Invest Clin 59(4): 293 - 301, 2018 https://doi.org/10.22209/IC.v59n4a01

Prognosis in pregnant women with systemic lupus erythematosus following pregnancy management.

En-Ling Liu1, Zheng Liu2, Bao-Feng Han3, Hong-Xiu Ma3, Shuai-Shuai Li3 and Yu-Xiu Zhou3

1. Department of Obstetrics and Gynecology, Tangshan Gongren Hospital, Hebei Medical University, Tangshan. China.

2. Rheumatism Immunity Branch, Tianjin Medical University General Hospital, Tianjin.

   China.

3. Rheumatism Immunity Branch, Tangshan Gongren Hospital, Hebei Medical University, Tangshan. China.

Key words: Systemic lupus erythematosus; pregnancy management; maternal and neonatal outcome; autoantibody to nuclear antigen; low immunoglobu- lin complement; pregnancy induced hypertension.

Abstract. This study was aimed to understand the effects of pregnancy man- agement in the prognosis for pregnant women with systemic lupus erythematosus (SLE). A total of 217 pregnant patients who were diagnosed with SLE were divided into two groups, the control group (n = 96) and the intervention group (n = 121). The intervention group was treated with routine treatment and nursing care with additional pregnancy management, while the control group was treated with only routine treatment and nursing care. Additionally, 195 normal pregnant women were selected as the healthy controls in the same period. No significant difference of clini- cal features was observed in the three groups. Compared with the healthy control, increased ANA titer and dsDNA, lower immunoglobulin complement, renal damage, blood system damage, increased SLEDAI score and BILAG score were observed in the control group and the invention group. Both the control group and the interven- tion group showed significant increases in the incidences of PIH, premature delivery, fetal loss and neonatal complications as well as a significant decrease in neonatal weight compared with the healthy control. SLE activity rate and incidences of PIH, premature delivery and neonatal complications were significantly decreased; while neonatal weight was greatly increased in the intervention group compared with the control group. Low immunoglobulin complement, renal damage, increased dsDNA, and low immunoglobulin complement were independent risk factors for increased SLE activity rate, fetal loss, premature delivery and neonatal complications, respec- tively. The present study indicates that pregnancy management for pregnant SLE patients could significantly improve maternal and neonatal outcomes.

Corresponding author: Yu-Xiu Zhou, Rheumatism Immunity Branch, Tangshan Gongren Hospital, Hebei Medical University, No. 27, Wenhua Road, Tangshan 063000, Hebei Province, P.R. China. Tel: +86-0315-2395279. E-mail: lf93ci@163.com

El pronóstico en las mujeres embarazadas con lupus eritematoso sistémico tras el manejo del embarazo. Invest Clin 2018; 59 (4): 293 - 301

Palabras clave: Lupus eritematoso sistémico; embarazo; gestión de los resultados

maternos y neonatales; autoanticuerpo antigeno nuclear de inmunoglobulina A, bajos complemento; hipertensión inducida por el embarazo.

Resumen. Este estudio tuvo como objetivo comprender los efectos del ma- nejo del embarazo en el pronóstico para embarazadas con lupus eritematoso sis- témico (SLE). Se estudiaron 217 embarazadas con diagnóstico de SLE divididas en dos grupos, control (n=96) y de intervención (n=121). El grupo de interven- ción recibió tratamiento de rutina y de enfermería con manejo del embarazo, mientras que el otro grupo solo tratamiento de rutina y de enfermería. Además, 195 embarazadas normales fueron seleccionadas como grupo control sano. Se observó mayor titulación ANA y dsDNA, menor complemento de inmunoglobu- linas, daño renal, daño del sistema arterial, aumento de la cuenta de SLEDAI y el índice BILAG en el grupo control y el de intervención, en comparación con el control sano. El grupo control y de intervención mostraron un aumento signifi- cativo en la incidencia de preeclampsia, parto prematuro, pérdida fetal y neona- tal, y disminución significativa de peso neonatal en comparación con el control sano. La tasa de actividad SLE y la incidencia de preeclampsia, parto prematuro y las complicaciones neonatales se redujeron significativamente, mientras que el peso neonatal aumentó considerablemente en el grupo de intervención, en comparación con el control. Los resultados del análisis de regresión logistica mostraron que el complemento de inmunoglobulina bajo, daño renal, aumento de inmunoglobulinas y complemento bajo dsDNA, fueron factores de riesgo in- dependientes para el aumento de la tasa de actividad de SLE, pérdida fetal, parto prematuro y complicaciones neonatales, respectivamente. El presente estudio sugiere que el manejo del embarazo en pacientes con SLE podría mejorar signi- ficativamente los resultados maternos y neonatales.

Recibido 06-03-2018 Aceptado 27-09-2018

INTRODUCTION

Systemic lupus erythematosus (SLE) is a serious multi-system disease affecting various organs, predominantly in women of childbearing age (female: male ratio ap- proximately 9:1) (1, 2). Generally, SLE is believed to have a correlation with heredity and the environmental factors particularly include ultraviolet light exposure and estro-

gen levels (3). The high estrogen levels are a major cause of SLE activity because the ris- ing estrogen levels enhances the prolactin levels, which result in increasing immune response even disorder. At the same time, pregnancy will aggravate the burden on heart and kidney in order to induce SLE ac- tivity (4). Pregnancy with SLE is considered as a kind of high risk pregnancy, because SLE activity will be increased during preg-

nancy which causes vital organs damage and subsequently affects fetus of patients (5). Moreover, the recurrence rate of SLE dur- ing pregnancy reached 13% to 68%, which may lead to spontaneous abortion, prema- ture birth, stillbirth, intrauterine growth re- tardation, premature rupture of membrane and neonatal lupus erythematosus (1). That means the recurrence rate of an SLE flare as SLE itself will not go away.

Currently, the treatment of SLE is mainly based on cortical hormone, and the

-enhancement of medical technology - helps the continuous progress in drug therapy and stem cell transplantation, so more and more SLE patients have reproduction re- quirements (6). Stem cell transplantation improves reproductive outcomes for women with SLE. Besides, one study has shown that the key for the reproduction of SLE patients is the timing of conception (7). However, routine treatment alone cannot completely meet the reproduction requirements of pa- tients (6), and it is important to explore the pregnancy management in pregnant SLE pa- tients for maternal and child prognosis. So the fertility levels of SLE patients could be improved via the timing of conception, cor- responding routine treatment and pregnan- cy management (8). This study aimed to ex- plore the effects of pregnancy management on the maternal and neonatal prognosis of pregnant SLE patients.

MATERIALS AND METHODS

Ethics statement

This study was performed with the ap- proval of the clinical management com- mittee in our hospital. All patients in this study have signed the informed consents. All procedures were strictly conducted in accordance with the Declaration of Helsinki involving human beings.

Study subjects

A total of 217 pregnant SLE patients (all selective pregnancy) who were admit-

ted and diagnosed at the Department of Rheumatology in our hospital from January 2010 to November 2015 were recruited and divided into two groups, that is, the control group (n = 96) and intervention group (n

= 121), in which the control group only re- ceived routine treatment and nursing while intervention group had additional pregnan- cy management. Meanwhile, a total of 195 pregnant women in the same period were included as normal group. The women in the healthy normal group did not have any underlying immune disorders, such as rheu- matoid arthritis and chronic hypertension. All cases in the control group and the inter- vention group were in accordance with the diagnostic criteria of SLE recommended by American College of Rheumatology (ACR) in 1997 (9). The women with SLE did not have any flares within the last six months prior to pregnancy and were not taking any medication for SLE prior to pregnancy. Ex- cept for tumor and connective tissue dis- eases, patients with four or more manifes- tations were diagnosed as SLE, including discoid erythema, cheekbone erythema, oral ulcer, photaesthesia, serositis, non-ero- sive arthritis, hematological abnormality, neural abnormality, immunological abnor- mality, renal lesion and positive antinuclear antibody. The systemic lupus erythemato- sus disease activity index (SLEDAI) was per- formed to classify clinical condition (10), that is, less than or equal to 4 points was regarded as non-active group, and greater than or equal to 5 points was regarded as active group. On the basis of lesion type, all patients were divided into skin lesion type, nephritis type, arthrosis type and non-posi- tive immune antibody type. All SLE patients were voluntarily participated in this study, and the patients with other autoimmune diseases, infection and organ function fail- ure were excluded.

Routine treatment and nursing method: prevention of cold and expectant treatment when having a fever; a good rest during SLE activity; avoiding of sunlight and high-light

exposure; forbiddance of photosensitive drugs and food, and a diet of high protein, high vitamin, low sugar, low salt and low fat; calcium supplement and forbiddance of smoking, drinking and spicy food; observa- tion of side effects upon using hormone and immunosuppressive agents.

Pregnancy management: during preg- nancy, patients were monitored by the De- partment Gynecology and Obstetrics and the Department of Rheumatology via regu- lar electrocardiogram, ultrasound and ul- trasound echocardiography and routine obstetric fetal monitoring, including deter- mining gestational age in early pregnancy, detecting fetal development by ultrasound in middle pregnancy to determine fetal mal- formation preliminarily, and the late detec- tion of fetal movement and fetal heart so as to determine periodic detection time and therapy, namely, prednisone 5-10 g/day to maintain stable condition, and hydroxychlo- roquine sulfate 0.1-0.2 g/day was added to original therapy if necessary (adjust dose and therapy according to the disease con- dition). Before delivery, the intramuscular injection of dexamethasone 10 mg/day was added for three days in order to promote the maturity of fetal lung. Three days after deliv- ery, patients recovered to the original dose. Once patients had SLE activity or complica- tions during detecting serological activity index, they need shock treatment with large doses of hormones even adding immunosup- pressive agents, and if necessary, they also need blood transfusion, platelet transfusion and protein supplement. The indications for pregnancy termination should be considered on the basis of maternal and fetal conditions. When the mother had severe complications, the pregnancy should be terminated right now no matter how long the pregnancy was. As for patients who were found placentas ag- ing with mature fetus, once they had fetal distress or obstetrical indication, the preg- nancy should be terminated via caesarean section or vaginal delivery.

Detection of disease index

3

The laboratory conducted regular de- tections for all patients in each group, in- cluding autoantibody to nuclear antigen (ANA), double stranded-DNA (dsDNA) anti- body, immunoglobulin complement C , liver

& kidney functions, blood routine examina- tion, routine urine test and 24-hour urinary protein quantity, in order to statistically ana- lyze the changes of related indexes in each group. SLEDAI and British Isles Lupus As- sessment Group (BILAG) were performed to score SLE patients (11).

Maternal and neonatal outcomes

During the research, all clinical features and the maternal and fetus outcomes were col- lected. Besides, SLE activity rate, incidence of pregnancy induced hypertension (PIH), incidence of premature delivery, incidence of fetal loss, and neonatal birth weight were observed and recorded. Moreover, whether newborns had fetal growth restriction (FGR), neonatal lupus syndrome (NLS) and neonatal asphyxia were also observed so as to register the incidence of neonatal complications.

Statistical analysis

The statistical analysis was performed using SPSS 21.0 (SPSS Inc, Chicago, IL, USA) software. All measurement data were expressed as mean ± standard deviation (SD), and t-test was used to compare the mean difference of continuous variable be- tween two groups. Enumeration data were expressed as percentage or ratio, which were compared by x2 test, p < 0.05 was consid- ered statistically significant.

RESULTS

Clinical feature of subjects among three groups

The clinical features of all the subjects in three groups were recorded. In the normal group, the age was 28.6 ± 5.2 years old, the weight was 55.7 ± 8.5 kg, and the gravidity

was 2.1 ± 1.2; in the control group, the age was 27.8 ± 4.5 years old, the weight was 56.6

± 3.2 kg, and the gravidity was 2.0 ± 1.0; in the intervention group, the age was 29.0

± 4.9 years old, the weight was 57.4 ± 3.5 kg, and the gravidity was 1.8 ± 1.5. As shown in Table I, the analysis results showed that there were no significant differences in age, weight and gravidity among three groups (all p > 0.05). Moreover, the analysis of clinical features including lesion type and disease condition type demonstrated no significant difference between the control group and the intervention group (all p > 0.05).

Comparisons of disease indexes in each group

As shown in Table II, the comparison of disease indexes in each group revealed that there were no changes in related disease in- dexes in the normal group. While in the con- trol group and the intervention group, the related disease indexes were changed, in- cluding increased ANA titer, increased dsD- NA titer, low immunoglobulin complement, renal damage, and blood system damage,

increased SLEDAI score and BILAG score. When compared with the control group, the rate of patients in the intervention group with changed disease indexes were signifi- cantly lower (all p < 0.05).

Comparisons of maternal and neonatal outcomes

During the research, the analysis results about clinical features and the maternal and neonatal outcomes showed that, when com- pared with the normal group, patients in the control group and the intervention group had an obvious increase in the incidences of PIH, premature delivery, fetal loss and neo- natal complications, and an evident decrea- se in neonatal weight (all p < 0.05). Compa- red with the control group, patients in the intervention group had an evident decrease in SLE activity rate and incidences of PIH, premature delivery and neonatal complica- tions (all p < 0.05), but a great increase in neonatal weight (p < 0.05). There was no significant difference in fetal loss between two groups (p > 0.05) (Table III).

TABLE I

BASIC CLINICAL INFORMATION FOR ALL PARTICIPANTS BEFORE TREATMENT

SLEDAI, Systemic lupus erythematosus disease activity index before treatment.

* (x±SD). ** n(%)

TABLE II

COMPARISONS OF DISEASE INDEXES IN EACH GROUP

SLEDAI, systemic lupus erythematosus disease activity index; BILAG, British Isles Lupus Assessment Group.

TABLE III

COMPARISONS OF DISEASE INDEXES IN EACH GROUP

Analysis of disease indexes related to the adverse maternal and neonatal outcomes

The data in the control group and the intervention group were combined to ana- lyze the disease indexes that affecting the adverse maternal and neonatal outcomes. The univariate analysis revealed that the ad- verse maternal and neonatal outcomes were correlated with the increased ANA titer and dsDNA titer, low immunoglobulin comple- ment, renal damage, and blood system dam- age as well as increased SLEDAI score and BILAG score (all p < 0.05). With the adverse maternal and neonatal outcomes as depen- dent variable and with the disease indexes showing significant differences by univariate

analysis as independent variables to conduct the logistic analysis. The results showed that low immunoglobulin complement, renal damage, increased dsDNA titer, increased dsDNA titer were independent risk factors for adverse maternal and neonatal outcomes (all p < 0.05) (Table IV).

DISCUSSION

SLE is a common chronic autoimmune disease affecting multiple organs with com- plicated clinical manifestations, which was once an important pregnancy contraindi- cation (12, 13). Moreover, when combined with normal pregnant women, the pregnant

TABLE IV

RISK FACTORS ASSOCIATED WITH ADVERSE MATERNAL AND NEONATAL OUTCOMES BY LOGISTIC MULTIVARIATE REGRESSION ANALYSIS

SLE patients have a significant increase in obstetric complications such as spontane- ous abortion, FGR, preeclampsia and intra- uterine fetal death (14), which even causes nephropathy and PIH (15). This study aimed to explore the effects of pregnancy manage- ment on maternal and neonatal prognosis in pregnant SLE patients.

The results showed after routine treat- ment, pregnant SLE patients had a decrease in ANA titer and dsDNA titer, an increase in low immunoglobulin complement, a re- duction in kidney and blood system damage and a decrease in SLEDAI score and BILAG score. Meanwhile, the proportion of deterio- rated disease condition in patients who had pregnancy management was significantly decreased. During pregnancy, the immune response for women is mainly based on Th2 dominant immune response since Th1/Th2 response imbalance occurs, which results in high reactivity of B cells (16, 17). Here, B cells mediates the internal immune response, so the excessive activity of B cells, namely high reactivity of B cells, is a kind of abnor- mal immune response (18). Furthermore, the high reaction of B cells in patients leads to abnormal immunological indexes involving complement levels, ANA titer, dsDNA titer and low immunoglobulin complement (19). During pregnancy management, prednisone was used to prevent the immune response

caused by cellular immunity and to control SLE activity, which can prevent further dete- rioration of SLE (20), and later the proper monitor and treatment can effectively reduce the relevant conditions. Correspondingly, the levels of several risk factors, like internal complement and dsDNA antibody could be reduced via intervention treatments such as timing of conception and drug therapy so as to reduce the incidence of PIH (21).

Moreover, this study reported that after pregnancy management, pregnant SLE pa- tients had a significant decrease in the in- cidence of SLE activity rate, PIH, premature delivery and neonatal complications and an evident increase in neonatal weight. The placenta sedimentation of immune complex and complement in serum in pregnant SLE patients leads to the damage of vascular en- dothelial cells and subsequently causes local microthrombus, thickened vessel wall and lumimal stenosis, which results in placental villi dysplasia, so their exchange function was affected, that is the nutrition supply to fetus was reduced, which finally gives rise to the higher incidences of recurrent spon- taneous abortion, FGR, premature delivery, stillbirth and perinatal anoxia and ischemia (22). Besides, a previous study also reported that the effective pregnancy management can reduce the incidences of fetal loss and premature delivery (23).

In addition, this study proved that low immunoglobulin complement, renal dam- age and dsDNA titer & low immunoglobulin complement were independent risk factors for increased SLE activity rate, fetal loss and neonatal complications, respectively. SLE patients’ pregnancies mainly bring damages to kidney and blood system, which accelerates the deterioration of renal func- tion, while the damages to skin and skeletal muscle are relatively mild (24, 25). There is some impact of SLE on maternal and fetal outcomes following pregnancy, and differ- ences in clinical features observed between childhood-onset versus adult-onset SLE (26, 27). Furthermore, spasm of uterus and rel- evant vessels caused by renal lesions leads to blood circulation disorder that blocks ma- ternal and fetal blood exchange, resulting in fetal hypoxia even death, and especially the lupus nephritis will enlarge the risk of fetal loss (7). As dexamethasone has been shown to have conflicting reports on fetal outcome but some positive benefit on maternal im- mune suppression one might expect more maternal benefit depending on when in ges- tation this was administered. In this present study, the gestational age of women in the SLE intervention group administered dexa- methasone were 30 to 38 weeks old.

To sum up, our study provides evidence that pregnancy management for pregnant SLE patients is able to significantly im- prove maternal and fetal outcomes. How- ever, this study neither further explored the mechanism of pregnancy management for pregnant SLE patients, nor optimized the pregnancy management. Therefore, with limitations in the results, it is necessary to further explore the treatment and optimi- zation of pregnancy management for preg- nant SLE patients.

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