Pregnancy outcome in systemic lupus erythematosus: Asia’s largest single centre study

Arch Gynecol Obstet (2011) 284:281–285 DOI 10.1007/s00404-010-1618-7 MATERNO-FETAL MEDICINE Pregnancy outcome in systemic lupus erythematosus: Asia’s largest single centre study Neelam Aggarwal • Ainharan Raveendran • Vanita Suri • Seema Chopra • Pooja Sikka • Aman Sharma Received: 20 May 2010 / Accepted: 19 July 2010 / Published online: 1 August 2010 Ó Springer-Verlag 2010 Abstract Aim To evaluate pregnancy outcome in women with systemic lupus erythematosus (SLE). Methods A total of 71 pregnancies in 35 women with SLE were evaluated for maternal and perinatal outcomes in a tertiary centre of Northern India. Thirty-five pregnancies were evaluated prospectively while details of previous 36 pregnancies in the same women were studied retrospectively. Results The Mean age of pregnant women with SLE was 26.89 ± 2.7 years and 14.57% were nulliparous. The presenting event was arthritis in 60% of the patients; others presented with febrile illness, renal manifestation and cutaneous manifestation. One woman was lupus anticoagulant positive. All women conceived while on disease quiescence period and were continued on the same pre-pregnancy dose of pharmacological agents. Hypertensive disorders of pregnancy were seen in 28.5% while chronic hypertension was seen in 5.6%. The incidence of abortion, preterm deliveries and perinatal loss was 33.8, 29.57 and 12.67%, respectively. Vaginal delivery rate was 47.88 and 18.3% underwent caesarean section. There was no case of neonatal lupus and none had disease flare-up in the postpartum period. Conclusion A better pregnancy outcome can be expected if clinical remission is achieved and disease activity is adequately controlled prior to pregnancy. Keywords Arthritis
Azathioprine
Lupus pregnancy
Neonatal lupus
Systemic lupus erythematosus Introduction N. Aggarwal
A. Raveendran (&)
V. Suri
S. Chopra
P. Sikka Department of Obstetrics and Gynaecology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India e-mail: rainharan@yahoo.co.in N. Aggarwal e-mail: chddialysis@rediffmail.com V. Suri e-mail: surivanita@yahoo.com S. Chopra e-mail: seemasyal769@yahoo.co.in A. Sharma Rheumatology Wing, Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India e-mail: amansharma74@yahoo.com Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a complex pathogenesis resulting in abnormal immune response. It commonly affects women of childbearing age whose fertility remains unaffected [1]. Most of the data on pregnancy in SLE is from developed countries with better health care facilities [2, 3]. There are only few reports of pregnancies in patients with SLE from developing nations particularly Asian countries where women have no choice about the timing of pregnancy [4–9]. The effect of pregnancy on SLE flares is controversial and the risk of flare seems to depend on the level of maternal disease activity in the preconceptual period [8]. We had reported our experience of pregnancies in SLE from a tertiary care hospital in Northern India about a decade ago [5]. Here, we once again review the outcome of pregnancy in lupus patients attending our clinic in the last decade. 123 282 Materials and methods During the 11-year period between 1998 and 2009, 35 patients with SLE were registered in our special Medical and Surgical Disorders Clinic at a tertiary care hospital in Northern India. A total of 71 pregnancies in these 35 women with SLE were evaluated for maternal and perinatal outcomes. Thirty-five pregnancies were evaluated prospectively while details of previous 36 pregnancies in the same women were studied retrospectively. The diagnosis of SLE was made by a rheumatologist according to the American College of Rheumatology (ACR) criteria for SLE [10]. Demographic data of the patients, age at diagnosis, number of ACR criteria identified and co-morbidities including hypertension, diabetes and thyroid disorder, etc. were recorded in detail. The medical history was recorded in detail regarding treatment received, activity of the disease at conception, SLE disease activity index (SLEDAI) [11] and the system involvement. Their past obstetrical history was reviewed in detail to evaluate the previous obstetrical performance and outcome. A complete physical and obstetrical examination was performed at the time of enrolment in our special clinic. Laboratory work-up included complete blood count, liver and renal function test, urine analysis, lupus anticoagulant, antinuclear antibodies immunoglobulin (IgG and IgM), anti-cardiolipin antibodies (aCL, enzyme-linked immunosorbent assay). Patients were followed up thrice weekly until 28 weeks of pregnancy and than twice weekly until 34 weeks and once weekly thereafter. The same pre pregnancy doses of steroids, hydroxychloroquine or immunosuppressants were continued unless relapse occurred. The criteria for relapse or flare-up of the disease included evidence of acute synovitis, serositis, pruritis, typical skin lesions, new psychological or neurological symptoms (in the absence of eclampsia), haematological parameter revealing leucopenia, thrombocytopenia or active renal disease. Renal involvement was defined as the following: proteinuria [500 mg/day (in the absence of preeclampsia), cellular casts in urine and dysmorphic hematuria [12]. The patient was hospitalized in case of disease flare and dose or type of therapy was tailored according to the need. Preeclampsia was defined as hypertension (BP C140/ 90 mmHg on two separate occasions) and proteinuria (C300 mg/day) arising de novo after 20th week of pregnancy, and foetal growth restriction as sonographically measured abdominal circumference \5th percentile for gestational age by local reference values (compared to our institute reference intrauterine growth curve) and also confirmed by serial assessment of foetal growth parameters [12]; low birth weight as birth weight \2,500 g at birth; premature birth (preterm) as live birth before 37 weeks’ gestation and foetal loss as foetal death after 22 weeks’ 123 Arch Gynecol Obstet (2011) 284:281–285 gestation. Diagnosis of antiphospholipid syndrome (APLA) was established according to the updated Sapporo criteria [13, 14]. Antenatal complications, incidence and timing of flare up, intrapartum maternal and foetal events, mode of delivery and perinatal outcome were recorded. Any deterioration of the disease activity in the purperium was also recorded. Statistical analysis The data were analyzed using SPSS version 15 statistical package. Variable measured in interval scales were described as the mean plus or minus the standard deviation (SD). Results A total of 71 pregnancies in 35 women with SLE were studied during the period. All women conceived naturally and majority (82%) after a preconceptual counseling. All were young between 22 and 33 years of age and commonly (60%) presented with musculoskeletal involvement. The details of the patient’s demographic profile, presenting events, age at diagnosis, duration of the disease are shown in Table 1. The mean age of the woman was 26.89 ± 2.7 years and the mean interval from diagnosis and pregnancy was 4.47 ± 2.7 years. The mean age of diagnosis was 27.69 ± 3.0 years and the mean inter pregnancy interval among the parous women was 18.5 ± 0.5 months. Out of 35 women, 16 were primigravidae with a nulliparity rate of 45.7%. Disease associated complications and pregnancy outcome Majority of our patients (60%) had features of arthritis. Next to musculoskeletal involvement febrile illness was the most common presenting event seen in 40% of the women. Renal involvement was seen in 34.28%. A combination of renal and musculoskeletal involvement was seen in 31.42%. One woman (2.8%) had lupus anticoagulant positive with features of arthritis. A combination of arthritis and cutaneous involvement was seen in 17% and isolated cutaneous involvement was seen in 11.42%. Uncommon manifestations, such as interstitial lung disease, Wolff–Parkinson–White syndrome, uveitis, pulmonary hypertension were also seen in one woman each (2.8%). Hypertensive disorders of pregnancy were seen in ten women (28.5%), while chronic hypertension was present in two women (5.6%).There were no cases of disease flare-up during the study. Arch Gynecol Obstet (2011) 284:281–285 Table 1 Comparing the pregnancy and neonatal outcome between our present study with that of our previous published data [5] 283 Characteristics Present study (n = 35) Previous published data [5] (n = 15) Mean age 26.89 ± 2.7 years 27.1 ± 3.8 years Mean age at diagnosis 22.40 ± 5.4 years 22.9 ± 4.3 years Interval between diagnosis and pregnancy 4.49 ± 2.7 years – Gestation at delivery 36 ± 2.6 weeks 35.9 ± 2.5 weeks Inter pregnancy interval among parous women 18.5 ± 0.5 months 4.2 ± 2.5 years Mean birth weight 2,433 ± 651 g 2,308 ± 701 g Primigravida 16/35 (45.7%) 46.7% Term 26/71 (36.6%) 42.8% Preterm 21/71 (29.57%) 33.3% Abortions 24/71 (33.8%) 39.1% Vaginal delivery LSCS 34/71 (47.88%) 13/71 (18.3%) 66.6% 26.6% Perinatal loss 9/71 (12.67%) 42.8% Out of all of the pregnant women who received medical therapy, the drugs used were corticosteroids, hydroxychloroquine and azothioprine. Corticosteroid in alone was used in 20% of the patients and 45.7% were receiving a combination of prednisolone and hydroxychloroquine and 5.7% received all three drugs in combination. Additional therapy in the form of antihypertensives, aspirin, low molecular weight heparin and thyroxine was prescribed for 28.5, 8.5, 5.7 and 8.5%, respectively. All women conceived during the disease quiescence period. A total of 71 pregnancies in 35 women were analysed and the incidence of abortion and preterm labour was 33.8% (24/71) and 29.57% (21/71), respectively. Fortyeight percent (34/71) had vaginal delivery and 18.3% (13/ 71) underwent caesarean section. Mean gestational age at delivery was 36 ± 2.6 weeks and mean birth weight was 2,433 ± 651 g. There were 9.8% perinatal deaths. There was no case of neonatal lupus or congenital malformations. None had postpartum haemorrhage, puerperal pyrexia or puerperal flare-up of the disease. Labour was induced in 80% (28/35) of the women for obstetrical indications and not for SLE per se. Discussion There is paucity of data with regards to lupus pregnancy from the Asian countries [4–8, 15–17]. Previous studies from India [4, 5, 8] and Thailand [6] reported high maternal flare-up rate, significant complications and associated increased foetal loss. This outcome was attributed to the lack of preconception counseling and contraceptive practice among the women from these countries. Other reports from developed Asian countries such as Singapore [16, 17] and Taiwan [18] reported better maternal and foetal outcome as most of their patients were in remission before conception and those countries had better healthcare facilities. Pregnancy complicated with lupus runs the risk of spontaneous miscarriage, preeclampsia, intrauterine foetal growth restriction, preterm labour, preterm rupture of membrane and foetal death [19]. These risks are increased in the presence of anticardiolipin antibodies or lupus anticoagulants, lupus nephritis or hypertension and if there is either active disease at the time of conception or first presentation the disease occurs during pregnancy [19]. The published results on the pregnancy outcome in lupus patients have been conflicting, but the overall outcome has improved progressively with time [20]. All 35 women who where progressively observed in our study resulted in 100% live births. Nevertheless, the incidence of spontaneous abortion in our study is 33.8% which is much higher than our national average of 8–10% [21]; this finding is similar to the other reported literatures from India. Several studies have found the frequency of foetal loss to vary between 0 and 22% [22]. In our present study, the rate of foetal loss was 12.67% which is far less than our earlier reported figure of 42.8% [5]. This change over the decade could be due to the awareness among the women and the practice of preconceptual counseling and delaying pregnancy till the disease is controlled. This increased rate of foetal loss in lupus women has been attributed to the immune complex deposition on the trophoblast basement membrane or transplacental passage of antiphospholipid antibodies [23]. Prematurity is a common complication in lupus pregnancies and further increased with renal involvement. Reported preterm births with lupus pregnancies vary between 5 and 46% [19, 24] and in our present study, it was 123 284 29.5% which is similar to our previous observation (33.3%) [5]. The high rate of prematurity in our patient cohort may be due to iatrogenic preterm labour. For women in remission but without hypertension and renal involvement is probably no higher than in the general population [7]. The frequency of hypertensive disease of pregnancy was 14.28% which was similar to previous studies. Though we used a predefined set of diagnostic criteria to differentiate lupus nephritis flare-up from preeclampsia superimposed on preexisting renal disease and proteinuria the differential diagnosis between these two conditions in the absence of a definite method is difficult [25]. The risk of intrauterine growth restriction (IUGR) is reported with incidence varying between 5 and 38% and vasculopathy of SLE could be a contributing factor. The incidence of IUGR in our present study was 9.8% which was far less than our earlier reported study (40%) [5]. The fall in the incidence of IUGR in our cohort could be due to quiescence of the disease during pregnancy and all women conceived when the disease was inactive and none had flare. It is important to note that, we define disease activity early in pregnancy and these findings underscore the importance of preconceptual counseling. The rate of caesarean delivery in our present study was 18.3%, whereas a study from Malaysia reported a caesarean rate 50% [7]. Out of 13 caesarean section carried out during the present pregnancy, 11 were done for intrapartum foetal distress, one for non-progress of labour and the other was done electively for severe preeclampsia with fixed hip joint deformity. Treatments used in SLE pregnant women include antiinflammatory drugs, anti-malarial, immunosuppressive and anticoagulants [1]. Discontinuation of a medication because of pregnancy may lead to more damage to the mother and foetus from worsening of maternal disease than the adverse effects of the drugs [1]. Prednisone and prednisolone are inactivated by enzymes in the placenta and cross the placenta in low quantities, consequently making them the drugs of choice [26]. In our group, 7/35 (20%) of the patients received corticosteroids alone while 31/35 (88.57%) used them alone or in combinations. The drug of choice to suppress immunity is Azathioprine [26]. It is not demonstrated to be teratogenic at doses used lupus in pregnancy [24]. In our group, 8/35 (22.85%) of the women received azathioprine and no teratogenic effects of the drug was observed. There were no cases of lupus flare in our study. Literature on the flare-up during pregnancy is controversial, studies by Petri et al. [27] and Ruitz-Irastorza et al. [28] have shown an increase in lupus flares, while others by Lockshin et al. [29] and Urowitz et al. [30] showed no flare with pregnancy. There were no cases of neonatal lupus in the form of skin lesions or congenital heart block or hepatic involvement or 123 Arch Gynecol Obstet (2011) 284:281–285 thrombocytopenia in our present study which is also supported by literature. There were also no cases of druginduced malformations in the foetuses further justifying the safety in continuation of these drugs once pregnancy is confirmed. Conclusion Pregnancy in women with SLE is high risk. The ideal management of lupus patients during pregnancy should actually start before the pregnancy occurs. Pregnancy is best undertaken when the general health of the patient is at its best and when the disease is in clinical remission for at least 6 months duration, if not 12–18 months according to most recent recommendations has been achieved [1]. In our cohort, the disease was controlled before the conception and relatively had a better pregnancy outcome, therefore, it is essential to control disease activity and to achieve clinical remission before conception to expect better outcome in lupus pregnancy. Conflict of interest None. References 1. Doria A, Tincani A, Lockshin MD (2008) Challenges of lupus pregnancies. Rheumatology 47:9–12 2. Buyon JP, Kalunian KC, Goldman RR, Petri MA, Lockshin MD, Irastorza GR (1999) Assessing disease activity in systemic lupus erythematosus patients during pregnancy. Lupus 8:677–684 3. Wagner SJ, Craici I, Reed D, Norby S, Bailey K, Wiste HJ et al (2009) Maternal and foetal outcome in pregnant patients with active lupus nephritis. Lupus 18:342–347 4. Handa R (2005) Pregnancy in Indian patients with systemic lupus erythematosus. Lupus 14:926–927 5. Aggarwal N, Sawhney H, Vasishta K, Chopra S, Bambery P (1999) Pregnancy in patients with systemic lupus erythematosus. Aust NZ J Obstet Gynaecol 39:28–30 6. Foocharoen C, Nanagara R, Salang L, Suwannaroj S, Mahakkanukrauh A (2009) J Med Assoc Thai 92:167–174 7. Teh CL, Wong JS, Negh NKN, Loh WLH (2009) Systemic lupus erythematosus pregnancies: a case series from a tertiary East Malaysian hospital. Lupus 18:278–282 8. Gupta R, Deepanjali S, Kumar A, Dadhwal V, Agarwal SK, Pandey RM et al A comparative study of pregnancy outcome and menstrual irregularities in northern Indian patients with systemic lupus erythematosus and rheumatoid arthritis. Rheumatol Int 2009 (Epub ahead of print) 9. Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JC, Tura BR et al (2001) Hydroxychloroquine (HCQ) in lupus pregnancy: double blinded and placebo controlled study. Lupus 10:401–404 10. Hochberg MC (1997) Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheumat 40:1725 11. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum 35:630–640 Arch Gynecol Obstet (2011) 284:281–285 12. Hughes EC (ed) (1972) Obstetric-gynaecologic terminology. FA Davis, Philadelphia, pp 423–442 13. Brandt JT, Barna LK, Triplett DA (1995) Laboratory identification of lupus anticoagulants: results of the second international workshop for identification of lupus anticoagulants. On behalf of the subcommittee on lupus anticoagulants/antiphospholipid antibodies of the ISTH. Thromb Haemost 74:1597–1603 14. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306 15. Chandran V, Aggarwal A, Misra R (2005) Active disease during pregnancy is associated with poor foetal outcome in Indian patients. Rheumatol Int 26:152–156 16. Tan LK, Tan HK, Lee CT, Tan AS (2001) Outcome of pregnancy in Asian women with systemic lupus erythematosus. J Matern Fetal Med 10:91–96 17. Tambyraja RL (2002) Fetal salvage in maternal systemic lupus erythematosus: experience from a single perinatal centre in Singapore. Ann Acad Med Singapore 31:290–295 18. Wong CH, Chen TL, Lee CS, Lin CJ, Chen CP (2006) Outcome of pregnancy in patients with systemic lupus erythematosus. Taiwan J Obstet Gynecol 45:120–123 19. Whitelaw DA, Hall D, Kotze T (2008) Pregnancy in systemic lupus erythematosus: a retrospective study from a developing community. Clin Rheumatol 27:577–580 20. Georgiou PE, Politi EN, Katsimbri P, Sakka V, Drosso AA (2000) Outcome of lupus pregnancy: a controlled study. Rheumatology 39:1014–1019 21. Babu NP, Nidhi, Verma RK (1998) Abortion in India: what does the national family health survey tell us. J Fam Welf 44:45–54 285 22. Mok CC, Wong RWS (2001) Pregnancy in systemic lupus erythematosus. Postgrad Med J 77:157–165 23. Grennan DM, Moseley A, Sloane D, Pumphrey R, Dick WC, Buchanan WW (1977) The significance of serial measurement of serum anti-native DNA antibodies and complement C3 and C4 components in the management of patients with systemic lupus erythematosus. Aust NZ J Med 7:625–629 24. Tincani A, Danieli E, Nuzzo M, Scarsi M, Motto M, Cimaz R et al (2006) Impact of in utero environment on the offspring of lupus patients. Lupus 15:801–807 25. Churg J, Bernstin J, Glassock RJ (1995) Lupus nephrits. In: Churg J, Bernstin J, Glassock RJ (eds) Renal diseases. Classification and atlas of glomerular diseases. Igaku Shoin, New York, p 151 26. D’ Cruz DP, Khamashta MA, Hughes GRV (2007) Systemic lupus erythematosus. Lancet 369:587–596 27. Petri M, Howard D, Repke J (1991) Frequency of lupus flare in pregnancy: The Hopkins lupus pregnancy center experience. Arthritis Rheum 34:1538–1545 28. Ruitz-Irastorza G, Lima F, Alves J, Khamashta MA, Simpson J, Hughes GR et al (1996) Increased rate of lupus flare during pregnancy and the puerperium. Br J Rheumatol 35:133–138 29. Lockshin MD, Reinitz E, Druzin ML, Murrman M, Estes D (1984) Lupus pregnancy: case control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. Am J Med 77:893–899 30. Urowitz MB, Gladman DD, Farewell VT, Stewart J, McDonald J (1993) Lupus and pregnancy studies. Arthritis Rheum 36: 1392–1397 123