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NDT Advance Access originally published online on November 26, 2008
Nephrology Dialysis Transplantation 2009 24(2):344-347; doi:10.1093/ndt/gfn651
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Lupus nephritis and pregnancy in the 21st century

Clara J. Day1, Graham W. Lipkin1 and Caroline O. S. Savage2

1 Department of Renal Medicine, University Hospital Birmingham, NHS Foundation Trust 2 School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

Correspondence and offprint requests to: Clara J. Day, University Hospital Birmingham, NHS Foundation Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. Tel: +44-121-627-2512; Fax: +44-121-627-2527; E-mail clara.day{at}uhb.nhs.uk

Keywords: Pregnancy; lupus nephritis

The outcome for women with SLE has undoubtedly improved with a significant fall in fetal loss over the last four decades [1] from 40% in 1960–65 to 17% 2000–03. However, pregnancy in women with lupus can still be associated with significant maternal and fetal complications. In a recent US study of 16.7 million pregnancies, 13 555 occurred in lupus patients with an increased maternal mortality of more than 20-fold and odds ratio of 1.7 for Caesarean section, 2.4 for pre-term labour and 3.0 for pre-eclampsia [2].

The maternal and fetal outcomes in patients with lupus nephritis appear to be influenced by various factors. Although some studies show no increase of flare rate in pregnancy [3,4], other studies suggest that flares of extra-renal lupus are more common in pregnancy [5] but are no more severe than in the non-pregnant state [6]. The available evidence shows that renal flare is more likely to occur in women with active disease at conception [7,8], and such pregnancies are associated with an increased fetal and maternal risk [7,8]. In addition, the spectrum of renal disease associated with lupus is wide and there is some evidence that Class III and IV lupus nephritis may be associated with more pre-eclampsia and hypertension than Class II and V [9]. Extra-renal manifestations of lupus, current or historic, will also affect pregnancy outcomes (e.g. severe pulmonary hypertension, cardiac failure, restrictive lung disease). All efforts should, therefore, be made to control lupus prior to pregnancy. Ideally multi-disciplinary, pre-pregnancy counselling should enable full discussion of risks to maternal and fetal health of pregnancy, together with a full review of medications (see Table 1). However, not all pregnancies in lupus patients are planned, and since lupus does not appear to affect fertility [10], it is vital that contraception and the need to plan any pregnancy are discussed regularly during the routine care of the patient [11].


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  		Table 1 Use of immunosuppressive agents in pregnancy

 
In addition to the adverse effects on pregnancy of active lupus nephritis, it is of equal importance to consider the effects of chronic kidney disease resulting from renal scarring following previous episodes of lupus nephritis.

In normal pregnancy, there is a rapid increase in renal blood flow and the glomerular filtration rate accompanied by an increase in production of erythropoietin and active vitamin D [12]. Such physiological adaptations are reduced in women with chronic kidney disease and virtually absent in those with a pre-pregnancy creatinine of >200 mmol/l [13]. The consequent physiological strain placed on renal function in those with significant renal impairment means that they are more likely to suffer progressive renal impairment as a result of pregnancy (summarized in [12]). In addition, such women are much more likely to have adverse pregnancy outcomes such as pre-eclampsia, pre-term delivery and intra-uterine growth retardation [14]. Moreover, hypertension is an independent predictor of fetal death in those with any kidney disease [14] or lupus nephritis [7]. Aspirin reduces the risk of pre-eclampsia and perinatal death and increases the birth weight in those with risk factors including renal disease [15] and should, therefore, be used in all women with chronic kidney disease without contra-indications. Control of blood pressure in pregnancy in those with renal disease is probably important and may minimize the progression of disease and prevent the adverse pregnancy outcomes seen in those with hypertension. However, safe levels of blood pressure are not established, and overtreatment can lead to fetal growth restriction [16]. Other factors to consider are summarized in Table 2.


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  		Table 2 Additional factors to consider during pregnancy with lupus nephritis

 
The measurement of parameters of renal disease is complicated by pregnancy. Although many laboratories now routinely report an estimated GFR derived from the Modification of Diet in Renal Disease equations, this is not appropriate in pregnancy, considerably underestimating GFR because of pregnancy-associated expansion in plasma volume [17]. There is some evidence that proteinuria can be accurately quantified by the measurement of either urinary albumin:creatinine or protein:creatinine ratios rather than 24-h collection [18], but this has yet to be confirmed in those with large amounts of proteinuria related to primary renal disease. Quantification of proteinuria is important to allow diagnosis of either lupus renal flare or pre-eclampsia. However, there is also a physiological rise in proteinuria associated with the increased glomerular filtration rate, and often an increase following cessation of ACE inhibitor therapy. This makes diagnosis of renal flare difficult, and an active urinary sediment with casts should always be sought, along with evidence of systemic and/or immunological lupus activity. Complement levels tend to increase in pregnancy, so a downward trend or low normal level may indicate lupus activity. The differentiation between renal flare and pre-eclampsia is complex; both can present with increasing proteinuria, hypertension, thrombocytopaenia and deterioration in renal function. Other evidence of lupus activity as described above may aid diagnosis, together with reduced umbilical artery Doppler flow [19] and speed of progression of proteinuria. However, it is quite possible for the patient to have concurrent active lupus nephritis and pre-eclampsia; only delivery will allow separation of the two components. The measurement of new biomarkers for pre-eclampsia such as vascular endothelial growth factor receptor (sFlt-1) or placental growth factor (PlGF) await evaluation in those with lupus or renal impairment [20,21].

Antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) increase the risk of fetal loss in pregnancy with a hierarchy of effect. Lupus anticoagulant presence shows the greatest association with late recurrent fetal loss with IgG anticardiolipin antibodies associated with both early and late fetal loss [22]. Their presence, even in the absence of renal disease, is one of the biggest risk factors for the development of pre-eclampsia [23]. Aspirin treatment has been shown to increase the live birth rate [24] in those with multiple pregnancy loss, but the combination of aspirin and heparin has been shown to be even more effective [25]. Most trial data are with unfractionated heparin combined with aspirin with only one trial with low molecular weight heparin, but this is now the more standard choice.

The accompanying paper describes both fetal and maternal renal outcomes in a large descriptive series of 113 pregnancies in 81 women being treated in a group of Italian hospitals [8]. All patients had a pre-pregnancy diagnosis of lupus nephritis; the majority had good pre-pregnancy renal function (only 11% had a GFR of <60 ml/min/1.73 m2), and most were in either complete (49%) or partial (27%) renal remission. In addition, the frequency of those with significant proteinuria (>1 g/24 h) was low at just 13%, and only 15% were hypertensive pre-conception. Such quiescent renal disease was reflected in immunosuppressive medication use with 21% on no therapy and a further 49% on low-dose steroids only. However, significant complications did arise. There were five neonatal deaths: one due to a cardiac malformation, and four through complications of prematurity, three ascribed to severe pre-eclampsia. In total, 11 patients were diagnosed with pre-eclampsia. Unfortunately, it is not clear what was the renal function of these patients, whether they were hypertensive prior to pregnancy or had a diagnosis of antiphospholipid syndrome, all of which would tend to increase their risk of developing pre-eclampsia. Moreover, it is not known whether these women were amongst those taking aspirin. In total, 34 renal flares were described, 17 of which were ante-natal. Renal flares tended to occur in those with more severe renal disease (as defined by the authors), but also arose in 8/56 in complete remission prior to conception. Interestingly, of the nine flares occurring in patients with no specific therapy for lupus nephritis at conception (n = 24), five occurred in the eight in partial remission and three in the four with proteinuria > 1 g/24 h. This re-enforces the importance of achieving good renal control prior to pregnancy. Further, it may be worth considering restarting therapy in pregnant patients who are on no therapy and in partial remission to reduce the probability of renal recurrence.

Overall the pre-term delivery rate in this cohort (defined as <37 weeks) was 31%, provoked mainly by pre-eclampsia or deterioration in renal function, and 34% of babies weighed <2500 g. High rates of pre-term delivery are seen in other series [26] and may reflect not only the complex nature of these pregnancies but also medical anxiety. Multivariable predictors of pregnancy loss were hypocomplementaemia at conception (RR 19.02) and, although the use of aspirin was not standardized, its usage was strongly associated with better fetal outcome (RR fetal loss 0.11). The 13% fetal loss reported in this series reflects the improved outcome seen in other modern series [1].

In previous times, women with lupus nephritis may have been advised against ever contemplating pregnancy, and there is no doubt that such pregnancies have increased rates of fetal and maternal complications. However, management within an experienced multi-disciplinary environment, with informed pre-pregnancy counselling and optimum lupus control, can now facilitate a much improved fetal and maternal outcome.

Conflict of interest statement. None declared.

(See related article by E. Imbasciati et al. Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome. Nephrol Dial Transplant 2009; 24: 519–525.)



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Received for publication: 1. 8.08
Accepted in revised form: 29.10.08


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