A Collaboration Among:
American Academy of Allergy, Asthma & Immunology (AAAAI)
Organization of Teratology Information Specialists Research Center at the University of California-San Diego (OTIS)
Slone Epidemiology Center at Boston University (SEC)
What is VAMPSS?
The Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) is a new nationwide post-marketing surveillance system established to comprehensively monitor the use and safety of vaccines and medications during pregnancy.
Why was VAMPSS developed?
Major congenital malformations occur in 3-5 % of all infants, and other complications, such as preeclampsia, preterm birth and intrauterine growth retardation occur in 10-15 % of pregnancies. Although pharmacologic agents are uncommon causes of these adverse outcomes, they are among the most preventable. Because adverse effects of a drug during pregnancy are not predictable based on preclinical studies or drug class and pregnant women are not usually included in pre-marketing trials, post-marketing surveillance is required to establish the risks or safety of medications and vaccines during pregnancy. Unfortunately, no systematic surveillance system for this purpose exists in this country, and so there is a lack of adequate safety information for most pharmacologic agents taken by pregnant women. This lack of information leads to a number of potential adverse consequences.
The major goal of VAMPSS is to provide the needed national systematic post-marketing surveillance system for pharmacologic therapy during pregnancy. With this system, we hope to identify as early as possible the circumstances in which a drug or immunization causes harm. In addition, we hope to provide reassuring data in a timely manner to all concerned for those drugs and immunizations (likely the majority) that are safe during pregnancy.
How is VAMPSS organized?
VAMPSS is coordinated by the American Academy of Allergy, Asthma & Immunology (AAAAI) and includes an Investigative Task Force and a standing independent Advisory Committee. The Investigative Task Force includes representatives from the AAAAI, the Organization of Teratology Information Specialists (OTIS), and the Slone Epidemiology Center (SEC) at Boston University. The Advisory Committee includes members from the Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), American College of Obstetrics and Gynecology (ACOG), American Academy of Pediatrics (AAP), as well as a biostatistician and a consumer representative.
Although VAMPSS activities are coordinated with relevant government agencies and professional organizations, VAMPSS represents an independent surveillance system serving the public and private sector. VAMPSS is currently supported through research grants from the U.S. Office of Biomedical Advanced Research and Development Authority (BARDA) and the Agency for Healthcare Research and Quality (AHRQ).
Frequently asked questions about VAMPSS
How does VAMPSS work?
The VAMPSS system provides a coordinated effort involving both prospective registry surveillance and case-control surveillance to study the safety of exposures in pregnancy. This unique partnership, led by AAAAI brings together two complementary methods of surveillance and takes advantage of the benefits of both.
The prospective surveillance arm of VAMPSS is coordinated by OTIS and involves prospective enrollment and follow-up of pregnant women exposed to selected vaccines or medications during pregnancy. Outcomes among participants exposed to a vaccine or medication under evaluation are compared to outcomes among participants not exposed.
The case-control surveillance arm of VAMPSS is coordinated by SEC and involves enrollment of mothers of infants with congenital malformations and infants without malformations. Among mothers of infants with each specific malformation, the prevalence of antenatal exposure to the vaccines and medications of interest is compared to the corresponding exposure prevalences in comparison groups: mothers of non-malformed infants and mothers of infants with other malformations.
Both arms of VAMPSS collect information directly from participating mothers, thus obtaining comprehensive data on actual exposures and important confounders such as alcohol and tobacco use. Because the system obtains exposure information directly from the subject, this coordinated effort will provide the ability to address questions regarding the safety of over-the-counter medications, dietary supplements and products not acquired by the pregnant woman in traditional medical settings.
What questions can VAMPSS help to answer?
Using complementary approaches, VAMPSS evaluates risks and safety of a wide range of pregnancy exposures with respect to spontaneous abortions, preeclampsia, fetal deaths, preterm births, intrauterine growth restriction, total major congenital malformations and specific major malformations. In addition, the case-control component of VAMPSS provides exposure prevalence data drawn from a population-based sample.
How will VAMPSS information be used?
Data will be analyzed initially to provide odds ratios and 95% confidence intervals for the exposures of interest in relation to each primary outcome. The standing Independent Advisory Committee works with the Investigative Task Force to determine if a risk signal or safety threshold is identified and develops a plan for communicating findings to the FDA that are meaningful to clinicians and the public.
How can clinicians help support VAMPSS?
The inaugural focus of VAMPSS is respiratory health of pregnant women. The target vaccines and medications for this initial effort include:1) seasonal and H1N1 influenza vaccines and antiviral medications used to treat or prevent the flu in pregnancy, and 2) asthma medications used in pregnancy. Clinicians can help support VAMPSS by referring pregnant patients exposed to influenza vaccines, influenza anti-viral medications, such as oseltamivir and zanamivir, or asthma medications to OTIS at (877) 311-8972. Patients will learn more about how they can participate in this important new effort.
How can pharmaceutical companies work with VAMPSS to assess the safety of their medications during pregnancy?
Pharmaceutical companies can act as Sponsors of individual medication surveillance projects. These projects can fulfill an FDA post-marketing commitment for newly-marketed medications or provide needed information for medications which are not newly marketed. Although Sponsors will have access to summaries of the accumulating data and input into their interpretation, all data are owned by VAMPSS, and all conclusions will be made independently by the Investigative Task Force and the Advisory Committee.
Lack of adequate safety information for medications and vaccines used in pregnancy leads to several types of adverse consequences First, potential prevention opportunities for drug-induced adverse outcomes are missed. Second, this lack of safety data may lead to under-treatment or under-prevention of medical problems, such as influenza or asthma, which themselves cause maternal morbidity and possible perinatal complications. Finally, using medications with uncertain effects on pregnancy or the infant causes substantial maternal anxiety, which is not optimal for mother or fetus.
Investigative Task Force
The Investigative Task Force coordinates all aspects of protocol development, data collection, data analyses, data interpretation, and generation of reports, and meets weekly by teleconference to discuss methodological issues and review progress. The Investigative Task Force includes the following members, representing the American Academy of Allergy Asthma and Immunology (AAAAI), the Organization of Teratology Information Specialists (OTIS) and the Slone Epidemiology Center (SEC) at Boston University:
Christina Chambers, PhD, MPH (OTIS)
Sheila Heitzig, JD (AAAAI Staff)
Kenneth Lyons Jones, MD (OTIS)
Allen A. Mitchell, MD (SEC)
Michael Schatz, MD, MS (AAAAI)
Lauri Sweetman (AAAAI Staff)
The independent Advisory Committee provides advice regarding overall VAMPSS goals, methods, resultsand reports. It provides independent, scientifically rigorous and confidential peer review of accumulating data and the related analyses.
The VAMPSS Influenza and Asthma Advisory Committee is composed of the following individuals, representing the indicated organizations:
- Joseph Bocchini, MD (AAP)
- Alison Bryant Mantha, MD, MPH (ACOG)
- Elizabeth Conradson Cleary, JD, MA (consumer representative)
- Peter Gergen, MD, MS (NIAID)
- Robert Glynn, ScD (Biostatistician)
- Margaret Honein, PhD MPH (CDC)
- James L. Mills, MD, MS (NICHD)
- Laura E. Riley, MD (ACOG)
- Dixie Snider, MD, MPH (CDC)
- Jo Schweinle, MD (BARDA non-voting)
- Anne Trontell, MD, MPH (AHRQ non-voting)
The Advisory Committee meets with the Investigative Task Force quarterly to review the accumulating data and makes recommendations to the Investigative Task Force regarding the methods and output of the surveillance and regarding risk and safety signals. The Advisory Committee also reviews all VAMPSS reports.
Prospective Surveillance Arm
Prospective registry surveillance is provided for VAMPSS by the Organization of Teratology Information Specialists (OTIS). OTIS is a North American-wide network of university or hospital-based teratology information services in existence since 1979. OTIS prospectively enrolls callers exposed to vaccines or medications during pregnancy. Depending on the gestational age at enrollment, up to three maternal interviews are conducted at standard time points during pregnancy and once post-partum, and outcomes are confirmed by chart review. Outcomes among subjects exposed to the vaccine or medication under evaluation will be compared to outcomes among participants not exposed. These latter participants will be recruited from pregnant callers who initiate contact with the OTIS services and who have not had exposure to known human teratogens or the exposures of interest.
Case Control Surveillance Arm
Case-control surveillance is provided by the Slone Epidemiology Center (SEC) at Boston University. The SEC initiated its case-control surveillance Birth Defects Study in 1976. Infants with the broad range of specific major malformations and infants without malformations are identified at birth hospitals and tertiary hospitals and via state-based birth defects surveillance programs; medical records are reviewed to confirm diagnoses. Mothers are interviewed by telephone within six months of delivery about all vaccines and medications used immediately before and during pregnancy. Among mothers of infants with each specific malformation, the prevalence of vaccines and drugs of interest will be compared to the corresponding prevalence in two control groups: mothers of non-malformed infants and mothers of infants with other malformations. Interviews of a population-based random sample of mothers of non-malformed infants also provide estimates of the prevalence of exposure to specific vaccines and medications.
Respiratory Health of Pregnant Women
The inaugural focus of VAMPSS is the respiratory health of pregnant women. The target vaccines and medications for this initial effort include seasonal influenza vaccines, H1N1 influenza vaccines, antiviral medications used to treat or prevent influenza, and asthma medications, with a focus on long-acting beta agonists (LABAs).
Pregnant women are at increased risk for influenza-related morbidity and mortality, and influenza vaccine is specifically recommended for use in pregnancy. However, few data are available on the safety during pregnancy of influenza vaccines. Presumably at least in part related to this lack of information, only a minority of pregnant women receive recommended influenza immunizations. Influenza anti-viral medications, such as oseltamivir and zanamivir, are often recommended for treatment of influenza symptoms in pregnant women or for prophylaxis in pregnant women exposed to known cases. However, inadequate safety information is available regarding their use as well during pregnancy. Support for the influenza surveillance comes from the U.S. Office of Biomedical Advanced Research and Development Authority (BARDA).
Asthma occurs in at least 8% of pregnant women, making it probably the most common potentially serious medical problem to complicate pregnancy. Because the illness is so common and often requires treatment, asthma medications are among the most commonly used medications during pregnancy. In addition, uncontrolled asthma itself is associated with increased pregnancy complications. LABA are recommended therapy for asthma not controlled by inhaled steroids, but there are virtually no safety data for LABA during pregnancy. Support for the asthma medication surveillance is through a research grant from the Agency for Healthcare Research and Quality (AHRQ).
The following confounders or risk modifiers are captured in both arms of VAMPSS and could be used for adjusted analyses:
- Markers of socioeconomic status
- Family history of birth defects
- Reproductive history
- Other exposures: Rx, OTC, herbal products, vitamins/minerals (including periconceptional folate-containing multivitamins)
- Medical illnesses, with specific attention to confirmed and unconfirmed influenza illnesses
- Settings in which antivirals are used/not used (to include whether the patient had drug but did not use it, had drug and used it appropriately, had drug and used in inappropriately, or borrowed drug from friends/neighbors/relatives or vice versa)
The following primary outcomes will be evaluated:
- Total major congenital malformations (OTIS)
- Specific malformations (SEC) [e.g, cardiovascular malformations, oral clefts, limb reduction defects, and anotia/microtia]
- Preeclampsia (OTIS)
- Preterm delivery (< 37 weeks) (OTIS, SEC)
- Small for gestational age (birth weight for gestational age ≤10th percentile) (OTIS, SEC)
- Rates of use in the pregnant population (SEC)
Other outcome information collected by OTIS includes spontaneous abortions, perinatal mortality, birth weight, length and head circumference, and gestational age. All diagnoses above are confirmed by medical record review.
Estimates of safety cannot be absolute; rather, they reflect the degree of confidence that is consistent with an observation of no increased risk between a given exposure and outcome. As more data are collected over time, power increases; for a null observation, increasing power leads to increasingly narrower confidence bounds and increasing assurance of relative safety, as reflected in the a priori criteria that follow:
- When an odds ratio approximating 1.0 (or less) is observed with an upper 95% confidence bound of 4.0 or less, the data will be brought to the Advisory Committee for review. The Committee may choose to define this observation as “no evidence of risk.”
- Whenever an odds ratio approximating 1.0 (or less) is observed with an upper 95% confidence bound of 2.0 or less, the data will be brought to the attention of the Advisory Committee for review. The Committee may choose to define this observation as “evidence of relative safety”.
Positive associations will be brought to the Advisory Committee for review under the following conditions:
- Whenever an unadjusted odds ratio with a 95% lower confidence bound greater than 1.0 is observed. In this case, adjusted analyses will also be performed for consideration by the Investigative Task Force and the Advisory Committee.
- Whenever any observed odds ratio is deemed by the Investigative Task Force as important or noteworthy. Examples would include risk estimates related to prior reports of an association (e.g., case reports, other epidemiologic studies) or observations supported by biologic plausibility based on animal or other studies.
Our objective in defining these criteria is to assure that no potential risk escapes notice by the Advisory Committee
. Therefore, we have deliberately set very broad parameters, recognizing that many observations that fit the criteria will not be meaningful and will not be subsequently deemed by the Advisory Committee
to constitute a risk signal.
For patients and consumers
Learn more about how to sign up for a VAMPSS study.
For pharmaceutical sponsors
Learn more about sponsoring a VAMPSS study.
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