Assessment of developmental risk information on medicines for inclusion on the WHO's Essential Medicines List.

BACKGROUND: The WHO develops biannually an Essential Medicines List (EML) of medications proposed for national formularies to be safe, effective and cost-effective. This satisfies the priority healthcare needs of most adult populations, but it does not consider the unique toxicological risks that occur from exposures during pregnancy. METHODS: Developmental toxicity risk information for the 451 specific agents on the 2017 EML were identified from four well-recognized compendia of teratological assessments. On this basis, each agent was classified as having known, suggested, or little to no developmental risk, or as having insufficient information. RESULTS: Thirteen (3%) EML agents posed known developmental risks, and 115 (25%) had evidence suggesting risk. For 170 (38%) agents, there was little or no evidence of such risk. Thus, risk classification could be determined for 66% of the agents. For an additional 153 (34%) agents, the information was insufficient for classification. CONCLUSION: It is feasible to expand the classification of most of the EML agents to include the risks from exposure during pregnancy.

Thomas H. Shepard, M.D., pioneer in embryology and teratology.

Dr. Thomas H. Shepard died on October 3, 2016 at the age of 93. He was a major figure in the fields of teratology, embryonic and fetal pathology, and pediatrics. He was beloved by his colleagues as he was by the many students and fellows whom he taught, mentored and befriended. His contributions to teratology are extraordinary and he is greatly missed. © 2017 Wiley Periodicals, Inc.

Exploring the Design and Role of Mobile Apps for Healthcare Providers to Find Teratogenic Information.

Healthcare providers (HCPs) caring for pregnant patients often need information on drug risks to the embryo or fetus, but such complex information takes time to find and is difficult to convey on an app. In this work, we first surveyed 167 HCPs to understand their current teratogen information-seeking practices to help inform our general design goals. Using the insights gained, we then designed a prototype of a mobile app and tested it with 22 HCPs. We learned that HCP 's information needs in this context can be grouped into 3 types: to understand, to decide, and to explain. Different sets of information and features may be needed to support these different needs. Further, while some HCPs had concerns about appearing unprofessional and unknowledgeable when using the app in front of patients, many did not. They noted that incorporating mobile information apps into practice improves information access, can help signal care and technology-savviness, in addition to providing an opportunity to engage and educate patients. Implications for design and additional features for reference apps for HCPs are discussed.

Should pregnant women be included in phase IV clinical drug trials?

Relatively few drugs, especially those recently approved by the US Food and Drug Administration, have published human pregnancy experience. Although all drugs contain animal reproduction data, these are usually not predictive of human risk. Clinical trials in pregnant women are rarely conducted because of ethical and legal concerns, and it may be many years before sufficient observational data are collected to guide clinical treatment decisions. Because many of these drugs will be used in pregnancy, human data are needed shortly after the drugs come to the market. Lack of human data leads to uncertainty over whether a drug can be safely prescribed for a pregnant patient. Unless there are compelling scientific and ethical reasons to exclude them, pregnant women should be included in phase IV clinical trials (postmarketing studies to obtain additional information, including the risks, benefits, and optimal use of a drug). This paper examines how physicians currently counsel pregnant women when there are no human data and proposes an alternative method in which knowledge regarding risks associated with the use of drugs during pregnancy can be enhanced in a clinical trial setting.

Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence.

Drugs that interfere with the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are widely used to manage hypertension and heart failure. Adequate functioning of the RAS is essential for normal fetal kidney development. The potential for ACEIs and ARBs to impair fetal and neonatal renal function if taken after the first trimester of pregnancy has been well documented. Although these drugs were not found to be teratogenic in animals, until recently little was known about the teratogenic effects of ACEIs and ARBs in humans when exposure was limited to the first trimester of pregnancy. New evidence from epidemiologic studies indicates that there may be an elevated teratogenic risk when these drugs are taken during the first trimester of pregnancy. However, this elevated risk does not appear to be specific to ACEIs and ARBs, but is instead related to maternal factors and diseases that typically coexist with hypertension in pregnancy, such as diabetes, advanced maternal age, and obesity. Women who become pregnant while being treated with an ACEI or ARB should be advised to avoid exposure to these drugs during the second and third trimesters of pregnancy by switching to a different class of antihypertensive drugs between weeks 8 and 10 after conception.

Reliability and validity of the 4-item perceived stress scale among pregnant women: results from the OTIS antidepressants study.

We aimed to estimate the reliability of the 4-item Perceived Stress Scale (PSS) and its validity in predicting maternal depression and quality of life (QoL). Data regarding stress, depression and QoL were collected during pregnancy among a sub-sample from the Organization of Teratology Information Specialists Antidepressants in Pregnancy Cohort. The 4-item PSS demonstrated acceptable internal consistency (Cronbach's alpha coefficient = .79), alternate forms stability reliability with the 10-item PSS (Pearson correlation coefficient r = .63; p < .001), convergent validity with the Edinburgh Postnatal Depression Scale (r = .67; p < .001), and concurrent validity with the mental health component of the Short-Form-12 (r = -.62; p < .001) as a measure of QoL. The 4-item PSS is a valid and useful tool for assessing maternal stress during pregnancy.

The art and science of teratogen risk communication.

Despite scientific advances in clinical teratology, exposures during pregnancy still cause great anxiety and misunderstanding. Patients and health care providers are frequently called upon to determine the health implications of scientific studies, which may involve limited and contradictory data. These findings are often conveyed numerically, which is a particularly difficult form of information for both patients and their health providers to understand and interpret. Almost half of the general population (and a substantial minority of physicians) have difficulty with numeracy. Patients with low numeracy tend to interpret information in an absolute manner and ignore uncertainty, have more difficulty using numeric information to inform their choices, and are more easily influenced by emotion and the format used in presenting information. Formats involved in conveying probability include positive or negative framing, use of relative versus absolute risk, and ratios and percentages. Health providers should communicate risk analysis in a fashion that facilitates comprehension and results in informed behavior. This is more likely to be achieved when risks are conceptualized as more than just numbers, and are considered in the context of individuals' life circumstances and values. Most teratogen risk communication is done over the telephone; this presents both advantages and challenges. Strategies are suggested to improve risk communication. These include avoiding the use of relative risk, using a consistent denominator, framing the information in a variety of ways (positive vs. negative), using verbal qualifiers judiciously, and employing visual aids.

Evolving knowledge of the teratogenicity of medications in human pregnancy.

A majority of pregnant women take at least one medication during pregnancy, although the safety of such drugs during pregnancy is not always known. We reviewed the safety during pregnancy of 172 drugs approved by the US Food and Drug Administration (FDA) from 2000 to 2010 using the TERIS risk rating system. We also reviewed safety information for 468 drugs approved by the FDA from 1980 to 2000 to determine if revisions in risk categories had been made in the last 10 years. The teratogenic risk in human pregnancy was "undetermined" for 168 (97.7%) of drug treatments approved between 2000 and 2010. Furthermore, the amount of data available regarding safety in pregnancy was rated as "none" for 126 (73.3%) of these drugs. For those drugs approved between 1980 and 2000, only 23 (5%) changed a full risk category or more in the past 10 years. Sources of data that led to a revised risk were derived from exposure cohort studies performed through record linkage studies, teratogen information services, large population-based case-control studies, and pregnancy registries. The mean time for a treatment initially classified as having an "undetermined" risk to be assigned a more precise risk was 27 years (95% confidence interval 26-28 years). The lack of information needed to assess the safety of drug treatments during human pregnancy remains a serious public health problem. A more active approach to post-marketing surveillance for teratogenic effects is necessary.

Safety of dermatologic drugs used in pregnant patients with psoriasis and other inflammatory skin diseases.

In patients with psoriasis, there is an increased availability of drugs for treatment. However, there are important questions about drug safety for mothers with psoriasis and their fetuses. Currently, there are limited safety data for many of the medications used. In this article, we review current pregnancy risk information for medications commonly used in the treatment of psoriasis. In addition, a list of teratology information resources is included to help practicing clinicians find up-to-date information regarding the safety of the medications they prescribe.

A survey of pregnant women using isotretinoin.

BACKGROUND: Isotretinoin is a known human teratogen, causing birth defects and/or subnormal cognitive performance in prenatally-exposed children. METHODS: A survey was conducted among women who called teratology information services throughout North America. Using a structured questionnaire, women with an isotretinoin-exposed pregnancy were prospectively interviewed before the outcome of the pregnancy was known. RESULTS: Almost 1/4 of the women surveyed (24%; 8/34) did not recall having contraception counseling before starting their medications. Once therapy was initiated, 62% (21/34) recalled using a birth control method, but only 29% (6/21) recalled using 2 forms of birth control, as specified by the voluntary pregnancy prevention programs. Monthly pregnancy tests were not always conducted during treatment, as recalled by the surveyed women (56%; 19/34). As many as 24% (8/34) of the women surveyed recalled that they were not screened using 2 pregnancy tests before receiving a prescription, another recommendation of the programs. Only a small number of the women (30%; 6/20) in the United States recalled being enrolled in any manufacturers' voluntary pregnancy prevention survey. CONCLUSIONS: Results demonstrate that essential components of voluntary pregnancy prevention programs were not consistently followed, which resulted in fetal exposures.

Medical genetics: 1. Clinical teratology in the age of genomics.

Teratogenic exposures are those that can cause an embryo or fetus to develop abnormally. Several factors determine whether an agent is teratogenic, including the gestational timing of the exposure, as well as the dose, route and nature of the agent itself. We review the general concepts of teratogenesis, as well as known genetic susceptibilities to teratogenic effects, with a special focus on antiepileptic drugs. We discuss general principles of risk counselling and risk reduction, and we describe several long-known teratogens, as well as several exposures recognized only recently to have teratogenic potential.

Developmental toxicity: web resources for evaluating risk in humans.

This review presents a brief overview of Internet resources that provides information on developmental toxicity. The advantages and limitations of these resources for evaluating human risk and where each one is useful for informing various stages of the risk assessment process (i.e. hazard characterization, dose-response assessment, exposure assessment and risk characterization) are reviewed. How these Internet resources can be utilized to obtain information on and evaluate the developmental risk associated with exposures during pregnancy will be illustrated using toluene. Translating information derived from laboratory and human population studies into clinical management prescriptions for individual patients is difficult. With the increasing availability of Internet resources that provide information relevant for developmental risk assessments, health care professionals will be better equipped to make more accurate estimations of potential risk for their patients.