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Obstetric APS and cancer
Group.5 However, since no control group was simultane- ously evaluated, the risk of cancer in patients with APS is still uncertain.
The Nîmes Obstetricians and Hematologists APS (NOH- APS) study6 was based on the recruitment of a cohort of women with no history of thrombosis, who had experi- enced pregnancy loss fulfilling the clinical criteria of obstet- ric APS, who were either positive for aPL antibodies (APS group), or positive for the F5 rs6025 or F2 rs1799963 poly- morphism (Thrombophilia group), or negative for throm- bophilia screening (Control group). This provided us with the opportunity to prospectively assess the comparative incidence of cancer in women who had been diagnosied with obstetric APS. This evaluation was carried out during the 2017 medical follow-up step, corresponding to a medi- an follow-up of 17 years. We used an external, local popu- lation-derived control group, the registry of tumors in Montpellier area (Registre des Tumeurs de l’Hérault7), to com- pute standardized incidence ratios.
Methods
Study design and patients
The NOH-APS study is a referral university hospital-based, lon- gitudinal cohort study which was initiated in 1995, with an inclu- sion period lasting 10 years. The recruitment is presented in Figure 1 and has been described in detail elsewhere.6,7-10 Patients were clas- sified as having had primary pregnancy loss (no previous success- ful pregnancy) or secondary pregnancy loss. The results of throm- bophilia screening generated (i) an APS group of 517 women with only canonical aPL antibodies: LA, aCL IgM antibodies (aCL-M), aCL IgG antibodies (aCL-G), anti-β2GP1 (aβ2GP1) IgM antibodies (aβ2GP1-M) or aβ2GP1 IgG antibodies (aβ2GP1-G)6; (ii) a Thrombophilia group of 279 women with isolated F5 rs6025 or F2 rs1799963 polymorphism; and (iii) a Control group of 796 women.
The patients have undergone clinical re-evaluation annually in our outpatient department. The loss of patients to follow-up (n=23: 1.44%) was minimized by directly contacting the general practitioners and the patients themselves. Symptoms were evalu- ated and the treatments taken during the year were recorded.
The management of the women included has already been detailed.6-10 APS patients received chronic primary thrombopro- phylaxis, i.e. low-dose aspirin (100 mg/day).
The study protocol and consent forms were approved by the Institutional Review Board of the University Hospital of Nîmes and the appropriate ethics committee (the local Comité de Protection des Personnes Participant à la Recherche Biomédicale). This clinical investigation was performed in accordance with the Helsinki Declaration, as formulated in 1975 and revised in 1996. All the women gave informed consent to participation. The study was declared to the Commission Nationale de l’Informatique et des Libertés (CNIL) under the number 2150873 v 0.
Outcome data
The incidence of a cancer diagnosis was the primary outcome. After questioning the patients and having performed their clinical examination, clinical details were obtained from the women’s medical charts and details were verified with the medical, surgical and oncological teams involved in the diagnosis and treatment of the various incident cancers, both in our University Hospital and, for a minority, in the external relevant medical institutions that had assumed care.
Details of the statistical analysis can be found in the Online Supplementary Material.
Results
The analyses included 1,592 women with no initial histo- ry of thrombosis but a history of unexplained pregnancy loss (recurrent abortions or fetal death), categorized accord- ing to the results of thrombophilia screening, who collec- tively contributed data for a total of 26,588 person-years.
The characteristics of the patients at baseline and at fol- low-up evaluation are presented in Table 1. Women in the Control group initially had an obstetric history including more recurrent abortions, women in the APS group more often had an inflammatory disease and women in the Thrombophilia group more often had a family history of venous thromboembolism (VTE) or of atherothrombosis. The mortality rate was higher among women in the APS group: this was true for both global mortality, and also death from non-cancer-related causes (catastrophic APS in 1, pulmonary embolism in 2, stroke in 3, myocardial infarc- tion in 3, viral infection in 4, bacterial infection in 8). Women in the APS group also more often developed an inflammatory non-cancerous disease (systemic lupus ery- thematosus in 47, rheumatoid arthritis in 7, systemic scle- rosis in 4, inflammatory bowel disease in 3, ANCA-associ- ated vasculitis in 2, sarcoidosis in 1). Focusing on the obstet- ric histories after inclusion into the cohort, fewer women in the APS group delivered at least one living neonate, and a higher percentage of them had a stillbirth, experienced a neonatal death, developed a placenta-mediated complica- tion during one of their pregnancies, had to be admitted into an intensive care unit due to pregnancy complications, or delivered a neonate who had to be admitted into a spe- cific intensive care unit. Focusing on vascular events that were diagnosed after inclusion into the cohort, a higher per- centage of women in the APS group had VTE (distal or proximal deep vein thrombosis, pulmonary embolism) despite primary thromboprophylaxis using low-dose aspirin. The rate of superficial vein thrombosis was also higher in this group. Furthermore, these women more often developed arterial thrombotic events (transient ischemic attacks/strokes and myocardial infarction).
A diagnosis of cancer was made in 52 women, the annu- alized rate of cancer being computed as 0.20% [95% confi- dence interval (95% CI): 0.15%-0.26%] in the whole cohort. We observed 29 breast cancers, seven colon cancers, four pancreatic cancers, three non-Hodgkin lymphomas, three thyroid cancers, three endometrial cancers, two pri- mary brain tumors and one lung cancer. Table 2A presents the incidence of cancer in the three groups of women: the risk of a cancer diagnosis was higher in the APS group than in the Control group, whereas it was not statistically differ- ent between the Thrombophilia group and the Control group. The incidence of cancer diagnosis remained signifi- cantly higher in the APS group than in the merged Control and Thrombophilia groups: hazard ratio (HR) 2.07 (95% CI: 1.30-3.57). The comparison between the APS and Thrombophilia groups did not reveal a statistically signifi- cant difference (HR 1.73; 95% CI: 0.78-3.81). The analysis adjusted (aHR) for characteristics of the women at inclusion and during follow-up (Table 2B) showed results similar to those of the unadjusted analysis (APS group: aHR 2.26; 95% CI: 1.20-4.24; P=0.0115). The Kaplan-Meier estimates of cancer-free survival among women are shown in Figure 2: the log-rank test revealed a statistically significantly increased incidence of cancers in women in the APS group.
Among women in the APS group, 64 (12.4%) developed
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