未分化结缔组织病患者的妊娠结局、疾病演变及其影响因素

doi:10.19723/j.issn.1671-167X.2023.06.014

摘要/Abstract

摘要：

目的: 研究未分化结缔组织病(undifferentiated connective tissue disease, UCTD)患者的妊娠结局、疾病演变及其影响因素。方法: 选择2009年1月至2022年8月在北京大学人民医院就诊并且符合UCTD分类标准孕妇的病例资料进行回顾性分析; 106例UCTD孕妇根据妊娠结局分为不良妊娠结局组(adverse pregnancy outcomes, APOs)(53例)和无APOs组(53例), 比较两组患者临床表现、实验室指标及妊娠结局的差异。不良妊娠结局包括流产、早产、子痫前期、胎膜早破(premature rupture of membranes, PROM)、宫内生长受限(intrauterine growth restriction, IUGR)、产后出血(postpartum hemorrhage, PPH)、死胎、小于胎龄儿(small for gestational age infant, SGA)、低出生体质量(low birth weight infant, LBW)、出生缺陷。采用Logistic回归分析不良妊娠结局的危险因素, 使用Kaplan-Meier法进行生存分析, 通过Cox回归分析筛选出UCTD演变为明确CTD的危险因素。结果: 在106例UCTD患者中, 99例(93.39%)为活产, 4例(3.77%)死胎, 3例(2.83%)流产, 20例(18.86%)早产, 6例(5.66%)SGA, 17例(16.03%)LBW, 11例(10.37%)子痫前期, 7例(6.60%)IUGR, 19例(17.92%)PROM, 10例(9.43%)PPH。APOs组抗SSA抗体阳性率较无APOs组更高(73.58% vs. 54.71%, P=0.036), 白细胞减少比例更高(15.09% vs. 3.77%, P=0.046), 血红蛋白水平较无APOs组明显降低[109.00 (99.50, 118.00) g/L vs. 124.00 (111.50, 132.00) g/L, P < 0.001]。多因素Logistic回归分析显示白细胞减少(OR=0.827, 95%CI: 0.688~0.994)是UCTD患者发生APOs的独立危险因素(P=0.042)。15例(14.15%)UCTD在平均随访5.00(3.00, 7.00)年内演变为明确的结缔组织病, 其中干燥综合征8例(7.54%), 系统性红斑狼疮(systemic lupus erythematosus, SLE)4例(3.77%), 类风湿关节炎4例(3.77%), 混合性结缔组织病1例(0.94%)。雷诺现象(Raynaud phenomenon, RP) (HR=40.157, 95%CI: 3.172~508.326)是UCTD患者妊娠期及产后演变为SLE的独立危险因素(P=0.003)。结论: 白细胞减少是UCTD患者发生APOs的独立危险因素, 雷诺现象是UCTD患者演变为SLE的独立危险因素, 严格的疾病监测、定期随访是预防UCTD合并妊娠患者发生不良妊娠结局和预测疾病演变的关键措施。

关键词: 未分化结缔组织病, 不良妊娠结局, 危险因素

Abstract:

Objective: To investigate the fetal and maternal outcomes, risk factors of disease progression and adverse pregnancy outcomes (APOs) in patients with undifferentiated connective tissue disease (UCTD). Methods: This retrospective study described the outcomes of 106 pregnancies in patients with UCTD. The patients were divided into APOs group (n=53) and non-APOs group (n=53). The APOs were defined as miscarriage, premature birth, pre-eclampsia, premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), postpartum hemorrhage (PPH), and stillbirth, small for gestational age infant (SGA), low birth weight infant (LBW) and birth defects. The differences in clinical manifestations, laboratory data and pregnancy outcomes between the two groups were compared. Logistic regression analysis was performed to analyze the risk factors for APOs and the progression of UCTD to definitive CTD. Results: There were 99 (93.39%) live births, 4 (3.77%) stillbirths and 3 (2.83%) miscarriage, 20 (18.86%) preterm delivery, 6 (5.66%) SGA, 17 (16.03%) LBW, 11 (10.37%) pre-eclampsia, 7 (6.60%) cases IUGR, 19 (17.92%) cases PROM, 10 (9.43%) cases PPH. Compared with the patients without APOs, the patients with APOs had a higher positive rate of anti-SSA antibodies (73.58% vs. 54.71%, P=0.036), higher rate of leukopenia (15.09% vs. 3.77%, P=0.046), lower haemoglobin level [109.00 (99.50, 118.00) g/L vs. 124.00 (111.50, 132.00) g/L, P < 0.001].Multivariate Logistic regression analysis showed that leucopenia (OR=0.82, 95%CI: 0.688-0.994) was an independent risk factors for APOs in UCTD (P=0.042). Within a mean follow-up time of 5.00 (3.00, 7.00) years, the rate of disease progression to a definite CTD was 14.15%, including 8 (7.54%) Sjögren's syndrome, 4 (3.77%) systemic lupus erythematosus (SLE), 4 (3.77%) rheumatoid arthritis and 1 (0.94%) mixed connective tissue disease. Multivariate Cox proportional risk regression analysis showed that Raynaud phenomenon (HR=40.157, 95%CI: 3.172-508.326) was an independent risk factor for progression to SLE. Conclusion: Leukopenia is an independent risk factor for the development of APOs in patients with UCTD. Raynaud's phenmon is a risk factor for the progression of SLE. Tight disease monitoring and regular follow-up are the key measures to prevent adverse pregnancy outcomes and predict disease progression in UCTD patients with pregnancy.

Key words: Undifferentiated connective tissue disease, Adverse pregnancy outcomes, Risk factor

中图分类号:

R593.2

游芳凝,罗靓,刘香君,张学武,李春. 未分化结缔组织病患者的妊娠结局、疾病演变及其影响因素[J]. 北京大学学报（医学版）, 2023, 55(6): 1045-1052.

Fang-ning YOU,Liang LUO,Xiang-jun LIU,Xue-wu ZHANG,Chun LI. Analysis of pregnancy outcomes, disease progression, and risk factors in patients with undifferentiated connective tissue disease[J]. Journal of Peking University (Health Sciences), 2023, 55(6): 1045-1052.

图/表 6

表1

两组患者临床特点及实验室指标差异"

Items	Total patients (n=106)	APOs (n=53)	Non-APOs (n=53)	Z/t/χ²	P value
Age at conception/years, ${\bar x}$±s	31.00±0.38	30.03±0.54	31.96±0.51	-2.570	0.012^*
Birth weight/g, ${\bar x}$±s	2 901.43±67.30	2 693.41±104.78	3 158.26±52.11	-4.113	0.000^*
Disease duration/weeks, M (P₂₅, P₇₅)	48.00 (23.50, 144.00)	96.00 (32.00, 144.00)	48.00 (12.00, 144.00)	-1.222	0.222
Mode of delivery
Vaginal, n (%)	56 (52.83)	23 (43.39)	33 (62.26)	2.457	0.117
Cesarean section, n (%)	45 (42.45)	25 (47.16)	20 (37.73)	2.099	0.147
Clinical manifestations of the disease
Arthritis, n (%)	12 (11.32)	9 (16.98)	3 (5.66)	3.383	0.066
Cutaneous manifestations, n (%)	14 (13.20)	8 (15.09)	6 (11.32)	0.329	0.566
Photosensitive, n (%)	5 (4.71)	4 (7.54)	1 (1.88)	1.889	0.169
RP, n (%)	6 (5.66)	3 (5.66)	3 (5.66)	0.001	0.981
Haematological	38 (35.84)	24 (45.28)	14 (26.41)	4.102	0.043^*
Leukopenia, n (%)	10 (9.43)	8 (15.09)	2 (3.77)	3.975	0.046^*
Thrombocytopaenia, n (%)	27 (25.47)	16 (30.18)	11 (20.75)	1.242	0.265
Haemolytic anaemia, n (%)	5 (4.71)	4 (7.54)	1 (1.88)	1.889	0.169
PLT/(×10⁹/L), M (P₂₅, P₇₅)	172.00 (103.50, 216.75)	171.00 (41.00, 234.50)	132.50 (132.50, 195.00)	-0.082	0.935
Hb/(g/L), M (P₂₅, P₇₅)	114.00 (106.75, 127.25)	109.00 (99.50, 118.00)	124.00 (111.50, 132.00)	11.999	0.001^*
Proteinuria, n (%)	18(16.98)	12(22.64)	6(11.32)	3.261	0.071
Laboratory features
ANA positive, n (%)	106 (100.00)	53(50.00)	53 (50.00)	0.913	0.339
Anti-ENA positive, n (%)	77 (72.64)	44 (83.01)	33 (62.26)	6.411	0.011^*
Anti-SSB antibodies, n (%)	11 (10.37)	8 (15.09)	3 (5.66)	2.547	0.110
Anti-SSA antibodies, n (%)	68 (64.15)	39 (36.79)	29 (27.35)	4.412	0.036^*
Anti-RNP antibodies, n (%)	8 (7.54)	5 (9.43)	3 (5.66)	0.543	0.461
Anti-U1RNP antibodies, n (%)	3 (2.83)	2 (3.77)	1 (1.88)	0.343	0.558
Anti-Ro52 antibodies, n (%)	29 (27.35)	16 (30.18)	13 (24.52)	0.434	0.510
Anti-ribosomal P protein antibodies, n (%)	5 (4.71)	4 (7.54)	1 (1.88)	1.893	0.169
Anti-nucleosome antibodies, n (%)	5 (4.71)	2 (3.77)	3 (5.66)	0.210	0.647
Anti-Sm antibodies, n (%)	1 (0.94)	0 (0.00)	1 (1.88)	1.010	0.315
Anti-cell membrane DNA antibodies	2 (1.88)	2 (3.77)	0 (0.00)	1.010	0.315
Anti-M2 antibodies, n (%)	2 (1.88)	2 (3.77)	0 (0.00)	2.040	0.153
Anti-dsDNA antibodies, n (%)	5 (4.71)	1 (1.88)	4 (7.54)	1.891	0.169
Low C3，n (%)	26 (24.52)	14 (26.41)	12 (22.64)	0.159	0.690
Low C4，n (%)	3 (2.83)	0 (0.00)	3 (5.66)	3.263	0.071
Low C3/C4, n (%)	26 (24.52)	1 4(26.41)	12 (22.64)	0.106	0.744
IgA positive, n (%)	1 (0.94)	0 (0.00)	1 (1.88)	1.138	0.286
IgG positive, n (%)	14 (13.20)	9 (16.98)	5 (9.43)	1.385	0.239
IgM positive, n (%)	4 (3.77)	3 (5.66)	2 (3.77)	0.104	0.747
LA positive, n (%)	17 (16.03)	6 (11.32)	11 (20.75)	1.426	0.232
aCL (IgG/IgM) positive, n (%)	10 (9.43)	4 (7.54)	6 (11.32)	0.212	0.645
Anti-β2GPⅠ(IgG/IgM) antibodies positive, n (%)	12 (11.32)	5 (9.43)	7 (13.20)	0.096	0.757
Coombs test positive, n (%)	6 (5.66)	4 (7.54)	2 (3.77)	2.649	0.104
D-diemer/(μg/L), M (P₂₅, P₇₅)	659 (346.25, 1 103.75)	747.00 (403.00, 1 603.00)	559.00 (337.00, 853.00)	-0.252	0.211
APTT/s, M (P₂₅, P₇₅)	27.80 (26.00, 30.00)	27.80 (26.30, 29.00)	27.35 (25.90, 30.12)	0.018	0.986
ESR/(mm/h), M (P₂₅, P₇₅)	16.00 (10.00, 34.00)	14.50 (9.25, 35.50)	21.00 (11.00, 40.00)	-0.674	0.500
CRP/(mg/L), M (P₂₅, P₇₅)	4.92 (1.82, 11.42)	8.09 (2.49, 22.00)	3.20 (1.66, 10.00)	-1.190	0.234
RF/(IU/mL), M (P₂₅, P₇₅)	15.00 (15.00, 21.15)	15.00 (15.00, 29.20)	15.00 (15.00, 15.00)	-0.985	0.325

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参考文献 30

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Variables	Univariate				Multivariate
Variables	B	Wald	P	OR(95%CI)	B	Wald	P	OR(95%CI)
Anti-SSA positive	-0.902	4.311	0.038^*	0.406 (0.173-0.951)
Anti-ENA positive	-1.232	6.038	0.014^*	0.292 (0.109-0.779)
Leucopenia	-0.239	6.786	0.009^*	0.788 (0.658-0.943)	-0.190	4.119	0.042^*	0.827(0.688-0.994)
Anemia	-0.051	12.497	0.000^*	0.950 (0.923-0.977)

Therapy	Before pregnancy, n(%)	During pregnancy, n(%)	Postpartum, n(%)
Low-dose aspirin	13 (12.26)	32 (30.18)	1 (0.94)
Low molecular weight heparin	6 (5.66)	29 (27.35)	3 (2.83)
Glucocorticosteroids	27 (25.47)	19 (17.92)	27 (25.47)
HCQ	51 (48.11)	78 (73.58)	61 (57.54)
Intravenous immunoglobulin	0 (0.00)	3 (2.83)	0 (0.00)
MMF	0 (0.00)	0 (0.00)	2 (1.88)
Ciclosporin	3 (2.83)	6 (5.66)	7 (6.60)
Iguratimod	0	0	3 (2.83)
Tacrolimus	1 (0.94)	2 (1.88)	2 (1.88)

CTD	Variables	CTD group	Control group	Z/t/χ²	P
SLE	RP, n (%)	3 (75.00)	3 (2.94)	37.427	0.000^*
	Anti-RNP, n (%)	2 (50.00)	6 (5.88)	10.237	0.030^*
SS	Anti-SSA, n (%)	8 (100.0)	60 (61.22)	4.340	0.037^*
	Arthritis, n (%)	3 (37.50)	11 (11.22)	4.455	0.025^*
	Salivary gland ultrasound, n (%)	3 (37.50)	0 (0.00)	101.00	0.000^*
RA	Arthritis, n (%)	3 (75.00)	11 (10.78)	13.846	0.007^*

CTD	Variables	Univariate					Multivariate
CTD	Variables	B	SE	Wald	P	HR(95% CI)	B	SE	Wald	P	HR(95% CI)
SLE	RP	3.894	1.155	11.360	0.001^*	49.120 (5.102－472.877)	3.693	1.295	8.130	0.004^*	40.157 (3.172-508.326)
	Anti-RNP	2.751	1.052	6.832	0.009^*	15.652 (1.990－123.117)
SS	Salivary gland ultrasound	3.417	0.736	21.537	0.000^*	30.487 (7.200－129.095)
RA	Arthritis	-3.101	1.157	7.182	0.007^*	0.045 (0.005－0.435)

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