Temporary practice pause then resumption (TPPR) study design: an extension of the withdrawal study design to complementary and alternative medicine mind and body interventions (CAM-MABI).

Study of complementary and alternative medicine's mind and body interventions (CAM-MABI) is hindered not only by the inability to mask participants and their teachers to the study intervention but also by the major practical hurdles of long-term study of practices that can be lifelong. Two other important methodological problems are that study of newly trained practitioners cannot directly address long-term practice, and that long-term practitioners likely self-select in ways that make finding appropriate controls (or a comparison group) challenging. The temporary practice pause then resumption study design (TPPR) introduced here is a new tool that extends the withdrawal study design, established in the field of drug evaluation, to the field of CAM-MABI. With the exception of the inability to mask, TPPR can address the other methodological problems noted above. Of great interest to investigators will likely be measures in practitioners of CAM-MABI that change with temporary pausing of CAM-MABI practice, followed by return of the measures to pre-pause levels with resumption of practice; this would suggest a link of the practice to measured changes. Such findings using this tool may enhance our insight into fundamental biological processes, leading to beneficial practical applications.

Characteristics of orphan drug applications that fail to achieve marketing approval in the USA.

The US Orphan Drug Act has fostered the development of drugs for patients with rare diseases by granting 'orphan designations', although several orphan drugs for which a marketing application has been submitted to the FDA have failed to obtain approval. This study identified the clinical trial design, the level of experience of the sponsor and the level of interaction with the FDA to be associated with non-approval. Sponsors, therefore, should engage in dialogue with the FDA and thoughtfully design pivotal clinical trials in accordance with FDA guidance documents.

Adverse Events Following Trivalent Inactivated Influenza Vaccination in Children: Analysis of the Vaccine Adverse Event Reporting System.

BACKGROUND: The Advisory Committee on Immunization Practices' recommendations for influenza vaccination of children have expanded from the long-standing recommendation to vaccinate high-risk children aged ≥6 months, to vaccinating all 6- to 23-month-olds (2004), 2- to 4-year-olds (2006), and 5- to 18-year-olds (2008). OBJECTIVE: To identify new or unexpected adverse events (AEs) after trivalent inactivated vaccine (TIV) in children. METHODS: We analyzed reports after TIV to the Vaccine Adverse Event Reporting System from 1990-2006 in children aged 2 to 17 years, and from the 2008-2009 influenza season in children aged 5 to 17 years. Empiric Bayesian data mining techniques were used to identify new or unexpected AEs during 1990-2006. RESULTS: During 1990-2006, the Vaccine Adverse Event Reporting System received 2054 reports of children aged 2 to 17 years with a peak in the 2003-2004 influenza season. In 2008-2009, 506 reports describing 5 to 17 year olds were received. The serious reports of tests performed after TIV were approximately 10% of all reports from 2001-2006, and 6% of the reports in the 2008-2009 season. Data mining showed an increased proportion of medication errors and Guillain Barré Syndrome (GBS). The findings of GBS could not be interpreted as causally related to vaccination. Among 201 reports of medication error, 94% had no AE reported other than the medication error itself. CONCLUSION: In this analysis, we found no unexpected AEs. Our review of medication error and GBS reports suggests that ongoing monitoring in these areas is appropriate.

Evaluation of Guillain-Barré Syndrome among recipients of influenza vaccine in 2000 and 2001.

BACKGROUND: The 1976-1977 swine influenza vaccine was associated with an elevated risk of Guillain-Barré Syndrome (GBS), especially within 6 weeks after vaccination. A 2004 IOM report concluded that evidence was inadequate to accept or reject a causal relationship between subsequent influenza vaccine formulations and GBS. Studies published after the IOM report have been limited by passively reported data or lack of validation of coded diagnoses. PURPOSE: To evaluate whether influenza vaccine is associated with GBS. METHODS: Controlled observational study using national data from the Medicare program, which ensures a predominantly elderly population. People included had a Medicare claim for influenza vaccination during September-December in 2000 or 2001. Medical records were reviewed to classify definite, probable, or possible GBS (or not a case) using a standardized case definition. In a risk interval design, the incidence rate of GBS during Weeks 0-6 after vaccination (exposed period) was compared to Weeks 9-14 after vaccination (comparison period). Data collection occurred during 2003-2007, and analysis was conducted during 2007-2009. RESULTS: Primary analysis included 22.2 million vaccinees, among whom 164 definite or probable GBS cases with onset during Weeks 0-6 or 9-14 were identified. The incidence rate ratio (IRR [95% CIs]) based on the GBS rate in the vaccine-exposed versus comparison periods, was 1.04 (0.76, 1.43) for combined years; 0.86 (0.52, 1.41) among people vaccinated in 2000; and 1.21 (0.79, 1.86) among people vaccinated in 2001. Secondary analysis additionally included 74 possible GBS cases; results were similar. CONCLUSIONS: Overall, the results do not support an association between influenza vaccine receipt and GBS among the elderly for the years studied (2000-2001 and 2001-2002 formulations).

Therapies for inborn errors of metabolism: what has the orphan drug act delivered?

OBJECTIVE: The 1983 US Orphan Drug Act established a process through which promising therapies are designated as orphan products and, later, with satisfactory safety and efficacy data, receive marketing approval and fiscal incentives. We examined accomplishments in drug development for inborn errors of metabolism (IEMs). METHODS: Food and Drug Administration data were used to identify orphan product designations and approvals for IEMs, and the trends for the past 26 years were summarized. Individual clinical development times (CDTs) from filing investigational new drug application to marketing approval were determined. RESULTS: We examined 1956 orphan product designations from 1983 through 2008 and found 93 (4.8%) for IEMs. Of those, 24 (25.8%) received marketing approval. This proportion of approval was significantly (P = .036) higher than that for non-IEM orphan products (17%). Among the IEM products, disorders of complex molecules received the most designations and approvals (61 and 11, respectively). Among the subgroups, lysosomal storage diseases received the most designations and approvals (43 and 9, respectively), whereas mitochondrial diseases (other than fatty acid oxidation disorders) received 7 designations with no approvals. We then examined the CDTs for the approved IEM products and found a median of 6.4 years (range: 2.6-25.1 years). Biological products had significantly shorter CDTs than drugs (mean: 4.6 vs 11.0 years; P = .003). CONCLUSION: For 26 years, the Orphan Drug Act has generated new therapies for IEMs. Why some IEMs have motivated successful drug development and others have not remains enigmatic; yet the needs of IEM patients without treatment are a certainty.

Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years.

The 1983 US Orphan Drug Act has stimulated the development of new therapies for rare diseases. To provide the first comprehensive overview of orphan-designated products and their indications, this article quantitatively analyses the characteristics and distribution of orphan designations and approvals by the US Food and Drug Administration from 1983 to August 2008. Of the 1,892 orphan-designated products, 326 received marketing approval, representing 247 different drugs and more than 200 different diseases. About half of the approvals had occurred by 4 years after designation was granted. The most common patient population size for orphan designations and approvals was fewer than 10,000 patients, and cancer was the most common disease area. The implications of such findings for future development and marketing of therapies for rare diseases are discussed.

What should an ideal vaccine postlicensure safety system be?

In 2007 the National Vaccine Program, along with the Centers for Disease Control and Prevention, the Food and Drug Administration, the National Institutes of Health, and the Health Resources and Services Administration, sponsored a public conference titled "Vaccine Safety Evaluation: Post Marketing Surveillance." The objective was to discuss enhanced approaches to postlicensure evaluation of vaccine safety, including active and passive surveillance systems and special studies. The conference participants reviewed the evolution of the assessment of vaccine safety, detailed current national approaches to postmarketing safety, and offered new approaches to evaluating vaccine safety. A number of the participants recommended that information systems be expanded to include reliable information on vaccination and health outcomes in large populations. We summarize the major meeting presentations and discussions.

Active influenza vaccine safety surveillance: potential within a healthcare claims environment.

BACKGROUND: Rapid safety assessment of novel vaccines, especially those targeted against pandemic influenza, is a public health priority. OBJECTIVES: Assess the feasibility of using healthcare claims data to rapidly detect influenza vaccine adverse events using sequential analytic methods. RESEARCH DESIGN: Retrospective pilot study simulating prospective surveillance using 6 cumulative monthly administrative claims data extracts. The first included encounters occurring in October; each subsequent extract included an additional month of encounters. Ten adverse events were evaluated, comparing postvaccination rates during the 2006-2007 influenza season to those expected based on rates observed in the prior season. SUBJECTS: Members of a large, multistate health insurer who had a claim for influenza vaccination during the 2005-2006 or 2006-2007 influenza seasons. MEASURES: The completeness of monthly claims extracts. RESULTS: Most vaccinations and outcomes were identified early in the 2006-2007 season; about 50% of vaccinations and short latency events were identified in the second monthly data extract, which would typically become available by mid-December, and 80% of vaccinations and events were identified in the third extract. With respect to overall claims lag, approximately 90% of vaccinations and events were identified within 1 to 2 months after vaccination, regardless of vaccination month. CONCLUSIONS: This study suggests that administrative claims data might contribute to same season influenza vaccine safety surveillance in large, defined populations, especially during a threat of pandemic influenza. Based on our previous work, we believe this method could be applied to multiple health plans' data to monitor a large portion of the US population.

Kawasaki disease after vaccination: reports to the vaccine adverse event reporting system 1990-2007.

BACKGROUND: Kawasaki disease (KD) is a multisystemic vasculitis primarily affecting children<5 years. A review of RotaTeq (rotavirus vaccine live) clinical trial data revealed higher, though not statistically significantly, KD rates among RotaTeq vaccines than placebo recipients. In June 2007, the RotaTeq label was revised accordingly. OBJECTIVES: To describe and assess KD reported to Vaccine Adverse Event Reporting System (VAERS) for all US licensed vaccines. METHODS: We reviewed all KD reports received by VAERS from 1990 through mid-October 2007. Cases were characterized by age, gender, onset interval, and vaccine type. Proportional reporting ratio (PRR) was used to evaluate KD reporting for each vaccine compared with all others. Reporting rates were calculated using number of doses distributed as denominator. RESULTS: Through October 14, 2007, 107 KD reports were received by VAERS: 26 were categorized as classic cases, 19 atypical, 52 possible, and 10 were noncases. Of the 97 cases, 91% were children<5 years. There was no clustering of onset intervals after day 1 postvaccination. Before the RotaTeq label revision, the KD PRR was elevated only for Pediarix (DTaP, hepB, and IPV combined) but the KD reporting rate for Pediarix (0.59/100,000 person-years) was much lower than the background incidence rate (9-19/100,000 person-years) for children<5 years in the United States. After the revision, reporting of KD for RotaTeq was stimulated but the reporting rate for RotaTeq (1.47/100,000 person-years) was still much lower than the background rate. CONCLUSIONS: Our review does not suggest an elevated KD risk for RotaTeq or other vaccines. Continued postmarketing monitoring for KD is ongoing.

Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine.

CONTEXT: In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years. OBJECTIVE: To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV. DESIGN, SETTING, AND PARTICIPANTS: Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting. MAIN OUTCOME MEASURES: Numbers of reported AEFIs, reporting rates (reports per 100,000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates. RESULTS: VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100,000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods. CONCLUSIONS: Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.

HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccination.

OBJECTIVE: To investigate whether persons with treatment-resistant Lyme arthritis-associated HLA alleles might develop arthritis as a result of an autoimmune reaction triggered by Borrelia burgdorferi outer surface protein A (OspA), the Lyme disease vaccine antigen. METHODS: Persons in whom inflammatory arthritis had developed after Lyme disease vaccine (cases) were compared with 3 control groups: 1) inflammatory arthritis but not Lyme disease vaccine (arthritis controls), 2) Lyme disease vaccine but not inflammatory arthritis (vaccine controls), and 3) neither Lyme disease vaccine nor inflammatory arthritis (normal controls). HLA-DRB1 allele typing, Western blotting for Lyme antigen, and T cell reactivity testing were performed. RESULTS: Twenty-seven cases were matched with 162 controls (54 in each control group). Odds ratios (ORs) for the presence of 1 or 2 treatment-resistant Lyme arthritis alleles were 0.8 (95% confidence interval [95% CI] 0.3-2.1), 1.6 (95% CI 0.5-4.4), and 1.75 (95% CI 0.6-5.3) in cases versus arthritis controls, vaccine controls, and normal controls, respectively. There were no significant differences in the frequency of DRB1 alleles. T cell response to OspA was similar between cases and vaccine controls, as measured using the stimulation index (OR 1.6 [95% CI 0.5-5.1]) or change in uptake of tritiated thymidine (counts per minute) (OR 0.7 [95% CI 0.2-2.3]), but cases were less likely to have IgG antibodies to OspA (OR 0.3 [95% CI 0.1-0.8]). Cases were sampled closer to the time of vaccination (median 3.59 years versus 5.48 years), and fewer cases had received 3 doses of vaccine (37% versus 93%). CONCLUSION: Treatment-resistant Lyme arthritis alleles were not found more commonly in persons who developed arthritis after Lyme disease vaccination, and immune responses to OspA were not significantly more common in arthritis cases. These results suggest that Lyme disease vaccine is not a major factor in the development of arthritis in these cases.

Adverse events after anthrax vaccination reported to the Vaccine Adverse Event Reporting System (VAERS), 1990-2007.

During the period March 1, 1998 to January 14, 2007, approximately 6 million doses of Anthrax vaccine adsorbed (AVA) vaccine were administered. As of January 16, 2007, 4753 reports of adverse events following receipt of AVA vaccination had been submitted to the Vaccine Adverse Event Reporting System (VAERS). Taken together, reports to VAERS did not definitively link any serious unexpected risk to this vaccine, and review of death and serious reports did not show a distinctive pattern indicative of a causal relationship to AVA vaccination. Continued monitoring of VAERS and analysis of potential associations between AVA vaccination and rare, serious events is warranted.

Preventable mix-ups of tuberculin and vaccines: reports to the US Vaccine and Drug Safety Reporting Systems.

BACKGROUND: Errors involving the mix-up of tuberculin purified protein derivative (PPD) and vaccines leading to adverse reactions and unnecessary medical management have been reported previously. OBJECTIVES: To determine the frequency of PPD-vaccine mix-ups reported to the US Vaccine Adverse Event Reporting System (VAERS) and the Adverse Event Reporting System (AERS), characterize adverse events and clusters involving mix-ups and describe reported contributory factors. METHODS: We reviewed AERS reports from 1969 to 2005 and VAERS reports from 1990 to 2005. We defined a mix-up error event as an incident in which a single patient or a cluster of patients inadvertently received vaccine instead of a PPD product or received a PPD product instead of vaccine. We defined a cluster as inadvertent administration of PPD or vaccine products to more than one patient in the same facility within 1 month. RESULTS: Of 115 mix-up events identified, 101 involved inadvertent administration of vaccines instead of PPD. Product confusion involved PPD and multiple vaccines. The annual number of reported mix-ups increased from an average of one event per year in the early 1990s to an average of ten events per year in the early part of this decade. More than 240 adults and children were affected and the majority reported local injection site reactions. Four individuals were hospitalized (all recovered) after receiving the wrong products. Several patients were inappropriately started on tuberculosis prophylaxis as a result of a vaccine local reaction being interpreted as a positive tuberculin skin test. Reported potential contributory factors involved both system factors (e.g. similar packaging) and human errors (e.g. failure to read label before product administration). CONCLUSIONS: To prevent PPD-vaccine mix-ups, proper storage, handling and administration of vaccine and PPD products is necessary.

Potential population-based electronic data sources for rapid pandemic influenza vaccine adverse event detection: a survey of health plans.

PURPOSE: A vaccine against pandemic influenza may be rapidly and widely distributed, and could be used in populations with little prior exposure to influenza vaccines. Under such conditions, it will be important to gain timely information about the rates of vaccine adverse events, ideally by using electronic data from large populations. Many public and private health plans and payers have such information. METHODS: Between May and September 2007, we conducted a decision maker interview and technical assessment with several health plans in the United States. The interview and survey evaluated technical capability, organizational capacity, and willingness to participate in a coordinated program of rapid safety research targeting pandemic and other influenza vaccines. RESULTS: Eleven health plans (eight private, three public) participated in the decision maker interview. Most interviewees were medical directors or held similar positions within their organizations. Participating plans provided coverage and/or care for approximately 150 million members in the U.S. Nine health plans completed a technical assessment survey. Most decision makers indicated interest and willingness to participate in a coordinated rapid safety surveillance program, and all reported the necessary claims data analysis experience. Respondents noted legal, procedural, budgetary, and technical barriers to participation. CONCLUSIONS: Senior decision makers representing private and public health plans were willing and asserted the ability of their organizations to participate in pandemic influenza vaccine safety monitoring. Developing working relationships, negotiating contracts, and obtaining necessary regulatory and legal approvals were identified as key barriers. These findings may be generalizable to other vaccines and pharmaceutical products.

Adverse event reports following yellow fever vaccination.

Yellow fever (YF) vaccine has been used for prevention of YF since 1937 with over 500 million doses administered. However, rare reports of severe adverse events following vaccination have raised concerns about the vaccine's safety. We reviewed reports of adverse events following YF vaccination reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) from 2000 to 2006. We used estimates of age and sex distribution of administered doses obtained from a 2006 survey of authorized vaccine providers to calculate age- and sex-specific reporting rates of all serious adverse events (SAE), anaphylaxis, YF vaccine-associated neurotropic disease, and YF vaccine-associated viscerotropic disease. Reporting rates of SAEs were substantially higher in males and in persons aged > or =60 years. These findings reinforce the generally acceptable safety profile of YF vaccine, but highlight the importance of physician and traveler education regarding the risks and benefits of YF vaccination, particularly for travelers > or =60 years of age. Vaccination should be limited to persons traveling to areas where the risk of YF is expected to exceed the risk of serious adverse events after vaccination, or if not medically contraindicated, where national regulations require proof of vaccination to prevent introduction of YF.

Effects of stratification on data mining in the US Vaccine Adverse Event Reporting System (VAERS).

BACKGROUND: Vaccines are administered differentially according to age and sex, and disease patterns also vary among people of different age and sex groups. Estimates of disproportionality should be calculated based on comparisons of groups that have a similar likelihood of receiving similar vaccines and experiencing similar adverse events, to prevent false disproportionality from occurring. Stratified empirical Bayesian (EB) methods have been compared with crude, but not stratified, proportional reporting ratios (PRRs) in their performance on adverse event data. OBJECTIVES: (i) to implement stratification of PRR; (ii) to quantify and compare vaccine-event pairs that are highlighted by PRR and EB05 (the lower bound of the 90% CI of the EB geometric mean), for both crude and stratified; and (iii) to evaluate the effects of stratification by age and sex, in identifying adverse events that are accepted to be caused by vaccines. METHODS: We applied EB and PRR data mining methods to data from the US Vaccine Adverse Event Reporting System (VAERS). We stratified PRR and EB05 by age and sex. To study the effects of stratification, we compared the crude PRR and stratified PRR. We also assessed the crude EB05 and stratified EB05, and then compared the effects of stratification on EB05 and PRR. RESULTS: Stratification not only changed the number of vaccine-event pairs that were highlighted, but also changed which pairs were highlighted. There were 283 vaccine-event pairs that were highlighted by the crude EB05, but not the stratified; 12 that were highlighted by the stratified EB05, but not the crude; and 162 that were highlighted by both. Similarly, there were 701 vaccine-event pairs that were highlighted by the crude PRR, but not the stratified; 139 that were highlighted by the stratified PRR, but not the crude; and 895 that were highlighted by both. There were 1466 vaccine-event pairs in which the effect of stratification was different for EB05 and PRR. CONCLUSION: To our knowledge, this is the first published analysis using stratified PRRs. In this analysis of passive surveillance data, stratification revealed and reduced confounding in EB and PRR, and also unmasked some vaccine-event pairs that the crude values did not highlight. Stratification should be applied if confounding is suspected. By decreasing the total number of highlighted vaccine-event pairs, stratification is likely to increase efficiency and therefore might reduce workload.

Postlicensure monitoring of intussusception after RotaTeq vaccination in the United States, February 1, 2006, to September 25, 2007.

BACKGROUND: In 1999, a previous rotavirus vaccine (RotaShield; Wyeth Laboratories, Marietta, PA) was withdrawn from the US market after postlicensure monitoring identified an association with intussusception. Although the new rotavirus vaccine (RotaTeq; Merck, West Point, PA) introduced in 2006 was not associated with intussusception in prelicensure trials, additional monitoring is important to ensure a complete safety profile. METHODS: We assessed intussusception reports after RotaTeq vaccination by using data from the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink, a cohort of children enrolled in managed care. Observed versus expected rate ratios were determined by using vaccine dose distribution data and Vaccine Safety Datalink background intussusception rates. RESULTS: Between February 1, 2006, and September 25, 2007, the Vaccine Adverse Event Reporting System received 160 intussusception reports after RotaTeq vaccination. With the assumptions that reporting completeness was 75% and that 75% of the distributed doses of RotaTeq were administered, the observed versus expected rate ratios were 0.53 and 0.91 for the 1-21 and 1-7 day interval after vaccination, respectively. In the Vaccine Safety Datalink, 3 intussusception cases occurred within 30 days after 111521 RotaTeq vaccinations, compared with 6 cases after 186722 non-RotaTeq vaccinations during the same period. If, like RotaShield, RotaTeq had a 37-fold increased risk of intussusception within 3 to 7 days after vaccination, then 8 intussusception cases would be expected within 3 to 7 days among the approximately 84000 infants vaccinated with the first dose of RotaTeq in the Vaccine Safety Datalink (N = 49902) and the prelicensure trial (N = 34035) combined, whereas no cases have been observed. CONCLUSIONS: Available data do not indicate that RotaTeq is associated with intussusception. Although an intussusception risk similar in magnitude to that of RotaShield can be excluded, continued monitoring is necessary for complete assessment of the safety profile of RotaTeq.

Elective termination of pregnancy after vaccination reported to the Vaccine Adverse Event Reporting System (VAERS): 1990-2006.

Generally, live-virus vaccines are contraindicated for pregnant women because of the theoretical risk of transmission of the vaccine virus to the fetus. Advisory groups recommend avoiding pregnancy in the immediate period after administration of such contraindicated vaccines (CVs) and stress benefit-to-risk evaluation for live or inactivated vaccines regarding pregnancy. Given the limited available data and theoretical risks associated particularly with live-virus vaccines, inadvertent immunization with CVs may lead to elective termination of pregnancy (ETP), despite advisory group statements that "vaccination is not ordinarily an indication to terminate the pregnancy." The Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system managed by the Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC), accepts reports of adverse events after vaccination. The objectives of this review were to describe reports of ETP in VAERS and characterize the circumstances of inadvertent administration of vaccines to pregnant women among ETP reports. We reviewed VAERS reports of ETP submitted from 1990 to 2006. Reports of ETP for reasons other than vaccination during or shortly before pregnancy, such as fetal abnormalities or deaths, were excluded. Of 80 ETP reports, 62 (78%) originated from the US; 79 (99%) were reported by manufacturers. Median age of vaccinees was 26 years (range: 13-43 years; 67 reports). Seventy-three vaccinees (91%) received a single vaccine; 65 (81%) received at least one live-virus vaccine. In 48 (60%) ETP reports, vaccinees were unaware of pregnancy at time of immunization. In 15 (19%) reports, vaccinees became pregnant within 3 months of vaccination; in 13 (16%) reports, vaccinees might have been pregnant before vaccination; in 4 (5%) reports, information was missing. All 80 reports of ETP involved vaccines for which possible effects on fetal development are unknown. However, no cases of vaccine-associated congenital rubella or varicella syndromes have been reported in the medical literature. Also, these syndromes have not been reported to varicella or rubella vaccine pregnancy registries. VAERS has the limitations of passive surveillance systems. Under-reporting of ETP in VAERS could be substantial. More attention may be needed to assess the likelihood of pregnancy when administering vaccines to women with child-bearing potential, and to inform women who learn they are pregnant shortly after being immunized of current information on risks. Quantifying the frequency of ETP related to CVs and the risk (if any) to the fetus of such vaccines can help to inform policy, practice, and individual decision making. Good quality information may be obtained from controlled observational studies.