Systemic Lupus Erythematosus and Pregnancy Complications and Outcomes: A Mendelian Randomization Study and Retrospective Validation

Figures & data

Figure 1 Study design flowchart of the Mendelian randomization study.

Table 1 Data Sources of This Study

Traits	Data Sources	Ancestry	Cases	Controls	Case (%)	Lambda
Exposure
Systemic lupus erythematosus	Bentham et al^Citation25	European	7219	15,991	31.10	0.992
Outcomes
Gestational diabetes mellitus		European	11,279	179,600	5.91	1.084
Preeclampsia/eclampsia		European	6436	176,113	3.53	1.068
Premature rupture of membranes	FinnGen^Citation26	European	6129	154,102	3.83	1.053
Polyhydramnios		European	1049	154,102	0.68	1.001
Premature delivery		European	7678	148,153	4.94	1.039
Prolonged pregnancy		European	3896	154,102	2.47	1.060

Notes: Lambda: Calculating the value of the Genomic Inflation Factor for GWAS data.

Table 2 Two-Sample Mendelian Randomization Estimations Showing the Effects, Heterogeneity and Horizontal Pleiotropy of SLE on the Risk of Pregnancy Complications or Outcomes

	Gestational Diabetes Mellitus	Preeclampsia/Eclampsia	Premature Rupture of Membranes	Polyhydramnios	Premature delivery	Prolonged pregnancy
Main analysis
IVW (Fixed)
OR (95% CI)	1.028 (1.006–1.050)	1.008 (0.981–1.037)	1.030 (1.001–1.060)	1.075 (1.004–1.151)	1.039 (1.013–1.066)	1.000 (0.965–1.036)
P value	0.011	0.555	0.040	0.038	0.003	0.993
IVW (Random)
OR (95% CI)	1.028 (1.006–1.050)	1.008 (0.981–1.037)	1.030 (1.000–1.061)	1.075 (1.004–1.151)	1.039 (1.013–1.066)	1.000 (0.965–1.036)
P value	0.011	0.555	0.047	0.038	0.003	0.993
MR Egger
OR (95% CI)	1.020 (0.969–1.074)	1.050 (0.982–1.122)	1.072 (0.998–1.150)	1.029 (0.875–1.210)	1.026 (0.964–1.092)	0.988 (0.905–1.077)
P value	0.460	0.162	0.066	0.735	0.424	0.782
Weighted median
OR (95% CI)	1.020 (0.990–1.050)	1.001 (0.963–1.041)	1.030 (0.988–1.074)	1.024 (0.928–1.129)	1.029 (0.990–1.069)	0.983 (0.933–1.036)
P value	0.188	0.949	0.165	0.638	0.143	0.516
Weighted mode
OR (95% CI)	1.021 (0.979–1.065)	0.979 (0.917–1.045)	1.064 (0.986–1.147)	1.002 (0.876–1.146)	1.035 (0.976–1.099)	0.941 (0.844–1.045)
P value	0.334	0.524	0.119	0.982	0.262	0.278
Maximum likelihood
OR (95% CI)	1.028 (1.006–1.050)	1.009 (0.981–1.038)	1.031 (1.001–1.061)	1.077 (1.005–1.154)	1.039 (1.013–1.066)	1.000 (0.965–1.036)
P value	0.012	0.549	0.040	0.036	0.003	0.993
MR-PRESSO
OR (95% CI)	1.028 (1.006–1.050)	1.008 (0.981–1.037)	1.030 (1.000–1.061)	1.075 (1.004–1.151)	1.039 (1.013–1.066)	1.000 (0.965–1.036)
P value	0.011	0.555	0.047	0.038	0.003	0.993
Sensitivity analysis
Cochran’s Q
Q-statistics	22.097	20.074	32.152	26.037	27.987	25.280
Q_df	30	28	30	29	30	30
P value	0.851	0.862	0.361	0.624	0.571	0.711
MR-Egger
Q-statistics	21.993	18.352	30.643	25.694	27.790	25.188
Q_df	29	27	29	28	29	29
P value	0.820	0.892	0.382	0.590	0.529	0.668
Egger intercept
Intercept	2.66E-3	−1.40E-2	1.36E-2	1.53E-2	4.50E-3	4.30E-3
P value	0.750	0.200	0.242	0.563	0.660	0.764
MR-PRESSO
P value	0.863	0.863	0.346	0.635	0.578	0.686

Figure 2 Mendelian randomization estimates of SLE on the risk for pregnancy complications and outcomes. OR, Odds ratio; CI, Confidence interval; IVW, inverse-variance weighted; IVW (fixed), fixed-effects inverse-variance weighted; MR-PRESSO, MR-pleiotropy residual sum and outlier.

Table 3 Clinical Data on the Correlation Between SLE and Six Pregnancy Complications or Outcomes

	SLE n=200	Control n=200	OR	P
GDM	42	25	1.861 (1.074–3.142)	0.023
Preeclampsia/eclampsia	14	5	2.935 (1.118–7.620)	0.034
Premature rupture of membranes	12	6	2.064 (0.790–5.479)	0.148
Polyhydramnios	3	4	0.746 (0.186–2.812)	0.746
Premature delivery	28	12	2.550 (1.251–5.005)	0.007
Prolonged pregnancy	1	3	0.330 (0.023–2.233)	0.315

Bentham J, Morris DL, Cunninghame Graham DS, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457–1464. doi:10.1038/ng.3434

 PubMed Web of Science ®Google Scholar

Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613(7944):508–518. doi:10.1038/s41586-022-05473-8

 PubMed Web of Science ®Google Scholar

Data Sharing Statement

All data generated or analysed during this study are included in this published article and its Supplementary Information Files.