Not all patients fulfil criteria for specific autoimmune rheumatic diseases (ARDs) and are then defined as having non-criteria (nc)ARD. It is uncertain whether well-recognised associations with adverse pregnancy outcomes in patients with criteria ARD also exist in patients with ncARD or undifferentiated connective tissue disease (UCTD). Therefore, we undertook a systematic review of the prevalence of adverse pregnancy outcomes in various ncARD and UCTD compared with criteria ARD to identify whether there are increased risks and to examine for any benefits of treatment.
Methods
This study was conducted in accordance with the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard. A systematic literature review was performed using online databases including Medline and PubMed from inception to the beginning of April 2021 using appropriate keywords for various ARD and pregnancy outcomes.
Results
After screening 665 articles, 36 articles were chosen for full text review and 15 selected for final analysis. There were eight studies of nc antiphospholipid syndrome (APS) of more than 7000 pregnancies and seven studies of UCTD of more than 1000 pregnancies. No studies of any other ncARD in pregnancy were identified. We found that patients with either ncAPS or UCTD seem to have an increased burden of poor pregnancy outcomes compared with the general population. Despite the heterogeneity and poor quality of the studies, we also noted that ncAPS and criteria APS patients may have similar rates of obstetric complications with standard and/or non-standard APS treatment regimens.
Conclusion
Our findings of increased risks of poor pregnancy outcomes in patients with ncAPS or UCTD will be helpful for pre-pregnancy counselling and management of these patients in pregnancy and support their referral to specialist obstetric-rheumatology and obstetric-haematology clinics.
JacobsonDLGangeSJRoseNR, et al.Epidemiology and Estimated Population Burden of Selected Autoimmune Diseases in the United States. Clin Immunol Immunopathol1997; 84: 223–243.
2.
CooperGSBynumMLSomersEC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun2009; 33: 197–207.
3.
SomersECThomasSLSmeethL, et al.Incidence of systemic lupus erythematosus in the United Kingdom, 1990-1999. Arthritis Rheum2007; 57: 612–618.
4.
SugawaraEKatoMFujiedaY, et al.Pregnancy outcomes in women with rheumatic diseases: a real-world observational study in Japan. Lupus2019; 28: 1407–1416.
5.
NalliCIodiceAAndreoliL, et al.The effects of lupus and antiphospholipid antibody syndrome on foetal outcomes. Lupus2014; 23: 507–517.
6.
Yan YuenSKrizovaAOuimetJM, et al.Pregnancy outcome in systemic lupus erythematosus (SLE) is improving: results from a case control study and literature review. Open Rheumatol J2008; 2: 89e98.
7.
BramhamKHuntBJBewleyS, et al.Pregnancy outcomes in systemic lupus erythematosus with and without previous nephritis. J Rheumatol2011; 38: 1906–1913.
8.
MiyakisSLockshinMDAtsumiT, et al.International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost2006; 4: 295–306.
9.
HochbergMC. Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725.
10.
PetriMOrbaiAMAlarcónGS, et al.Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum2012; 64: 2677–2686.
11.
Alijotas-ReigJEsteve-ValverdeEFerrer-OliverasR, et al.Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS, (NC-OAPS): report of 1640 cases from the EUROAPS registry. Rheumatology (Oxford)2020; 59: 1306–1314.
12.
ArachchillageDRMachinSJMackieIJ, et al.Diagnosis and management of non-criteria obstetric antiphospholipid syndrome. Thromb Haemost2015; 113: 13–19.
13.
JaraLJMedinaGCruz-CruzP, et al.Non-Criteria or Seronegative Obstetric Antiphospholipid Syndrome?Isr Med Assoc J2017; 19: 382–386.
14.
MoscaMNeriRBombardieriS. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol1999; 17: 615–620.
15.
MoscaMNeriRStriginiF, et al.Pregnancy outcome in patients with undifferentiated connective tissue disease: a preliminary study on 25 pregnancies. Lupus2002; 11: 304–307.
16.
LiberatiAAltmanDGTetzlaffJ, et al.The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ2009; 339: b2700.
17.
GravaCRuffattiAMilanesiO, et al.Isolated congenital heart block in undifferentiated connective tissue disease and in primary Sjogren's syndrome: a clinical study of 81 pregnancies in 41 patients. Reumatismo2005; 57: 180–186.
18.
GuyattGHOxmanADVistGE, et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ2008; 336: 924–926.
19.
FrediMAndreoliLAggogeriE, et al.Risk Factors for adverse maternal and fetal outcomes in women with confirmed aPL positivity: results from a multicenter study of 283 pregnancies. Front Immunol2018; 9: 864.
20.
MekinianALoire-BersonPNicaise-RolandP, et al.Outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels. J Reprod Immunol2012; 94: 222–226.
21.
Ofer-ShiberSMoladY. Frequency of vascular and pregnancy morbidity in patients with low vs. moderate-to-high titers of antiphospholipid antibodies. Blood Coagul Fibrinolysis2015; 26: 261–266.
22.
Sugiura-OgasawaraMOzakiYNakanishiT, et al.Occasional antiphospholipid antibody positive patients with recurrent pregnancy loss also merit aspirin therapy: a retrospective cohort-control study. Am J Reprod Immunol2008; 59: 235–241.
23.
LoHWChenCJTsaiEM. Pregnancy outcomes for women with non-criteria antiphospholipid syndrome after anticoagulant therapy. Eur J Obstet Gynecol Reprod Biol2020; 244: 205–207.
24.
SpinilloABellingeriCDe MaggioI, et al.The impact of various entities of antiphospholipid antibodies positivity on adverse pregnancy outcome. An epidemiological perspective. J Reprod Immunol2021; 145: 103304.
25.
XiFCaiYLvM, et al.Anticardiolipin Positivity Is Highly Associated With Intrauterine Growth Restriction in Women With Antiphospholipid Syndrome. Clin Appl Thromb Hemost2020; 26: 1076029620974455.
26.
BlencoweHCousensSJassirFB, et al.National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis. Lancet Glob Health2016; 4: e98–e108.
27.
KramerMS. The epidemiology of adverse pregnancy outcomes: an overview. J Nutr2003; 133: 1592S–1596S.
28.
HutcheonJLisonkovaKJosephK. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol2011; 25: 391–403.
29.
SpinilloABeneventiFLocatelliE, et al.The impact of unrecognized autoimmune rheumatic diseases on the incidence of preeclampsia and fetal growth restriction: a longitudinal cohort study. BMC Pregnancy Childbirth2016; 16(1): 313.
30.
ZucchiDTaniCMonacciF, et al.Pregnancy and undifferentiated connective tissue disease: outcome and risk of flare in 100 pregnancies. Rheumatology (Oxford)2020; 59: 1335–1339.
31.
SpinilloABeneventiFEpisOM, et al.The effect of newly diagnosed undifferentiated connective tissue disease on pregnancy outcome. Am J Obstet Gynecol2008; 199: 632.
32.
RadinMSchreiberKCecchiI, et al.A multicentre study of 244 pregnancies in undifferentiated connective tissue disease: maternal/fetal outcomes and disease evolution. Rheumatology (Oxford)2020; 59: 2412–2418.
33.
BrucatoAFrassiMFranceschiniF, et al.Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected bycounterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum2001; 44: 1832–1835.
34.
LockshinMDBonfaEElkomK, et al.Neonatal lupus risk to newborns of mothers with systemic lupus erythematosus. Arthritis Rheum1998; 31: 697–701.
35.
TektonidouMGAndreoliLLimperM, et al.Management of thrombotic and obstetric antiphospholipid syndrome: a systematic literature review informing the EULAR recommendations for the management of antiphospholipid syndrome in adults. RMD Open2019; 5: e000924.
36.
ContiFAndreoliLCrisafulliF, et al.Does seronegative obstetric APS exist? “pro” and “cons”. Autoimmun Rev2019; 18: 102407.
37.
BujoldERobergeSLacasseY, et al.Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol2010 Aug; 116(2 Pt 1): 402–414.
38.
LlurbaEBellaMBurgosJ, et al.Early prophylactic enoxaparin for the prevention of preeclampsia and intrauterine growth restriction: a randomized trial. Fetal Diagn Ther2020; 47(11): 824–833.
39.
ContiFCapozziATrugliaS, et al.The mosaic of "seronegative" antiphospholipid syndrome. J Immunol Res2014; 2014: 389601.
40.
PignatelliPEttorreEMenichelliD, et al.Seronegative syndrome, antiphospholipid syndrome: Refining the value of “non-criteria” antibodies for diagnosis and clinical management. Haematol2020; 105: 562–572.
JørgensenKTNielsenNMPedersenBV, et al.Hyperemesis, gestational hypertensive disorders, pregnancy losses and risk of autoimmune diseases in a Danish population-based cohort. J Autoimmun2012; 38: J120–8.
43.
ArkemaEVPalmstenKSjowallC, et al.What to expect when expecting with systemic lupus erythematosus (sle): a population-based study of maternal and fetal outcomes in SLE and pre-SLE. Arthritis Care Res (Hoboken)2016; 68: 988–994.
44.
OstensenMAndreoliLBrucatoA, et al.State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun Rev2015; 14: 376–386.
45.
OstensenMCetinI. Autoimmune connective tissue disease. Best Pract Res Clin Obstet Gynaecol2015; 29: 658–670.
46.
AbrahamsVMChamleyLWSalmonJE. Emerging treatment models in rheumatology: antiphospholipid syndrome and pregnancy: pathogenesis to translation. Arthritis Rheumatol2017; 69: 1710–1721.
47.
NakkenBBodolayESzodorayP. Cytokine milieu in undifferentiated connective tissue disease: a comprehensive review. Clin Rev Allergy Immunol2015; 49: 152–162.
