Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) was a randomized double-blind placebo-controlled trial to test whether hydroxyurea could reduce the rate of painful crises in adults who had at least 3 painful crises per year. Because hydroxyurea is known to be carcinogenic, mutagenic, and teratogenic in animals, a major inclusion criterion in MSH was the use of contraceptives both by females and males in order to avoid exposure of the fetus to hydroxyurea. Despite this precautionary measure, some women became pregnant while taking hydroxyurea or their male partners were on hydroxyurea. We followed surviving patients who were enrolled in the original MSH trial for up to 17 years postrandomization. Our findings suggest that exposure of the fetus to hydroxyurea does not cause teratogenic changes in those pregnancies that terminate in live birth whether full-term or premature. This seems to be true whether the parent taking hydroxyurea was the mother or the father. The same argument seems to apply for exposure to opioids. However, it will take a much longer follow-up of many more hydroxyurea-exposed sickle cell disease subjects to establish the results conclusively.

Bone mass density in adults with sickle cell disease.

Sickle cell disease (SCD) leads to many complications including osteoporosis and osteopenia. We studied the prevalence and predisposing factors of low bone mass density (BMD) in adults with SCD. In this retrospective study, dual X-ray absorptiometry bone scans were used to determine BMD in the lumbar spine, femoral neck and ultra distal radius of 103 patients (73 females, 30 males, aged 15-80 years). Chart reviews and a patient questionnaire were used to collect patient characteristics, disease course and severity, and low BMD risk factors. The 79.6% of patients (mean age 36.5 +/- 12.5 years) had an abnormal BMD, with a predilection for the lumbar spine (P = 0.001). Analysis by 3 (low BMD versus very low BMD versus normal) or by 2 groups (abnormal versus normal) showed that abnormal BMD was associated with lower body mass index (BMI) (P = 0.003), lower Hb level (P = 0.001) and higher ferritin (P = 0.003). Low BMD patients were more likely to be SS, SC or Sbeta(0)thal than Sbeta(+)thal (P = 0.022). Abnormal BMD was not related to age, sex, menarche, SCD complications, number of crises, iron overload, treatment with hydroxycarbamide or desferal, renal disease, smoking or alcohol. Patients treated with hydroxycarbamide for at least 6 months were more likely to have an abnormal BMD. In this SCD population, abnormal BMD seemed to be independent of sex, age and menopause, whereas BMI, ferritin level, Hb type and level appeared to play a major role.

A model for automated screening of thalassemia in hematology (math study).

BACKGROUND: beta-thalassemia screening is primarily limited to pregnant women. The ratio of the mean corpuscular volume (MCV) and red blood cell count (RBC) can be automatically calculated with any of the newer hematology analyzers. METHODS: The results of 398 patient screens were collected. Data from the set were divided into training and validation subsets. The Mentzer ratio was determined through a receiver operating characteristic (ROC) curve on the first subset, and screened for thalassemia using the second subset. HgbA2 levels were used to confirm beta-thalassemia. RESULTS: We determined the correct decision point of the Mentzer index to be a ratio of 20. Physicians can screen patients using this index before further evaluation for beta-thalassemia (P < .05). CONCLUSION: The proposed method can be implemented by hospitals and laboratories to flag positive matches for further definitive evaluation, and will enable beta-thalassemia screening of a much larger population at little to no additional cost.

Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease.

Iron-overload associated endocrinopathy is the most frequently reported complication of chronic transfusion therapy in patients with thalassaemia (Thal). This study compared iron-overloaded subjects with Thal (n = 142; 54%M; age 25.8 +/- 8.1 years) and transfused sickle-cell disease (Tx-SCD; n = 199; 43%M, 24.9 +/- 13.2 years) to non-transfused SCD subjects (non-Tx-SCD; n = 64, 50%M, 25.3 +/- 11.3 years), to explore whether the underlying haemoglobinopathy influences the development of endocrinopathy. Subjects were recruited from 31 centres in the USA, Canada and the UK. Subjects with Thal had more evidence of diabetes (13% vs. 2%, P < 0.001), hypogonadism (40% vs. 4%, P < 0.001), hypothyroidism (10% vs. 2%, P = <0.001) and growth failure (33% vs. 7%, P < 0.001), versus Tx-SCD. Fifty-six per cent of Thal had more than one endocrinopathy compared with only 13% of Tx-SCD (P < 0.001). In contrast, Tx-SCD was not different from non-Tx-SCD. Multivariate analysis indicated that endocrinopathy was more likely in Thal than SCD [Odds Ratio (OR) = 9.4, P < 0.001], with duration of chronic transfusion a significant predictor (OR = 1.4 per 10 years of transfusion, P = 0.04). Despite iron overload, endocrinopathy was not increased in Tx-SCD versus non-Tx-SCD, suggesting that the underlying disease may modulate iron-related endocrine injury. However, because transfusion duration remained a significant predictor of endocrinopathy, these data should be confirmed in SCD subjects that have been chronically transfused for longer periods of time.

Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.

CONTEXT: Hydroxyurea increases levels of fetal hemoglobin (HbF) and decreases morbidity from vaso-occlusive complications in patients with sickle cell anemia (SCA). High HbF levels reduce morbidity and mortality. OBJECTIVE: To determine whether hydroxyurea attenuates mortality in patients with SCA. DESIGN: Long-term observational follow-up study of mortality in patients with SCA who originally participated in the randomized, double-blind, placebo-controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), conducted in 1992-1995, to determine if hydroxyurea reduces vaso-occlusive events. In the MSH Patients' Follow-up, conducted in 1996-2001, patients could continue, stop, or start hydroxyurea. Data were collected during the trial and in the follow-up period. SETTING: Inpatients and outpatients in 21 sickle cell referral centers in the United States and Canada. PATIENTS: Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up. Follow-up data through May 2001 were complete for 233 patients. INTERVENTION: In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147). MAIN OUTCOME MEASURE: Mortality, HbF levels, painful episodes, acute chest syndrome, and blood cell counts. The randomized trial was not designed to detect specified differences in mortality. RESULTS: Seventy-five of the original 299 patients died, 28% from pulmonary disease. Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality (P =.002). Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15% when HbF levels were 0.5 g/dL or higher (P =.03 ). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P =.02). Patients with 3 or more painful episodes per year during the trial had 27% mortality compared with 17% of patients with less frequent episodes (P =.06). Taking hydroxyurea was associated with a 40% reduction in mortality (P =.04) in this observational follow-up with self-selected treatment. There were 3 cases of cancer, 1 fatal. CONCLUSIONS: Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events. Whether indications for hydroxyurea treatment should be expanded is unknown.