Current Approaches to the Management of Rheumatic Diseases in Pregnancy: Risk Stratification, Therapeutic Advances, and Maternal–Fetal Outcomes
Abstract
1. Introduction
2. Methods and Materials
2.1. Study Design
2.2. Search Strategy
2.3. Study Selection
2.4. Eligibility Criteria
- Prospective and retrospective cohort studies;
- Randomized controlled trials (RCTs);
- Systematic reviews and meta-analyses.
- Case reports or small case series;
- Non-peer-reviewed publications;
- Studies not addressing pregnancy-related outcomes or management strategies.
2.5. Data Extraction and Synthesis
3. Results
3.1. Systemic Lupus Erythematosus (SLE) and Pregnancy
3.1.1. Maternal and Fetal Outcomes
3.1.2. Preconception Risk Assessment
3.1.3. Pregnancy Management and Therapy
Screening and Baseline Interventions
Medication Strategies
- Hydroxychloroquine (HCQ):
- Glucocorticoids:
- Immunosuppressive agents:
- Aspirin (ASA):
Special Considerations
3.2. Antiphospholipid Syndrome (APS) and Pregnancy
3.2.1. Pathophysiology and Diagnostic Subtypes
- Obstetric morbidity APS (OMAPS): Clinical features consistent with APS in the absence of full laboratory confirmation;
- Non-criteria OAPS (NC-OAPS): Presence of laboratory markers without meeting the required clinical criteria.
3.2.2. Maternal and Fetal Outcomes
- Fetal Growth Restriction (FGR): Strongly associated with anticardiolipin (aCL) and anti-β2-glycoprotein I (anti-β2 GPI) antibodies but not significantly linked with lupus anticoagulant (LA) positivity [47];
- Preterm Birth: More commonly observed in women with multiple aPL positivity, particularly those with triple positivity [48];
- Stillbirth at (≥10 weeks): APS was identified as the underlying etiology in approximately 10.3% of cases, suggesting possible underdiagnosis. This underscores the need for repeat serological testing and extended postpartum follow-up in affected women [49];
- Severe Thrombocytopenia (at <50 × 109/L): Associated with heightened risks of preterm delivery, uteroplacental insufficiency, and small-for-gestational-age (SGA) neonates [50].
3.2.3. Preconception Risk Assessment
3.2.4. Fetal Surveillance and Predictive Modeling
3.2.5. Treatment Strategies
Standard Therapy
Adjunctive Therapy
- Hydroxychloroquine (HCQ):
- Low-dose prednisone:
- Intravenous immunoglobulin (IVIg):
Comprehensive Regimens
Evidence Synthesis
3.3. Sjogren’s Disease and Pregnancy
3.3.1. Maternal and Fetal Outcomes
3.3.2. Preconception Risk Assessment
3.3.3. Treatment Strategies
3.4. Systemic Sclerosis and Pregnancy
3.4.1. Maternal and Fetal Outcomes
3.4.2. Preconception Counseling
- Cardiopulmonary assessment (e.g., echocardiography and pulmonary function tests);
- Renal function evaluation;
- Autoantibody screening, including anti-Scl-70 and anti-RNA polymerase III;
- Screening for subclinical pulmonary hypertension.
3.4.3. Treatment Strategies
- Hydroxychloroquine;
- Azathioprine;
- Sulfasalazine (with folic acid supplementation);
- Selected TNF inhibitors, such as certolizumab pegol (which has minimal placental transfer and can be continued throughout pregnancy) and etanercept (which may also be used in selected cases).
3.5. Rheumatoid Arthritis and Pregnancy
3.5.1. Maternal and Fetal Outcomes
3.5.2. Preconception Counseling
3.5.3. Treatment Strategies
- Hydroxychloroquine;
- Sulfasalazine;
- Azathioprine;
- Cyclosporine;
- Tacrolimus;
- Selected TNF inhibitors (e.g., adalimumab and etanercept).
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
aCL | anticardiolipin antibodies |
aPL | antiphospholipid antibodies |
APS | antiphospholipid syndrome |
ASA | acetylsalicylic acid |
AZA | azathioprine |
BP | blood pressure |
CHB | congenital heart block |
CI | confidence interval |
CRP | C-reactive protein |
CTD | connective tissue disease |
DMARDs | disease-modifying antirheumatic drugs |
FGR | fetal growth restriction |
GI | Gastrointestinal |
GWAS | genome-wide association study |
HCQ | Hydroxychloroquine |
IVIg | intravenous immunoglobulin |
LA | lupus anticoagulant |
LDA | low-dose aspirin |
LMWH | low-molecular-weight heparin |
LN | lupus nephritis |
NC-OAPS | non-criteria obstetric antiphospholipid syndrome |
OAPS | obstetric antiphospholipid syndrome |
OMAPS | obstetric morbidity APS |
OR | odds ratio |
PAH | pulmonary arterial hypertension |
PEX | plasma exchange |
RA | rheumatoid arthritis |
RCT | randomized controlled trial |
SC | Subcutaneous |
SGA | small for gestational age |
SLE | systemic lupus erythematosus |
SLEPDAI | systemic lupus erythematosus pregnancy disease activity index |
SLICC | systemic lupus international collaborating clinics |
SS | Sjögren’s syndrome |
SSc | systemic sclerosis |
TNF | tumor necrosis factor |
UFH | unfractionated heparin |
VTE | venous thromboembolism |
References
- Marder, W.; Littlejohn, E.A.; Somers, E.C. Pregnancy and autoimmune connective tissue diseases. Best Pr. Res. Clin. Rheumatol. 2016, 30, 63–80, Erratum in Best Pr. Res. Clin. Rheumatol. 2020, 34, 101490. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Nodler, J.; Moolamalla, S.R.; Ledger, E.M.; Nuwayhid, B.S.; Mulla, Z.D. Elevated antiphospholipid antibody titers and adverse pregnancy outcomes: Analysis of a population-based hospital dataset. BMC Pregnancy Childbirth 2009, 9, 11. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Clark, C.A.; Spitzer, K.A.; Laskin, C.A. Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J. Rheumatol. 2005, 32, 1709–1712. [Google Scholar] [PubMed]
- Merz, W.M.; Fischer-Betz, R.; Hellwig, K.; Lamprecht, G.; Gembruch, U. Pregnancy and autoimmune disease: Diseases of the nervous system, connective tissue, and the bowel. Dtsch. Arztebl. Int. 2022, 119, 145–146. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Girardi, G.; Longo, M.; Bremer, A.A. Social determinants of health in pregnant individuals from underrepresented, understudied, and underreported populations in the United States. Int. J. Equity Health 2023, 22, 186. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Barber, M.R.W.; Falasinnu, T.; Ramsey-Goldman, R.; Clarke, A.E. The global epidemiology of SLE: Narrowing the knowledge gaps. Rheumatology 2023, 62 (Suppl. S1), i4–i9. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Khogali, H.I.; Al-Bluwi, G.S.M.; Pedo, V.G.; Al Dhanhani, A.M. Maternal and fetal health outcomes in systemic lupus erythematosus pregnancies in the Emirati population: A comparative study. Lupus 2023, 32, 1453–1461. [Google Scholar] [CrossRef] [PubMed]
- Lu, J.; Xu, D.; Wan, Q.; Chen, H. Pregnancy outcomes and risk factors analysis in patients with systemic lupus erythematous. BMC Pregnancy Childbirth 2024, 24, 495. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bin Joo, Y.; Kim, K.-J.; Park, K.-S.; Park, Y.-J. Pregnancy rates and perinatal outcomes in women with systemic lupus erythematosus: Data from the Korean national health claims database. Clin. Rheumatol. 2021, 40, 2243–2250. [Google Scholar] [CrossRef] [PubMed]
- Tsuda, S.; Sameshima, A.; Sekine, M.; Kawaguchi, H.; Fujita, D.; Makino, S.; Morinobu, A.; Murakawa, Y.; Matsui, K.; Sugiyama, T.; et al. Pre-conception status, obstetric outcome and use of medications during pregnancy of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) in Japan: Multi-center retrospective descriptive study. Mod. Rheumatol. 2020, 30, 852–861. [Google Scholar] [CrossRef] [PubMed]
- Al-Riyami, N.; Salman, B.; Al-Rashdi, A.; Al-Dughaishi, T.; Al-Haddabi, R.; Hassan, B. Pregnancy Outcomes in Systemic Lupus Erythematosus Women. Sultan Qaboos Univ. Med. J. 2021, 21, e244–e252. [Google Scholar] [CrossRef] [PubMed Central]
- Poh, Y.J.; Yii, I.Y.L.; Goh, L.H.; Li, H.H.; Yang, L.; Tan, H.K.; Thumboo, J.; Tan, L.K. Maternal and Fetal Outcomes in Systemic Lupus Erythematosus Pregnancies. Ann. Acad. Med. Singap. 2020, 49, 963–970. [Google Scholar] [CrossRef] [PubMed]
- Erazo-Martínez, V.; Nieto-Aristizábal, I.; Ojeda, I.; González, M.; Aragon, C.C.; Zambrano, M.A.; Tobón, G.J.; Arango, J.; Echeverri, A.; Aguirre-Valencia, D. Systemic erythematosus lupus and pregnancy outcomes in a Colombian cohort. Lupus 2021, 30, 2310–2317. [Google Scholar] [CrossRef] [PubMed]
- Bremme, K.; Honkanen, S.; Gunnarsson, I.; Chaireti, R. The presence of lupus nephritis additionally increases the risk of preeclampsia among pregnant women with systemic lupus erythematosus. Lupus 2021, 30, 1031–1038. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Çetin, Ç.; Saraç-Sivrikoz, T.; Ateş-Tıkız, M.; Zaralı, S.; Ersoy, A.; Yalçınkaya, Y.; Gül, A.; İnanç, M.; Has, R.; Kalelioğlu, İ.; et al. The correlation between pregnancy, disease activity and adverse pregnancy outcomes in patients with systemic lupus erythematosus. Lupus 2023, 32, 1509–1517. [Google Scholar] [CrossRef] [PubMed]
- Braga, A.; Barros, T.; Faria, R.; Marinho, A.; Carvalheira, G.; Rocha, G.; Farinha, F.; Neves, E.; Vasconcelos, C.; Braga, J. Systemic lupus erythematosus and pregnancy: A retrospective single-center study of 215 pregnancies from Portugal. Lupus 2021, 30, 2165–2175. [Google Scholar] [CrossRef] [PubMed]
- Mokbel, A.; Attia, D.H.; Zayed, H.S.; Naeem, N.E.; Mahmoud, G.; Riad, R.; Elewa, S.A.; Youssef, M.; Haggag, H.; Mohamed, S.S. Pregnancy outcomes among Egyptian women with systemic lupus erythematosus: A prospective cohort study. Lupus 2023, 32, 521–530. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Di, W.; Ye, L.; Hu, Y.; Jiang, M.; Wu, J.; Bu, J.; Sun, J.; Bei, F. Association of preterm outcome with maternal systemic lupus erythematosus: A retrospective cohort study. Ital. J. Pediatr. 2023, 49, 43. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Madanchi, N.; Fava, A.; Goldman, D.W.; Magder, L.S.; Petri, M. Association Between 25-hydroxyvitamin D Levels and Adverse Pregnancy Outcomes in Systemic Lupus Erythematosus. Arthritis Care Res. 2025, 77, 432–439. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Muñoz, C.M.; Goulden, B.; Ahmed, K.; Alijotas-Reig, J.; Giles, I. Risk of adverse pregnancy outcomes prior to the onset of an autoimmune rheumatic disease: A systematic review. Rheumatology 2023, 62, 497–511. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Laíño-Piñeiro, M.-C.; Rúa-Figueroa, I.; Jiménez, N.; Lozano, M.J.C.; Martínez-Barrio, J.; Serrano, B.; Galindo-Izquierdo, M.; Nack, A.; Loricera, J.; Tomero-Muriel, E.; et al. Pregnancy outcomes in 1869 pregnancies in a large cohort from the Spanish Society of Rheumatology Lupus Register (RELESSER). Semin. Arthritis Rheum. 2023, 61, 152232. [Google Scholar] [CrossRef] [PubMed]
- Wind, M.; Fierro, J.J.; Bloemenkamp, K.W.M.; de Leeuw, K.; Lely, A.T.; Limper, M.; Sueters, M.; Teng, Y.K.O.; Walter, I.J.; Kooiman, J. Pregnancy outcome predictors in systemic lupus erythematosus: A systematic review and meta-analysis. Lancet Rheumatol. 2024, 6, e667–e683. [Google Scholar] [CrossRef] [PubMed]
- Crisafulli, F.; Andreoli, L.; Zucchi, D.; Reggia, R.; Gerardi, M.C.; Lini, D.; Tani, C.; Zatti, S.; Franceschini, F.; Mosca, M.; et al. Variations of C3 and C4 Before and During Pregnancy in Systemic Lupus Erythematosus: Association with Disease Flares and Obstetric Outcomes. J. Rheumatol. 2023, 50, 1296–1301. [Google Scholar] [CrossRef] [PubMed]
- Hiramatsu, Y.; Isoda, K.; Kotani, T.; Nakamura, E.; Wada, Y.; Fujiki, Y.; Makino, S.; Fujita, D.; Takeuchi, T. Pre-pregnancy serum complement C3 level is a predictor of preterm birth for pregnancies with systemic lupus erythematosus. Arthritis Res. Ther. 2021, 23, 140. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Radin, M.; Cecchi, I.; Crisafulli, F.; Klumb, E.M.; de Jesús, G.R.; Lacerda, M.I.; Saavedra, M.Á.; Reyes-Navarro, G.V.; Iaccarino, L.; Larosa, M.; et al. Complement levels during the first trimester predict disease flare and adverse pregnancy outcomes in systemic lupus erythematosus: A network meta-analysis on 532 pregnancies. Autoimmun. Rev. 2023, 22, 103467. [Google Scholar] [CrossRef] [PubMed]
- Ong, S.G.; Ding, H.J. Predictors of adverse pregnancy outcome in a cohort of women with systemic lupus erythematosus in Malaysia. Med. J. Malays. 2021, 76, 466–473. [Google Scholar] [PubMed]
- Zucchi, D.; Fischer-Betz, R.; Tani, C. Pregnancy in systemic lupus erythematosus. Best Pr. Res. Clin. Rheumatol. 2023, 37, 101860. [Google Scholar] [CrossRef] [PubMed]
- Huang, J.; Zhu, Q.; Wang, B.; Wang, H.; Xie, Z.; Zhu, X.; Zhao, T.; Yang, Z. Antiphospholipid antibodies and the risk of adverse pregnancy outcomes in patients with systemic lupus erythematosus: A systematic review and meta-analysis. Expert Rev. Clin. Immunol. 2024, 20, 793–801. [Google Scholar] [CrossRef] [PubMed]
- Zamani, B.; Shayestehpour, M.; Esfahanian, F.; Akbari, H. The study of factors associated with pregnancy outcomes in patients with systemic lupus erythematosus. BMC Res. Notes 2020, 13, 185. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Ravindran, V.; Bhadran, S.; Divakaran, M.; Reshma, V.M. Lupus pregnancy outcomes in women with previous adverse outcomes: A prospective cohort study. Clin. Rheumatol. 2024, 43, 2911–2917. [Google Scholar] [CrossRef] [PubMed]
- Janardana, R.; Haridas, V.; Priya, V.; Bhat, V.; Singh, Y.; Rao, V.K.; Jois, R.; Srikantiah, C.; Pinto, B.; Shobha, V. Maternal and fetal outcomes of lupus pregnancies: A collective effort by Karnataka Rheumatologists. Lupus 2020, 29, 1397–1403. [Google Scholar] [CrossRef] [PubMed]
- Duan, J.; Ma, D.; Wen, X.; Guo, Q.; Gao, J.; Zhang, G.; Xu, K.; Zhang, L. Hydroxychloroquine prophylaxis for preeclampsia, hypertension and prematurity in pregnant patients with systemic lupus erythematosus: A meta-analysis. Lupus 2021, 30, 1163–1174. [Google Scholar] [CrossRef] [PubMed]
- Clowse, M.E.B.; Eudy, A.M.; Balevic, S.; Sanders-Schmidler, G.; Kosinski, A.; Fischer-Betz, R.; Gladman, D.D.; Molad, Y.; Nalli, C.; Mokbel, A.; et al. Hydroxychloroquine in the pregnancies of women with lupus: A meta-analysis of individual participant data. Lupus Sci. Med. 2022, 9, e000651. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Do, S.C.; Rizk, N.M.; Druzin, M.L.; Simard, J.F. Does Hydroxychloroquine Protect Against Preeclampsia and Preterm Delivery in Systemic Lupus Erythematosus Pregnancies? Am. J. Perinatol. 2020, 37, 873–880. [Google Scholar] [CrossRef] [PubMed]
- Hu, Z.; Gao, R.; Huang, W.; Wang, H.; Qin, L. Effect of Hydroxychloroquine on Lupus Activity, Preeclampsia and Intrauterine Growth Restriction in Pregnant Women with Systemic Lupus Erythematosus and/or Antiphospholipid Syndrome: A Systematic Review and Meta-Analysis. J. Clin. Med. 2023, 12, 485. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Shimada, H.; Wakiya, R.; Kanenishi, K.; Miyatake, N.; Nakashima, S.; Mansour, M.M.F.; Kato, M.; Miyagi, T.; Sugihara, K.; Ushio, Y.; et al. Preterm birth is strongly affected by the glucocorticoid dose during pregnancy in women complicated by systemic lupus erythematosus. Arthritis Res. Ther. 2022, 24, 10. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Louthrenoo, W.; Trongkamolthum, T.; Kasitanon, N.; Wongthanee, A. Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus. Medicine 2021, 100, e24553. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Irino, K.; Arinobu, Y.; Ayano, M.; Kawano, S.; Kimoto, Y.; Mitoma, H.; Akahoshi, M.; Akashi, K.; Horiuchi, T.; Niiro, H. Predictive factors of fetal and maternal pregnancy outcomes in Japanese patients with systemic lupus erythematosus: A STROBE-compliant study. Lupus 2021, 30, 1637–1643. [Google Scholar] [CrossRef] [PubMed]
- Tani, C.; Zucchi, D.; Haase, I.; Gerosa, M.; Larosa, M.; Cavagna, L.; Bortoluzzi, A.; Crisafulli, F.; Mucke, J.; Strigini, F.A.L.; et al. Impact of low-dose acetylsalicylic acid on pregnancy outcome in systemic lupus erythematosus: Results from a multicentre study. Lupus Sci. Med. 2022, 9, e000714. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Nakai, T.; Kitada, A.; Fukui, S.; Okada, M. Risk of adverse pregnancy outcomes in Japanese systemic lupus erythematosus patients with prior severe organ manifestations: A single-center retrospective analysis. Lupus 2021, 30, 1415–1426. [Google Scholar] [CrossRef] [PubMed]
- Fierro, J.J.; Prins, J.R.; Verstappen, G.M.; Bootsma, H.; Westra, J.; de Leeuw, K. Preconception clinical factors related to adverse pregnancy outcomes in patients with systemic lupus erythematosus or primary Sjögren’s syndrome: A retrospective cohort study. RMD Open 2023, 9, e003439. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Dabit, J.Y.; Valenzuela-Almada, M.O.; Vallejo-Ramos, S.; Duarte-García, A. Epidemiology of Antiphospholipid Syndrome in the General Population. Curr. Rheumatol. Rep. 2022, 23, 85. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Alijotas-Reig, J.; Esteve-Valverde, E.; Ferrer-Oliveras, R.; Sáez-Comet, L.; Lefkou, E.; Mekinian, A.; Belizna, C.; Ruffatti, A.; Hoxha, A.; Tincani, A.; et al. Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): Report of 1640 cases from the EUROAPS registry. Rheumatology 2021, 59, 1306–1314, Erratum in Rheumatology 2021, 60, 5883.. [Google Scholar] [CrossRef] [PubMed]
- D’ippolito, S.; Barbaro, G.; Paciullo, C.; Tersigni, C.; Scambia, G.; Di Simone, N. Antiphospholipid Syndrome in Pregnancy: New and Old Pathogenetic Mechanisms. Int. J. Mol. Sci. 2023, 24, 3195. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Mineo, C.; Shaul, P.W.; Bermas, B.L. The pathogenesis of obstetric APS: A 2023 update. Clin. Immunol. 2023, 255, 109745. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Xu, J.; Chen, D.; Tian, Y.; Wang, X.; Peng, B.; Athalye-Jape, G.K. Antiphospholipid Antibodies Increase the Risk of Fetal Growth Restriction: A Systematic Meta-Analysis. Int. J. Clin. Pr. 2022, 2022, 4308470. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Iordache, O.; Anastasiu, D.M.; Kakarla, M.; Ali, A.; Bratosin, F.; Neamtu, R.; Dumitru, C.; Olaru, F.; Erdelean, I.; Gherman, A.; et al. Influence of Antiphospholipid Antibody-Associated Thrombophilia on the Risk of Preterm Birth: A Systematic Review. J. Clin. Med. 2023, 12, 5316. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Xie, A.; Jin, Z.; Li, C.; Li, C.; Luo, G.; Zhang, X.; Jian, S.; Li, D.; Xie, Y.; Xie, L.; et al. Antiphospholipid syndrome in patients with fetal death: A prospective longitudinal cohort study. Clin. Exp. Med. 2025, 25, 78. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Jin, J.; Zhang, M.; Cai, X.; Hou, Y.; Xiang, X.; Hou, L.; Li, J.; Li, C. Severe thrombocytopenia is associated with adverse pregnancy outcomes in patients with obstetric antiphospholipid syndrome. Eur. J. Med Res. 2025, 30, 465. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Walter, I.J.; Haneveld, M.J.K.; Lely, A.T.; Bloemenkamp, K.W.M.; Limper, M.; Kooiman, J. Pregnancy outcome predictors in antiphospholipid syndrome: A systematic review and meta-analysis. Autoimmun. Rev. 2021, 20, 102901. [Google Scholar] [CrossRef] [PubMed]
- Tanimura, K.; Saito, S.; Nakatsuka, M.; Nagamatsu, T.; Fujii, T.; Fukui, A.; Deguchi, M.; Sasagawa, Y.; Arase, N.; Arase, H.; et al. The β2-Glycoprotein I/HLA–DR Complex as a Major Autoantibody Target in Obstetric Antiphospholipid Syndrome. Arthritis Rheumatol. 2020, 72, 1882–1891. [Google Scholar] [CrossRef] [PubMed]
- Matraszek, V.V.; Krofta, L.; Hromadnikova, I. Even low levels of anticardiolipin antibodies are associated with pregnancy-related complications: A monocentric cohort study. Acta Obstet. Gynecol. Scand. 2025, 104, 897–905. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Murarasu, A.; Guettrot-Imbert, G.; Le Guern, V.; Yelnik, C.; Queyrel, V.; Schleinitz, N.; Ferreira-Maldent, N.; Diot, E.; Urbanski, G.; Pannier, E.; et al. Characterisation of a high-risk profile for maternal thrombotic and severe haemorrhagic complications in pregnant women with antiphospholipid syndrome in France (GR2): A multicentre, prospective, observational study. Lancet Rheumatol. 2022, 4, e842–e852. [Google Scholar] [CrossRef] [PubMed]
- Wang, B.; Wang, Q.; Yu, D.; Zhang, N.; Wang, Z.; Sun, X.; Liu, M.; Su, X. Using Doppler ultrasound to assess fetal cardiac function and pregnancy outcomes in obstetric antiphospholipid syndrome pregnancies: A case–control study. Arch. Gynecol. Obstet. 2025, 310, 2461–2468. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Moyle, K.A.; Branch, D.W.; Peterson, L.K.; Guerra, M.M.; Allshouse, A.A.; Benson, A.E.; Salmon, J.E. Association Between Novel Antiphospholipid Antibodies and Adverse Pregnancy Outcomes. Obstet. Gynecol. 2024, 145, 55–64. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Yang, Z.; Shen, X.; Zhou, C.; Wang, M.; Liu, Y.; Zhou, L. Prevention of recurrent miscarriage in women with antiphospholipid syndrome: A systematic review and network meta-analysis. Lupus 2021, 30, 70–79. [Google Scholar] [CrossRef] [PubMed]
- Frishman, M.; Radin, M.; Schreiber, K. Hydroxychloroquine and antiphospholipid antibody-related pregnancy morbidity: A systematic review and meta-analysis. Curr. Opin. Obstet. Gynecol. 2020, 32, 351–358. [Google Scholar] [CrossRef] [PubMed]
- Khizroeva, J.; Bitsadze, V.; Tincani, A.; Makatsariya, A.; Arslanbekova, M.; Babaeva, N.; Tsibizova, V.; Shkoda, A.; Makatsariya, N.; Tretyakova, M.; et al. Hydroxychloroquine in obstetric antiphospholipid syndrome: Rationale and results of an observational study of refractory cases. J. Matern. Neonatal Med. 2022, 35, 6157–6164. [Google Scholar] [CrossRef] [PubMed]
- Hooper, A.; Bacal, V.; Bedaiwy, M.A. Does adding hydroxychloroquine to empiric treatment improve the live birth rate in refractory obstetrical antiphospholipid syndrome? A systematic review. Am. J. Reprod. Immunol. 2023, 90, e13761. [Google Scholar] [CrossRef] [PubMed]
- Gerde, M.; Ibarra, E.; Mac Kenzie, R.; Suarez, C.F.; Heer, C.; Alvarez, R.; Iglesias, M.; Balparda, J.; Beruti, E.; Rubinstein, F. The impact of hydroxychloroquine on obstetric outcomes in refractory obstetric antiphospholipid syndrome. Thromb. Res. 2021, 206, 104–110. [Google Scholar] [CrossRef] [PubMed]
- Riancho-Zarrabeitia, L.; Lopez-Marin, L.; Cacho, P.M.; López-Hoyos, M.; del Barrio, R.; Haya, A.; Martínez-Taboada, V.M. Treatment with low-dose prednisone in refractory obstetric antiphospholipid syndrome: A retrospective cohort study and meta-analysis. Lupus 2022, 31, 808–819. [Google Scholar] [CrossRef] [PubMed]
- Urban, M.L.; Bettiol, A.; Serena, C.; Comito, C.; Turrini, I.; Fruttuoso, S.; Silvestri, E.; Vannacci, A.; Ravaldi, C.; Petraglia, F.; et al. Intravenous immunoglobulin for the secondary prevention of stillbirth in obstetric antiphospholipid syndrome: A case series and systematic review of literature. Autoimmun. Rev. 2020, 19, 102620. [Google Scholar] [CrossRef] [PubMed]
- Kaneko, K.; Tsutsumi, S.; Fujita, D.; Sugiura-Ogasawara, M.; Mitsuda, N.; Matsubara, K.; Atsumi, T.; Inoue, E.; Takimoto, T.; Murashima, A. Intravenous immunoglobulin treatment for obstetric antiphospholipid syndrome refractory to conventional therapy: A single-arm, open-labelled multicentre clinical trial. Mod. Rheumatol. 2024, 34, 515–522. [Google Scholar] [CrossRef] [PubMed]
- Hoxha, A.; Tormene, D.; Campello, E.; Simioni, P. Treatment of Refractory/High-Risk Pregnancies with Antiphospholipid Syndrome: A Systematic Review of the Literature. Front. Pharmacol. 2022, 13, 849692. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Ruffatti, A.; Tonello, M.; Favaro, M.; Del Ross, T.; Calligaro, A.; Ruffatti, A.T.; Gervasi, M.T.; Hoxha, A. The efficacy and safety of second-line treatments of refractory and/or high risk pregnant antiphospholipid syndrome patients. A systematic literature review analyzing 313 pregnancies. Semin. Arthritis Rheum. 2021, 51, 28–35. [Google Scholar] [CrossRef] [PubMed]
- Geng, B.; Zhang, K.; Huang, X.; Chen, Y. A meta-analysis of the effect of Sjögren′s syndrome on adverse pregnancy outcomes. Clinics 2022, 77, 100140. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Maleki-Fischbach, M.; Kastsianok, L.; Koslow, M.; Chan, E.D. Manifestations and management of Sjögren’s disease. Arthritis Res. Ther. 2024, 26, 43. [Google Scholar] [CrossRef]
- Yang, Y.; Huang, X.-X.; Huo, R.-X.; Lin, J.-Y. Impact of Sjögren’s syndrome on maternal and fetal outcomes following pregnancy: A systematic review and meta-analysis of studies published between years 2007–2022. Arch. Gynecol. Obstet. 2024, 309, 1135–1149. [Google Scholar] [CrossRef] [PubMed]
- Oliveira, F.R.; Valim, V.; Pasoto, S.G.; Fernandes, M.L.M.S.; Lopes, M.L.L.; Fialho, S.C.d.M.S.; Pinheiro, A.C.; dos Santos, L.C.; Appenzeller, S.; Fidelix, T.; et al. 2021 recommendations of the Brazilian Society of Rheumatology for the gynecological and obstetric care of patients with Sjogren’s syndrome. Adv. Rheumatol. 2021, 61, 54, Erratum in Adv. Rheumatol. 2022, 61, 8. [Google Scholar] [CrossRef] [PubMed]
- Fernández-Buhigas, I. Obstetric management of the most common autoimmune diseases: A narrative review. Front. Glob. Women’s Health 2022, 3, 1031190. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Kaizer, A.M.; Lindblade, C.; Clancy, R.; Tebo, A.E.; Drewes, B.; Masson, M.; Chang, M.; Fraser, N.; Buyon, J.P.; Cuneo, B.F. Reducing the burden of surveillance in pregnant women with no history of fetal atrioventricular block using the negative predictive value of anti-Ro/SSA antibody titers. Am. J. Obstet. Gynecol. 2022, 227, 761.e1–761.e10. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bairkdar, M.; Rossides, M.; Westerlind, H.; Hesselstrand, R.; Arkema, E.V.; Holmqvist, M. Incidence and prevalence of systemic sclerosis globally: A comprehensive systematic review and meta-analysis. Rheumatology 2021, 60, 3121–3133. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Lazzaroni, M.-G.; Crisafulli, F.; Moschetti, L.; Semeraro, P.; Cunha, A.-R.; Neto, A.; Lojacono, A.; Ramazzotto, F.; Zanardini, C.; Zatti, S.; et al. Reproductive Issues and Pregnancy Implications in Systemic Sclerosis. Clin. Rev. Allergy Immunol. 2023, 64, 321–342. [Google Scholar] [CrossRef] [PubMed]
- Chung, M.P.; Kolstad, K.D.; Dontsi, M.; Postlethwaite, D.; Manwani, P.; Zhao, H.; Kesh, S.; Simard, J.F.; Chung, L. Increased Rates of Obstetric Complications Prior to Systemic Sclerosis Diagnosis. Arthritis Care Res. 2022, 74, 912–917. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Braun, J.; Balbir-Gurman, A.; Toledano, K.; Tavor, Y.; Braun-Moscovici, Y. Favourable outcome of planned pregnancies in systemic sclerosis patients during stable disease. Scand. J. Rheumatol. 2022, 51, 513–519. [Google Scholar] [CrossRef] [PubMed]
- Sammaritano, L.R.; Bermas, B.L.; Chakravarty, E.E.; Chambers, C.; Clowse, M.E.B.; Lockshin, M.D.; Marder, W.; Guyatt, G.; Branch, D.W.; Buyon, J.; et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Care Res. 2020, 72, 461–488. [Google Scholar] [CrossRef] [PubMed]
- Russell, M.D.; Dey, M.; Flint, J.; Davie, P.; Allen, A.; Crossley, A.; Frishman, M.; Gayed, M.; Hodson, K.; Khamashta, M.; et al. British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: Immunomodulatory anti-rheumatic drugs and corticosteroids. Rheumatology 2023, 62, e48–e88, Erratum in Rheumatology 2023, 62, 2021. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Neuman, R.I.; Smeele, H.T.W.; Danser, A.H.J.; Dolhain, R.J.E.M.; Visser, W. The sFlt-1 to PlGF ratio in pregnant women with rheumatoid arthritis: Impact of disease activity and sulfasalazine use. Rheumatology 2022, 61, 628–635. [Google Scholar] [CrossRef] [PubMed]
- Venetsanopoulou, A.I.; Alamanos, Y.; Voulgari, P.V.; Drosos, A.A. Epidemiology and Risk Factors for Rheumatoid Arthritis Development. Mediterr. J. Rheumatol. 2023, 34, 404–413. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Huang, W.; Wu, T.; Jin, T.; Zhang, Y.; Wang, J.; Qi, J.; Li, Y.; Jiang, H.; Zhang, J.; Jiang, Z.; et al. Maternal and fetal outcomes in pregnant women with rheumatoid arthritis: A systematic review and meta-analysis. Clin. Rheumatol. 2023, 42, 855–870. [Google Scholar] [CrossRef] [PubMed]
- Sim, B.L.B.; Daniel, R.S.B.; Hong, S.S.B.; Matar, R.H.B.; Ganiel, I.B.; Nakanishi, H.M.; Mansour, R.B.; Than, C.A.; Alrahmani, L. Pregnancy Outcomes in Women with Rheumatoid Arthritis. Am. J. Clin. Oncol. 2023, 29, 36–42. [Google Scholar] [CrossRef] [PubMed]
- Lv, J.; Xu, L.; Mao, S. Association between disease activity of rheumatoid arthritis and maternal and fetal outcomes in pregnant women: A systematic review and meta-analysis. BMC Pregnancy Childbirth 2023, 23, 724. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Zhang, D.; Hu, Y.; Guo, W.; Song, Y.; Yang, L.; Yang, S.; Ou, T.; Liu, Y.; Zhang, Y. Mendelian randomization study reveals a causal relationship between rheumatoid arthritis and risk for pre-eclampsia. Front. Immunol. 2022, 13, 1080980. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Tian, L.M.; Zhang, Z.M.; Mao, Y.M.; Zong, M. Association between pregnant women with rheumatoid arthritis and preeclampsia: A systematic review and meta-analysis. Medicine 2023, 102, e34131. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Knudsen, S.; Thomsen, A.; Deleuran, B.; Bech, B. Maternal rheumatoid arthritis during pregnancy and neurodevelopmental disorders in offspring: A systematic review. Scand. J. Rheumatol. 2021, 50, 253–261. [Google Scholar] [CrossRef] [PubMed]
- Saulescu, I.C.; Panaitescu, A.M.; Gică, N.; Grădinaru, E.; Opris-Belinski, D. Pre-Pregnancy Counselling for Women with Rheumatoid Arthritis: A Guide on Risks, Evaluations, and Multidisciplinary Approaches. J. Clin. Med. 2024, 14, 114. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Peterson, E.A.P.; Lynton, J.P.; Bernard, A.P.; Santillan, M.K.; Bettendorf, B. Rheumatologic Medication Use During Pregnancy. Obstet. Gynecol. 2020, 135, 1161–1176. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Siegel, C.H.; Sammaritano, L.R. Safety of Medications Used to Treat Autoimmune Rheumatic Diseases During Pregnancy and Lactation. Am. J. Clin. Oncol. 2024, 30 (Suppl. S1), S25–S33. [Google Scholar] [CrossRef] [PubMed]
- Barenbrug, L.; Groen, M.T.; Hoentjen, F.; van Drongelen, J.; van den Reek, J.M.; Joosten, I.; de Jong, E.M.; van der Molen, R.G. Pregnancy and neonatal outcomes in women with immune mediated inflammatory diseases exposed to anti-tumor necrosis factor-α during pregnancy: A systemic review and meta-analysis. J. Autoimmun. 2021, 122, 102676. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, H.; Ahmed, K.; Luo, W.; Flint, J.; Giles, I. A Systematic Review of the safety of non-TNF inhibitor biologic and targeted synthetic drugs in rheumatic disease in pregnancy. Semin. Arthritis Rheum. 2021, 51, 1205–1217. [Google Scholar] [CrossRef] [PubMed]
- Raine, C.; Austin, K.; Giles, I. Mechanisms determining the amelioration of rheumatoid arthritis in pregnancy: A systematic review. Semin. Arthritis Rheum. 2020, 50, 1357–1369. [Google Scholar] [CrossRef] [PubMed]
- Mouyis, M. Postnatal Care of Woman with Rheumatic Diseases. Adv. Ther. 2020, 37, 3723–3731. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Skorpen, C.G.; Hoeltzenbein, M.; Tincani, A.; Fischer-Betz, R.; Elefant, E.; Chambers, C.; da Silva, J.; Nelson-Piercy, C.; Cetin, I.; Costedoat-Chalumeau, N.; et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann. Rheum. Dis. 2016, 75, 795–810. [Google Scholar] [CrossRef] [PubMed]
- Taylor, P.C.; Weinblatt, M.E.; McInnes, I.B.; Atsumi, T.; Strand, V.; Takeuchi, T.; Bracher, M.; Brooks, D.; Davies, J.; Goode, C.; et al. Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: A phase III randomised trial (contRAst 3). Ann. Rheum. Dis. 2023, 82, 1527–1537. [Google Scholar] [CrossRef] [PubMed]
- Kim, C.Y.P.; Suh, C.H. The safety of medications during pregnancy and lactation in patients with inflammatory rheumatic diseases. EMJ Rheumatol. 2021, 8, 44–51. [Google Scholar] [CrossRef]
- Mysler, E.; Monticielo, O.A.; Al-Homood, I.A.; Lau, C.S.; Hussein, H.; Chen, Y.-H. Opportunities and challenges of lupus care in Latin America, the Middle East, and Asia-Pacific: A call to action. Mod. Rheumatol. 2024, 34, 655–669. [Google Scholar] [CrossRef] [PubMed]
- Flower, C. Clinical Images: Diffuse systemic sclerosis, skin bleaching, and telangiectasia. Arthritis Rheumatol. 2021, 74, 262. [Google Scholar] [CrossRef] [PubMed]
- Shen, G.; Swaminathan, M.; Huang, I.; Louden, D.; Feterman, D.; Tahir, M.W.; Singh, N. Racial disparities in pregnancy outcomes among women with rheumatic diseases: A systematic literature review. Semin. Arthritis Rheum. 2023, 60, 152193. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Hassan, M.; Awan, F.M.; Naz, A.; Deandrés-Galiana, E.J.; Alvarez, O.; Cernea, A.; Fernández-Brillet, L.; Fernández-Martínez, J.L.; Kloczkowski, A. Innovations in Genomics and Big Data Analytics for Personalized Medicine and Health Care: A Review. Int. J. Mol. Sci. 2022, 23, 4645. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
Disease | High-Risk Features | Recommended Therapies | Monitoring Focus | Main Pregnancy Risks |
---|---|---|---|---|
Systemic Lupus Erythematosus (SLE) | Active nephritis, hypocomplementemia, anti-Ro/La+, and APS overlap | Hydroxychloroquine (HCQ), low-dose aspirin (LDA), azathioprine (AZA), and low-dose steroids | Complement (C3/C4), anti-dsDNA, proteinuria, and fetal growth scans | Preterm birth, FGR, preeclampsia, lupus flare, and miscarriage |
Antiphospholipid Syndrome (APS) | Triple aPL positivity, prior thrombosis, LA positivity, and FGR/stillbirth history | LDA + LMWH; in refractory cases, consider HCQ, low-dose prednisone, and IVIg | Fetal Doppler/echocardiography, aPL profile, and placental function | Stillbirth, preterm birth, FGR, thrombosis, and placental failure |
Sjögren’s Syndrome (SS) | Anti-Ro/SSA and/or anti-La/SSB positivity, aPL positivity, and CHB history | HCQ (especially in Ro+) and corticosteroids only if indicated | Weekly fetal echocardiography (16–28 weeks) and maternal anti-Ro/La titers | CHB, miscarriage, preterm birth, SGA, and neonatal lupus |
Systemic Sclerosis (SSc) | Pulmonary arterial hypertension, renal crisis history, ILD, and diffuse cutaneous disease | Nifedipine (Raynaud’s), HCQ, AZA, and LDA; avoid teratogenic agents | Cardiopulmonary evaluation, renal function, fetal growth, and BP | Preterm birth, miscarriage, low birthweight, and maternal complications |
Rheumatoid Arthritis (RA) | Active disease at conception, high CRP, and chronic corticosteroid use | HCQ, sulfasalazine, AZA, and selected TNF inhibitors (certolizumab and etanercept) | Disease activity score, BP, fetal growth, and drug exposure timing | Preterm birth, miscarriage, FGR, congenital anomalies, and cesarean delivery |
Medication | Typical Dosage During Pregnancy | Main Indications | Pregnancy Safety | Key Side Effects |
---|---|---|---|---|
Hydroxychloroquine (HCQ) | 200–400 mg/day (≤6.5 mg/kg/day) | SLE, APS (adjunct), Sjögren’s syndrome, and RA | Safe in all trimesters | Retinopathy (rare) and gastrointestinal upset |
Azathioprine (AZA) | ≤2 mg/kg/day | SLE, RA, and other autoimmune connective tissue diseases | Safe if ≤2 mg/kg/day | Bone marrow suppression and hepatotoxicity |
Low-Dose Aspirin (LDA) | 75–150 mg/day | Prevention of preeclampsia; APS | Safe | Gastrointestinal bleeding and hypersensitivity |
Low-Molecular-Weight Heparin (LMWH) | Prophylactic: 40 mg/day SC; Therapeutic: 1 mg/kg SC every 12 h | APS and prevention of venous thromboembolism (VTE) | Safe (does not cross placenta) | Injection-site hematoma and thrombocytopenia |
Prednisone/Prednisolone | ≤10–20 mg/day (short courses up to 1 mg/kg/day) | SLE flares, RA, and exacerbations of connective tissue diseases | Safe (preferably <20 mg/day) | Gestational diabetes, hypertension, and risk of preterm birth |
Tacrolimus | 0.05–0.1 mg/kg/day (adjusted to trough levels) | Refractory SLE, lupus nephritis (LN), and RA | Considered as safe | Nephrotoxicity, hypertension, and hyperglycemia |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Giannakaki, A.-G.; Giannakaki, M.-N.; Bothou, A.; Nikolettos, K.; Machairiotis, N.; Pappa, K.I.; Tsikouras, P. Current Approaches to the Management of Rheumatic Diseases in Pregnancy: Risk Stratification, Therapeutic Advances, and Maternal–Fetal Outcomes. J. Pers. Med. 2025, 15, 406. https://doi.org/10.3390/jpm15090406
Giannakaki A-G, Giannakaki M-N, Bothou A, Nikolettos K, Machairiotis N, Pappa KI, Tsikouras P. Current Approaches to the Management of Rheumatic Diseases in Pregnancy: Risk Stratification, Therapeutic Advances, and Maternal–Fetal Outcomes. Journal of Personalized Medicine. 2025; 15(9):406. https://doi.org/10.3390/jpm15090406
Chicago/Turabian StyleGiannakaki, Aikaterini-Gavriela, Maria-Nektaria Giannakaki, Anastasia Bothou, Konstantinos Nikolettos, Nikolaos Machairiotis, Kalliopi I. Pappa, and Panagiotis Tsikouras. 2025. "Current Approaches to the Management of Rheumatic Diseases in Pregnancy: Risk Stratification, Therapeutic Advances, and Maternal–Fetal Outcomes" Journal of Personalized Medicine 15, no. 9: 406. https://doi.org/10.3390/jpm15090406
APA StyleGiannakaki, A.-G., Giannakaki, M.-N., Bothou, A., Nikolettos, K., Machairiotis, N., Pappa, K. I., & Tsikouras, P. (2025). Current Approaches to the Management of Rheumatic Diseases in Pregnancy: Risk Stratification, Therapeutic Advances, and Maternal–Fetal Outcomes. Journal of Personalized Medicine, 15(9), 406. https://doi.org/10.3390/jpm15090406