Faculty Bibliography

This prospective, multi-center study investigated the utility of pre-conditioning test pharmacokinetics (PK) of intravenous busulfan (IV Bu) to optimize dosing in 204 subjects with Hodgkin (n=64) and B-cell non-Hodgkin lymphoma (n=140) at 32 centers in the US and Canada. PK studies were conducted twice during the study: test PK on Day -14 to -11 and confirmatory PK on the first day of conditioning, Day -8. The test PK used a 2-hour infusion of a single IV Bu dose (0.8 mg/kg) in order to determine the area under the concentration-time curve (AUC). The test PK dosing was based on adjusted ideal body weight (AIBW) for all patients except for the subjects whose actual BWwas less than or equal to the ideal BW, where actual BW was used. AIBW was calculated by adding 25% of the difference between ideal BW and actual BW to ideal BW. The conditioning dose of daily IV Bu was then calculated to achieve 20,000 mM*min as a total AUC. The same individualized Bu dose was administered over 3 hours once daily from Day -8 to Day -5. If needed, dose was further adjusted on Days -6 and -5 based on confirmatory PK results. VP-16 (1.4 g/m²) was administered on Day -4, followed by 2.5 g/m²/day of cyclophosphamide on Days -3 and -2. Test PK from 204 subjects showed that 6 subjects (2.9%) had higher AUC than expected (>1,500 mM*min) and 68 subjects (33.3%) had lower AUC (<1,000 mM*min). Therefore, total AUC would have fallen outside the target range in 74 subjects (36.3%) if PK-directed dose adjustment had not been performed. The discrepancy between expected and observed exposure was not predicted by subject height, actual body weight, body mass index (BMI) or body surface area. For example, although a greater proportion of patients with high BMI were underexposed compared with those with normal BMI, the difference was not significant [Table 1]. In addition, all patients who had AUC>1,500 mM*min had normal or high BMI. Thus, it is not possible to prospectively identify the subpopulation which has a risk of suboptimal Bu exposure and would gain the most benefit from PK-directed dose optimization. Hence,PK-directed dose optimization should be considered for all subjects when tight regulation of Bu exposure is critical, and should not be limited to subpopulations. Out of 200 patients whose confirmatory PK results were evaluable, 190 subjects (95.0%) fell within the target range (AUC: 20,000 mM*min +/- 20%). Eight (4.0%) and two (1.0%) patients required dose reductions and increases, respectively, for the last two days of Bu dosing. Again, no predictive factor was identified for these patients. In conclusion, a pre-conditioning small dose of IV Bu estimated individual PK parameters and predicted Day-8 PK in 95% of the subjects. This relatively large PK study identified no factor that could predict outliers linked to Bu metabolism. Therefore, when Bu exposure has to be tightly controlled, PK-directed dose optimization should be conducted for all patients. (Table Presented)

OBJECTIVES: The purpose of this study was to evaluate the gestational age at sonographic detection of placenta previa as a predictor of previa persistence until delivery in twin gestations. METHODS: A retrospective cohort of twin pregnancies with placenta previa in a single ultrasound unit was analyzed from 2005 to 2010. Pregnancies were ascertained from a database. Diagnoses were confirmed by transvaginal imaging. Previa was categorized as complete if the placenta completely covered the internal os or marginal if the inferior placental edge reached within 2 cm. Gestational ages were grouped into intervals from 15 to 35 weeks. The study outcome was placenta previa at delivery. Only twin pregnancies at 25 weeks' gestation and later were analyzed using nonparametric statistics as appropriate, with P < .05 as significant. RESULTS: Placenta previa was detected in 120 twin pregnancies in the second trimester: 32 complete and 88 marginal. Of those with placenta previa at 15 to 19, 20 to 23, 24 to 27, 28 to 31, and 32 to 35 weeks, previa persisted until delivery in 8.3%, 19.2%, 50%, 75%, and 92.5%, respectively. Only at 15- to 19- and 20- to 23-week intervals was complete previa more likely to persist than marginal previa (P < .001). CONCLUSIONS: The likelihood of placenta previa persistence in twins is dependent on the gestational age at sonographic detection. Only at earlier gestations does the type of previa affect its persistence. As gestational age advances, the likelihood of resolution of placenta previa diminishes regardless of the type noted.

To estimate the risk of preterm birth in asymptomatic women with twin pregnancies with a normal cervical length (CL) and a positive fetal fibronectin (fFN), we reviewed a retrospective cohort of twin pregnancies delivered in our practice from 2005 to 2010. Patients were screened from 22 to 32 weeks with CL and fFN at 2- to 4-week intervals. We examined 244 patients with twin pregnancies and a normal CL (>25 mm) between 22 and 32 weeks and compared outcomes based on the fFN result. Fourteen (5.7%) patients had a positive fFN and 230 (94.3%) patients had a negative fFN. Positive fFN was associated with an increased the risk of spontaneous preterm birth < 37 weeks (85.7% versus 38.3%, p = 0.001), < 35 weeks (50% versus 11.8%, p < 0.001), < 34 weeks (35.7% versus 6.9%, p < 0.001), and < 32 weeks (21.4% versus 2.2%, p < 0.001). On adjusted analysis, a positive fFN was independently associated with preterm birth < 32 weeks (odds ratio 6.8, 95% confidence interval 1.42, 32.2) and gestational age at delivery (p = 0.001). In the setting of a normal CL, a positive fFN is significantly associated with preterm birth in asymptomatic twin pregnancies. Contingency model screening of fFN in asymptomatic twin pregnancies solely based on CL evaluation may fail to identify a cohort of at-risk patients.

OBJECTIVE: To examine the effect of obesity on maternal and neonatal outcomes in women diagnosed with gestational diabetes mellitus (GDM) and managed with diet only, glyburide, or insulin. STUDY DESIGN: Women with singleton gestations enrolled for outpatient services diagnosed with GDM and without history of pregnancy-related hypertension at enrollment or in a prior pregnancy were identified in a database. Women with GDM controlled by diet only (n = 3918), glyburide (n = 873), or insulin without prior exposure to oral hypoglycemic agents (n = 2229) were included. Pregnancy outcomes were compared for obese versus nonobese women within each treatment group and also compared across treatment groups within the obese and nonobese populations. RESULTS: Within each treatment group, obesity was associated with higher rates of cesarean delivery, pregnancy-related hypertension, macrosomia, and hyperbilirubinemia (all p < 0.05). Higher rates of pregnancy-related hypertension and hyperbilirubinemia were observed in women receiving glyburide. CONCLUSION: Obesity adversely affects pregnancy outcome in women with GDM. Higher rates of pregnancy-related hypertension and hyperbilirubinemia were observed in pregnant women receiving glyburide.