Management and outcomes of pregnancy with or without lupus nephritis: a systematic review and meta-analysis

Figures & data

Figure 1 Flow diagram demonstrating the study selection process.

Table 1 Characteristics of studies included in the systematic review and meta-analysis

Study	Year	Type of study	Setting	Year of patients’ enrollment	Percent biopsy proven on study entry (n/total)	Pregnancies with LN (n)	Pregnancies without LN (n)	Mean maternal age at delivery (years)* (LN/non-LN)	NOS scores	STROBE checklist (total=22)
Carmona et al^Citation21	2005	Cohort	Spain	1995–2001	100% (45/45)	54	54	29.2/29.7	8/9	17
Cavallasca et al^Citation49	2008	Cohort	Argentina	1986–2004	NA	20	52	28.1	7/9	13
Whitelaw et al^Citation50	2008	Cohort	South Africa	1992–2002	100% (10/10)	15	32	28.3	7/9	13
Wagner et al^Citation22	2009	Cohort	USA	1976–2007	73.1% (19/26)	43	47	26.4/28.3	7/9	16
Al Arfaj and Khalil^Citation51	2010	Cohort	Saudi Arabia	1980–2006	NA	153	230	25.6	9/9	19
Gladman et al^Citation20	2010	Cohort	Canada	1970–2003	NA	81	112	28.3/30.8	9/9	18
Bramham et al^Citation24	2011	Cohort	UK	2000–2008	100% (31/31)	43	64	31.6/32.5	9/9	21
Ko et al^Citation52	2011	Cohort	Korea	1998–2010	NA	37	144	30	8/9	20
Kwok et al^Citation26	2011	Cohort	Hong Kong	1985–2008	100% (30/30)	30	25	30.1/30.7	8/9	19
Saavedra et al^Citation13	2012	Cohort	Mexico	2005–2009	74.3% (26/35)	35	60	26.2/26.9	7/9	19
Fatemi et al^Citation53	2013	Cohort	Iran	1998–2012	38.5% (5/13)	14	58	28.7/25.8	9/9	19
Madazli et al^Citation54	2014	Cohort	Turkey	2002–2011	NA	9	56	28.8	7/9	14
Lv et al^Citation25	2015	Cohort	People’s Republic of China	2005–2013	54.2% (13/24)	24	28	28.5/29.4	9/9	20
Mbuli et al^Citation55	2015	Cohort	South Africa	2003–2013	100% (29/29)	29	32	27.2	7/9	19
Ku et al^Citation23	2016	Cohort	People’s Republic of China	2004–2014	NA	29	35	28.2	7/9	19
Teh et al^Citation19	2017	Cross-sectional	Malaysia	2006–2015	80.6% (29/36)	49	66	29.7	6/8	16

Notes: Total scores are 9 for the cohort studies, and 8 for the cross-sectional studies.

* If there is only one value in the table, it refers to the mean age of both women with lupus nephritis and non-lupus nephritis.

Abbreviations: LN, lupus nephritis; NOS, Newcastle-Ottawa Scale; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; NA, not available.

Table 2 Outcomes reported, SLE diagnostic criteria, lupus nephritis diagnostic criteria, disease activity rates, and flare definition upon study enrollment in the studies included for analysis

Study	Maternal outcomes	Fetal outcomes	SLE diagnostic criteria	LN diagnosis criteria	Disease activity	Flare
Carmona et al^Citation21	Spontaneous abortion, gestational hypertension, preeclampsia, cesarean section, flare, renal flare, aPL positive, active disease at conception	Fetal loss, stillbirth, premature birth, live birth	1	1	4	1
Cavallasca et al^Citation49	Spontaneous abortion, gestational hypertension, preeclampsia	Stillbirth, premature birth, full-term birth, LBW	2	NA	1	1
Whitelaw et al^Citation50	Spontaneous abortion	Premature birth, full-term birth, IUGR, live birth	1	1	3	1
Wagner et al^Citation22	Spontaneous abortion, gestational hypertension, preeclampsia, cesarean section	Premature birth, full-term birth, SGA, fetal loss, stillbirth, neonatal death, neonatal lupus	1	1	1	1
Al Arfaj and Khalil^Citation51	Miscarriages	Premature birth, full-term birth, stillbirth, IUGR, live birth	2	NA	NA	1
Gladman et al^Citation20	Spontaneous abortion, gestational hypertension, preeclampsia, GDM, medicine, aPL positive, SLE flare	Live birth, stillbirth, LBW, congenital malformation, neonatal lupus	NA	NA	2, 6	2
Bramham et al^Citation24	Preeclampsia, cesarean section, SLE flare, renal flare, aPL positive, APS, medication	Live birth, intrauterine death, SGA, 1-min Apgar <7	1	1	1	1
Ko et al^Citation52	Miscarriages	Stillbirth, neonatal death, live birth, preterm birth, full-term birth, IUGR	1	NA	3	1
Kwok et al^Citation26	Spontaneous abortion, SLE flares, preeclampsia, APS, medications	Stillbirth, fetal loss, SGA, IUGR, preterm birth	2	1	3, 5	1
Saavedra et al^Citation13	Spontaneous abortion, cesarean section, active SLE at conception, SLE flares, PROM, renal flare, preeclampsia, APS, proteinuria, medication	Stillbirth fetal loss, neonatal death, live birth, LBW, preterm birth	1, 2	1, 3	1	1
Fatemi et al^Citation53	Abortion, SLE flare, preeclampsia, APS, low C3, C4, medication	Stillbirth, premature birth	1	2	2	3
Madazli et al^Citation54	IUGR and/or preeclampsia	Fetal loss, premature birth, IUGR and/or preeclampsia	1	NA	1	1
Lv et al^Citation25	Gestational hypertension, preeclampsia, flare, renal damage, low C3, low C4, acL and β2GPI positive, proteinuria	Live births, gestational age, SGA, fetal loss, fetal malformation, 1-min Apgar scores	1	NA	7	4
Mbuli et al^Citation55	Miscarriage, cesarean section, flare, preeclampsia	Stillbirth, premature birth, full-term birth, live birth	1	NA	1	1
Ku et al^Citation23	SLE flare, proteinuria, hypocomplementemia, disease activity, gestational hypertension, proteinuria	Fetal loss, premature birth, IUGR, neonatal lupus, neonatal heart disease, 1-min Apgar scores	1	NA	2	1
Teh et al^Citation19	SLE flare, aPL positive, hypertension, preeclampsia, PROM, eclampsia, GDM	Premature birth, IUGR, fetal loss, live births	1	1	3, 8	1, 3, 5

Notes: Diagnostic criteria: 1) ACR 1997 criteria;⁵⁶ 2) ACR 1982 criteria.⁵⁷ Histological lupus nephritis: 1) The 1995 World Health Organization categorization for lupus nephritis;⁵⁸ 2) the 2004 classification of the International Society of Nephrology/Renal Pathology Society;⁵⁹ 3) nephritis was established clinical and biochemically. Activity: 1) Organ involvement and laboratory abnormalities; 2) SLEDAI-2k; 3) SLEDAI; 4) lupus activity criteria count; 5) Systemic Lupus Erythematosus Pregnancy Disease Activity Index; 6) Adjusted Mean Systemic Lupus Erythematosus Disease Activity Index; 7) LAI-P; 8) PGA. Flare: 1) New signs of active disease by clinical and laboratory variables or change in therapy; 2) SLEDAI-2k; 3) SLEDAI score; 4) change in LAI-P; 5) change in PGA. aPL include lupus anticoagulant, anticardiolipin antibodies, and β2-glycoprotein I. APS was defined according to the Sapporo criteria.

Abbreviations: SLE, systemic lupus erythematosus; LN, lupus nephritis; aPL, antiphospholipid antibodies; LBW, low birth weight; NA, not available; IUGR, intrauterine growth restriction; SGA, small for gestational age; GDM, gestational diabetes mellitus; APS, antiphospholipid syndrome; PROM, premature rupture of membranes; β2GPI, β2-glycoprotein; ACR, American College of Rheumatology; SLEDAI-2k, Systemic Lupus Erythematosus Disease Activity Index 2000; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; LAI-P, Lupus Activity Index in Pregnancy; PGA, Physician Global Assessment.

Figure 2 Maternal outcomes observed in pregnant women with SLE with lupus nephritis versus those without lupus nephritis.

Abbreviations: SLE, systemic lupus erythematosus; LN, lupus nephritis; aPL+, antiphospholipid antibodies positive; APS, antiphospholipid syndrome; anti-SSA/Ro+, anti-Sjögren’s syndrome-related antigen A/Ro autoantibodies positive.

Table 3 Results of meta-analysis

Outcomes analyzed	No. of studies involved (n)	OR with 95% CI	I^2
Maternal outcomes
Spontaneous abortion	9	1.25 (0.92, 1.70)	0%
Gestational hypertension	5	5.65 (2.94, 10.84)	0%
Preeclampsia	10	2.84 (1.87, 4.30)	0%
SLE flare	9	2.66 (1.51, 4.70)	69%
Renal flare	4	15.18 (5.89, 39.14)	0%
Cesarean section	5	1.17 (0.79, 1.74)	38%
aPL and APS	8	0.98 (0.71, 1.35)	0%
Proteinuria	3	8.86 (4.75, 16.52)	0%
SSA+	4	0.57 (0.33, 0.98)	43%
Hypocomplementemia	3	2.86 (1.68, 4.87)	0%
Fetal outcomes
Live birth	15	0.62 (0.49, 0.80)	0%
Stillbirth	9	1.68 (0.95, 2.98)	0%
Preterm birth	13	1.92 (1.49, 2.49)	0%
LBW/IUGR/SGA	11	1.43 (1.08, 1.91)	0%
Antenatal management
Steroids	5	2.48 (1.59, 3.87)	27%
Antimalarials	5	0.67 (0.30, 1.49)	72%
Immunosuppressives	5	6.77 (3.30, 13.89)	53%

Abbreviations: OR, odds ratio; SLE, systemic lupus erythematosus; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; SSA+, Sjögren’s syndrome-related antigen A positive LBW, low birth weight; IUGR, intrauterine growth restriction; SGA, small for gestational age.

Table 4 Sensitivity analyses

A
Study omitted	PQ	I^2	OR	95% CI
Carmona et al^Citation21	0.01	61%	3.11	1.80, 5.37
Gladman et al^Citation20	0.0006	73%	2.69	1.38, 5.24
Bramham et al^Citation24	0.02	59%	3.12	1.83, 5.32
Kwok et al^Citation26	0.001	71%	2.51	1.36, 4.62
Saavedra et al^Citation13	0.0008	72%	2.58	1.36, 4.89
Lv et al^Citation25	0.02	59%	2.22	1.34, 3.68
Mbuli et al^Citation55	0.0006	73%	2.63	1.40, 4.96
Ku et al^Citation23	0.0006	73%	2.63	1.40, 4.96
Teh et al^Citation19	0.0007	72%	2.63	1.38, 5.01
B
Gladman et al^Citation20	0.002	79%	0.66	0.20, 2.12
Bramham et al^Citation24	0.002	79%	0.64	0.21, 1.95
Kwok et al^Citation26	0.25	28%	0.89	0.54, 1.46
Saavedra et al^Citation13	0.004	78%	0.59	0.21, 1.62
Fatemi et al^Citation53	0.02	69%	0.52	0.23, 1.16
C
Bramham et al^Citation24	0.28	20%	4.66	2.04, 10.66
Kwok et al^Citation26	0.005	81%	7.34	1.63, 33.09
Saavedra et al^Citation13	0.007	80%	7.8	1.34, 45.38
Fatemi et al^Citation53	0.08	61%	11.64	3.94, 34.38

Notes: (A) Outcome: SLE flare. (B) Outcome: antimalarials. (C) Outcome: immunosuppressant-azathioprine.

Abbreviations: SLE, systemic lupus erythematosus; OR, odds ratio.

Figure 3 Fetal outcomes observed in pregnant women with SLE with lupus nephritis versus those without lupus nephritis.

Abbreviations: SLE, systemic lupus erythematosus; LN, lupus nephritis; LBW, low birth weight; IUGR, intrauterine growth restriction; SGA, small for gestational age.

Figure 4 Antenatal management observed in pregnant women with SLE with lupus nephritis versus those without lupus nephritis.

Abbreviations: SLE, systemic lupus erythematosus; LN, lupus nephritis.

Figure 5 Funnel plot of the association between lupus nephritis and maternal outcomes.

Abbreviations: SE, standard error; OR, odds ratio; aPL+, antiphospholipid antibodies positive; APS, antiphospholipid syndrome; anti-SSA/Ro+, anti-Sjögren’s syndrome-related antigen A/Ro autoantibodies positive; SLE, systemic lupus erythematosus.

Figure 6 Funnel plot of the association between lupus nephritis and fetal outcomes.

Abbreviations: SE, standard error; OR, odds ratio; LBW, low birth weight; IUGR, intrauterine growth restriction; SGA, small for gestational age.

Figure 7 Funnel plot of the association between lupus nephritis and antenatal management.

Abbreviations: SE, standard error; OR, odds ratio.

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