Obstetric outcome in systemic lupus erythematosus

Obstetric Outcome in Systemic Lupus Erythematosus

Fernanda Lima, Nell M.M. Buchanan, Munther A. Khamashta, Sign Kerslake, and

Graham R.V. Hughes

A prospective study was performed to investigate the fetal and maternal outcome of 108 pregnancies in 90 lupus patients. The protocol was based on shared care of the patients by a rheumatologist and an obstetrician, with input from a hematologist, if necessary. Lupus flares were treated with low-dose prednisolone, azathioprine and hydroxychloroquine. The live birth rate was increased from 31% in the patients' previous obstetric history to 82%. A high incidence of prematurity was observed (43%). Lupus patients with secondary antiphospholipid syndrome presented a higher risk for fetal loss (P = .006). Flares occurred in 57% of the pregnancies, but most were mild (skin and joints). Flare during pregnancy did not increase the risk of fetal loss. We believe that careful monitoring and management of the lupus pregnancy has substantially improved the fetal outcome. Copyright © 1995by W.B. Saunders Company

INDEX WORDS: Systemic lupus erythematosus; pregnancy; fetal loss; antiphospholipid antibodies.

T HERE ARE MANY uncertainties about the interaction between pregnancy and

systemic lupus erythematosus (SLE). Pregnancy causes changes in the hormonal and immuno- logic systems, which may interact with the disease. 1,2 The incidence of disease exacerbation during pregnancy and puerperium varies between 10% and 75% in the literature. 3

Fetal outcome in lupus pregnancies is charac- terized by a lower survival rate and higher rates of preterm deliveries and intrauterine growth retardation (IUGR) when compared with normal populations. Multiple factors have been identified associated with this less successful

From the Lupus Pregnancy Clinic and the Lupus Research Unit, St. Thomas'Hospital, London, England.

Fernanda Lima MD: Rheumatologist, Research Fellow, Lupus Pregnancy Clinic, St. Thomas Hospital, London, En- gland; Neil M.M. Buchanan MD: Consultant Rheumatolo- gist, Lupus Pregnancy Clinic, St. Thomas Hospital; Mun- ther A. Khamashta MD, PhD: Deputy-Director, Lupus Research Unit, St. Thomas Hospital; Sifin Kerslake MD: Senior Registrar in Obstetrics, Lupus Pregnancy Clinic, St. Thomas Hospita# Graham R.V. Hughes MD: Director, Lupus Research Unit, St. Thomas Hospital.

Address reprint requests to Dr. Munther Khamashta, Lupus Research Unit, The Rayne Inst#ute, St. Thomas' Hospital, London SEI 7EH, England.

Copyright © 1995 by W.B. Saunders Company 0049-0172/95/2503-000455.00/0

outcome, among them are lupus activity during pregnancy and antiphospholipid (aPL) antibodies, represented by anticardiolipin antibody (aCL) and lupus anticoagulant (LA). 4,5

We studied prospectively 108 pregnancies in 90 SLE patients followed in a multidisciplinary clinic and submitted to a specific treatment protocol. Our objective was to analyze the fetal outcome and the influence of lupus flare in these pregnancies.

PATIENTS AND METHODS

Patients

Over the last 5 years, 136 pregnancies in 112 patients were followed in our Lupus Pregnancy Clinic. From this group, 90 patients meeting four or more of The American College of Rheumatology criteria for the classification of SLE 6 were analyzed in our study. The patients were referred to the clinic from the General

Abbreviations: aCL, anticardiolipin antibodies; aPL, antiphospholipid; APS, antiphospholipid syndrome; CHB, congenital heart block; CTG, cardiotocography; FD, fetal distress; IUD, intrauterine death; IUGR, intrauterine growth retardation; LA, lupus anticoagulant; NND, neonatal death; NNL, neonatal lupus; PNP, postnatal period; PROM, premature rupture of membrane; TOP, termination of pregnancy; WHO, World Health Organization.

184 Seminars in Arthritis and Rheumatism, VoI 25, No 3 (December), 1995: pp 184-192

LUPUS IN PREGNANCY 185

Lupus Clinic of St. Thomas' Hospital or from other London and regional medical centers.

These patients were seen in the Lupus Preg- nancy Clinic simultaneously by a rheumatologist, an obstetrician and, when necessary by a hematologist. The strategy of management and the obstetric monitoring of the lupus pregnancies used in this clinic, previously described, 7 consisted of the following: Antenatal visits were booked monthly from conception to 26 weeks, fortnightly from 26 weeks to 32 weeks, and weekly from 32 weeks to delivery. Every patient was followed 12 weeks postpartum. Weight and blood pressure were measured at each visit. Urinalysis was performed using Multistix (Ames, Miles Inc, USA). Besides the routine laboratory antenatal assessments, all patients had the following tests performed at least once: total blood count, erythrocyte sedimentation rate, serum and urinary biochemical profile, 24-hour urine collection for total protein, total complement, C3 and C4. Antinuclear antibodies were deter- mined by indirect immunofluorescence on Hep-2 cell slides.' Anti-double-stranded DNA was studied on Crithidia luciliae slides and by the Farr assay (Amersham, Little Chalfont, England). Anti-extractable nuclear antigen (ENA) antibodies were analyzed by counterimmunoelectro- phoresis using rabbit kidney and human spleen as substrate; LA was established by a prolonged activated partial thromboplastin time that did not correct to within 2 SD of the mean when retested as a 1:1 mix of patients and normal pooled plasma and by using the dilute Russel Viper Venon Time; immunoglobulin (Ig)G and IgM aCL were detected by an enzyme-linked immunosorbent assay, in which results were reported negative (IgG < 5,0 GPL units and IgM < 3.2 MPL units), low-positive (IgG 5 to 15 GPL units and IgM 3.2 to 6.0 MPL units), moderate (IgG 15 to 80 GPL units and IgM 6 to 50 MPL units) and high (IgG > 80 GPL units and IgM > 50 MPL units).

Fetal growth was assessed by uterine palpa- tion, measurement of symphysis-fundal height, and ultrasound. Fetal well-being was checked by Doppler flow assessment of placental perfu- sion from the 16th week of pregnancy onward and cardiotocography (CTG) from 24 weeks onward.

Treatment

Administration of prednisolone, hydroxychloroquine (200 mg to 400 mg daily) and azathioprine (50 to 100 mg daily) were continued in patients receiving them before pregnancy or were introduced or increased if signs of lupus activity occurred. Those with a history of fetal loss in the presence of aPL antibodies received aspirin (75 mg daily). If they had suffered previous thrombosis, subcutaneous unfraction- ated heparin or low-molecular weight heparin was added to the treatment.

ActivitY of Disease

Lupus activity was defined as the occurrence of vasculitic or other typical skin lesions, arthritis, serositis, psychosis or convulsion (excluding those related to eclampsia), leukopenia < 2,000/m 3 and thrombocytopenia < 100,000/ m3--not associated with antiphospholipid syndrome (APS)--or Coombs' positive hemolytic anemia. Diagnosis of renal flare was based on presence of one or more of the following: persistent proteinuria >0.5g/day (in the absence of preeclampsia), presence of cellular casts in urine, hematuria, decrease in the complement CH50, a response to specific treatment (steroids and/or immunosuppressors) and, when possible, renal biopsy results. Flares were classified as mild, moderate or severe, on the basis of clinical and laboratory assessment.

Definitions of Terms

Pregnancy loss included both spontaneous abortions (<12 weeks' gestation) and fetal death (> 12 weeks' gestation). Premature birth was considered as a spontaneous or induced termination of pregnancy with a live birth between 21 and 37 weeks. Termination of pregnancy was a voluntary induced abortion. Puerpe- rium was the 8 weeks after the delivery or loss. Neonatal death (NND) was considered as death within 7 days from birth. Premature rupture of membranes (PROM), was spontaneous rupture of membranes before the onset of the labor and delivery. The diagnosis of fetal distress (FD) was made using fetal movements, CTG, serial ultrasound, and Doppler as parameters. The identification of IUGR was based on ultrasonic examination values of the head and abdominal

186

circumference of the fetus falling below the 10th percentile of normal population values. We defined a successful outcome as a pregnancy that ended with a live baby.

Statistical Analysis

Proportions were compared using X 2 o r Fish- er's exact test. Means were compared using Student t test from normally distributed vari- ables. The previous obstetric history of the patients was analyzed using the Mann Whitney U test. When corresponding P values were smaller than .05, results were considered significant.

RESULTS

Demographic Parameters

Details of race, age, and past obstetric experience are listed in Table 1. The average time to onset of the first pregnancy after SLE was diagnosed was 6.3 _+ 12.6 years. Eighteen patients had a previous thrombotic event (20%). Thirteen patients had thrombocytopenia (14%). Apart from the diagnosis of lupus, 35 patients (39%) fulfilled the criteria for APS, 8 4 patients presented a concomitant diagnosis of hypothy- roidism (4%), 2 of myasthenia gravis (2%), 1 of gout (1%), and 1 of psoriasis (1%). The main lupus manifestations in these patients before their pregnancies were cutaneous and articular (65%), as shown in Table 1. The laboratory features and drugs used at the date of the first visit are also listed in Table 1.

Maternal Outcome

Ten patients had signs of activity at the onset of the pregnancy (9%). In 2 of these pregnancies, a termination was undertaken because of severe activity. The other 8 patients developed a further flare in the pregnancy or puerperium. Their pregnancy outcomes were 7 live babies and 1 case of intrauterinedeath (IUD)

In the 108 cases studied, flares during pregnancy and/or postnatal period were observed in 62 pregnancies (57%). The total number of flares were 74, with a flare rate per person/ month of 0.073 + 0.04. Forty-eight flares occurred during pregnancy (65%), and 26 occurred in the puerperium (35%). The trimester most affected was the second trimester, with 38% of the 74 flares, followed by the puerpe-

LIMA ET AL

Table 1: Materna l Profile

Patients Characteristics (n = 90)

Mean age +- SD (yr) 30.7 -+ 4.9 Mean duration of SLE _+ SD (yr) 6.3 -+ 12.6 Race

White 71 (79)* Black 11 (12) Asian 7 (8) Chinese 1 (1)

Main SLE manifestations Cutaneous lesions and synovitis 33 (37) Cutaneous lesions only 14 (16) Renal disease 14 (16) Synovitis only 11 (12) Hematologic disease 9 (10) Neuropsychiatric symptoms 8 (9)

Previous thrombotic event 18 (20) Previous obstetric history (184

pregnancies) Terminations of pregnancy 25/184 (14) Spontaneous abortion 44/184 (24) Fetal death 58/184 (32) Live birth 57/184 (31)

Drugs at the onset of pregnancy Prednisolone 55 (51) Aspirin 47 (43) Azathioprine 15 (14) Hydroxychloroquine 14 (13)

Laboratory features Anti-Ro 34 (38) Anti-La 16 (18) Anti-Sm 5 (6) Anti-RNP 12 (13) Anti-phospholipid$ 44 (49) Venereal Disease Research Labo-

ratory false-positive 4 (4)

Abbreviation: SLE, systemic lupus erythematosus. *Parenthetical numbers represent percentages. 1"Lupus anticoagulant and/or anticardiolipin antibodies.

rium (35%), the third trimester, (19%) and then, the first trimester (8%). Mild activity was observed in 56% of the flares, moderate in 24%, and severe in 20%.

Comparing the pregnancies in which a flare was observed (43 pregnancies) and those without (46 pregnancies), we found no significant difference in terms of pregnancy loss, FD, IUGR, prematurity, and length of gestation of the successful pregnancies. The influence of flare during pregnancy on the fetal outcome is shown in Table 2.


Table 2: Obstetric Outcome and Lupus Flare

Pregnancy

With Without Outcome Flare* Flare P

Pregnancyloss 6/43 (14%) 12/46 (26%) NS Successful preg-

nancies Fetal distress 16/37 (43%) 14/34 (41%) NS Intrauterine

growth retardation 11/37 (30%) 11/34 (32%) NS

Prematurity 16/37 (43%) 14/34 (41%) NS Length of gesta-

tion (wk) (_+SD) 35 -+ 3.5 36 _+ 3.8 NS

Abbreviations: NS, not significant. *Excluding puerperium flares.

Renal involvement secondary to lupus activity occurred in 12 pregnancies, preeclampsia in 3, and eclampsia in 1. In 2 other cases, both preeclampsia and renal flare were recorded (Table 3). The outcome of the pregnancies that presented renal flare before delivery was 3 live babies, 3 IUDs, 1 NND, and 1 termination. The 2 patients who presented both renal flare and

preeclampsia had 2 live babies. The fetal outcome in the eclampsia/preeclampsia cases were 3 live babies and 1 IUD. A previous history of renal lupus was recorded in 75% of patients who presented with preeclampsia and in 57% of those with current renal flare.

Fetal Outcome

Ninety mothers had 108 pregnancies during the study period. Sixteen mothers had 2 pregnancies and 1 had 3. Nineteen pregnancies (18%) ended unsuccessfully. The mean maternal age of this group was 29.7 _+ 5.4 years. Two terminations were performed in the 6th and 9th weeks because of a neurological and a renal flare respectively. There were 7 cases of spontaneous abortion (37%) with a median age of 9 weeks (range = 8 to 10 weeks). None of the patients who experienced spontaneous abortion presented signs of activity of lupus, but 6 of 7 had a secondary diagnosis of APS (86%). The other 10 pregnancies ended in FD (53%), with a median age of 21 weeks (range = 12 to 28 weeks). Of these pregnancies, 5 mothers did not flare during pregnancy, 3 experienced renal flare, 1 developed eclampsia, and 1 a renal flare

Table 3: Renal Involvement

Pregnancies

Previous Renal Fetal Renal

Involvement Period Outcome Diagnosis Disease

1 Flare 3rd trimester IUD WHO III Yes 2 Flare 2nd trimester LB RT No 3 Flare PNP LB WHO V No 4 Flare 3rd trimester NND WHO III Yes 5 Flare PNP IUD WHO III Yes 6 Flare PNP LB WHO III No 7 Flare PNP LB WHO II Yes 8 Flare 2nd trimester LB WHO IVa No 9 Flare 1st trimester TOP WHO IIIc Yes

10 Flare 2nd trimester IUD RT No 11 Flare 2nd trimester IUD RT No 12 Flare 2nd trimester LB RT Yes 13 Flare/preeclampsia 2nd trimester LB RT Yes 14 Flare/preeclampsia 3rd trimester LB WHO III*/RT Yes 15 Preeclampsia 2nd trimester LB RT Yes 16 Preeclampsia 3rd trimester LB RT Yes 17 Preeclampsia 3rd trimester LB RT No 18 Eclampsia 2nd trimester IUD RT Yes

Abbreviations: PNP, Postnatal period; LB, Live baby; IUD, Intrauterine death; TOP, Termination of pregnancy; RT, Response to treatment; NND, neonatal death; WHO, World Health Organization classification of lupus nephritis. *Before pregnancy.

188 LIMA ET AL

in the postnatal period. Seven of these 10 had a secondary diagnosis of APS (70%). Eighty-nine pregnancies ended successfully (82%) with the delivery of 90 live babies (1 twin pregnancy). The mean maternal age of this subgroup was 30.9 _ 4.8 years and the median gestational age was 37 weeks (range = 26 to 40 weeks).

Labor was spontaneous in only 29 pregnancies (32%). The main indication for induction of vaginal delivery or ceasarian section was a combination of suspected IUGR and FD in 18 pregnancies (30%), FD in 19 (32%), suspected IUGR in 11 (18%), PROM in 4 (7%), maternal disease in 3 (5%), poor obstetric history in 2 (3%), breech presentation in 2 (2%), and a combination of PROM and IUGR in 1 pregnancy (2%).

Prematurity occurred in 38 of the successful pregnancies (43%). In 76% of these deliveries (29 pregnancies), labor was induced because of IUGR, FD, or a combination of both. The median gestational age of these babies was 34 weeks' (range = 26 to 36 weeks). We analyzed factors that might be used as predictors of prematurity. Neither disease activity during pregnancy nor a secondary diagnosis of APS were predictors for this outcome. The other variable that we considered was a minimum dose of 15 mg of prednisolone per day at the onset of the pregnancy. Again, no statistical significance was reached.

Four cases of NND occurred of 89 successful pregnancies (4.5%). All were of 26 weeks gestation and the mean weight was 618 _+ 158 g. In all cases labor was induced because of a combination of IUGR and FD. In 3 of the NND cases, the mothers had APS. In addition, 2 of these mothers presented renal activity before delivery.

To analyze the factors that could predict the fetal outcome, we studied only the first pregnancies of our study group; results are shown in Table 4. A previous poor obstetric history was associated with a subsequent failure (P = .01). APS was another important predictor of unsuc- cessful fetal outcome (P = .006). The presence of flare and hypertension during pregnancy were not significant as predictors of fetal outcome. When we analyzed separately the presence of the aPL antibodies, we found that aCL (]gG or IgM) was a statistically significant

Table 4: Predictors of Outcome (First Treated Pregnancies)

Success Failure Group Group

(n = 73) (n = 17)

Previous pregnancy loss median (range) 0 (0-6) 2 (0-13) .01

Flare during pregnancy 37 (51)* 6 (35) NS

Hypertension 32 (44) 6 (35) NS Antiphosphol ipid

syndrome 23 (31) 12 (70) .006 Anticardiolipin

antibodies 25 (34) 12 (70) .01 Lupus anticoagu-

lant 26 (36) 11 (65) NS Low C3/C4 18 (25) 7 (41) NS Anti-DNA 13 (18) 2 (12) NS Anti-Ro 29 (40) 5 (23) NS Anti-La 14 (19) 2 (12) NS Anti-Sm 4 (5) 1 (6) NS Anti-RNP 8 (11) 4 (24) NS

Abbreviations: NS, not significant. *Parenthetical numbers represent percentages.

predictor (P = .01), but LA had a borderline significance as a predictor (P = .056) of failure. Neither the other antibodies analyzed (ENA and DNA) nor low levels of C3/C4 showed any statistical significance in predicting fetal loss.

Neonatal lupus (NNL) occurred in 9 of 108 total pregnancies (8%). Anti-Ro was positive in all of these mothers and anti-La in 55%. Six babies had rash, 1 had congenital heart block (CHB), 1 had a combination of CHB and rash, and 1 presented an inflammatory myocardiopathy. This last baby developed congestive failure and died after undergoing a heart transplant when he was 2 years old. Table 5 describes all mothers who had at least 1 baby with NNL, previously or during the follow-up in our clinic. No specific pattern of recurrence was observed. One 32-year-old patient had a newborn with Down syndrome. No evidence for teratogenicity was observed in pregnancies in which the mother used azathioprine and/or hydroxychloroquine.

LITERATURE REVIEW AND DISCUSSION

Fertility in lupus patients has been reported to be similar to the normal population. 9 Mater- nal outcome has been studied since the 1950s.


Table 5: Neonatal Lupus

Mothers anti-Ro+ anti-La+ Baby 1 Baby 2 Baby 3 Baby 4

1 pos pos Normal

2 pos neg Normal

3 pos pos Rash 4 pos pos Rasll 5 pos neg Normal

6 pos pos $ Platelets

7 pos neg Normal

8 pos neg Normal

9 pos pos Normal

10 pos neg Rash/CHB

Rash CHBt

Normal*

Normal

CHB CHB

Rash Inflammatory

myocardiopathy Normal

Rash

CHB Rash

CHB Normal

Abbreviations: CHB, congenital heart block. NOTES. No bold = previous pregnancy; bold = *Twins. "i'Baby died,

current pregnancies. ~ Platelets = thrombocytopenia.

Rates of pregnancy or postpartum flare were in the range of 50% to 75%. 10'11 The earliest reports a°,al recommended lupus patients avoid or terminate pregnancy, suspecting a negative effect on their disease. Since then, the outlook has changed: a better comprehension of the pathology of lupus has been achieved, improved laboratory methods lead to earlier diagnosis and intervention, and increased experience with steroids and immunosuppressive drugs has greatly improved the prognosis of lupus patients. The better outlook was shown in reports published between the 1960s and 1970s, 9,12,13 in which the rate of flare during pregnancy and the postpartum period decreased to half when compared with that in the 1950s. In the last 15 years, several retrospective and a few prospective studies have addressed the influence of pregnancy on the exacerbation of lupus. The largest series are listed in Table 6.

In lupus pregnancy, the key issues include the incidence and severity of flare, effects on renal disease, the risks of fetal loss, and the possibility of NNL. Obstetric risks and drug safety also must be considered.

Lupus activity is difficult to assess in the gravid state because pregnancy may lead to joint discomfort, cutaneous erythema, and changes in the erythrocyte sedimentation rate and in complement metabolism. 14 Despite this, flare during pregnancy and puerperium was observed in 57% of the cases, with a flare rate per patient/month of 0.073. This rate is similar to

others published previously, 15,16 but because we did not use a control group we could not determine whether disease activity was more frequent during pregnancy. Results from our unpublished data suggest that patients flared more during pregnancy and puerperium when compared with age and sex-matched controls and with themselves in the year after pregnancy. In 5 other prospective studies published in the last 10 years, 15-2° the percentage of flare varied

Table 6: Incidence of Flare in Major Reported Series

Flare Study (yr) Type Pregnancies (%)

Tozman et al (1980) 34

Varner et al (1983) 35

Meehan et al (1987) 33

Nossent et al (1990) 18

Lockshin et al

(1984) 19 Prospective

Mintz et al (1986) 17 Prospective

Wong et al (1991) 15 Prospective

Retrospective

Retrospective

Retrospective

Retrospective

Petri et al (1991) 22 Prospective

Tincani et al

(1992) 16 Prospective

Huong et al (1994) 36 Prospective

Lima et al (1995) Prospective

24 25

38 35

22 45

39 74

33 21

102 60

29 45

39 60

25 40

103 26

108 57

190 LIMA ET AL

from 21% to 74%, but those trials that included a control group presented conflicting results regarding pregnancy related lupus exacerbation. Zulman et al 2I found that patients were more likely to flare during pregnancy as op- posed to before pregnancy. Lockshin et a119 reported similar flare rates in 28 pregnant and 21 nonpregnant patients and Mintz et a117 reported 55 exacerbations in 909 months at risk in their pregnant patients, which was not signifi- cantly different from 19 exacerbations in 486 months in their nonpregnant patients. Petri et a122 found the flare rate during pregnancy (29 patients with 36 pregnancies) was increased compared with that after pregnancy in the same patients, and compared with flares in nonpregnant lupus patients. The timing of flare was studied by several authors. The most recent studies 21-23 showed a trend to flare occurring in the third trimester and postpartum, although the earlier work 17 showed an increased incidence in the first trimester.

Renal lupus is one of the main risks during pregnancy. A previous history of no renal involvement does not exclude the possibility of developing kidney disease during pregnancy or the puerperium. In the precorticosteroid era, several authors reported a catastrophic maternal and obstetric outcome. 11,13,24,25 Recent reports suggest that lupus nephritis has a better prognosis if it has been inactive for 3 to 6 months before conception. 23,26,27 Packham et al, 28 in a series of 46 pregnancies in patients with previous renal involvement, showed a good outcome with no maternal death and no progres- sion to end-stage renal failure, although irreversible hypertension and irreversible proteinuria were observed in 7% and 2%, respectively. Preeclampsia occurred in 23% of lupus patients in a report from Rotterdam] 8 compared with 5% to 10% in the general Dutch population. Lockshin et aP 9 found a high incidence of preeclampsia and pregnancy induced hypertension (31%), most of them occurring in patients with prior lupus nephritis (64%). According to Zulman et al, 2a the need to differentiate lupus renal flare from preeclampsia occurs in 25% of lupus pregnancies. There is no definitive method to distinguish between these diagnoses. The current clinical and laboratory measurements

discriminate poorly between flare and preeclampsia. 29 Buyon et al found that complement components C3 and C4 and more recently complement split products, were of potential value to distinguish between these two condi- tions.30, 31

Two thirds of the flares in our patients were mild, affecting predominantly skin and joints and not requiring hospital admission. Renal lupus was less common in our series. In most of our patients, we were able to confirm this diagnosis by performing a renal biopsy postna- tally. In general, the prognosis of the cases with renal flare was good. Except for 2 patients, 1 who developed progressive renal failure and a second with persistent hypertension, the other renal flare patients recovered renal function similar to prepregnancy levels. Prednisolone and azathioprine treatment was given during pregnancy, and intravenous cyclophosphamide was usually given after delivery.

Pregnancy loss after the diagnosis of lupus is higher than in the normal population. The many retrospective studies 9,26,3e-35 and the few prospective studies 15,17A9,36 have not been able to resolve the major controversies regarding the effect of lupus on pregnancy. In a study of 183 pregnancies before SLE onset by Fraga et al, 9 23% ended in spontaneous abortion, with 13% in 288 control pregnancies. After SLE onset, spontaneous abortion rose to 41%. The incidence of pregnancy loss (spontaneous abortion and fetal death) during the last decade was 27% 37 but was between 11% to 24% in recent prospective studies. 15,19 Excluding termination of pregnancy, because it included nonmedical requests, the rate of previous pregnancy loss in our patients was 64%. For the studied pregnancies, this rate decreased to 18%. The most important reasons for this improvement may be closer monitoring and timely obstetric intervention.

Obstetric complications are frequently observed in lupus pregnancy--FD, IUGR, prematurity, and PROM. 29 In our series, we observed a rate of 41% of FD, 32% of IUGR, and 11% of PROM. This last complication was not as high as expected, probably because the number of term pregnancies was small and PROM is associated with term gestations.

Because our policy is to deliver the baby in


those pregnancies when FD and/or IUGR was present, we observed a high frequency of prematurity (43%). This frequency was similar to other prospective studies, varying from 19% to 49o~.15-18,20,36

The influence of lupus activity at conception on pregnancy loss and prematurity has been investigated a7,23,27 but the results are unclear. This may reflect different criteria for diagnosing flare and different profiles of disease severity. The impression that flare does not affect pregnancy outcome is shared by some authors. 15,18,2° Mild flares (cutaneous vasculitis, skin rash or arthritis) in our series, did not lead to fetal loss or prematurity. However, all our successful renal flare mothers had premature deliveries and 40% experienced pregnancy failure, in keeping with 2 large series of women with renal disease, in which the overall fetal loss rates were 34% 28 and 38%. 27 The severity of lupus flare and its pattern of organ involvement, therefore, does affect pregnancy outcome. Some studies 38,39 suggest that high anticardiolipin levels or LA :in lupus pregnancies were high risk factors for fetal loss, but 2 recent prospective studies do not support these conclusions. 15,t8 In our study, we fi3und a strong association between aCL and fetal loss. For LA, we found a borderline association, similar to that described by Petri et al 4° in a retrospective case-control study. We also found that patients with a secondary diagnosis of APS presented statistically more fetal losses than those with "pure" SLE. In our patients, the finding of aPL antibodies or the presence of criteria for APS were important predictors of fetal loss. As in previous reports, we noted that a poor past obstetric history is an important predictor of future pregnancy loss. 4,41

The major clinical manifestations of NNL are cardiac, dermatologic, and hepatic with congenital heart block being the most significant lesion. Less commonly, hemolytic anemia and thrombocytopenia are seen. 42 In our series of NNL, the anticipated association with anti-Ro antibody was observed (100% of the mothers were positive); anti-La antibody was less frequent (55%). The overall prevalence of NNL in live births of SLE mothers, derived from the largest prospective study, was 1.2%. 17 In our series, NNL occurred in 8% of the pregnancies. We believe this higher frequency could be partly explained by a greater awareness of this complication, so that an NNL rash, which is usually a transient and sometimes minor sign, could be recorded more easily. One author reported a 25% risk of a further affected child after 1 had NNL, which may increase to 50% if 2 or more have been affected. 43 In our series, we did not observe any special pattern of recurrence of NNL features in mothers who presented it previously, as illustrated in Table 5.

Fifteen of our patients used azathioprine and 14 patients used hydroxychloroquine, at least during the first trimester of gestation. No evidence of congenital malformation was observed in the newborns. Long-term follow-up of the children is planned.

In conclusion, we believe that despite the increased risk of obstetric complications, espe- cially in renal and aPL-positive patients, and a more than 50% chance of experiencing flare during pregnancy and puerperium, lupus patients should not be discouraged from becoming pregnant as flares tend to be mild and control- lable with usual therapy. The fetal loss rate can be reduced by close obstetric monitoring.

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Obstetric outcome in systemic lupus erythematosus