Faculty Bibliography

OBJECTIVE: To estimate the effectiveness of antepartum surveillance and delivery at 41 weeks in reducing the risk of stillbirth in advanced maternal age (AMA) patients. STUDY DESIGN: Retrospective cohort study of all patients managed in one maternal-fetal medicine practice from June 2005 to May 2012. We included all singleton pregnancies delivered at >/=20 weeks of gestation. All AMA patients (age >/=35 years at their estimated delivery date) underwent weekly biophysical profile testing beginning at 36 weeks, as well as planned delivery at 41 weeks, or sooner if indicated. We compared the rate of fetal death at >/=20 weeks and fetal death at >/=36 weeks in AMA vs. non-AMA patients. Fetal deaths due to lethal and chromosomal abnormalities were excluded. RESULTS: 4469 patients met the inclusion criteria: 1541 (34.5%) were AMA and 2928 (65.5%) were non-AMA. Using our AMA protocol for surveillance and timing of delivery, the incidence of stillbirth was similar to the non-AMA population (stillbirth >/=20 weeks: 3.9 per 1000 vs. 3.4 per 1000, p=0.799; stillbirth >/=36 weeks: 1.4 per 1000 vs. 1.1 per 1000, p=0.773). When looking at women age <35, age 35-39, and age >/=40, the incidence of stillbirth >/=20 weeks and >/=36 weeks did not increase across the three groups. Our findings were similar when we excluded all patients with other indications for antepartum surveillance. CONCLUSIONS: In AMA patients, antepartum surveillance and delivery at 41 weeks appears to reduce the risk of stillbirth to that of the non-AMA population. Routine antepartum surveillance should be considered in all AMA patients.

BACKGROUND: A randomized study published in 2003 by the National Institute of Child Health and Human Development Maternal Fetal Medicine Units network showed efficacy of 17-alpha hydroxyprogesterone caproate (17P) for the prevention of recurrent preterm delivery. Between 2003 and 2011 the drug was often provided by compounding pharmacies. In 2011, the US Food and Drug Administration (FDA) approved the drug for this indication. OBJECTIVE: The objective of this study was to evaluate the impact of FDA approval on physician attitudes and perceptions regarding use of 17P as a drug for preventing recurrent preterm delivery. METHODS: A 10-min online survey using a structure closed-ended questionnaire format was designed and administered from 17 June 2011 to 7 July 2011 among 401 obstetricians distributed evenly throughout the USA. RESULTS: There is nearly universal awareness of 17P for the prevention of preterm birth (93 %), with a large majority (80 %) of obstetricians having reported prescribing the medication. However, surveyed physicians reported that the average proportion of eligible patients seen in their practice but not prescribed 17P in 2009-2010 was 41 %. Financial and logistical barriers carried the most weight (approximately 75 %) in the decision not to prescribe 17P to an eligible patient. Forty-one percent of respondents cited lack of FDA approval of 17P as a deterrent to prescribing the medication. Thirty-nine percent of respondents had professional liability concerns regarding prescribing compounded 17P. Assuming the same out-of-pocket expense for patients, two-thirds of obstetricians would choose to prescribe Makena((R)). CONCLUSION: Awareness of 17P for the prevention of preterm birth among obstetricians is high. FDA-approved medications seem to have physician preference due to enhanced assurance for product efficacy and safety.

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)

Objective: To compare the efficacy of Shirodkar to McDonald cerclage in patients with singleton pregnancies undergoing an ultrasound-indicated cerclage. Methods: Historical cohort of all patients with singleton pregnancies undergoing cerclage for the indication of a short cervix on ultrasound (ultrasound indicated) at one institution in 2005-2010. We compared outcomes based on cerclage type, Shirodkar or McDonald. Outcome measures were gestational age (GA) at delivery, delivery >/=35 weeks, >/=32 weeks, and PPROM. Multivariable regression analysis was performed to control for significant variables. Results: Seventy-four patients with singleton pregnancies underwent an ultrasound-indicated cerclage in the study period (47 Shirodkar, 27 McDonald). Shirodkar was associated with later GA at delivery (mean GA at delivery 36.98 +/- 3.39 vs. 33.34 +/- 6.37 weeks, p = 0.006), a higher likelihood of delivering >/=35 weeks (83 vs. 55.6%, p = 0.011) and >/=32 weeks (91.5 vs. 59.3%, p = 0.001), and a lower likelihood of preterm premature rupture of membrane (PPROM) (13.0 vs. 46.2%, p = 0.002). On adjusted analysis controlling for differing baseline characteristics, Shirodkar remained significantly associated with an increased incidence of delivery >/=32 weeks (odds ratio [OR]: 5.180, 95% CI: 1.024-26.205). Conclusion: Compared to the McDonald technique, the Shirodkar technique was more effective in prolonging pregnancy in patients with singleton pregnancies undergoing ultrasound-indicated cerclage. A prospective trial is needed to compare these two techniques.