Class III–IV Proliferative Lupus Nephritis and Pregnancy: A Study of 42 Cases

Class III–IV Proliferative Lupus Nephritisand Pregnancy: A Study of 42 Cases

INTRODUCTION

Systemic lupus erythematosus (SLE) is the autoim-mune disease that most frequently compromises preg-nancy.1,2 The coexistence of SLE and pregnancy is byno means a rare event, as SLE has a predilection forwomen of childbearing age. Maternal morbidity maybe severe during an SLE exacerbation, and treatmentitself is limited by pregnancy. On the contrary, activeSLE places the embryo, fetus and neonate at enormousrisk.1,3 Studies published in the 1960s underlined theincreased fetal and maternal risk and recommendedprotection against pregnancy in lupus patients. Morerecently, however, it has been reported that pregnancyin patients with SLE should not be regarded as anunacceptable high-risk condition for the mother or herbaby provided that conception is accurately planned

and patients are managed according to a carefulmultidisciplinary treatment schedule.4–6

The above notwithstanding, renal disease was theonly significant predictor of fetal loss in a recentmultivariate analysis.7 A number of studies haveevaluated the reciprocal impact of pregnancy andlupus nephritis. However, available data often provi-ded conflicting results and pregnancy outcome accord-ing to the severity of lupus nephritis was notconsidered in previous reports.6,8–10 The presentstudy summarizes maternal and fetal outcome in42 pregnancies in 35 SLE patients with the prolifera-tive forms (class III or IV) of lupus nephritis which areconsidered to represent the whole spectrum of the samepathogenetic group, generally follow a progressivecourse, share a similar clinical pattern and naturalhistory, and are the most severe forms in terms of

American Journal of Reproductive ImmunologyAJRI 2005; 53: 182–188Copyright � Blackwell Munksgaard, 2005

Carmona F, Font J, Moga I, Lazaro I, Cervera R, Pac V, Balasch J.Class III–IV proliferative lupus nephritis and pregnancy: a study of42 cases. AJRI 2005; 53:182–188 � Blackwell Munksgaard, 2005

PROBLEM: A growing number of women with lupus nephritis wishpregnancy. Our aim was to analyze maternal and fetal outcome inpregnancies with the most severe forms (proliferative or class III–IV)of lupus nephritis.METHOD OF STUDY: Forty-two pregnancies in 35 women withclass III or IV lupus nephritis confirmed by renal biopsy (group 1); 12pregnancies in 10 patients having histologically proven lupus nephritisclass II or V (group 2); and 54 pregnant women randomly selectedamong our cohort of pregnant lupus patients without nephropathywho were matched for age, parity and duration of lupus to patientswith class III or IV lupus nephritis (group 3) were studied.RESULTS: Pregnancy outcome and mean gestational age of neonateswere similar in the three groups studied with hypertension andpreeclampsia, being significantly more prevalent in patients in group 1(37.1%) than among patients in groups 2 (11.1%) and 3 (11.6%)(P < 0.05). Mean birthweight (�S.D.) was significantly lower in group1 (2214 � 802 g) than in groups 2 (2783 � 721 g) and 3 (2870 � 835 g)(P < 0.05).CONCLUSION: Lupus nephritis class III–IV is a risk factor forhypertensive disease during pregnancy, but it does not contraindicategestation.

Francisco Carmona1, Josep Font2,Isabel Moga3, Isabel L�zaro1,Ricard Cervera2, Visitaci�n Pac3,Juan Balasch11Institut Cl�nic of Gynecology, Obstetrics, andNeonatology, Barcelona, Spain; 2Department ofAutoimmune Diseases, Faculty of Medicine, University ofBarcelona, Hospital Cl�nic, Institut d'InvestigacionsBiom�diques August Pi i Sunyer (IDIBAPS), Barcelona,Spain; 3Department of Internal Medicine, Hospital deBellvitge-Pr�nceps d'Espanya, L'Hospitalet de Llobregat,Spain

Key words: Hypertensive disorders, lupus nephritis,pregnancy, SLE

Address reprint requests to J. Balasch, MD, Institut Cl�nicof Gynecology, Obstetrics, and Neonatology, HospitalCl�nic, C/Casanova 143, 08036 Barcelona, Spain.E-mail: [email protected]

Submitted October 29, 2004;revised January 14, 2005;accepted January 21, 2005.

� BLACKWELL MUNKSGAARD, 2005

prognosis. In contrast, class I and II represent minimalhistologic damage with very good prognosis and classV is a distinct group with rather good prognosis interms of renal function.11

MATERIAL AND METHODS

PatientsBetween January 1995 and December 2001, a total of42 pregnancies occurred in 35 women with previouslydiagnosed class III or IV lupus nephritis confirmed byrenal biopsy. These patients constituted the studygroup (group 1). Pregnancies occurring before thediagnosis of lupus nephropathy or nephropathy occur-ring after delivery were not taken into account.Histological patterns of SLE nephritis were assessedaccording to the 1995 WHO criteria.12 All patientsfulfilled the 1997 American College of Rheumatologycriteria for SLE.13 Antiphospholipid syndrome wasdiagnosed according to accepted criteria.14

For comparative purposes, two control groups wereused. Group 2 included 12 pregnancies in 10 SLEpatients previously diagnosed as having histologicallyproven lupus nephritis class II or V during the samestudy period. Finally, group 3 comprised 54 pregnantwomen randomly selected among our cohort of preg-nant SLE patients without lupus nephropathy whowere matched for age, parity and duration of SLE topatients in group 1.

All the SLE patients from three groups wereattending the two tertiary Department of AutoimmuneDiseases/Internal Medicine referral centers in Barce-lona and were followed up during pregnancy in a singleInstitute of Gynecology, Obstetrics and Neonatologyby a multidisciplinary team composed of obstetricians,autoimmunologists/internists, neonatologists andnephrologists. Institutional review board approvalwas not required because there were no interventionsother than those for the standard care of these patients.

Medical ManagementAt the time of pregnancy diagnosis, a completephysical examination was performed and visits werescheduled every 2 or 3 weeks (or more often whennecessary) until the 26th week; from 27th to 35thweeks, patients were scheduled fortnightly and then,weekly until delivery. After delivery, patients were seenevery 3 weeks until the second postpartum month.

The following laboratory tests were performedwithin 3 months before attempting conception and atthe first pregnancy visit and then, repeated monthly:hematological parameters (including hemoglobin, redand white cell and platelet counts and erythrocytesedimentation rate), serum levels of creatinine, uric

acid, proteins, sodium, alanine and aspartate amino-transpherases, urine microscopy and 24-hr urine col-lection for measurement of creatinine clearance, totalproteinuria and sodium and calcium excretion. Immu-nological evaluation was performed within 3 monthsbefore attempting conception and at the first preg-nancy visit and then, repeated every 10–12 weeksduring pregnancy and included: lupus anticoagulant(LA) and anticardiolipin antibodies (aCL) usingmethods previously described,15–18 antinuclear anti-bodies (ANA) (indirect immunofluorescence usingmouse liver as substrate), antidouble-stranded DNAantibodies (Farr’s technique), C3, C4 (radial immuno-diffusion) and CH50 (Lachmann’s hemolytic tech-nique) complement components as well as Coombs�test for autoimmune hemolysis and determination ofthe rheumatoid factor activity (latex fixation andWaaler-Rose tests). Precipitating antibodies to extract-able nuclear antigens (ENA) including Ro (SS-A) andLa (SS-B), RNP, and Sm (counter immunoelectropho-resis) were determined performed within 3 monthsbefore attempting conception and at the first preg-nancy visit.

Disease activity was determined according to thelupus activity criteria count,19 an overall and clinicallyuseful method of disease activity evaluation,20 that hasbeen used in many clinical studies.4,21–23 A flare wasconsidered when a clinical manifestation attributableto disease activity appeared during the course of thestudy period.

Patients were advised to become pregnant when SLE(including lupus nephropathy) was inactive for at least6 months and they were taking no cytotoxic drugs inthe previous 12 months (except azathioprine, whichwas given to 12 patients in group 1 at daily dosesof 50–100 mg). Hydroxycloroquine, 200 mg/day(15 patients in groups 1 and 2, and nine patients ingroup 3) and prednisone (5–20 mg/day) (all patients ingroups 1 and 2, and 24 patients in group 3) weremaintained in those patients who were previouslytaking these drugs. Lupus flare was treated withprednisone (0.25–1 mg/kg/day, depending on severity);after remission, prednisone was continued at a dose aslow as possible. In patients testing positive for LA and/or aCL, aspirin (100 mg/day) was added from 1 monthbefore attempting conception and throughout preg-nancy, as previously reported.24–26 Heparin was alsoadded if previous thrombotic events were present orwhen there were previous pregnancy losses undertreatment with aspirin alone.

Obstetrical ManagementObstetrical visits were scheduled as for medical man-agement. As SLE pregnancies are high-risk pregnan-cies, in addition to routine pregnancy management,

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obstetrical care included sequential ultrasonographic,feto-placental Doppler and fetal echocardiographicexaminations. Ultrasound examinations were per-formed during the first trimester of gestation, at19–21 weeks and then once a month throughoutpregnancy. Feto-placental Doppler blood flow exami-nations were started at 17–20 weeks of gestation andrepeated monthly. Foetal echocardiography was per-formed at 17–18 weeks repeated at 24th and 30thweeks when the mother tested positive for anti SS-Aand/or anti SS-B antibodies. Foetal non-stress testswere performed weekly from 26 weeks gestationonwards. Pregnancy was ended in cases of foetaldistress and/or when the maternal state was seriouslycompromised.Pregnancy complications were defined as previously

reported:27 spontaneous abortion: spontaneous termin-ation of pregnancy prior to 20 weeks of gestation;elective abortion: voluntarily induced termination ofpregnancy; stillbirth or intrauterine fetal death: spon-taneous termination of pregnancy after 20 weeks ofgestation; fetal loss: sum of spontaneous abortions andstillbirths; neonatal death: death of a newborn within30 days of birth; premature birth: spontaneous termin-ation of pregnancy with a live birth between 21 and37 weeks of gestation; gestational hypertension: pres-ence of blood pressure ‡140/90 mmHg on at least twooccasions ‡6 hr apart, during the second half ofpregnancy in a previously normotensive woman;Preeclampsia: pregnancy-induced hypertension with

proteinuria of >0.3 g/L in the absence of urinary tractinfection, or abrupt onset of hypertension and pro-teinuria after 24 weeks of gestation.

Statistical AnalysisComparison of quantitative variables was performedusing the Kruskal–Wallis test. Comparison of qualit-ative variables was carried out using the chi-square testor the Fisher’s exact test when appropriate. Statisticalsignificance was defined as P < 0.05.

RESULTS

Results are summarized in Tables I–III and Fig. 1.There was equal distribution between all three groupsfor baseline characteristics of patients including age,duration of SLE, activity of the disease at conception,and number of subjects screening positive for anti-phospholipid antibodies (aPL) (Table I). The distribu-tion of patients having the antiphospholipid syndrome(defined by the presence of circulating aPL and ahistory of thrombosis and/or fetal losses) was similar inthe three groups studied (four patients in group 1, twopatients in group 2, and five patients in group 3). Only21.4% (group 1), 33.3% (group 2) and 11.1% (group3) had active disease at conception. The outcome ofpregnancy was also similar in groups 1, 2 and 3(Table II). Elective abortion was always the patient’schoice. Spontaneous abortions occurred in a similar

TABLE I. Baseline Clinical Charac-

teristics of Patients in the Three

Groups Studied

Group 1

(n ¼ 42)

Group 2

(n ¼ 12)

Group 3

(n ¼ 54) P-value

Age (years) 29.05 � 5.4 29.9 � 4.8 29.7 � 5.2 NS

SLE duration (years) (%)

<1 2 (4.7) 0 3 (5.5) NS

1–5 15 (35.7) 5 (41.6) 18 (33.3)

>5 25 (59.5) 7 (58.3) 33 (61.1)

Active disease at

conception (%)

9 (21.4) 4 (33.3) 6 (11.1) NS

aPL positive (%) 11 (26.1) 4 (33.3) 16 (29.6) NS

aPL, antiphospholipid antibodies.

TABLE II. Outcome of Pregnancy in

the Three Groups StudiedPregnancy outcome

Group 1

(n ¼ 42)

Group 2

(n ¼ 12)

Group 3

(n ¼ 54) P-value

Elective abortion (%) 4 (9.5) 1 (8.3) 2 (3) NS

Spontaneous abortion (%) 6 (14.2) 2 (16.6) 9 (16.6) NS

Viable pregnancy (%) 32 (76.1) 9 (75) 43 (79.6) NS

Fetal loss 1 0 0

Live birth 31 9 43

184 / CARMONA ET AL.


percentage in all three groups and they were associatedwith the presence of aPL (10.3% in patients withoutaPL and 29% in patients with aPL; P < 0.05).

Medical and obstetrical complications in potentiallyviable pregnancies are presented in Table III. Themost striking difference between study groups was thathypertension and preeclampsia were more prevalentamong patients in group 1. Cesarean rate tended to behigher in group 1 when compared with groups 2and 3, although this was not statistically significant(P ¼ 0.06). Birth weight of neonates was lesser ingroup 1 when compared with groups 2 and 3 (P ¼0.02). However, the mean gestational age of neonateswas not significantly different in the three groupsstudied. As reported in Tables I and III there was notstatistically significant difference in disease activity atconception or during pregnancy among patients in thethree groups studied when stratified by active andinactive disease or flare rate. Flare rates were similarin the three groups of patients. Four patients in group1 and one in group 2 presented renal flare, mainlycharacterized by increased proteinuria and renalfunction impairment. They were treated by increasingthe dose of prednisone (0.25 to 1 mg/kg/day) andadding azathioprine (100 mg/day). All patientsimproved after delivery. The clinical manifestationsof flares in the remaining patients in groups 1, 2 and 3,included mainly cutaneous (n ¼ 2 in group 1; n ¼ 2 ingroup 2; n ¼ 7 in group 3) or articular (n ¼ 1 in group1; n ¼ 1 in group 2; n ¼ 5 in group 3) symptoms orboth.

Fig. 1 shows sequential renal function evaluationduring pregnancy and at 6–8 weeks postpartum. Pro-teinuria was significantly increased on the thirdtrimester of pregnancy with respect to baseline valuesobserved before conception in groups 1 and 2 but notin non-nephropathy controls. The percentage changein proteinuria from baseline values was significantlyhigher in group 1 when compared with patients ingroup 2 (Fig. 1). Plasma creatinine levels showed no

significant changes throughout pregnancy in the threegroups studied (Fig. 1).

DISCUSSION

As many women with SLE are of childbearing age andhave normal fertility, the clinician often faces manyproblems relating to pregnancy in patients with lupus

TABLE III. Obstetrical and Medical

Complications of Viable Pregnancies

in the Three Groups Studied

Group 1

(n ¼ 32)

Group 2

(n ¼ 9)

Group 3

(n ¼ 43) P-value

Hypertension (%) 12 (37.5) 1 (11.1) 5 (11.6) 0.01

Preeclampsia (%) 9 (28.1) 0 2 (4.6) 0.005

Gestational age (weeks) 35.6 � 2.6 36.8 � 3.3 37.2 � 4.2 NS

Preterm delivery (%) 10 (34.6) 3 (26.6) 8 (18.6) NS

Cesarean (%) 14 (43.7) 3 (33.3) 8 (18.6) 0.06

Birthweight (g) 2214 � 802 2783 � 721 2870 � 835 0.02

Flare* (%) 8 (19) 4 (33.3) 15 (27.7) NS

Renal flare 4 1 0

*Including flares in non-viable pregnancies.

Figures are mean � S.E.M.

Fig. 1. Proteinuria and creatinine plasma levels throughout preg-

nancy in patients with class III–IV lupus nephritis (open bars), class

II and V lupus nephritis (black bars) and SLE patients without lupus

nephritis (dashed bars).



nephritis. These include the influence of lupus nephritison fetal outcome, obstetric complications, and theinfluence of pregnancy on lupus nephropathy. Thissubject has been thoroughly reviewed in a recent reportincluding retrospective and prospective nephrologicaland obstetrical studies conducted with at least15 patients published between 1980 and 2001.6

Reports on lupus pregnancy from the 1950s and1960s mention patients with nephritis, usually in thecontext of severe flare, increasing proteinuria, azote-mia or acute anuric renal failure, hypertension,preeclampsia, onset of nephritis during pregnancy,and even maternal deaths.27 On the contrary, in the1970s and 1980s, several papers reported on uneventfulcourse of pregnancy, or a better prognosis, when renalfunction is normal, and lupus nephritis has beeninactive for 3–6 months before conception. This trendhas continued through the 1990s.10,27

At present, it is accepted that most lupus pregnan-cies do well, but there is an increased incidence ofadverse fetal outcome.28 Theoretically, several factorscan account for the increased frequency of fetal loss inSLE patients, but in a recent multivariate analysis,maternal renal disease was the only statistically signi-ficant predictor for fetal loss and hypertension for poorfetal outcome.7 The risk of fetal loss in lupus nephritispatients has been established as between 12 and 38%.6

Miscarriage accounted for 8–24% of fetal loss, whilestillbirths or neonatal deaths accounted for 4–24%.6

On the contrary, preeclampsia is more likely to occurin women with renal disease, arterial hypertension andaPL.10,27,29,30 Remarkably, a recent study30 has shownthat aPL are associated with an increased risk forchronic renal insufficiency in patients with lupusnephritis.The above result is in agreement with those in the

present study when: (i) both medical and obstetricalcomplications were associated mainly with the pres-ence of circulating aPL; and (ii) hypertensive disorderswere significantly more prevalent in group 1 than incontrol groups. The relative low incidence of obstet-rical and medical complications related to aPL may beexplained by the fact that all our patients receivedappropriate treatment25 which was started beforeconception. In lupus pregnancy, up to 25% of patientsdevelop significant proteinuria and hypertension in thesecond half of pregnancy.27 Opinions have variedwidely as to whether this represents preeclampsia oractive lupus nephritis. However, it is accepted thatinvestigation of serum complement levels (C3), anti-DNA antibodies, and urinary sediment, as done in thepresent study, can help to differentiate between activelupus nephritis and preeclampsia. A lupus flare isfrequently associated with hypocomplementenemia,high titers of anti-DNA antibodies, and an active

urinary sediment (red and white blood cells andcellular casts).6,27 Thus, according to our results,hypertensive disease but not lupus flare in pregnancyis significantly associated with advanced classes oflupus nephritis.

In pregnancy with maternal renal disease other thanlupus nephritis, hypertension develops in 41% of thesewomen, with a higher risk for severe hypertension inwomen with diffuse proliferative nephritis or withnephrosclerosis.27 This is in agreement with results inthe present investigation when showing that hyperten-sive disease was significantly more prevalent amongpatients in group 1 having class III or IV nephritis. Inthese women too, hypertension occurs most oftenduring the third trimester. Women with prior chronichypertension may develop preeclampsia in pregnancy,and the term �superimposed preeclampsia� is used.27

Superimposed preeclampsia occurred in 44% of ourpreeclamptic patients in group 1.

Preeclampsia is caused by shallow placentation,insufficient development of the spiral arteries in theuteroplacental vasculature, which results in placentalischemia, oxidative stress, destruction of trophoblastictissue, and infarction. It results in increased resistanceof the uteroplacental circulation, atherosis of theplacental vessels, systemic endothelial dysfunction,and ischemia with intrauterine growth restriction inthe fetus and hypertension in the mother.27 This mayexplain both the increased rate of cesarean section andlow-birth-weight neonates observed in group 1 in ourstudy. Remarkably, however, fetal loss rate was notsignificantly increased in patients in group 1 whencompared with groups 2 and 3.

The potential impact of pregnancy on lupus activityhas been debated for decades without a consensus.Data on the potential impact of pregnancy in patientswith lupus nephritis are scanty. Thus, Moroni et al.31

reported that the incidence of renal flares observed inthe period from the diagnosis of lupus nephritis to thebeginning of pregnancy was similar to that observedduring pregnancy and 6 months after delivery. This isin agreement with results in our study where the lupusflare and renal flare rates during pregnancy andpuerperium were similar in patients with SLE withoutnephropathy and lupus nephritis patients irrespectiveof the lupus nephritis class. In this regard, it has beenrecently stressed9 that in a nephrological seriesincluding only women with SLE nephritis diagnosedbefore pregnancy, flares rates of 0 and 9% werefound in the most recent studies, probably becausemost pregnancies had begun when SLE was inremission. On the contrary, in the older studiesincluding women with SLE nephritis diagnosedduring pregnancy, higher flare rates, up to 81%,were seen.



There was a potential limitation to this study.Patients were classified on the basis of renal histologyat time of renal biopsy but not at time of start ofpregnancy. Thus, several years could have passedbetween these two times for a number of patients.Considering that lupus nephritis is a treatable condi-tion with possibility, under treatment, of completeremission or change of class of renal histology, wecannot be entirely sure that initial histological class ofnephropathy could be responsible of the pregnancyoutcome. However, this is a common feature in studiesreporting on pregnancy outcome in women with long-standing SLE nephritis and what seems clear from thecurrent investigation and previous reports6,8–10 is thatthe risk of obstetrical and medical complications inpatients with lupus nephritis continues to be higherthan in pregnancies in healthy women and SLE patientswithout lupus nephritis. This is to be noted consideringthat, as recently stressed,9 a growing number of womenwith nephritis in the past wish to be pregnant.

In conclusion, in our experience, pre-existing renalinvolvement in the form of lupus nephritis class III–IVis clearly a risk factor for hypertensive disease duringpregnancy, but it does not contraindicate gestationprovided that careful planning of conception andmultidisciplinary monitoring and treatment are carriedout.

AcknowledgementsThis work was supported in part by grants from theInstituto de Salud Carlos III (RCMN C03/08), and theComissionat per a Universitat i Recerca-Generalitat deCatalunya (2001SGR 00372).

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Class III–IV Proliferative Lupus Nephritis and Pregnancy: A Study of 42 Cases

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