Pregnancy Outcomes in Systemic Lupus Erythematosus with and without Previous Nephritis

MATERIALS AND METHODS

Antenatal clinic lists at St. Thomas’ Hospital (January 2000-October 2008) were reviewed for women with SLE. Women were excluded if SLE was diagnosed during the current pregnancy or they delivered elsewhere. Women received local obstetric care if they were well, near term, or lived too far from St. Thomas’. All patients fulfilled the American College of Rheumatology criteria for SLE (1997)¹⁵. Histological features of renal disease were assessed by the 1995 World Health Organization (WHO) classification¹⁶, because most renal biopsies were performed before recent classification changes¹⁷.

Glomerular filtration rate was estimated (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation (using creatinine, age, sex, and race, prepregnancy and postpregnancy¹⁸). Proteinuria at 10–13 weeks’ gestation was defined by standard urinalysis of ≥ 1+, protein:creatinine ratio > 30 mg/μmol or total protein excretion > 300 mg/24 hours.

Active SLE was defined by the presence of arthritis, malar rash, vasculitis, oral or nasal ulcers, serositis, neurological manifestations, leukopenia, thrombocytopenia not associated with antiphospholipid antibodies (aPL), or Coombs-positive autoimmune hemolytic anemia. Any extrarenal disease manifestation requiring a change in treatment up to 6 months postpartum was considered a flare¹⁹. Renal flare was defined as the development of urine protein > 500 mg/24 h (in the absence of preeclampsia), or worsening proteinuria (defined as an increase by 2 g/24 h if baseline proteinuria was < 3 g/24 h or doubling of proteinuria in women previously with nephrotic-range proteinuria²), urinary casts, dysmorphic hematuria, reduced levels of C3 and/or C4, or a rise in serum creatinine of > 30%.

Antiphospholipid syndrome (APS) was defined according to the Sapporo criteria²⁰ because the study period started before more recent guidelines were published²⁰. Women with both thrombotic and obstetric APS were classified and managed according to the thrombotic protocol (Table 1) to achieve appropriate anticoagulation to prevent recurrent thromboses.

Obstetric definitions were miscarriage: spontaneous fetal loss < 20 weeks’ gestation; intrauterine death: spontaneous death of fetus > 20 weeks’ gestation; preterm birth: live birth between 21 and 36+6 weeks; SGA: birth weight < 10th centile according to customized charts (available from: www.gestation.net/birthweight_centiles/centile_online.htm).

Preeclampsia was diagnosed according to International Society of Study of Hypertension in Pregnancy guidelines²¹. For women with preexisting hypertension or proteinuria, preeclampsia was diagnosed after identification of additional clinical or biochemical markers.

All women were managed by a multidisciplinary team, including maternal-fetal-medicine obstetrician, hematologist, rheumatologist, obstetric physician, specialist midwives, and nephrologists. Women were seen for prepregnancy counseling and advised to conceive after their SLE had been in remission, or at least stable, for at least 6 months. Those receiving mycophenolate mofetil requiring ongoing immunosuppression were transferred to azathioprine.

Second trimester uterine artery Doppler waveform analysis was performed at 20 weeks anomaly scan (and repeated at 24 weeks if abnormal – defined as bilateral notching). Low molecular weight heparin was used in aPL patients according to local protocol (Table 1).

Statistical analysis was performed using SPSS V17. Logistic regression analysis with generalized link function to correct pregnancy outcomes for > 1 pregnancy in the same woman was performed with corrections for age and ethnicity. Chi-squared, 2-sided Fisher’s exact test and the Mann-Whitney U test were used for nonparametric data and the paired Student t-tests were used for parametric data. Logistic regression assessed the predictive value of each demographic variable on binary outcomes. Differences were considered to be significant if p < 0.05. Terminations and miscarriages were excluded from final analysis because of incomplete data collection.

RESULTS

Over 8 years, 86 women with SLE had 110 pregnancies. Three were excluded (2 miscarried at 13 and 18.5 weeks’ gestation, and 1 had twins), leaving 83 women with 107 pregnancies. Clinical details are summarized in Table 2.

Women with PN predominantly had WHO Class III or IV renal disease (26/43, 60%) and had higher prepregnancy creatinine and lower eGFR than women without PN (Table 2). They were more likely to have received cyclophosphamide or mycophenolate mofetil prior to pregnancy; were more frequently taking low-dose aspirin, prednisolone or azathioprine; more commonly had proteinuria and hematuria at booking. Median systolic and diastolic booking blood pressures (BP) were higher in women with PN.

DISCUSSION

Our study shows that with modern care, women with SLE and PN can achieve successful pregnancies without an effect on longterm renal function, although they experience significantly higher rates of preterm delivery than those without PN.

The evolution of immunosuppression has reduced mortality and dramatically improved outcomes for individuals with PN. Together with prepregnancy counseling, this has resulted in women entering pregnancy with increased likelihood of success. Reported rates of fetal loss fell from 40% in 1960–65 to 17% in 2000–3²². Previous studies included women with severe renal impairment and/or active disease on older immunosuppressive regimes; they are less relevant to modern counseling for women with SLE and PN^7,11,14. Our study adds to the literature regarding pregnancy outcome in women with predominantly quiescent PN and relatively preserved renal function^7,11,14. Our study is important because there are few data regarding pregnancy complications in women with SLE and PN managed in the 21st century.

Other authors have studied only white women¹⁴ or not reported ethnicity. Our cohort includes an ethnically diverse population, about one-third of African or Afro-Caribbean origin, which has previously been associated with worse pregnancy outcome for LN²³. However, this study shows that black ethnicity was not a predictor of preeclampsia, preterm delivery, or SGA.

Limitations of the research include its retrospective design, which precluded the use of disease activity indices, and study size, which prevented identification of subtle associations with pregnancy complications. The exclusion of women who delivered at other hospitals may have introduced bias toward women with more complex medical and obstetric histories.

Differentiation between a flare of LN and preeclampsia in women with PN is a challenging clinical dilemma, particularly in late pregnancy. The definition of proteinuria used for a flare of LN in pregnancy is not evidence-based but has been published by other authors². Our study demonstrated a temporal difference in presentation; preeclampsia occurred between 30–37 weeks, while first episodes of renal flare occurred at 9–25 weeks and responded to adjustment in immunosuppression. In 1 woman, LN presented de novo several days postpartum, and therefore differentiation from preeclampsia was possible by renal biopsy.

Because of retrospective analysis, only pregnancies 10–13 weeks after the 8–12 weeks’ antenatal visit were included, thus missing early miscarriages, so that total fetal loss rates cannot be reliably reported.

In our study, preterm delivery rates were significantly higher in women with SLE who had PN than in women who did not have PN (30% vs 11%), in agreement with a recent metaanalysis of women with SLE PN showing a rate of 39%⁴. Our data suggests that even if active renal disease has resolved with normal GFR and urinalysis, women with PN remain at risk for preterm delivery.

About half of preterm deliveries were spontaneous in another series of SLE pregnancies including 35% with PN²⁴. Premature rupture of membranes was identified as the most common cause of preterm delivery in a larger series of women with SLE, more commonly than in controls²⁵. Others report a similar rate of preterm delivery (27%) to our cohort for women who entered pregnancy in complete remission¹⁴; women with preterm deliveries tended to be induced because of deterioration in renal function or progressive preeclampsia. In our study, women with PN were more likely to have preterm deliveries but over half had spontaneous labor, demonstrating that medical intervention is not always a factor in pregnancy outcome.

Only 10–13 weeks systolic BP > 130 mmHg in women with PN was a predictor of preterm delivery, independent of the development of preeclampsia. Hypertension has been seen to be a predictor of fetal death in women with PN², as well as a predictor of preterm delivery in all with SLE²⁴. Others have found these predictors of preterm delivery: the use of prednisolone^24,26, lack of aspirin¹⁴, Afro-Caribbean race²³, Raynaud’s phenomenon²⁷, and aPL^26,28. Oviasu, et al found that preterm deliveries occurred only in women with WHO Class III, IV, and V LN³, although other studies, like ours, found no association with histological class of nephritis^1,7,14,29. This is in keeping with recent evidence suggesting that proteinuria may not always be consistent with histological disease activity in nonpregnant individuals³⁰. Active nephritis has been shown in several studies^24,27,31,32, including a metaanalysis of 2751 pregnancies, to be associated with increased rates of early delivery⁴; however, we report high rates of preterm delivery despite the majority of women with PN having quiescent disease.

Women with PN developed preeclampsia at significantly earlier gestations than those without. Markers of renal disease (prepregnancy eGFR < 90 ml/min/1.73 m², proteinuria at booking) and hypertension at booking (diastolic BP > 80 mmHg) were predictors of preeclampsia in women with PN, and have been noted^2,33. BMI > 30 and hypertension at booking were predictors of preeclampsia in women without PN. Preeclampsia affects between 21–30% of SLE pregnancies^{24,27,29,34,35}, particularly in the presence of aPL^36,37 and renal disease^1,24,33,38. Preeclampsia occurred in 21% of our SLE cohort but tended to be more frequent in women with PN (28% vs 16%).

Others have also found more maternal complications in women with PN, including preeclampsia, eclampsia, and HELLP syndrome, than in those with SLE without PN^4,7. Preeclampsia has been associated with LN WHO Class III and IV rather than Class II and V²⁹ but no associations were found in a metaanalysis of 9 studies of women with PN⁴. We found no relationship between preeclampsia and disease class, but we found a significantly earlier onset of preeclampsia in women with renal involvement, which is important for prepregnancy counseling.

Bilateral midtrimester uterine artery notches have been associated with impaired trophoblast migration and consequent preeclampsia, growth restriction, and placental abruption³⁹. In 100 pregnancies complicated by SLE and/or APS, including 19 women with PN, Le Thi Huong, et al found unilateral or bilateral notching was the only predictor of adverse pregnancy outcome, including fetal death, FGR, and preeclampsia, using multivariate analysis⁴⁰. Although not comparable, in our study there was a < 50% negative predictive value for the development of preeclampsia, an important negative finding for the management of these women in clinical practice (i.e., not to be reassured by the presence of normal Dopplers).

Moreover, our recent review of the utility of uterine artery Dopplers in a cohort of women with APS (which included 10 women from our study) found high sensitivity and specificity for placental dysfunction⁴¹. Given that uterine artery Doppler is a surrogate assessment of placental function, one could speculate that women with PN have relatively adequate placentation, but other preexisting maternal abnormalities such as endothelial dysfunction may be the predominant underlying pathophysiology for developing preeclampsia and/or SGA.

Rates of SGA < 10th customized centile were higher than background. Other studies have reported varying proportions of noncustomized SGA in infants of women with PN (4–24%). FGR has been shown to be more common in pregnancies complicated by SLE than in healthy controls, regardless of gestational age, even when controlled for hypertension and renal disease⁴², and those with mild disease³². Another recent report identified 46% and 20% of infants of women with and without current nephritis were SGA, according to customized centiles¹¹. There was no significant deterioration in renal function in women with SLE with or without PN at a median of 39 months followup postpartum. Factors previously reported to be associated with worsening renal impairment did not predict postpartum decline in eGFR, i.e., prepregnancy eGFR, disease activity during pregnancy, and preexisting hypertension. In a review of 17 studies of pregnancy in 276 women with PN, including some from over 20 years ago, 11% developed acute renal failure. In 3% the decline in renal function was permanent, without requiring dialysis, and 6% progressed to endstage renal failure or death⁴³.

A recent study of 81 women managed between 1985–2004, which included 11% with chronic kidney disease (CKD) stage 3, found 2% of women suffered a progressive deterioration in eGFR and 1% needed dialysis¹⁴. Reassuringly, 12% of our cohort had CKD stage 3 but none required renal replacement therapy nor experienced a permanent loss of eGFR. A deterioration in GFR > 20 ml/min/1.73 m² was found in 10% and 16% of women with and without PN respectively, suggesting that PN prior to pregnancy carries no greater risk of progression of renal disease.

Women with PN can have successful pregnancies in tertiary centers with multidisciplinary teamwork. However, women should be counseled before conception about early onset preeclampsia, preterm delivery, and SGA. Women with PN and prepregnancy eGFR < 90 ml/min/1.73 m², proteinuria, and diastolic BP > 80 mmHg at booking have increased risk of preeclampsia. Systolic BP > 130 mmHg at booking predicts preterm delivery. Reassurance can be provided about the low risk of permanent decline of renal function during and after pregnancy. A normal uterine artery Doppler is of limited value in prediction of preeclampsia and/or SGA in women with PN.