SSc is a rare disease and pregnancy after disease onset used to be anecdotal until recent years. To our knowledge this is the first study reporting that SSc patients have a higher risk of adverse pregnancy outcomes (a composite endpoint including fetal losses, IUGR, SGA newborns, preeclampsia, preterm births and neonatal deaths) when compared to SLE patients and HC, while having a considerable risk, even though not significantly higher, in comparison to APS. Therefore, a strict monitoring along with a multidisciplinary management for these patients are warranted, and these pregnancies should be considered as high-risk ones.
A recent systematic review and metanalysis  including articles published between 1950 and 2018, reported an increased rate of miscarriages, IUGR, preterm births, newborns with low birth weight, gestational hypertension, and caesarean delivery. Our results confirm most of these findings. In fact, in our series, we found an increased risk of first trimester miscarriages, IUGR, SGA newborns, preeclampsia, and preterm births.
For instance, miscarriages were more frequent in our SSc population in comparison to healthy controls. The association between SSc and miscarriages confirm the results of the metanalisis by Blagojevic et al. . However, four of the 5 miscarriages detected in our population occurred in 2 patients and the possibility of other factors influencing the outcome cannot be excluded. Moreover, it must be considered that there were no miscarriages in our HC group.
IUGR and SGA newborns rates were significantly higher in SSc patients in comparison to HC. Chakravarty et al. and Taraborelli et al [12, 18] also found a higher frequency of IUGR in their cohorts. A possible explanation for this phenomenon may be found in placental vasculopathy, as shown by pathological findings of placenta from SSc patients, which included decidual vasculopathy with stromal fibrosis, placental mesenchymal villous dysplasia, infarcts, and reduction of uteroplacental perfusion .
The frequency of preeclampsia was higher in our SSc population compared to healthy controls, as found by several authors [12, 16]. However, three among 4 cases of preeclampsia were documented in twin pregnancies. Therefore, this association might be incidental and further data are needed.
Preterm delivery rate was high in SSc patients, being superior to HC and SLE patients. Prematurity was more frequent in diffuse SSc than other subset, as found by other authors [14, 26]. In the Italian IMPRESS study (Italian Multicentric Study on Pregnancy in Systemic Sclerosis), the authors found that patients who experienced preterm deliveries had a higher rate of IUGR and corticosteroids use, while folic acid intake and anti-topoisomerase antibodies were protective . These results were not confirmed in our cohort, even though the frequency of IUGR and corticosteroids intake was higher in SSc patients in comparison to HC. This might be due to lack of power because of our relatively small sample. Finally, the protective effect of anti-topoisomerase antibodies was not confirmed.
In concordance with most recent literature [18, 26], the disease remained stable, and no increased activity, clinical worsening or scleroderma renal crisis have been registered during the whole pregnancy and up to one year after delivery. The fact that our population did not include patients with disease duration less than 4 years might have favoured this outcome. Conversely, no improvement in several disease manifestations, such as Raynaud phenomenon or digital ulcers, has been registered. However, all our SSc patient have been for quite long time in a stable phase of the disease when they got pregnant, therefore no improvement was expected.
A main strength of our study is the fact that all pregnancies were prospectively followed in our autoimmune-obstetric clinic, so data about pregnancy course were directly collected and not assessed via questionnaires as in several previous studies, or, as in one case, through an administrative database . Moreover, most patients fulfilled the SSc ACR/EULAR criteria guaranteeing uniformity of our population . The control groups were followed prospectively as well, which makes a main difference compared to all former studies. For instance, the reported prevalence of each obstetric manifestation in all the study groups (including healthy controls) was real and not drawn from literature. Furthermore, comparing SSc pregnancies to other autoimmune diseases implicated in pregnancy morbidity, such as SLE and APS, has provided novel information, as the increased rate of APO in SSc patients compared to SLE and the higher frequency of preterm delivery in SSc compared to SLE patients.
Our study also has several limitations: first, its retrospective design. Second, the small sample due to its unicentric design, which makes possible that a type II error occurred when analysing the association with the various outcomes. Moreover, the fact that not all patients were tested for the whole spectrum of SSc specific antibodies, may limit the range of our results. Finally, we could not assess the presence of chromosomal abnormalities in patients who suffered from early miscarriages. Therefore, even though we found a higher frequency of miscarriages in SSc compared to HC, this aspect needs to be further investigated.