Maternal outcome in pregnant women with lupus nephritis. A prospective multicenter study

doi:10.1016/j.jaut.2016.06.012

Journal of Autoimmunity

Volume 74, November 2016, Pages 194-200

https://doi.org/10.1016/j.jaut.2016.06.012 Get rights and content

Highlights

•
In pregnant women with lupus nephritis adverse maternal outcomes continue to be relatively common.
•
In stable lupus nephritis, pregnancy complications are reversible when promptly diagnosed and treated.
•
Immunological activity, arterial hypertension and BMI predispose to maternal complications.
•
A multidisciplinary monitoring of lupus pregnant women is necessary to minimize maternal complications.

Abstract

Retrospective studies reported a high incidence of maternal complications in pregnant women with lupus. In this paper we prospectively assessed the rate of risk and the risk factors of maternal outcome in women with stable lupus nephritis who received pre-pregnancy counseling.

This prospective multicenter study includes 71 pregnancies in 61 women with lupus nephritis who became pregnant between 2006 and 2013. Complete renal remission was present before pregnancy in 56 cases (78.9%) and mild active nephritis in 15 cases. All women underwent a screening visit before pregnancy and were closely monitored by a multidisciplinary team. Lupus anticoagulant, serum C3 and C4 complement fractions, anti-DNA antibodies, anti-C1q antibodies, anticardiolipin IgG and IgM antibodies, anti-beta2 IgG and IgM antibodies were tested at screening visit, at first, second, third trimester of pregnancy, and one year after delivery. Renal flares of lupus during or after pregnancy, pre-eclampsia, and HELLP syndrome were defined as adverse maternal outcomes.

Fourteen flares (19.7%), six cases of pre-eclampsia (8.4%) and two cases of HELLP (2.8%) occurred during the study period. All flares responded to therapy and the manifestations of pre-eclampsia and HELLP were promptly reversible. Low C3, high anti-DNA antibodies and predicted all renal flares. High anti-C1q antibodies and low C4 predicted early flares. The body mass index (BMI) was associated with increased risk of late flares. History of previous renal flares and the presence of clinically active lupus nephritis at conception did not increase the risk of renal flares during pregnancy. History of renal flares before pregnancy, arterial hypertension, and longer disease predicted pre-eclampsia/HELLP.

In pregnant women with lupus nephritis adverse maternal outcomes were relatively common but proved to be reversible when promptly diagnosed and treated. Immunological activity, arterial hypertension and BMI may predispose to maternal complications.

Introduction

According to the Nationwide Inpatient Sample, maternal mortality is 20-fold higher in pregnant women with systemic lupus erythematosus (SLE) than in those without. Preterm labor, preeclampsia, and serious medical complications are also more frequent in women with lupus [1]. Among other risk factors, lupus nephritis, particularly in its active phase, is a well-recognized predictor of poor maternal and pregnancy outcome [2], [3], [4], [5], [6], [7], [8], [9]. However, our knowledge of the rate and predictors of maternal complications in lupus nephritis is based on retrospective studies. Available information on pregnancy outcome in women with lupus nephritis was typically collected over a long period of time during which treatments of the disease were heterogeneous and pre-pregnancy counseling was sporadically used [2], [10], [11], [12], [13].

This multicenter prospective observational study was designed by “The Pregnancy Study Group” of the Italian Society of Nephrology with the aim of assessing the present rate risk and the risk factors for severe maternal complications in pregnant women with a history of lupus nephritis who were closely monitored by a multidisciplinary team.

Section snippets

Patients

Four Renal Units and four Rheumatology Units participated in the study. To be enrolled, patients had to meet the following inclusion criteria: i) SLE diagnosis according to the ACR criteria [14]; ii) lupus nephritis diagnosed either by renal biopsy or on clinical grounds; iii) pregnancy between October 2006 and December 2013; iv) a counseling visit within 3 months before the beginning of pregnancy; v) signed informed consent.

The protocol was not submitted to the Ethic Committee as the collected

Characteristics of patients (Table 1)

According to the inclusion criteria, 71 pregnancies in 61 women with lupus nephritis were considered in this prospective study (Fig. 1). All the pregnancies were planned. Two women were of Asian origin and 59 were Caucasians. The mean age at conception was 32.7 + 4.5 years (median 32.9 years). The duration of SLE and lupus nephritis were respectively 130.4 + 73.1 (median 120) and 100.8 + 72.4 months (median 80.5). The diagnosis of lupus nephritis was confirmed by renal biopsy in 56 patients.

Discussion

In the present study we analyzed the risk of serious maternal complications in pregnant women with lupus nephritis who received pre-pregnancy counseling and who were prospectively followed. Not many studies have focused on pregnancies in patients with lupus nephritis and the results reporting maternal and fetal outcomes were somewhat contrasting [2], [11], [12], [22], [23], [24], [25]. This is the largest prospective study that evaluated in depth the maternal outcomes in pregnant women with

Conclusions

In this cohort of pregnant women with lupus nephritis, maternal complications developed in one third of pregnancies. Although complications were generally mild and reversible, their incidence was higher than expected. Indeed, most of these women had inactive SLE and renal disease at conception, all of them had received a pre-pregnancy counseling, and were prospectively followed by a multidisciplinary team. It seems, therefore, that an intensive surveillance can reduce the severity and

Funding source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Competing interests

None.

Acknowledgments

We gratefully acknowledge the following Medical Doctors for their contribution enrolling patients into the study: Paola Castellana Ospedale San Paolo, Milano; Fausta Catapano Nefrologia, Ospedale Policlinico Sant’Orsola-Malpighi, Bologna; Antonio del Giudice Nefrologia, Fondazione Casa Sollievo della Sofferenza, San Giovanni Rotondo Foggia; Cristina Izzo Nefrologia, Azienda Ospedaliera Universitaria Maggiore della Carita’ Novara; Monica Limardo Nefrologia Ospedale A. Manzoni, Lecco.

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Little is known about the effect tubulointerstitial nephropathies have in modulating maternal-fetal outcomes in pregnancy. Therefore, we analyzed the main outcomes of pregnancy in these women to gain a better understanding of the role of a reduction in maternal kidney mass. From the Torino Cagliari Observational Study (TOCOS) cohort, we selected 529 patients with a diagnosis of tubulointerstitial disease and focused on 421 patients with chronic kidney disease (CKD) stage 1, without hypertension but with proteinuria less than 0.5 g/day at referral. From a cohort of 2969 singleton deliveries from low-risk pregnancies followed in the same settings we selected a propensity score matched control cohort of 842 pregnancies match 2:1 for age, parity, body mass index, ethnicity, and origin. Time to delivery was significantly shorter in the study cohort 38.0 (Quartile 1-Quartile 3: 37.0-39.0) versus 39.0 (Q1-Q3 38.0-40.0) weeks, with respect to controls. Incidence of delivery of less than 37 gestational weeks significantly increased from controls (7.4%) to women with previous acute pyelonephritis (10.8%), other tubulointerstitial diseases (9.7%) and was the highest in patients with a single kidney (31.1%). Similarly, neonatal birthweight significantly and progressively decreased from controls (3260 g [Q1-Q3: 2980-3530]), previous acute pyelonephritis (3090 g [Q1-Q3: 2868-3405], other tubulointerstitial diseases (3110 g [Q1-Q3: 2840-3417]), and to solitary kidney (2910 g [Q1-Q3: 2480-3240]). Risk of developing preeclampsia was significantly higher in the CKD cohort (3.6% vs 1.7% in low-risk controls). Thus, even a small reduction in functional kidney mass, such as a pyelonephritic scar, is associated with a shorter duration of pregnancy and an increased risk of preterm delivery. The risk is proportional to the extent of parenchymal reduction and is highest in cases with a solitary kidney.
Complement levels during the first trimester predict disease flare and adverse pregnancy outcomes in systemic lupus erythematosus: A network meta-analysis on 532 pregnancies
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Complement levels have been proposed as candidate biomarkers of disease activity and obstetric risk in systemic lupus erythematosus (SLE) pregnancies, but their reliability has been questioned due to the physiologic fluctuations of complement during gestation. Thus, this network meta-analysis aimed at assessing the clinical significance of complement fluctuations in lupus pregnant women.
Corresponding authors of 19 studies meeting inclusion criteria were invited to contribute with additional data including C3 and C4 levels [before pregnancy, at conception, in every trimester (T) and 3 months after delivery]; data were pooled together in a network meta-analysis.
A total of 532 lupus women from four studies were included in the analysis. In SLE women, C3 and C4 increased progressively during gestation: levels remained stable during T1 and peaked in T2 to decrease in T3. Patients with previous lupus nephritis (LN) and those who experienced flares during pregnancy had significantly lower mean levels of C3 and C4 at all timepoints. The lowest levels of complement were observed, particularly during T1, in patients with LN and gestational flare. Both reduction and the lack of increase of C3 and C4 levels at T1 versus conception were associated with gestational flares, particularly in LN patients. Pregnancies with flare had a statistically significant higher rate of maternal and fetal complications(60% versus 50.3%; p = 0.03).
Low complement levels, particularly in T1, were associated with a higher frequency of gestational flare. Either reduction or smaller increase of C3 and/or C4 levels, even within normal range, might predict flares especially in early gestation.
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To assess pregnancy outcomes in women with SLE from the RELESSER cohort after 12 years of follow-up.
A multicentre retrospective observational study was conducted. In addition to data from the RELESSER register, data were collected on obstetric/gynaecological variables and treatments received. The number of term pregnancies was compared between women with pregnancies before and after the diagnosis of SLE. Further, clinical and laboratory characteristics were compared between women with pregnancies before and after the diagnosis, on the one hand, and with and without complications during pregnancy, on the other. Bivariate and multivariate analyses were carried out to identify factors potentially associated with complications during pregnancy.
A total of 809 women were included, with 1869 pregnancies, of which 1395 reached term. Women with pregnancies before the diagnosis of SLE had more pregnancies (2.37 vs 1.87) and a higher rate of term pregnancies (76.8% vs 69.8%, p < 0.001) compared to those with pregnancies after the diagnosis. Women with pregnancies before the diagnosis were diagnosed at an older age (43.4 vs 34.1 years) and had more comorbidities. No differences were observed between the groups with pregnancies before and after diagnosis in antibody profile, including anti-dsDNA, anti-Sm, anti-Ro, anti-La, lupus anticoagulant, anticardiolipin or anti-beta-2-glycoprotein. Overall, 114 out of the 809 women included in the study experienced complications during pregnancy, including miscarriage, preeclampsia/eclampsia, foetal death, and/or preterm birth. Women with complications had higher rates of antiphospholipid syndrome (40.5% vs 9.9%, p < 0.001) and higher rates of positivity for IgG anticardiolipin (33.9% vs 21.3%, p = 0.005), IgG anti-beta 2 glycoprotein (26.1% vs 14%, p = 0.007), and IgM anti-beta 2 glycoprotein (26.1% vs 16%, p = 0.032) antibodies, although no differences were found regarding lupus anticoagulant. Among the treatments received, only heparin was more commonly used by women with pregnancy complications. We did not find differences in corticosteroid or hydroxychloroquine use.
The likelihood of term pregnancy is higher before the diagnosis of SLE. In our cohort, positivity for anticardiolipin IgG and anti-beta-2- glycoprotein IgG/IgM, but not lupus anticoagulant, was associated with a higher risk of poorer pregnancy outcomes.
Pregnancy in systemic lupus erythematosus
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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which frequently affects women of childbearing age. Nowadays, pregnancy is not contraindicated in cases of well-controlled disease activity, but pregnancies are still at higher risk of maternal and fetal complications compared to the general population. During pregnancy and puerperium patients are at risk of disease flare, and obstetric complications are more frequent in cases of active disease at conception/beginning of pregnancy, a history of lupus nephritis, and concomitant presence of antiphospholipid syndrome.
To improve pregnancy outcomes in SLE patients, appropriate preconception counseling with changes in medication, if necessary, and close rheumatological and obstetrical monitoring are fundamental.
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Consensus document of the Spanish Group for the Study of the Glomerular Diseases (GLOSEN) for the diagnosis and treatment of lupus nephritis
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A significant number of patients with systemic lupus erythematosus (between 20% and 60% according to different reported series) develop lupus nephritis in the course of its evolution, which directly influences their quality of life and vital prognosis. In recent years, the greater knowledge about the pathogenesis of systemic lupus and lupus nephritis has allowed relevant advances in the diagnostic approach and treatment of these patients, achieving the development of drugs specifically aimed at blocking key pathogenic pathways of the disease. Encouragingly, these immunomodulatory agents have shown in well-powered, randomized clinical trials good clinical efficacy in the medium-term, defined as proteinuria remission and preservation of kidney function, with an acceptable safety profile and good patient tolerability. All this has made it possible to reduce the use of corticosteroids and other potentially more toxic therapies, as well as to increase the use of combined therapies. The present consensus document carried out by the Glomerular Diseases Working Group of the Spanish Society of Nephrology (GLOSEN), collects in a practical and summarized, but rigorous way, the best currently available evidence about the diagnosis, treatment, and follow-up of lupus nephritis patients, including cases of special situations, with the main objective of providing updated information and well-founded clinical recommendations to treating physicians, to improve the diagnostic and therapeutic approach to our patients.
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Dr Susan Hou began her illustrious nephrology career at a time when pregnancy in women with chronic kidney disease (CKD) was hazardous and actively discouraged. Her pioneering research in women’s health provided much of the early outcome data that shaped our current understanding of CKD and pregnancy. Although many uncertainties regarding optimal management of this vulnerable patient group remain, recent decades have witnessed important advances and renewed interest in improving care for pregnant women with CKD. Many nephrologists have been inspired by Dr Hou’s lifetime of work and are grateful for her generous collaborations. In this In Practice Review, we honor her legacy by providing an update of current literature and clinical management guidance in the context of a clinical case vignette that challenges us to consider the many complex aspects to the counseling and care of women with CKD who desire a pregnancy.

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¹: Gabriella Moroni and Andrea Doria: equally contributing first authors.

²: Marta Mosca and Pietro Ravani: equally contributing senior authors.

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Published by Elsevier Ltd.

Maternal outcome in pregnant women with lupus nephritis. A prospective multicenter study

Highlights

Abstract

Introduction

Section snippets

Patients

Characteristics of patients (Table 1)

Discussion

Conclusions

Funding source

Competing interests

Acknowledgments

Am. J. Kidney Dis.

Kidney Int.

Am. J. Obstet. Gynecol.

Blood

Kidney Int.

Kidney Int.

Kidney Int.

Rheum. Dis. Clin. North Am.

Autoimmun. Rev.

Am. J. Obstet. Gynecol.

Rheum. Dis. Clin. North Am.

Best. Pract. Res. Clin. Rheumatol.

Lancet

Autoimmun. Rev.

Thromb. Res.

A national study of the complications of lupus in pregnancy

Am. J. Obstet. Gynecol.

Maternal and foetal outcomes in pregnant patients with active lupus nephritis

Lupus

Pregnancy-related systemic lupus erythematosus: clinical features, outcome and risk factors of disease flares a case control study

PLoS One

A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis

Clin. J. Am. Soc. Nephrol.

Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus

Lupus

The effect of lupus nephritis on pregnancy outcome and fetal and maternal complications

J. Rheumatol.

Impact of previous lupus nephritis on maternal and fetal outcomes during pregnancy

Clin. Rheumatol.

Pregnancy outcomes in systemic lupus erythematosus with and without previous nephritis

J. Rheumatol.

Pregnancy in past or present lupus nephritis: a study of 32 pregnancies from a single centre

Ann. Rheum. Dis.

Class III-IV proliferative lupus nephritis and pregnancy: a study of 42 cases

Am. J. Reprod. Immunol.

Pregnancy and patients with preexisting lupus nephritis: 15 years of experience at a single center in Korea

Lupus