Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association?

Abstract

Undifferentiated connective tissue diseases (UCTDs) are a heterogeneous group of disorders characterized by symptoms and signs suggestive of systemic autoimmune rheumatic disease (ARD), but which do not fulfill all the established criteria for definite diagnosis of a condition. Although a third of UCTDs can progress to a definite ARD within months or years, most UCTDs can remain stable for years with minimal disease activity. The annual incidence of UCTD in the general population ranges from 14 to 140 per 100 000 people. UCTDs are associated with the persistence of several circulating autoantibodies including antinuclear, antiphospholipid or antithyroid antibodies. Immunological evaluation of subjects with UCTDs suggests a proinflammatory state and dysregulation of the Th1/Th2 balance. Autoantibodies have well-known deleterious effects on placentation and have been associated with an increased risk of prematurity, fetal growth restriction (FGR), preeclampsia, and congenital atrioventricular heart block. Although epidemiological and biological data suggest a potential negative impact on reproductive outcomes, the relationship between UCTD and pregnancy outcomes has not been adequately studied. While awaiting definitive data from large studies, obstetricians should be aware that rheumatic disorders in their early, incomplete, or undifferentiated phases can adversely affect pregnancy outcomes, increasing the likelihood of pregnancy loss, FGR, preeclampsia, and prematurity.

Preeclampsia: a gestational cardiorenal syndrome

“…), obesity and metabolic syndrome (Whaley‐Connell & Sowers, ), connective tissue disorders (Spinillo et al . ) or systemic diseases such as lupus erythematodes and antiphospholipid syndrome (Fischer‐Betz & Specker, ), sarcoidosis (Hadid et al . ), amyloidosis (Mordel et al .…”

“…Clinical risk factors predisposing to the development of cardiorenal syndromes and preeclampsia are shared: pre-existing renal (Vellanki, 2013;Piccoli et al 2018) (Gallos et al 2013), obesity and metabolic syndrome (Whaley-Connell & Sowers, 2014), connective tissue disorders (Spinillo et al 2017) or systemic diseases such as lupus erythematodes and antiphospholipid syndrome (Fischer-Betz & Specker, 2017), sarcoidosis (Hadid et al 2015), amyloidosis (Mordel et al 1993), thrombotic thrombocytopenic purpura (Vesely, 2015), and sickle cell anaemia (Bartsch et al 2016).…”

A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine and low-dose prednisone to treat recurrent pregnancy loss in women with undifferentiated connective tissue diseases: Protocol for the immunosuppressant regimens for Living FEtuses (ILIFE) Trial

“…UCTD is the most common rheumatic disease diagnosed during the rst trimester of pregnancy and plays a potential causal role of autoimmune disorders in the occurrence of pregnancy complications [7]. Antinuclear antibodies and in ammation in UCTD may impair platelet activity, unbalance coagulation/anticoagulation, increase the risk of thrombosis, cause collagen synthesis defect and endothelial dysfunction [8][9][10]. Therefore, it could increase uterine artery resistance, inhibit placenta development and remodelling, and thus increase the risk of pre-eclampsia, intrauterine growth retardation (IUGR), small for gestational age infant (SGA) and recurrent spontaneous abortion (RSA) [3,[11][12][13][14].…”

A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine and low-dose prednisone on recurrent spontaneous abortion with undifferentiated connective tissue diseases: Protocol for the immunosuppressant regimens for Living FEtuses (ILIFE) Trial

“…UCTD is the most common rheumatic disease diagnosed during the first trimester of pregnancy and plays a potential causal role of autoimmune disorders in the occurrence of pregnancy complications [7]. Antinuclear antibodies and inflammation in UCTD may impair platelet activity, unbalance coagulation/anticoagulation, increase the risk of thrombosis, cause collagen synthesis defect and endothelial dysfunction [8][9][10]. Therefore, it could increase uterine artery resistance, inhibit placenta development and remodelling, and thus increase the risk of pre-eclampsia, intrauterine growth retardation (IUGR), small for gestational age infant (SGA) and recurrent spontaneous abortion (RSA) [4,[11][12][13][14].…”