Deleterious Consequences of Diamond Blackfan Anemia on Reproductive Health and Pregnancy Outcomes: A Report from the Diamond Blackfan Anemia Registry (DBAR)

Background: Diamond Blackfan anemia (DBA) is a rare, congenital bone marrow failure syndrome characterized by red cell aplasia, birth anomalies, and a predisposition to cancer. Due to a primarily autosomal dominant mode of inheritance, DBA affects males and females at a ratio of 1:1. Treatment consists of corticosteroid administration and chronic red cell transfusion therapy and in some cases hematopoietic stem cell transplantation. Current clinical observations suggest that women with DBA may experience delayed puberty, irregular menstrual cycles, and decreased fertility. Women who do become pregnant may sustain a higher than average risk of pregnancy complications, including miscarriage, placental abruption, and stillbirth, and others of vascular-placental origin (Faivre et al. Haematologica, 2006). Anecdotal reports suggest that DBA women experience changes to treatment response and remission status during periods characterized by hormonal fluctuations; namely, puberty and pregnancy. The etiology of these complications is unclear.

Methods: Questionnaires were sent to females greater than 15 years of age (n=224) participating in the Diamond Blackfan Anemia Registry of North America (DBAR), a comprehensive database of 720 patients who are enrolled after obtaining informed consent. The questionnaires ask about menstrual and gynecologic health and pregnancies, focusing on complications, treatment requirements, and outcomes. We grouped patients by steroid and/or transfusion dependence status and/or remission before age 12 to analyze the effects of treatment on menarche. The patients were regrouped based on the majority of their treatment to evaluate for gynecologic health and pregnancy complications. The Fisher’s exact test was used to examine associations between variables. When compared to the general population, normal values were obtained from a variety of sources including the American Academy of Pediatrics, the National Institutes of Aging and the March of Dimes.

Results and Conclusions: We reviewed results from 84 women aged 15 to 62 years (median age 28.6 years). Menarche was delayed in both steroid dependent and transfusion dependent girls, with 39.5% and 77.8%, respectively experiencing menarche at age 15 or later (vs 2% normal). Transfusion dependent girls were significantly more likely to have delayed menarche compared to the steroid dependent and remission groups (p<.005). Additionally, transfusion dependent females were significantly more likely to experience premature ovarian failure, compared to those who were either steroid dependent or in remission (32.1% vs 8.6%; p<.025). Of those who report entering menopause, 75% stopped by age 40 or younger (vs average, 51 years). Women who are transfusion dependent were more likely to report having taken medication to regulate their menstrual cycle, as compared to steroid dependent and remission groups (48.1% vs 22.9%; p<.06). Of the 50 pregnancies reported in 23 women, 30 resulted in live births (60%). Of the total live births, 43.3% were preterm (vs 11.5% normal). Interestingly, steroid dependent women as well as those in remission had the highest percentage of preterm deliveries at 66.7% and 63.6%, respectively. 26% of the pregnancies resulted in miscarriage, and 4.3% resulted in stillbirth (vs normal, 15% and 0.6%, respectively) and 4.3% of pregnancies were complicated by placental abruption (vs normal, <1%). During pregnancy, 52.2% of women reported requiring transfusions; specifically, 100% of the women who were steroid dependent at conception required transfusions during pregnancy. 7.4% of women in the study had a hysterectomy, half of whom were under age 40. We also noted an increased incidence of endocrinopathies: transfusion dependent women reported a significantly higher prevalence of thyroid disorders compared to the steroid dependent group (42.9% vs 11.1%; p<.03). Additionally, there was a higher prevalence of diabetes in the transfusion group as compared to the steroid dependent group (14.3% vs 0%, p=NS). These findings suggest an important role of iron overload in menstrual abnormalities, reproductive issues and endocrinopathies in DBA women. Pregnancy complications are in excess of those seen in the normal population. Future analyses will determine whether there is a correlation between menstrual abnormalities and/or pregnancy complications and specific DBA genotypes.