Carla M. Van Bennekom

A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures

Background Phenobarbital, once widely prescribed to prevent febrile seizures, is now in disfavor because of its side effects and lack of efficacy. Diazepam, administered only during episodes of fever, may be a safe, effective agent to prevent the recurrence of febrile seizures. Methods We conducted a randomized, double-blind, placebo-controlled trial among 406 children (mean age, 24 months) who had at least one febrile seizure. Diazepam (0.33 mg per kilogram of body weight) or placebo was administered orally every eight hours during all febrile illnesses. Results During a mean follow-up of 1.9 years (a period during which 90 percent of febrile seizures recur), our intention-to-treat analysis showed a reduction of 44 percent in the risk of febrile seizures per person-year with diazepam (relative risk = 0.56; 95 percent confidence interval, 0.38 to 0.81; P = 0.002). A survival analysis of the length of time to the first recurrent febrile seizure did not show a significant difference between the treatment gr...

Safety of the 2011-12, 2012-13, and 2013-14 seasonal influenza vaccines in pregnancy: Preterm delivery and specific malformations, a study from the case-control arm of VAMPSS.

BACKGROUND Pregnant women have higher risks of influenza complications, but vaccine coverage is incomplete. Because concern about fetal harm limits uptake, we investigated risks for preterm delivery (PTD) and specific birth defects following vaccination in the 2011-12 through 2013-14 influenza seasons. METHODS We used data from the Slone Epidemiology Centers Birth Defects Study. For PTD, propensity score-adjusted time-varying hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for exposure anytime in pregnancy and for each trimester. For 42 specific major birth defects or birth defect categories, propensity score-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. RESULTS For PTD (1803 fullterm deliveries, 107 PTD for all seasons combined), an elevated adjusted risk was observed for only the 2nd trimester of the 2011-12 season (HR=2.60, 95% CI 1.21, 5.61) - a reduction in gestational length of <2days. For the 42 specific defects or categories of defects (2866 cases, 1411 controls for all seasons combined) most adjusted risks were close to 1.0; the highest was 2.38 for omphalocele and the lowest was 0.50 for atrioventricular canal defects. None had lower confidence bounds >1.0. For each season separately, only one elevated OR had a lower 95% CI >1.0: omphalocele in 2011-12 (OR=5.19, 95% CI 1.44, 18.7). CONCLUSIONS Our results regarding risks for PTD and birth defects are generally reassuring. The few risks that were observed are compatible with chance, but warrant testing in other data. Given that vaccine components and manufacturing processes vary, continuing studies are needed to evaluate risks and safety of each seasons vaccine and specific products.

Vasoactive exposures during pregnancy and risk of microtia

BACKGROUND Little is known about the etiology of nonsyndromic microtia. This study investigated the hypothesis that microtia is caused by vascular disruption. METHODS The study analyzed data from the population-based National Birth Defects Prevention Study (NBDPS) for deliveries between 1997 and 2005. Four hundred eleven nonsyndromic cases of microtia, with or without additional defects, were compared to 6560 nonmalformed infants with respect to maternal exposures to vasoactive medications and smoking during the periconceptional period and conditions that have previously been associated with vascular events (multiple gestation, maternal history of type 1, type 2, or gestational diabetes, and hypertension). Odds ratios (ORs) were estimated with multivariable models, controlling for the effects of race/ethnicity, education, periconceptional folic acid use, and study center. RESULTS Risk estimates for vasoactive medications and smoking were not meaningfully increased. Maternal type 1/2 diabetes was diagnosed before or during the index pregnancy in 4% and 1% of cases, respectively, compared to 1% and 0.05% of controls; the adjusted OR for these two groups combined was 7.2 (95% confidence interval [CI], 3.9-13.1). Gestational diabetes was observed for 9% of cases and 6% of controls; the OR was moderately elevated (OR, 1.4; 95% CI, 0.9-2.0). ORs were also increased for multiple gestations (OR, 2.5; 95% CI, 1.5-4.2) and pre-existing hypertension (OR, 1.6; 95% CI, 1.0-2.5). CONCLUSIONS Because ORs were only elevated for diabetes and not for vasoactive exposures or other potential vascular events, findings suggest that some microtia occurrences may be part of the diabetic embryopathy rather than manifestations of vascular disruption. Birth Defects Research (Part A), 2013.

Classification of the myelodysplastic syndrome in a national registry of recently diagnosed patients

BACKGROUND It is not known to what extent the WHO classification scheme for MDS has been adopted in clinical practice. METHODS We reviewed the medical records of 200 newly diagnosed MDS patients enrolled in our national registry during the years 2006-2008 to determine the scheme used. RESULTS Clear WHO subtypes were recorded for 45.0% of patients, compared to 5.5% for FAB subtypes; 28.0% had MDS documented but without WHO or FAB subtype, and for 22.5%, the schema was unclear. CONCLUSION Although many MDS patients do not have a subtype or schema documented, when they do, the WHO system is widely used.

Tdap Vaccination Coverage During Pregnancy — Selected Sites, United States, 2006–2015

Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended during the third trimester of each pregnancy to provide protection to newborns, who are at risk for pertussis-related morbidity and mortality (1). As part of its case-control surveillance study of medications and birth defects, the Birth Defects Study of the Slone Epidemiology Center at Boston University (the Birth Defects Study) has recorded data on vaccinations received during pregnancy since 2006. Among 5,606 mothers of infants without structural birth defects in this population (control group), <1% had received Tdap vaccine before 2009. By 2012, the percentage of mothers of infants in the control group (control infants) who had received Tdap increased to approximately 9%, and then in 2013 and continuing through 2015, increased markedly, to 28% and 54%, respectively. As the prevalence of maternal Tdap vaccination increased, so did the proportion of pregnant women who received Tdap in the third trimester, as recommended (94%-100% from 2010 to 2015). The vast majority of Tdap vaccinations (96%) were received in a traditional health care setting (e.g., the office of the womans obstetrician or primary care physician or her prenatal clinic). Increasing vaccination coverage during pregnancy could help reduce the impact of pertussis on infant morbidity and mortality.

Metformin in the first trimester and risks for specific birth defects in the National Birth Defects Prevention Study

BACKGROUND We assessed associations between first-trimester metformin use for pregestational diabetes and specific major birth defects. METHODS We compared risks associated with first-trimester metformin use by diabetic women to nondiabetic women on no diabetes medication; we calculated crude odds ratios by exact logistic regression and adjusted by inverse probability weighting. Confounding by diabetes was assessed by comparing risks for metformin-exposed diabetic women to those for insulin-exposed diabetics and nondiabetics treated with metformin for subfertililty. RESULTS Among 9,279 nonmalformed controls and 24,375 malformed cases, diabetics who used metformin (with or without insulin) had increased adjusted odds ratios (aORs) for several birth defects associated with diabetes. However, women treated with metformin for subfertility had aORs similar to or lower than those for diabetic metformin users, and many approximated the null. For atrial septal defect secundum, anorectal defects, and limb reduction defects, the estimates for metformin when used for subfertility were 2-3-fold. CONCLUSION While metformin use for diabetes was associated with an increased risk of many birth defects, when metformin was used for subfertility most defects had aORs that approximated the null, while only three defects had modestly increased aORs, two of which had lower confidence bounds that included the null. Our study does not suggest that metformin poses an appreciable risk for major birth defects, but further studies are necessary.

Comments on: Are Food and Drug Administration prescription drug safety plans working? A case study of isotretinoin

Fain and Alexander1 commented on the database study by Pinheiro et al.2 that evaluated the effectiveness of iPledge, the Risk Evaluation and Mitigation Strategy (REMS) for isotretinoin, noting several limitations to the approach used. They also suggested that surveybased analyses are “fraught with methodological challenges.” Although their latter point may be true for some surveys, we believe that it is feasible to design and perform scientifically rigorous surveys to evaluate REMS. Indeed, from 1989 to 2003, the Slone Epidemiology Center conducted the Accutane Survey, an independent evaluation of the Pregnancy Prevention Program for Accutane (the first risk management program directed at pregnancy prevention), which was initiated in 1988. In our 1995 report in the New England Journal of Medicine on over 177000 women3 (and in subsequent reports to the Food and Drug Administration on over 492000 women4) who were followed during their isotretinoin treatment and for 6months thereafter, we provided the distribution of the contraceptive methods reported by women in the Survey. In addition, the Survey asked about sexual activity, which allowed us to identify the proportion of women who reported abstinence. Importantly, because the Survey captured information on the primary outcome of interest—pregnancy—we were also able to estimate method-specific pregnancy rates, which were lower than those for typical use of each method.5 Motivation is a well-established predictor of successful contraception,5 and in the context of a REMS targeted toward pregnancy prevention, women may be more highly motivated to use contraception properly. Our findings suggest that method-specific failure rates derived from the population at large should not be generalized to REMS participants, making survey-specific rates a critical element in evaluating the effectiveness of a REMS. A carefully designed and rigorously executed Survey can provide information on pregnancies as well as the wide range of pregnancy prevention behaviors and thereby overcome one of the limitations Pinheiro faced in using surrogate measures.