Pre-disease pregnancy complications and systemic sclerosis: pathogenic or pre-clinical?

Akin to many autoimmune diseases with a strong female predominance, relationships between pre-disease pregnancies and subsequent development of systemic sclerosis (SSc) have been the source of a great deal of study, often with conflicting results.Fetal microchimerism - the bidirectional transfer of cells between mother and fetus during gestation and delivery, followed by perpetuation of small amounts of foreign cells or DNA in the host for years or decades, potentially leading to a graft-versus-host-like effect - has been implicated in the pathogenesis of SSc based upon epidemiologic and immunological studies. While the fetal microchimerism theory of SSc carries compelling biologic plausibility given the clinical resemblance of diffuse cutaneous SSc and graft-versus-host disease, as well as the increased presence of fetal cells in women with SSc, purely epidemiologic studies without translational, immunological, or cellular correlates cannot directly support a causal association.The current study by van Wyk and colleagues is an excellent example of a well-performed epidemiologic study identifying a positive association between pregnancy complications (hypertensive disorders of pregnancy (HTN) and intrauterine growth restriction (IUGR)) prior to diagnosis and the future development of SSc [1]. The authors conducted a case-control study of parous women with SSc compared with healthy women. Reproductive history was obtained through questionnaires. The mean age at enrollment was 57 years, approximately 30 years after the first pregnancy for both groups. Results showed a statistically significant increase of HTN as well as IUGR among women who later developed SSc. Notably, the rates of HTN and IUGR among women in this study who were later diagnosed with SSc were not demonstrably different from the rates reported for women with preexisting SSc (22.9% HTN [2] and 5 to 20% IUGR [2,3]).Despite the merits of this study, it remains difficult to interpret the results as directl