Disease flare-ups and obstetric outcomes in pregnant women with systemic lupus erythematosus

Abstract

Aim: The purpose of this study was to review the maternal and fetal outcomes in pregnant women with systemic lupus erythematosus (SLE), and to evaluate the prognostic risk factors that may contribute to obstetric outcomes or SLE flare-ups.

Methods: We evaluated 100 births in 97 SLE patients who were seen at Osaka University from 1995 to 2013. Main outcome measures included obstetric outcomes and SLE flare-ups.

Results: The mean patient age was 30.7±4.6 years, and the nulliparity rate was 62.8%. Corticosteroids were taken by 75.3% of the patients, and 48.5% were on a dosage of ≥7.5 mg/day. Disease flare-up and preeclampsia occurred in 17.5% and 11.3% of the patients, respectively. Seven SLE flare-ups (41.2%) occurred after delivery. Fourteen of the patients with a flare-up were taking high dose corticosteroids (≥7.5 mg/day) and showed significantly poorer obstetric outcomes compared to patients taking low dose corticosteroids (<7.5 mg/day) (P=0.0021).

Conclusions: A multidisciplinary approach in the care of pregnant women with SLE is important for good maternal and fetal outcomes. Furthermore, a high daily dosage of corticosteroids may be a prognostic risk factor for adverse SLE flare-ups.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder that affects various organs including the joints, skin, heart, lungs, nervous system, and kidneys.¹⁾ The disease mainly affects women of childbearing age. Although SLE patients usually have normal fertility,²⁾ they have higher maternal and fetal mortality and morbidity rates. Clowse et al. reported that maternal morbidity is 20-fold higher in women with SLE than in those without.³⁾

Pregnancies in SLE patients are more likely to end in spontaneous miscarriage, and are more susceptible to fetal growth restriction, fetal death, preeclampsia, and preterm delivery.^1,3) In addition, neonates may be at a higher risk of having congenital heart block or neonatal lupus erythematosus, because these conditions are related to the presence of anti-Ro/SSA and anti-La/SSB antibodies in the mother.⁴⁾ Hypocomplementemia, active lupus, renal involvement, existence of antiphospholipid antibodies, and history of fetal loss are also associated with an increased risk of obstetric complications.^3,4,5)

The association between SLE flare-up and pregnancy has been a subject of debate. Some studies have shown an increase in SLE flare-ups during pregnancy and the postpartum period, whereas other studies have not. The risk of a flare-up reportedly increases if SLE is active during the 6–12 months period prior to conception.⁶⁾ Therefore, clinicians often advise patients to plan pregnancy when SLE is in remission.

The present study aimed to clarify the influence of pregnancy on SLE course by investigating maternal and fetal outcomes in pregnancies in patients with SLE and evaluating the prognostic risk factors that may affect obstetrical outcomes and SLE flare-ups.

Materials and methods

We retrospectively reviewed pregnancy outcomes in 97 women with SLE (including three twin pregnancies) in our hospital between January 1995 and June 2013. All patients met at least four of the 1997 Revised American College of Rheumatology criteria for SLE.

Baseline maternal characteristics included age, nulliparity rate, past obstetric history, SLE duration, previous renal disease, medications, and the presence of antiphospholipid syndrome. Demographic data, disease activity, obstetric complications during pregnancy and puerperium, and medication given during pregnancy were recorded. Laboratory data included complete blood count, liver function tests, serum creatinine levels, urinalysis, and levels of lupus anticoagulant, antinuclear antibodies, anti-SSA/SSB antibodies, anticardiolipin antibodies, and serum complement levels. Levels of lupus anticoagulant were measured with dilute Russell’s viper venom time, antinuclear antibodies with radioimmuno-assay, and the other antibodies with enzyme linked immunosorbent assay.

Patients were assessed for SLE flare-up using the criteria from the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) trial, which included new or worsened cutaneous disease, nasopharyngeal ulcers, pleuritis, pericarditis, arthritis, fever attributable to SLE, a change in SLE Disease Activity Index of >3 points, the addition of a nonsteroidal anti-inflammatory drug or hydroxychloroquine, or an increase in prednisone dosage of <0.5 mg/kg/day. A severe flare-up was defined as new or worsened central nervous system disease; vasculitis; nephritis; myositis; hemolytic anemia; platelet count <60,000/μl; the necessity of addition of cyclophosphamide, azathioprine, or methotrexate; hospitalization for SLE-related manifestations; or an increase in prednisone dosage of >0.5 mg/kg/day.

Fetal growth restriction, premature birth, preeclampsia, hemolysis, elevated liver enzymes, low platelets (HELLP syndrome), and fetal loss were evaluated. Fetal growth restriction was defined as birth weight <5th percentile of the normal growth curve. Preeclampsia was defined as hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg on two separate occasions) and proteinuria (>300 mg/24 h) arising de novo after the 20th week of pregnancy.⁷⁾ Fetal loss was defined as fetal death after 22 weeks of gestation and premature birth (preterm) as live birth before 37 weeks of gestation. Diagnosis of antiphospholipid syndrome was established according to the updated Sapporo classification.⁸⁾ All newborns were examined for neonatal lupus erythematosus and atrioventricular block by a pediatrician.

Variables measured in interval scales were described as mean±standard deviation, and statistical comparisons between groups were performed using the Chi-squared test with GraphPad Prism (GraphPad Software, San Diego, CA). Significant differences were defined as P<0.05.

Results

Patient characteristics

Clinical characteristics of the patients are summarized in Table 1. The mean maternal age was 30.7±4.6 years, and the nulliparity rate was 62.8%. Renal involvement (lupus nephritis) was present in 30 patients (30.9%). Lupus anticoagulant and anticardiolipin antibodies were positive in 14.4% and 11.3% of the patients, respectively. Of these, seven (7.2%) fulfilled the criteria for antiphospholipid syndrome.

Table 1. Demographic characteristics of patients (n=97)

Characteristics
Maternal age (y)	30.7±4.6
Nulliparity	61 (62.8%)
History of spontaneous abortion	14 (14.4%)
History of IUFD (>12 wks)	2 (2%)
Duration of disease (y)	8.3±0.6
Previous renal disease	30 (30.9%)
History of positive dsDNA	51 (52.6%)
History of positive SSA/SSB	46 (47.4%)/5 (5.2%)
Diagnosis of APS	7 (7.2%)
Positive lupus anticoagulant	14 (14.4%)
Positive anticardiolipin	11 (11.3%)
Medical therapy
Corticosteroids ≥7.5 mg/day	47 (48.5%)
Corticosteroids <7.5 mg/day	26 (26.8%)
Immunosuppressive drugs	5 (5.2%)
None	24 (24.7%)

IUFD, intrauterine fetal death; APS, antiphospholipid antibody syndrome.

The details of the pregnant women who received medical therapy are presented in Table 1. The drugs used included corticosteroids, azathioprine, cyclosporine, and methotrexate. Corticosteroids were used in 73 (75.3%) patients, and 47 (48.5%) patients were on a dosage of ≥7.5 mg/day. The seven patients who met the criteria for antiphospholipid syndrome were treated with anticoagulants along with corticosteroids. Six (6.2%) patients were undergoing steroid pulse therapy during their pregnancy or after delivery and were considered to have had active disease.

SLE pregnancy-associated flare-ups

Obstetrical and perinatal outcomes of the patients are presented in Tables 2 and 3, respectively. Seventeen SLE flare-ups were documented, of which seven (41.2%) were severe. Flare-ups occurred mainly during the postpartum period (41.2%) and the third trimester (29.4%), as shown in Table 3. Flare-ups were significantly more frequent in the 14 patients on high dose corticosteroids (≥7.5 mg/day) compared to those on <7.5 mg/day (29.2% vs. 6%, P=0.0021). Previous renal disease was present in eight of the 17 flare-up cases and appeared to increase the risk of disease flare-up, albeit not significantly (P=0.25). No significant association was confirmed between elevated autoantibodies and any of the adverse maternal outcomes.

Table 2. Maternal outcomes

Outcome	Total	Corticosteroids (≥7.5 mg/day)	Corticosteroids (<7.5 mg/day)
Onset during pregnancy	4 (4.1%)
Flare-up during pregnancy	17 (17.5%)	14/47 (29.2%)	3/50 (6%)
Mild to moderate	10 (10.3%)	8	2
Severe	7 (7.2%)	6	1
Preeclampsia	11 (11.3%)	6/47 (12.8%)	5/50 (10%)
HELLP syndrome	1 (1.0%)

HELLP, hemolysis, elevated liver enzyme levels and a low platelet count.

Table 3. Distribution of 17 flare-ups during and after pregnancy

Flare-up occurrence	No. patients (%)
1st trimester	2 (11.8%)
2nd trimester	3 (17.6%)
3rd trimester	5 (29.4%)
Puerperium	7 (41.2%)

Obstetrical complications and perinatal outcomes

Eleven patients were diagnosed with preeclampsia; five (45.5%) were severe and one (9.0%) was complicated by HELLP syndrome (Table 2). Six patients were on high dose corticosteroids (≥7.5 mg/day), whereas five were on low doses. There was no significant difference in the occurrence of preeclampsia by corticosteroid dose.

Mean gestational age at delivery was 37.4±3.5 weeks, and mean birth weight was 2,498±554 g. Deliveries before 37 and 32 gestational weeks occurred in 21% and 6% of patients, respectively. Fetal growth restriction was diagnosed in 21 patients (21%), and preeclampsia developed in five (23.8%) of these patients. Stillbirths occurred in three patients (3%) at 15, 19, and 30 weeks of gestation (Table 4).

Table 4. Fetal outcomes (n=100)

Outcome	No. patients (%)
Stillbirth	4 (4%)
Premature birth	5 (5%)
<37 weeks of generation	21 (21%)
32–37 weeks	15 (15%)
28–32 weeks	5 (5%)
<28 weeks	1 (1%)
Birth weight (g)	2,498±554
Fetal growth restriction	21
Caesarean section	24 (24.7%)
Atrioventricular block	0
Neonatal lupus	3 (3%)

We could detect no remarkable association between assumed prognostic risk factors (anticardiolipin antibodies, antiphospholipid syndrome, renal involvement, and SLE flare-up during pregnancy; Table 1) and obstetric outcomes (fetal loss, fetal growth restriction, and/or preeclampsia and preterm birth). Patients with preeclampsia had a higher rate of fetal growth restriction (45.5%) than patients with flare-ups (17.6%), although no significant difference was found (P=0.2).

Discussion

Pregnancy outcomes for SLE patients have improved in recent years due to better care during the preconception and prenatal periods. However, maternal and fetal complications still occur, and the impact of maternal SLE on pregnancy outcomes remains unclear. Despite some evidence suggesting that regulatory T cells affect disease flare-ups in SLE patients, the underlying mechanism has yet to be characterized. Furthermore, the differentiation between disease flare-up and preeclampsia is sometimes difficult. We reviewed obstetric outcomes in patients with SLE and compared our results with those of prior studies to evaluate potential predictors of poor pregnancy outcomes.

Our study suggested that corticosteroid dosage could be a predictor of disease flare-up, with a threshold of 7.5 mg/day. According to a previous study, the risk of flare-up depends on the level of maternal disease activity in the 6–12 months period before conception.⁶⁾ Kobayashi et al. reported that 75% of pregnant patients with flare-ups had been in active disease phase at the onset of pregnancy, whereas 13% had been in remission.⁹⁾ In addition, the frequency of premature deliveries in patients who had received more than 15 mg/day of prednisolone was significantly higher compared with pregnancies maintained on 0–15 mg/day prednisolone. However, no report has investigated the relationship between corticosteroid dosage and disease flare-up rate.

With respect to the effects of pregnancy on SLE, there have been conflicting reports regarding SLE flare-ups during pregnancy. This likely stems from the differences in the definition of flare-up and the number of patients included in the studies, as well as the methodological differences in study designs. SLE flare-ups during pregnancy have been reported to occur at rates in the range of 7.7–68%.^10,11,12) Flare-up rates appear to decrease if pregnancies are postponed until a period of disease remission.⁶⁾ The SLE flare-up rate was 17.5% in our study, which is in agreement with the literature published recently.^10,11) Pregnancy-associated flare-ups are observed mainly during the second trimester (42%) and in the year after delivery (25%).¹⁰⁾ In our study, SLE flare-ups occurred mainly during the third trimester (29.4%) and puerperium (41.2%). Although the rates differ slightly between these studies, knowing typical flare-up rates during pregnancy and puerperium may help clinicians differentiate between a disease flare-up and preeclampsia.

Overall, pregnancies in SLE patients are at greater risk of spontaneous miscarriage, preeclampsia, fetal growth restriction, fetal death, and preterm delivery.^3,13,14) Preeclampsia rate was 11.3% in our study, which falls within the range of 5–38% reported by previous reports.^3,15,16) There was no significant association between the occurrence of preeclampsia and dosage of corticosteroid or previous renal disease. Fetal growth restriction was present in 45.5% of the patients with preeclampsia and appeared to increase the risk of preeclampsia, with no statistical significance (P=0.2).

Pregnancies complicated by SLE have spontaneous abortion rates in the range of 6–35%, which are higher than in the general population.¹⁶⁾ Because our study group consisted of SLE patients who were under regular antenatal follow-up, patients who had an abortion in the present pregnancy were not included in the study. However, 16.4% of our multiparous women had a history of abortion or intrauterine fetal death, consistent with previous studies. Previous studies reported that 17% of pregnant women with SLE had positive test results for antiphospholipid antibodies;^17,18) this rate is higher than the 7.2% found in our study.

Live birth rate in our study was 96%, which is in agreement with recently reported live birth rates of >85% in SLE patients.^1,19) The fetal growth restriction rate in our patient population was similar (21%) to previously reported rates (10–30%).²⁰⁾ The incidence of fetal loss was 4% in our study, whereas reported frequencies of fetal loss vary between 0% and 22%;^16,21) these differences may be attributed to factors such as variation in patient selection and use of modern obstetric care and treatment. We found that 21% of deliveries occurred before 37 weeks in our SLE patients, which is higher than in non-SLE pregnancies. This finding agrees with a previous report, which showed that preterm delivery rate increases nearly six-fold in SLE pregnancies.¹⁵⁾ As for the neonatal outcomes, we detected no atrioventricular block and noted neonatal lupus in three. These findings were consistent with previous reviews.

Some studies suggest that elevated dsDNA antibody, presence of renal involvement, hypocomplementemia, and antiphospholipid syndrome are prognostic risk factors for adverse obstetrical outcomes in SLE pregnancies;^15,16,22) however, significant influences of these prognostic risk factors on adverse obstetric outcomes have not been fully demonstrated.¹²⁾ We also detected no association between these factors and SLE flare-ups, or with any adverse outcomes.

Currently, no method exists for distinguishing between a disease flare-up and preeclampsia during pregnancy. Yet, correct diagnosis is critical for optimal management. Initiation or intensification of immunosuppressive therapy is required when SLE flare-ups occur, whereas delivery of the child and the placenta is the only cure available for severe preeclampsia. In our retrospective review, the reported daily corticosteroid dosage helped us distinguish between these two conditions. The soluble fms-like tyrosine kinase 1/placental growth factor ratio defined by Verdonk et al. may also help identify a disease flare-up.²³⁾

Pregnancy in SLE patients is considered high risk, and management should start before conception. Pregnancy should be planned when patient health is optimal, i.e., when the disease is in clinical remission for at least 6 months, and while on a decreased steroid dosage. Most SLE patients have successful pregnancies and deliver healthy babies with appropriate rheumatological, obstetric, and neonatal monitoring. However, some cases have severe complications, emphasizing the importance of clinician’s role in monitoring and diagnosing disease flare-up or preeclampsia, and selecting appropriate management depending on the condition.

Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research (25462555, 23592402) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the Japan Society for the Promotion of Science.

Conflict of interest

We declare no conflicts of interest.

References

• 1.   D’Cruz  DP,  Khamashta  MA,  Hughes  GRV. Systemic lupus erythematosus. Lancet. 2007; 369: 587–596.
• 2.   Lawrenz  B,  Henes  J,  Henes  M, et al. Impact of systemic lupus erythematosus on ovarian reserve in premenopausal women: evaluation by using anti-muellerian hormone. Lupus. 2011; 20: 1193–1197.
• 3.   Clowse  ME,  Jamison  M,  Myers  E,  James  AH. A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol. 2008; 199: 127.e1–6.
• 4.   Brucato  A,  Frassi  M,  Franceschini  F, et al. Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counter immunoelectrophoresis. A prospective study of 100 women. Arthritis Rheum. 2001; 44: 1832–1835.
• 5.   Cortés-Hernández  J,  Ordi-Ros  J,  Paredes  F,  Casellas  M,  Castillo  F,  Vilardell-Tarres  M. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology. 2002; 41: 643–650.
• 6.   Doria  A,  Tincani  A,  Lockshin  M. Challenges of lupus pregnancies. Rheumatology. 2008; 47 (suppl 3): iii9–12.
• 7.   Watanabe  K,  Naruse  K,  Tanaka  K,  Metoki  H,  Suzuki  Y. Statement of the Society: Outline of Definition and Classification of “Pregnancy induced Hypertension (PIH).” Hypertens Res Pregnancy. 2013; 1: 3–4.
• 8.   Miyakis  S,  Lockshin  MD,  Atsumi  T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006; 4: 295–306.
• 9.   Kobayashi  N,  Yamada  H,  Kishida  T, et al. Hypocomplementemia correlates with intrauterine growth retardation in systemic lupus erythematosus. Am J reprod Immunol. 1999; 42: 153–159.
• 10.   Carvalheiras  G,  Vita  P,  Marta  S, et al. Pregnancy and systemic lupus erythematosus: review of clinical features and outcome of 51 pregnancies at a single institution. Clinic Rev Allerg Immunol. 2010; 38: 302–306.
• 11.   Madazli  R,  Yuksel  MA,  Oncul  M,  Imamoglu  M,  Yilmaz  H. Obstetric outcomes and prognostic factors of lupus pregnancies. Arch Gynecol Obstet. 2013; in press.
• 12.   Cavallaca  JA,  Laborde  HA,  Ruda-Vega  H,  Nasswetter  GG. Maternal and fetal outcomes of 72 pregnancies in argentine patients with systemic lupus erythematosus (SLE). Clin Rheumatol. 2008; 27: 41–46.
• 13.   Molad  Y,  Borkowski  T,  Monselise  A, et al. Maternal and fetal outcome of lupus pregnancy: a prospective study of 29 pregnancies. Lupus. 2005; 14: 145–151.
• 14.   Stojan  G,  Baer  AN. Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management. Expert Rev Clin Immunol. 2012; 8: 439–453.
• 15.   Chakravarty  EF,  Colon  I,  Langen  ES, et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol. 2005; 192: 1897–1904.
• 16.   Mok  CC,  Wong  RWS. Pregnancy in systemic lupus erythematosus. Postgrad Med J. 2001; 77: 157–165.
• 17.   Georgiou  PE,  Politi  EN,  Katsimbri  P,  Sakka  V,  Drosos  AA. Outcome of lupus pregnancy: a controlled study. Rheumatology. 2000; 39: 1014–1019.
• 18.   Mavragani  CP,  Dafni  UG,  Tzioufas  AG,  Moutsopoulos  HM. Pregnancy outcome and anti-Ro/SSA in autoimmune disease. A retrospective cohort study. Br J Rheumatol. 1998; 37: 740–745.
• 19.   Al Arfaj  AS,  Khalil  N. Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia. Lupus. 2010; 19: 1665–1673.
• 20.   Witter  FR,  Petri  M. Antenatal detection of intrauterine growth restriction in patients with systemic lupus erythematosus. Int J Gynaecol Obstet. 2000; 71: 67–68.
• 21.   Clowse  ME,  Magder  LS,  Witter  F,  Petri  M. Early risk factors for pregnancy loss in lupus. Obstet Gynecol. 2006; 107: 293–299.
• 22.   Whitelaw  DA,  Hall  D,  Kotze  T. Pregnancy in systemic lupus erythematosus: a retrospective study from a developing community. Clin Rheumatol. 2008; 27: 577–580.
• 23.   Verdonk  K,  Visser  W,  Russcher  H,  Jan Danser  AH,  Steegers  EA,  van den Meiracker  AH. Differencial diagnosis of preeclampsia: remember the solble fms-like thyrosine kinase 1/placental growth factor ratio. Hypertension. 2012; 60: 884–890.