Clinical study of factors associated with pregnancy outcomes in pregnant women with systemic lupus erythematosus in the southern China.

Objectives: This study aims to estimate predicted factors for maternal and fetal outcomes in Hakka pregnant women with systemic lupus erythematosus (SLE) in the southern China. Patients and methods: Between June 2014 and February 2020, we retrospectively analyzed the data of a total of 123 singleton pregnant women with SLE (mean age: 27.1±4.1 years; range, 19 to 39 years) who were referred to our rheumatology clinic. Demographic, clinical, and laboratory data of the patients were recorded. Adverse pregnancy outcomes (APOs) were assessed.
Results: Multivariate logistic regression analysis revealed that preeclampsia was associated with the increased odds of APOs (odds ratios [OR]=9.538, 95% confidence interval [CI]: 2.055-44.271, p=0.004), premature birth (OR=14.289, 95% CI: 3.596-56.777, p<0.001) and low birth weight (OR=8.275, 95% CI: 2.117-32.345, p=0.002). Anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody positivity was the predictor of APOs (OR=2.165, 95% CI: 1.034-4.532, p=0.040), premature birth (OR=2.849, 95% CI: 1.220-6.657, p=0.016) and pregnancy loss (OR=3.004, 95% CI: 1.086-8.305, p=0.034). The use of hydroxychloroquine and prednisone was associated with the decreased odds of APOs (OR=0.412, 95% CI: 0.198-0.860, p=0.018) and pregnancy loss (OR=0.304, 95% CI: 0.111-0.831, p=0.020).
Conclusion: Our study results indicate that preeclampsia, anti-dsDNA antibody positivity, and the use of hydroxychloroquine and prednisone are independent predictors of pregnancy outcomes.

Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with an incidence of 20 to 70 per 100,000 person-years worldwide.[1] In particular, SLE is associated with a strong female predominance and diagnosed more frequently in their reproductive years.[2] It is currently well-documented that pregnancy in SLE-affected women encounter an increased risk of obstetric complications such as preeclampsia, miscarriage, preterm delivery, fetal growth restriction, and low fetal birth weight.[3,4] Indeed, pregnancy outcomes in pregnant women with SLE have dramatically improved due to meaningful management, including pre-pregnancy counseling, prenatal diagnosis, progression of immunosuppressive therapy, and family planning.[5,6] Nevertheless, the diagnosis and management of pregnant women with SLE have proven to be complicated and are still challenging either for physicians or patients.

Systemic lupus erythematosus is an inflammatory multi-system disease characterized by a broad range of clinical manifestations and prognosis.[7] Although several studies have shown that SLE has adverse effects on pregnant women and their offspring, the underlying pathogenesis contributing to pregnancy complications remains being actively investigated.[8] Identification of clinical and laboratory predictors of adverse pregnancy outcomes (APOs) have significantly reduced the maternal and fetal risks in pregnant women with SLE. Previous studies have demonstrated that disease-related factors such as active disease, renal involvement, high dose use of corticosteroid and cyclophosphamide have a great predictive value for the occurrence of APOs in pregnant women with SLE.[9-11] Moreover, other factors including socioeconomic status, behavior, and genetic factors have been also implicated in the major maternal, obstetrical, and neonatal complications.[12] Of particular interest is the fact that the results of these studies are controversial and vary according to region and ethnicity.[13,14] To the best of our knowledge, there is a paucity of data on the pregnancy of Hakka women with SLE in the literature. In this study, therefore, we aimed to identify predictors of maternal and fetal outcomes in Hakka pregnant women with SLE in the southern China.

Patients and Methods

This single-center, retrospective study was conducted at the rheumatology clinic of the Meizhou People’s Hospital of the Southern China between June 2014 and February 2020. The data of a total of 123 singleton pregnant women with SLE (mean age: 27.1±4.1 years; range, 19 to 39 years) who were referred to our clinic were analyzed. All pregnant women who underwent prenatal follow-up and diagnosed with SLE and met the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) 2012 diagnostic criteria[15] were collected. Rheumatologists and fetal-maternal medicine specialists treated the patients regularly. Exclusion criteria were as follows: age <18 years, having a malignancy, having missing data, and those who were lost-to-follow-up or who did not give birth at our institution. A written informed consent was obtained from each patient. The study protocol was approved by the Meizhou People’s Hospital, Ethics Committee (No: MPH-HEC 2014-A-02). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Data collection and definitions

Using the hospital electronic database, the medical records of patients were comprehensively reviewed to collect demographic and clinical information and laboratory data. Recorded findings included maternal age at pregnancy age, gestational age at delivery, mode of delivery, disease duration of SLE, gravidity, previous pregnancy loss, blood pressure, type of current medications, lupus nephritis, thrombocytopenia, preeclampsia, diabetes, hypoalbuminemia, and Appearance, Pulse, Grimace, Activity and Respiration (APGAR) score at 1 min and 5 min. Disease activity scores were evaluated using the SLE Disease Activity Index (SLEDAI). Medication use during pregnancy was restricted to hydroxychloroquine, prednisone, and cyclosporine for the treatment of SLE. Hydroxychloroquine was prescribed to patients with a dose of 100 to 400 mg daily. Prednisone was prescribed 10 to 15 mg daily to patients with mild disease activity, 15 to 30 mg daily to patients with moderate disease activity, and over 30 mg daily to patients with high disease activity. Therapeutic doses of cyclosporine ranged from 25 to 100 mg twice daily. Laboratory parameters included serum levels of the antinuclear antibody (ANA), anti-phospholipid antibodies, anti-doublestranded deoxyribonucleic acid (anti-dsDNA) antibodies, anti-Sjögren syndrome antigen A (anti-SSA)/Ro antibodies, Sjögren syndrome antigen B (SSB)/La antibodies, complement 3, and complement 4. All laboratory tests were performed according to the manufacturer's protocols.

Preeclampsia was defined as a de novo persistent hypertension (blood pressure >140/90 mmHg) with proteinuria >300 mg/24 h collection after 20 weeks of gestation. Premature birth was defined as births less than 37 weeks of pregnancy. Low-birth-weight was defined as weight at birth of <2,500 g. Fetal growth restriction (FGR) was defined as an estimated fetal weight below the 10th percentile for a given gestational age plus abnormal Doppler flow velocimetry waveform. Pregnancy loss included spontaneous abortions, therapeutic abortion, elective abortion, stillbirth, and neonatal death. Among these, stillbirth was defined as the occurrence of intrauterine fetal demise after at or 22 weeks of gestation. Neonatal death was defined as death within the first 28 days of birth. Adverse pregnancy outcomes were defined as the occurrence of one or more of the following: preterm delivery, low birth weight, pregnancy loss, FGR, and fetal distress.

Statistical analysis

Statistical analysis was performed using the PASW version 18.0 software (SPSS Inc., Chicago, IL, USA). Descriptive data were expressed in mean ± standard deviation (SD), median (minmax) or number and frequency. Continuous variables were compared using the Student t-test, while categorical variables were compared using the chi-square test or Fisher exact test. Univariate and multivariate logistic regression analyses were performed to identify factors yielding odds ratios (ORs) and 95% confidence intervals (CIs). A p value of <0.05 was considered statistically significant.

Results

Maternal and pregnancy outcomes in pregnant women with SLE are summarized in Table 1. Among the patients, 32/107 (29.9%) had normal vaginal delivery and 75/107 (70.1%) had cesarean-section delivery, resulting in 62/107 (57.9%) had normal birth weight and 45/107 (42.1%) had low birth weight. In addition, 17/123 (13.8%) had preeclampsia and 14/123 (11.4%) had diabetes. The full-term birth and premature birth were calculated as 74/107 (69.2%) and 33/107 (30.8%), respectively. Our study showed 7/107 (6.5%) had FGR and 12/107 (11.2%) had fetal distress. In cases of pregnancy loss (n=19), four (3.3%) had spontaneous abortion, nine (7.3%) had therapeutic abortion, three (2.4%) had stillbirth, and three (2.4%) had neonatal death.

Demographic and baseline clinical characteristics of the patients with and without APOs are shown in Table 2. The frequencies of preeclampsia were 25.4% (n=15) for the patients with APOs and 3.1% (n=2) for the patients without APOs, indicating a statistically significant difference (p=0.001). The rates of anti-dsDNA antibody positivity were significantly higher in patients with APOs, compared to those without APOs (50.8% vs. 7.9%, respectively; p=0.030). The rate of hydroxychloroquine use was significantly lower in patients with APOs than that without APOs (44.1% vs. 67.2%, respectively; p=0.012).

The univariate and multivariate logistic regression analyses of predictive factors for adverse maternal and fetal outcomes are shown in Table 3. After adjusting for age, preeclampsia was associated with the increased odds of APOs (OR=9.538, 95% CI: 2.055-44.271, p=0.004), premature birth (OR=14.289, 95% CI: 3.596-56.777, p<0.001) and low birth weight (OR=8.275, 95% CI: 2.117-32.345, p=0.002). Anti-dsDNA antibody positivity was the predictor of APOs (OR=2.165, 95% CI: 1.034-4.532, p=0.040), premature birth (OR=2.849, 95% CI: 1.220-6.657, p=0.016), and pregnancy loss (OR=3.004, 95% CI: 1.086-8.305, p=0.034). In contrast, the use of hydroxychloroquine and prednisone was associated with the decreased odds of APOs (OR=0.412, 95% CI: 0.198-0.860, p=0.018) and pregnancy loss (OR=0.304, 95% CI: 0.111-0.831, p=0.020).

Discussion

Maternal and pregnancy outcomes in pregnant women with SLE are summarized in Table 1. Among the patients, 32/107 (29.9%) had normal vaginal delivery and 75/107 (70.1%) had cesarean-section delivery, resulting in 62/107 (57.9%) had normal birth weight and 45/107 (42.1%) had low birth weight. In addition, 17/123 (13.8%) had preeclampsia and 14/123 (11.4%) had diabetes. The full-term birth and premature birth were calculated as 74/107 (69.2%) and 33/107 (30.8%), respectively. Our study showed 7/107 (6.5%) had FGR and 12/107 (11.2%) had fetal distress. In cases of pregnancy loss (n=19), four (3.3%) had spontaneous abortion, nine (7.3%) had therapeutic abortion, three (2.4%) had stillbirth, and three (2.4%) had neonatal death.

Demographic and baseline clinical characteristics of the patients with and without APOs are shown in Table 2. The frequencies of preeclampsia were 25.4% (n=15) for the patients with APOs and 3.1% (n=2) for the patients without APOs, indicating a statistically significant difference (p=0.001). The rates of anti-dsDNA antibody positivity were significantly higher in patients with APOs, compared to those without APOs (50.8% vs. 7.9%, respectively; p=0.030). The rate of hydroxychloroquine use was significantly lower in patients with APOs than that without APOs (44.1% vs. 67.2%, respectively; p=0.012).

The univariate and multivariate logistic regression analyses of predictive factors for adverse maternal and fetal outcomes are shown in Table 3. After adjusting for age, preeclampsia was associated with the increased odds of APOs (OR=9.538, 95% CI: 2.055-44.271, p=0.004), premature birth (OR=14.289, 95% CI: 3.596-56.777, p<0.001) and low birth weight (OR=8.275, 95% CI: 2.117-32.345, p=0.002). Anti-dsDNA antibody positivity was the predictor of APOs (OR=2.165, 95% CI: 1.034-4.532, p=0.040), premature birth (OR=2.849, 95% CI: 1.220-6.657, p=0.016), and pregnancy loss (OR=3.004, 95% CI: 1.086-8.305, p=0.034). In contrast, the use of hydroxychloroquine and prednisone was associated with the decreased odds of APOs (OR=0.412, 95% CI: 0.198-0.860, p=0.018) and pregnancy loss (OR=0.304, 95% CI: 0.111-0.831, p=0.020).

Table 1

Maternal and pregnancy outcomes in pregnant women with SLE (n=123)

	Pregnant women with SLE
	n	%	Mean±SD
Maternal outcomes
Maternal age at pregnancy (years)			27.1±4.1
Mean gestational age at delivery (weeks)			37.3±2.9
Normal vaginal delivery	32/107	29.9
Cesarean section	75/107	70.1
Preeclampsia	17/123	13.8
Diabetes	14/123	11.4
Live birth
Average birth weight (g)			2,582±615
Normal birth weight	62/107	57.9
Low birth weight	45/107	42.1
Full-term birth	74/107	69.2
Premature birth	33/107	30.8
Intrauterine growth retardation	7/107	6.5
Fetal distress	12/107	11.2
APGAR score
1 min			9.25±1.72
5 min			9.75±0.96
Pregnancy loss
Spontaneous abortion	4/123	3.3
Therapeutic abortion	9/123	7.3
Stillbirth	3/123	2.4
Neonatal death	3/123	2.4
SLE: Systemic lupus erythematosus; SD: Standard deviation; APGAR: Appearance, Pulse, Grimace, Activity and Respiration.

Table 2

Clinical characteristics of patients with and without APOs (n=123)

	With APOs (n=59)			Without APOs (n=64)			p
	n	%	Mean±SD	n	%	Mean±SD
Maternal age at pregnancy (year)			26.4±3.7			27.7±4.3	0.093
SLE duration (year)			5.0±3.3			6.1±3.6	0.103
SLEDAI			4.6±2.7			3.9±2.6	0.108
Primigravida	34	57.6		31	48.4		0.367
Previous pregnancy loss	21	35.6		32	50.0		0.145
SLE activity during pregnancy
Lupus flare	13	22.0			9	14.1	0.347
Lupus nephritis	6	10.2			4	6.3	0.520
Arthritis	0	0			1	1.6	1.000
Mucocutaneous	5	8.5			3	4.7	0.479
Serositis	4	6.8			4	6.3	1.000
Thrombocytopenia	4	6.8			1	1.6	0.196
Lupus flare	13	22.0			9	14.1	0.347
Lupus nephritis	6	10.2			4	6.3	0.520
Arthritis	0	0			1	1.6	1.000
Laboratory testing
ANA positivity	41	69.5			37	57.8	0.195
Anti-phospholipid positivity	3	5.1			5	7.8	0.719
Anti-dsDNA antibody positivity	30	50.8			20	31.3	0.030
Anti-Sm antibody positivity	9	15.3			16	25.0	0.262
Anti-Ro/SSA antibody positivity	27	45.8			32	50.0	0.719
Anti-La/SSB antibody positivity	5	8.5			5	7.8	1.000
Hypoalbuminemia	12	20.3			6	9.4	0.125
Hypocomplementemia	29	49.2			32	50.0	1.000
Medication during pregnancy
Hydroxychloroquine	26	44.1			43	67.2	0.012
Prednisone	37	62.7			50	78.1	0.075
Cyclosporine	4	6.8			2	3.1	0.425
Aspirin	3	5.1			5	7.8	0.719
Low-molecular weight heparin	3	5.1			3	4.7	0.721
APOs: Adverse pregnancy outcomes; SD: Standard deviation; SLE: Systemic lupus erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; ANA: Antinuclear antibody; Anti-dsDNA: Anti-double-stranded deoxyribonucleic acid.

Table 3

Univariate and multivariate analysis results

	Univariate logistic regression			Multivariate logistic regression
	Crude OR	95% CI	p	Crude OR	95% CI	p*
APOs
Preeclampsia	10.167	2.213-46.710	0.003	9.538	2.055-44.271	0.004
Anti-dsDNA antibody positivity	2.150	1.033-4.475	0.041	2.165	1.034-4.532	0.040
Hyd roxychloroquine	0.409	0.197-0.849	0.016	0.412	0.198-0.860	0.018
Premature birth
Preeclampsia	13.524	3.486-52.460	<0.001	14.289	3.596-56.777	<0.001
Anti-dsDNA antibody positivity	2.836	1.216-6.619	0.016	2.849	1.220-6.657	0.016
Low birth weight
Preeclampsia	7.152	1.882-27.175	0.004	8.275	2.117-32.345	0.002
Pregnancy loss
Anti-dsDNA antibody positivity	2.977	1.080-8.208	0.035	3.004	1.086-8.305	0.034
Prednisone	0.300	0.110-0.819	0.019	0.304	0.111-0.831	0.020
OR: Odds ratio; CI: Confidence interval; APOs: Adverse pregnancy outcomes; Anti-dsDNA: Anti-double-stranded deoxyribonucleic acid; * Adjusted for age.