: 19e30. 15 Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 2012; 126: 76e82. 16 Bramham K, Chusney G, Lee J, Lightstone L, Nelson-Piercy C. Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants. Clin J Am Soc Nephrol 2013; 8: 563e7.
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Practice points C
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The normal range for serum creatinine in pregnant women is significantly lower than in non-pregnant women e beware creatinine greater than 75 micromol/litre Do not overlook the fact that a patient is a woman of childbearing age e 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 kidney disease, the outlook for mother and baby is better in the presence of normal kidney function and blood pressure; therefore, in chronic progressive diseases recommend the patient becomes pregnant sooner rather than later Kidney disease caused by pregnancy may mimic underlying kidney disease, may lead to irreversible kidney decline and is more common in women with pre-existing kidney disease and hypertension, in whom it has a worse prognosis
Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Lightstone L, Kidney disease and pregnancy, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.06.003
Kidney disease and pregnancy
pre-pregnancy planning and antenatal care can reduce the risks for both mother and baby, and because these women are usually highly motivated it is possible to counsel them about problems while expecting a successful outcome.
Liz Lightstone
Preconception advice for women with kidney disease When to become pregnant The main influence on the course of pregnancy in a woman with kidney disease is the degree of kidney impairment (Figure 1a and b) and whether this is associated with hypertension. All published data suggest that, in general, obstetric, fetal and kidney prognoses are excellent in women with serum creatinine lower than 120 micromol/litre and no hypertension.1 The current renal approach in non-pregnant patients is always to consider kidney function in terms of estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease (MDRD) equation.2 This is because serum creatinine is hugely influenced by body size, muscle mass, diet, ethnicity, age and gender, and does not tend to rise above the normal range until about 70% of the GFR has been lost. However, in pregnancy, the MDRD formula does not work well and published data suggest that serum creatinine remains the best marker of kidney function.3 Obstetric and kidney outlook are poorer in women with moderate kidney impairment (creatinine >125e250 micromol/litre), with or without hypertension, and severe kidney impairment is associated with a poor prognosis for both mother and fetus. Pregnancy in patients having dialysis is usually unexpected (and therefore identified late) and commonly associated with major problems for mother and baby, although recent work has demonstrated that intensive haemodialysis can markedly improve prognosis.4 Nevertheless, such pregnancies should always be managed in tertiary centres specializing in difficult dialysis and high-risk pregnancies. Kidney transplant patients are advised to postpone pregnancy for at least 1 year until graft function is stable, and immunosuppression is at a relatively low level.5e7 Patients with kidney disease that is likely to progress should be advised to consider pregnancy early in the course of their disease. Circumstances in which a delay may be necessary are listed in Table 1. Conventional advice to switch from angiotensin-converting enzyme inhibitors (ACEI) use before pregnancy was based on evidence from a survey of children exposed to ACEI only in the first trimester, who demonstrated an excess incidence of congenital (especially cardiac and neurological) malformations. However, a more recent (also retrospective) study found a lower incidence, related to the use of antihypertensives as a whole and not to ACEI in particular.8,9 The risk to the fetus must be balanced against the risk of reduced maternal kidney protection. For example, it is reasonable to advise a woman with mild kidney impairment, minimal proteinuria and easily manageable blood pressure to avoid ACEI before pregnancy, whereas in a woman with diabetic nephropathy, the risk of kidney progression would be significant if treatment with ACEI were stopped for a significant period. As a compromise, it might be reasonable to suggest that women at higher risk continue their ACEI until no later than 5e6 weeks of pregnancy, once they have been apprised of the balance of benefit and harm.
Abstract Women with kidney disease should be counselled about the risks pregnancy may pose to mother and fetus before they conceive. Although impaired baseline function and hypertension are associated with worse outcome, all women with renal disease should be advised that they may suffer irreversible kidney damage, may well need to change their medications in advance of pregnancy and face a higher risk of preeclampsia with its attendant risks to the fetus. They need to consider the implications of having a premature baby. Compared with the probability that pregnancy will exacerbate existing kidney disease, pregnancyinduced kidney disease in women with previously normal renal function is less common and kidney failure rare. The commonest causes are those associated with severe pre-eclampsia and are usually managed by early delivery. Proteinuria can persist for months after pre-eclampsia. Women with kidney disease who present in pregnancy should be assessed and a diagnosis made where possible. If their disease is relatively mild, they can be managed expectantly and monitored post partum. Arrangements for appropriate renal follow-up should be made for all women who present in pregnancy, to ensure that a diagnosis is secured and a proper management plan is in place. Women with kidney disease must generally be considered as having high-risk pregnancies; they need to be aware of this and to be managed in a centre with appropriate obstetric and kidney expertise.
Keywords hypertension; kidney function; post-partum management; pre-eclampsia; preconception advice; pregnancy; systemic lupus erythematosus
Physicians must be able to advise women with kidney disease about the possible effects of pregnancy upon their longterm health and kidney function, and of the disease and its treatment upon the fetus. Advice should include information on the effects of kidney disease and its treatment upon fertility, and the benefits of adjusting treatment before conception wherever possible. Occasionally, this is impossible because kidney disease can manifest for the first time during pregnancy. Ultimately, physicians can only advise women on the risks of becoming pregnant, and some women will risk losing kidney function in exchange for what may be their only chance of pregnancy. It is well recognized that the presence of kidney disease is associated with adverse outcomes for both mother (pre-eclampsia, eclampsia and abruption) and fetus (prematurity, low birth weight or neonatal death).1 However, meticulous
Liz Lightstone PhD FRCP is Professor of Renal Medicine and Honorary Consultant Renal Physician at Imperial College London and the Imperial AHSC Renal and Transplant Centre, Hammersmith Hospital, London, UK. Competing interests: none declared.
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Risks associated with pregnancy in women with pre-existing kidney disease Women with heavy proteinuria are likely to become overtly nephrotic early in pregnancy, with an increased risk of intravascular volume depletion and thromboses. Women with reflux nephropathy are likely to develop significant urinary tract infections during pregnancy and should be advised to take prophylactic antibiotics throughout. A single dose of an oral cephalosporin at night is often suitable. Trimethoprim and quinolones, such as ciprofloxacin, should be avoided during pregnancy.
a. Increasing risks to fetus with worsening renal function 100
Estimate of infants affected (%)
90 80 70 60 50 40
Influence of treatment for kidney disease on future fertility 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 aged over 32 years.
30 20 10 0
FGR
Preterm
Perinatal death
Influence of progression of kidney disease on future fertility Many kidney diseases have an indolent, protracted course, and once end-stage kidney failure occurs it may be several years before a kidney 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.
Estimates of percentage of infants affected by fetal growth retardation (FGR), preterm delivery (Preterm) or perinatal death according to maternal serum creatinine pre pregnancy
b. Risk to the mother of > 25% decline in renal function during and after pregnancy and/or developing pre-eclampsia (PET) according to pre-pregnancy serum creatinine
Preconception investigations and management Preconception counselling in women with kidney disease contemplating pregnancy requires assessment of kidney function and any accompanying anaemia, and effective management of hypertension and any associated systemic disease. The key areas to address are summarized in Table 2 and reviewed elsewhere.10,11
80
Risk to the mother (%)
70 60 50 40
Kidney disease presenting in pregnancy
30
Commonly, women are found to have proteinuria at their first clinic visit or early in pregnancy. It is important to make a diagnosis, and kidney biopsy is safe during early pregnancy. In later pregnancy, it is vital to differentiate primary kidney causes of proteinuria and pregnancy-induced kidney disease. Recurrent urinary tract infections (UTIs) are also common in those with underlying structural abnormalities (e.g. chronic pyelonephritis, reflux nephropathy). The presence of haematuria and proteinuria almost always suggests the presence of glomerular disease. Isolated haematuria is not uncommon in the general population.
20 10 0
During pregnancy
Persists post
ESRF 1 yr
PET
Creatinine pre-pregnancy (micromol/litre) >180 On dialysis <125 125–180 Williams, D. and J. Davison, Chronic kidney disease in pregnancy. Br Med J 2008; 336: 211–5.
Figure 1
Kidney disease caused by pregnancy The most common cause of pregnancy-induced kidney disease is acute tubular necrosis associated with acute volume depletion
Indications for delay in conception C
C C
C
Patients with relapsing/remitting diseases (e.g. kidney lupus, systemic vasculitis) are advised to wait until the disease has been in remission for at least 6 months and they are taking medications ‘safe’ for use in pregnancy Patients taking cytotoxic or teratogenic agents such as cyclophosphamide or mycophenolate mofetil must avoid becoming pregnant Patients with severe hypertension (even those with ostensibly normal function) should be made aware that drugs contraindicated in pregnancy (e.g. angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) may need to be discontinued before pregnancy and definitely in the first trimester Kidney transplant patients are advised to delay pregnancy until 1 year after transplantation when they have more stable renal function
Table 1
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Preconception counselling and preparation for pregnancy Assess level of kidney function C Estimate glomerular filtration rate (MDRD formula) C Ultrasound scan (kidney size, scars, obstruction) micturating cystogram Assess anaemia C Correct iron or other deficiencies C Assess likelihood of need for erythropoietin (EPO) during pregnancy (aim to avoid transfusions) Treat hypertension effectively C Good control important for kidney and pregnancy prognosis but do not overtreat C Switch ACE inhibitors (ACEI) or angiotensin II receptor blockers (ARB) to pregnancy-friendly anti-hypertensives (e.g. methyldopa, labetalol, and nifedipine) C If ACEI or ARB mandated for kidney protection, advise of possible increased risk of congenital abnormalities even with first trimester exposure; must stop/change no later than 5e7 weeks of pregnancy (otherwise risk of ACE fetopathy) if keen not to change before conception. Assess activity of kidney disease or underlying systemic disease C Urinary sediment and urine protein:creatinine ratio to measure proteinuria; consider biopsy to ensure inactive disease/absence of rejection C Women with systemic lupus erythematosus (SLE) e clinical assessment to include screening for pulmonary hypertension, serology to assess disease activity, stabilize immunosuppression and ensure not taking cyclophosphamide, methotrexate or mycophenolate mofetil for at least 3 months before conception. In those with lupus nephritis, consider renal biopsy to evaluate level of disease activity and ensure quiescence before pregnancy. C Women with renal transplants e should have stable function, having withdrawn teratogenic drugs and switched to safe alternatives such as azathioprine instead of mycophenolate mofetil. If any doubts about the presence of rejection or other problems, arrange renal biopsy to ensure stable graft histologically. General advice for all women contemplating pregnancy C Stop smoking (independent kidney progression risk factor); take folic acid, reduce alcohol intake C Until ready to try to conceive, use contraception Advise re post-partum management C Need to use contraception again C Need to re-introduce appropriate BP medications C Need to review renal function early, especially if declining in pregnancy Table 2
Is the patient’s condition a primary kidney disease or a pregnancy-associated syndrome? 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 kidney disease (though this also predisposes to pre-eclampsia which may be severe enough to cause acute kidney injury). Pre-eclampsia may rarely present as a pure nephrotic syndrome that may take more than 6 months post partum to resolve. Acute kidney dysfunction associated with pre-eclampsia or HELLP syndrome has an excellent prognosis. However, a significant proportion of patients with pre-existing kidney disease or hypertension suffer irreversible decline or even loss of kidney function; HUS generally has a much worse prognosis.
(Table 3). However, pre-eclampsia, particularly the HELLP (haemolysis, elevated liver enzymes and low platelet count) variant, can cause specific kidney lesions that may mimic primary kidney disease.12e14 Furthermore, pregnant patients appear particularly at risk from the serious complication of cortical necrosis, which results in irreversible kidney failure. Less commonly, patients present early post partum with haemolytic euraemic syndrome (HUS). Physicians must consider the following questions.
Acute kidney injury (AKI) in pregnancy Secondary to: C Hyperemesis C Sepsis C Haemorrhage C Pre-eclampsia/HELLP (haemolysis, elevated liver enzymes and low platelet count) syndrome/acute fatty liver of pregnancy/haemolytic uraemic syndrome C Obstruction Much rarer than it used to be (<1/20,000 pregnancies) in developed countries. Early diagnosis and appropriate resuscitation (e.g. fluids, clotting) often prevents onset of acute tubular necrosis.
Timing of kidney impairment: the later the appearance of kidney impairment during gestation, the more likely it is to reflect pregnancy-induced kidney disease. Pre-eclampsia and HELLP syndrome usually occur ante partum (though kidney 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 e the group most likely to develop acute kidney failure (8%).
Table 3
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in pregnant patients).18 For comparison, a PCR of 30 mg/mmol is equivalent to 300 mg proteinuria/24 hours, 100 mg/mmol to approximately 1 g/24 hours, and over 300 mg/mmol suggests nephrotic-range proteinuria.
Hypertension: new-onset hypertension with or without proteinuria in the third trimester strongly suggests pregnancyinduced kidney dysfunction. However, up to 20% of women who develop pre-eclampsia and/or HELLP syndrome may never be frankly hypertensive.
Excluding structural abnormalities and other aetiologies for kidney impairment identified in pregnancy Kidney 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 complement and auto-antibody screens (including dsDNA and antineutrophil cytoplasmic antibodies, anticardiolipin antibodies, lupus anticoagulant). Serum immunoglobulins are determined. Serology (hepatitis B and C, and HIV when appropriate) is performed. Urine is sent for microscopy (to quantitate red cells) and culture.
Effect of kidney disease on the fetus The worse the maternal kidney function or hypertension, the greater is the likelihood of intrauterine growth restriction and premature labour (Figure 1a), with attendant risks to the baby. Antibodies can cross the placenta and babies can develop neonatal lupus, a self-limiting disorder. However, antibodies to the extractable nuclear antigens, Ro and La, are associated with the development of cardiac abnormalities and congenital heart block (CHB), which can be life threatening if overlooked. Hydroxychloroquine reduces the risk of developing CHB15 and is recommended in all women with lupus during pregnancy as it also reduces the likelihood of flare. All pregnant women with SLE-like syndromes should be screened for the presence of these antibodies and referred for expert fetal cardiac ultrasonography by 18 weeks if antibodies are detected. In a baby born to a mother with abnormal kidney function, serum urea and creatinine are similar to the mother’s at birth; the baby 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. Breast-feeding should not be discouraged in women taking azathioprine or tacrolimus.16,17
Managing kidney disease in pregnancy Management of kidney disease identified for the first time in pregnancy If proteinuria is less than 1 g/24 hours, kidney function normal, immune screen negative and there is no hypertension, it is reasonable to advise the woman that, although she may have underlying kidney disease, her proteinuria may increase during pregnancy and she may need further investigations post partum, her renal prognosis is excellent (Figure 1a and 1b).19 Similarly, isolated haematuria needs no further investigation during pregnancy once structural abnormalities have been excluded; however, it is worth enquiring about a family history as this could be a manifestation of hereditary nephritis.20 In early pregnancy (<18 weeks generally) if the woman is nephrotic, or has kidney impairment without an evident cause, kidney biopsy should be performed. This procedure carries no excess risk when performed by an experienced operator in early pregnancy,21 and is preferable to blind therapy with corticosteroids. In women who are more than 30 weeks pregnant, expediting delivery before making a kidney diagnosis may be considered.22
Essential investigations Quantifying kidney function GFR rises by 50% in pregnant women with normal kidney function. As a consequence of this, a serum creatinine over 75 micromol/litre after 6 weeks’ gestation should raise the suspicion of kidney impairment. In patients with impaired function, a fall in creatinine during early pregnancy suggests significant kidney reserve. Table 4 gives normal values in pregnancy. Quantifying proteinuria Proteinuria of 80 mg/day is normal in early pregnancy, and can increase to 300 mg/day (at the limit of detection with dipstick) by 38 weeks. Proteinuria is quantified using a spot urine (ideally second of the day) using protein:creatinine ratio (PCR, validated
Management of underlying kidney disease during pregnancy Pregnant women with underlying kidney disease must be referred to a centre with combined expertise and facilities for regular monitoring of maternal and fetal health. Kidney 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 if they have had prior ureteric re-implantation, may need monitoring
Normal levels of serum creatinine and urea
Non-pregnant women Pregnant women
Serum creatinine (mmol/litre) (mean)
Serum urea (mmol/litre) (mean)
73 (0.82 mg/dl) 51 (0.5 mg/dl)
4.3 (25 mg/dl) 3.3 (20 mg/dl)
Table 4
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for renal obstruction with regular kidney ultrasonography. Renal tract dilatation is normal in pregnancy and is commonly worse on the right side e if there is doubt whether functional obstruction is present, it is safe to perform a diethylene triamine penta-acetic acid (DTPA) scan with furosemide to assess outflow. If there is maternal kidney obstruction, the baby should be delivered; if the fetus is not sufficiently mature, nephrostomies, or retrograde stents (if feasible) should be considered to drain the kidneys and are mandated if there is evidence of infection or pain. Unrelieved obstruction can lead to irreversible loss of function. Anaemia is monitored and treated with intravenous iron supplementation and erythropoietin if necessary.23 In women with treated hypertension, treatment should be targeted to maintain a blood pressure reading of 120e139/ 70e85 mmHg (labetalol, nifedipine and methyldopa are all considered safe in pregnancy). Hydralazine often induces unacceptable tachycardia. Unopposed b-adrenoceptor blockade should be avoided as it is associated with intrauterine growth restriction. ACEI and angiotensin II receptor blockers (ARB) should ideally have been stopped antenatally (see earlier), or no later than 5e6 weeks’ gestation, unless patients have renal scleroderma. High-risk patients (i.e. nearly all women with underlying renal disease) should be offered low-dose aspirin from early pregnancy to protect against pre-eclampsia (PET).24 PET is difficult to diagnose in women with significant proteinuria and hypertension. Regular fetal monitoring is essential to detect decreases in fetal growth rate from 24 weeks’ gestation and new biomarkers may be able to predict the onset of PET.25 In chronic diseases such as vasculitis and SLE, relapses during pregnancy should be avoided. The author continues pregnancy-safe immunosuppression at stable levels throughout and does not to try to withdraw it. There is extensive and encouraging worldwide data on the use of prednisolone, azathioprine and hydroxychloroquine during pregnancy. Ciclosporin and tacrolimus are safe, though they may be associated with an increased risk of hypertension. Mycophenolate mofetil, methotrexate and cyclophosphamide are teratogenic and should be avoided during pregnancy. A stable alternative such as azathioprine should be substituted at least 3 months before conception. Patients with anti-cardiolipin antibodies (ACA) would normally be advised to take aspirin. However, in ACApositive patients with a poor obstetric history, and in those women with nephrotic-range proteinuria, it is usual to prescribe anticoagulant prophylaxis with low-molecularweight heparin, which women learn to self-inject. If kidney function deteriorates rapidly, if there is evidence of a proliferative kidney 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 intrauterine growth retardation are major risks and the uterine environment may be more hostile than neonatal intensive care.
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The outlook for most babies of 30 weeks’ gestation or more is so good that risking the well-being of the mother by undue protraction of the pregnancy is not justified. If the mother has advanced chronic kidney disease, and if serum urea is rising to around 18 mmol/litre, the choice is to commence dialysis or consider delivery. Urea at high concentration is fetotoxic. The outcome of a pregnancy in which dialysis has been started during pregnancy are generally better than for those in which the woman is already having dialysis at the time of conception.26 Management of pregnancy-induced kidney disease When pre-eclampsia or its related syndromes are the cause, delivery is the only effective treatment. 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 kidney 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 compromise maternal kidney function further and harm 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 preeclampsia are susceptible to life-threatening pulmonary oedema caused by leakage via damaged pulmonary capillary endothelium. Hypertension should be controlled vigorously and magnesium sulphate given as prophylaxis against eclampsia. Blood loss should be replaced and clotting abnormalities corrected (disseminated intravascular coagulation is common in pre-eclampsia and rare in pure HUS). Kidney function often deteriorates post partum and dialysis may be required. Eclampsia can also occur post partum. Referral to the NICE guidelines on the management of severe gestational hypertension or preeclampsia is recommended.27 There is little evidence that delivery alters the outcome of pure HUS, which is 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 preeclampsia. Patients should be re-evaluated at 6 weeks e if significant proteinuria or kidney impairment remains, kidney biopsy should be considered, though the timing will depend on rate of change of proteinuria and any accompanying renal dysfunction. In some cases a wait and watch approach will be reasonable, in others, early biopsy. The prognosis is good in women with ‘pure’ pre-eclampsia who wish to contemplate another pregnancy. The earlier and the more severe the pre-eclampsia, the greater is the likelihood of recurrence. In those with impaired kidney function and/or hypertension, there is a high risk of recurrence and worsening kidney function; 20% of women with HELLP syndrome in one pregnancy develop preeclampsia (but seldom HELLP syndrome) in subsequent pregnancies.
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Further information
17 Sau A, Clarke S, Bass J, Kaiser A, Marinaki A, Nelson-Piercy C. Azathioprine and breastfeeding: is it safe? Br J Obs Gynaecol 2007; 114: 498e501. 18 Quadri KH, Bernardini J, Greenberg A, Laifer S, Syed A, Holley JL. Assessment of renal function during pregnancy using a random urine protein to creatinine ratio and Cockcroft-Gault formula. Am J Kidney Dis 1994; 24: 416e20. 19 Lightstone L. Post partum follow up of antenatally identified problems. In: Davison J, Nelson-Piercy C, Baker P, eds. RCOG 54th study group consensus on renal disease in pregnancy. London: RCOG, 2008; 53e60. 20 McKnight AJ, Currie D, Maxwell AP. Unravelling the genetic basis of renal diseases; from single gene to multifactorial disorders. J Pathol 2010; 220: 198e216. 21 Day C, Hewins P, Hildebrand S, et al. The role of renal biopsy in women with kidney disease identified in pregnancy. Nephrol Dial Transpl 2008; 23: 201e6. 22 de Swiet M, Lightstone L. Glomerular endotheliosis in normal pregnancy and pre-eclampsia. Br J Obs Gynaecol 2004; 111: 191e2 (author reply 193e5;discussion 195). 23 Krafft A, Bencaiova G, Breymann C. Selective use of recombinant human erythropoietin in pregnant patients with severe anemia or nonresponsive to iron sucrose alone. Fetal Diagn Ther 2009; 25: 239e45. 24 Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan KS. Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Obstet Gynecol 2003; 101: 1319e32. 25 Bramham K, Seed P, Nelson-Piercy C, et al. [42-OR]: Diagnostic accuracy of placental growth factor in women with chronic kidney disease or hypertension and suspected preeclampsia: a prospective cohort study. Pregnancy Hypertens 2015; 5: 21. 26 Jesudason S, Grace BS, McDonald SP. Pregnancy outcomes according to dialysis commencing before or after conception in women with ESRD. Clin J Am Soc Nephrol 2014; 9: 143e9. 27 Redman CW. Hypertension in pregnancy: the NICE guidelines. Heart 2011; 97: 1967e9.
In the UK, practical advice about the risks of drugs in pregnancy can be obtained from the National Teratology Information Service at the NHS Northern and Yorkshire Regional Drug and Therapeutics Centre, Newcastle upon Tyne. http://rdtc.nhs.uk/ services/teratology. A REFERENCES 1 Williams D, Davison J. Chronic kidney disease in pregnancy. Br Med J 2008; 336: 211e5. 2 Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: third national health and nutrition examination survey. Am J Kidney Dis 2003; 41: 1e12. 3 Smith MC. Assessment of glomerular filtration rate during pregnancy using the MDRD formula. Br J Obs Gynaecol 2008; 115: 109e12. 4 Hladunewich MA, Hou S, Odutayo A, et al. Intensive hemodialysis associates with improved pregnancy outcomes: a Canadian and United States cohort comparison. J Am Soc Nephrol 2014; 25: 1103e9. 5 Blume C, Pischke S, von Versen-Hoynck F, Gunter HH, Gross MM. Pregnancies in liver and kidney transplant recipients: a review of the current literature and recommendation. Best Pract Res Clin Obstet Gynaecol 2014; 28: 1123e36. 6 Wyld ML, Clayton PA, Jesudason S, Chadban SJ, Alexander SI. Pregnancy outcomes for kidney transplant recipients. Am J Transpl 2013; 13: 3173e82. 7 Josephson MA, McKay DB. Women and transplantation: fertility, sexuality, pregnancy, contraception. Adv Chron Kidney Dis 2013; 20: 433e40. 8 Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. Br Med J 2011; 343: 5931. 9 Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443e51. 10 Lightstone L. Preconception counselling and risk assessment: general overview. In: Davison J, Nelson-Piercy C, Baker P, eds. RCOG 54th study group consensus on renal disease in pregnancy. London: RCOG, 2008; 21e30. 11 Wiles KS, Bramham K, Vais A, et al. Pre-pregnancy counselling for women with chronic kidney disease: a retrospective analysis of nine years’ experience. BMC Nephrol 2015; 16: 28. 12 Van Hook JW. Acute kidney injury during pregnancy. Clin Obstet Gynecol 2014; 57: 851e61. 13 Acharya A, Santos J, Linde B, Anis K. Acute kidney injury in pregnancy-current status. Adv Chron Kidney Dis 2013; 20: 215e22. 14 Machado S, Figueiredo N, Borges A, et al. Acute kidney injury in pregnancy: a clinical challenge. J Nephrol 2012; 25: 19e30. 15 Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 2012; 126: 76e82. 16 Bramham K, Chusney G, Lee J, Lightstone L, Nelson-Piercy C. Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants. Clin J Am Soc Nephrol 2013; 8: 563e7.
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Practice points C
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The normal range for serum creatinine in pregnant women is significantly lower than in non-pregnant women e beware creatinine greater than 75 micromol/litre Do not overlook the fact that a patient is a woman of childbearing age e 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 kidney disease, the outlook for mother and baby is better in the presence of normal kidney function and blood pressure; therefore, in chronic progressive diseases recommend the patient becomes pregnant sooner rather than later Kidney disease caused by pregnancy may mimic underlying kidney disease, may lead to irreversible kidney decline and is more common in women with pre-existing kidney disease and hypertension, in whom it has a worse prognosis
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Please cite this article in press as: Lightstone L, Kidney disease and pregnancy, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.06.003