The long-term impact of receiving incidental findings on parents undergoing genome-wide sequencing.

Genome-wide (exome or genome) sequencing (GWS) has the potential to detect incidental findings (IFs): variants unrelated to the primary indication for testing that may be of medical or personal utility. As GWS becomes increasingly common in clinical practice, it is important to understand the impact of IFs on the individuals and their families. Our goal was to explore the immediate and long-term lived experience of individuals who received IFs as part of diagnostic GWS. We interviewed parents who received an IF as part of the CAUSES translational research study at Children's and Women's Health Centre of British Columbia. Five hundred families were offered trio-based GWS for their child with a suspected, undiagnosed genetic condition. Nine hundred and one of the 1000 parents chose to find out about IFs and 21 parents received an IF for themselves. Twelve of these parents participated in this study. They were interviewed an average of 2.3 years after the IFs were returned. Thematic analysis of transcribed interviews revealed that the participants' decisions and motivations to receive IFs were influenced by personal values and beliefs and by having a child with a suspected genetic condition. Participants' experiences were also influenced by the type of IF received, having a personal or family history of a related condition, their personal interpretation and perceived utility of the information, and the impact of the IF on other family members. Participants expressed either no regret or mild decisional regret on the Decisional Regret Scale. Two years post results, most participants reported little negative impact from receiving the IF. The utility of the information varied: some reported lifestyle changes and proactive screening, while others felt the information may be more relevant in the future. Understanding the immediate and longer term impact of receiving IFs from GWS can inform both pre- and post-test genetic counseling.

Long term outcomes of biomaterial-mediated repair of focal cartilage defects in a large animal model.

The repair of focal cartilage defects remains one of the foremost issues in the field of orthopaedics. Chondral defects may arise from a variety of joint pathologies and left untreated, will likely progress to osteoarthritis. Current repair techniques, such as microfracture, result in short-term clinical improvements but have poor long-term outcomes. Emerging scaffold-based repair strategies have reported superior outcomes compared to microfracture and motivate the development of new biomaterials for this purpose. In this study, unique composite implants consisting of a base porous reinforcing component (woven poly(ε-caprolactone)) infiltrated with 1 of 2 hydrogels (self-assembling peptide or thermo-gelling hyaluronan) or bone marrow aspirate were evaluated. The objective was to evaluate cartilage repair with composite scaffold treatment compared to the current standard of care (microfracture) in a translationally relevant large animal model, the Yucatan minipig. While many cartilage-repair studies have shown some success in vivo, most are short term and not clinically relevant. Informed by promising 6-week findings, a 12-month study was carried out and those results are presented here. To aid in comparisons across platforms, several structural and functionally relevant outcome measures were performed. Despite positive early findings, the long-term results indicated less than optimal structural and mechanical results with respect to cartilage repair, with all treatment groups performing worse than the standard of care. This study is important in that it brings much needed attention to the importance of performing translationally relevant long-term studies in an appropriate animal model when developing new clinical cartilage repair approaches.

Assessing Shared Decision-Making Clinical Behaviors Among Genetic Counsellors.

Shared decision-making (SDM) is a collaborative approach in which clinicians educate, support, and guide patients as they make informed, value-congruent decisions. SDM improves patients' health-related outcomes through increasing knowledge, reducing decisional conflict, and enhancing experience of care. We measured SDM in genetic counselling appointments with 27 pregnant women who were at increased risk to have a baby with a genetic abnormality. The eight experienced genetic counsellors who participated had no specific SDM training and were unaware that SDM was being assessed. Audio transcripts of appointments were scored using 'Observing Patient Involvement in Decision Making' (OPTION12). Patients' anxiety and decisional conflict were also assessed. The genetic counsellors' mean OPTION12 score was 42.4% (SD 9.0%; possible range 0-100%). Specific SDM behaviours that scored highest included introducing the concept of equipoise and listing all options with their pros and cons. Behaviours that scored lowest included eliciting patients' preferred approach to receiving information and desired degree of involvement in decision-making. Patients' levels of anxiety and decisional conflict were unassociated with genetic counsellors' OPTION12 scores. Some SDM behaviours were better demonstrated in this prenatal genetic counselling study than others. Formal training of genetic counsellors in SDM may enhance use of this approach in their professional practice.

Creation of an international registry to support discovery in schwannomatosis.

Schwannomatosis is a tumor suppressor syndrome that causes multiple tumors along peripheral nerves. Formal diagnostic criteria were first published in 2005. Variability in clinical presentation and a relative lack of awareness of the syndrome have contributed to difficulty recognizing affected individuals and accurately describing the natural history of the disorder. Many critical questions such as the mutations underlying schwannomatosis, genotype-phenotype correlations, inheritance patterns, pathologic diagnosis of schwannomatosis-associated schwannomas, tumor burden in schwannomatosis, the incidence of malignancy, and the effectiveness of current, or new treatments remain unanswered. A well-curated registry of schwannomatosis patients is needed to facilitate research in field. An international consortium of clinicians and scientists across multiple disciplines with expertise in schwannomatosis was established and charged with the task of designing and populating a schwannomatosis patient registry. The International Schwannomatosis Registry (ISR) was built around key data points that allow confirmation of the diagnosis and identification of potential research subjects to advance research to further the knowledge base for schwannomatosis. A registry with 389 participants enrolled to date has been established. Twenty-three additional subjects are pending review. A formal process has been established for scientific investigators to propose research projects, identify eligible subjects, and seek collaborators from ISR sites. Research collaborations have been created using the information collected by the registry and are currently being conducted. The ISR is a platform from which multiple research endeavors can be launched, facilitating connections between affected individuals interested in participating in research and researchers actively investigating a variety of aspects of schwannomatosis. © 2016 Wiley Periodicals, Inc.

DECIDE: a Decision Support Tool to Facilitate Parents' Choices Regarding Genome-Wide Sequencing.

We describe the rationale, development, and usability testing for an integrated e-learning tool and decision aid for parents facing decisions about genome-wide sequencing (GWS) for their children with a suspected genetic condition. The online tool, DECIDE, is designed to provide decision-support and to promote high quality decisions about undergoing GWS with or without return of optional incidental finding results. DECIDE works by integrating educational material with decision aids. Users may tailor their learning by controlling both the amount of information and its format - text and diagrams and/or short videos. The decision aid guides users to weigh the importance of various relevant factors in their own lives and circumstances. After considering the pros and cons of GWS and return of incidental findings, DECIDE summarizes the user's responses and apparent preferred choices. In a usability study of 16 parents who had already chosen GWS after conventional genetic counselling, all participants found DECIDE to be helpful. Many would have been satisfied to use it alone to guide their GWS decisions, but most would prefer to have the option of consulting a health care professional as well to aid their decision. Further testing is necessary to establish the effectiveness of using DECIDE as an adjunct to or instead of conventional pre-test genetic counselling for clinical genome-wide sequencing.

Debris Flow Occurrence and Sediment Persistence, Upper Colorado River Valley, CO.

Debris flow magnitudes and frequencies are compared across the Upper Colorado River valley to assess influences on debris flow occurrence and to evaluate valley geometry effects on sediment persistence. Dendrochronology, field mapping, and aerial photographic analysis are used to evaluate whether a 19th century earthen, water-conveyance ditch has altered the regime of debris flow occurrence in the Colorado River headwaters. Identifying any shifts in disturbance processes or changes in magnitudes and frequencies of occurrence is fundamental to establishing the historical range of variability (HRV) at the site. We found no substantial difference in frequency of debris flows cataloged at eleven sites of deposition between the east (8) and west (11) sides of the Colorado River valley over the last century, but four of the five largest debris flows originated on the west side of the valley in association with the earthen ditch, while the fifth is on a steep hillslope of hydrothermally altered rock on the east side. These results suggest that the ditch has altered the regime of debris flow activity in the Colorado River headwaters as compared to HRV by increasing the frequency of debris flows large enough to reach the Colorado River valley. Valley confinement is a dominant control on response to debris flows, influencing volumes of aggradation and persistence of debris flow deposits. Large, frequent debris flows, exceeding HRV, create persistent effects due to valley geometry and geomorphic setting conducive to sediment storage that are easily delineated by valley confinement ratios which are useful to land managers.

Growth in neurofibromatosis 1 microdeletion patients.

Microdeletions of the entire NF1 gene and surrounding genomic region occur in about 5% of patients with neurofibromatosis 1 (NF1). NF1 microdeletion patients usually have more cutaneous and plexiform neurofibromas and a higher risk of developing malignant peripheral nerve sheath tumors than other people with NF1. Somatic overgrowth has also been observed in NF1 microdeletion patients, an observation that is remarkable because most NF1 patients are smaller than average for age and sex. We studied longitudinal measurements of height, weight, and head circumference in 56 patients with NF1 microdeletions and 226 NF1 patients with other kinds of mutations. Although children with NF1 microdeletions were much taller than non-deletion NF1 patients at all ages after 2 years, the lengths of deletion and nondeletion NF1 patients were similar in early infancy. NF1 microdeletion patients tended to be heavier than other NF1 patients, but height or weight more than 3 standard deviations above the mean for age and sex was infrequent in children with NF1 microdeletions. Head circumference and age of puberty were similar in deletion and non-deletion NF1 patients. The pattern of growth differs substantially in deletion and non-deletion NF1 patients, but the pathogenic basis for this difference is unknown.

Bipolar I and II versus unipolar depression: clinical differences and impulsivity/aggression traits.

OBJECTIVE: To investigate distinguishing features between bipolar I, II and unipolar depression, and impulsivity/aggression traits in particular. METHODS: Six hundred and eighty-five (n=685) patients in a major depressive episode with lifetime Unipolar (UP) depression (n=455), Bipolar I (BP-I) disorder (n=151), and Bipolar II (BP-II) (n=79) disorder were compared in terms of their socio-demographic and clinical characteristics. RESULTS: Compared to unipolar patients, BP-I and BP-II depressed patients were significantly younger at onset of their first depressive episode, and were more likely to experience their first depressive episode before/at age of 15. They also had more previous affective episodes, more first- and second-degree relatives with history of mania, more current psychotic and subsyndromal manic symptoms, and received psychopharmacological and psychotherapy treatment at an earlier age. Furthermore, BP-I and BP-II depressed patients had higher lifetime impulsivity, aggression, and hostility scores. With regard to bipolar subtypes, BP-I patients had more trait-impulsivity and lifetime aggression than BP-II patients whereas the latter had more hostility than BP-I patients. As for co-morbid disorders, Cluster A and B Personality Disorders, alcohol and substance abuse/dependence and anxiety disorders were more prevalent in BP-I and BP-II than in unipolar patients. Whereas the three groups did not differ on other socio-demographic variables, BP-I patients were significantly more often unemployed that UP patients. CONCLUSION: Our findings comport with major previous findings on differences between bipolar and unipolar depression. As for trait characteristics, bipolar I and II depressed patients had more life-time impulsivity and aggression/hostility than unipolar patients. In addition, bipolar I and II patients also differed on these trait characteristics.

Recurrent triploidy due to a failure to complete maternal meiosis II: whole-exome sequencing reveals candidate variants.

Triploidy is a relatively common cause of miscarriage; however, recurrent triploidy has rarely been reported. A healthy 34-year-old woman was ascertained because of 18 consecutive miscarriages with triploidy found in all 5 karyotyped losses. Molecular results in a sixth loss were also consistent with triploidy. Genotyping of markers near the centromere on multiple chromosomes suggested that all six triploid conceptuses occurred as a result of failure to complete meiosis II (MII). The proband's mother had also experienced recurrent miscarriage, with a total of 18 miscarriages. Based on the hypothesis that an inherited autosomal-dominant maternal predisposition would explain the phenotype, whole-exome sequencing of the proband and her parents was undertaken to identify potential candidate variants. After filtering for quality and rarity, potentially damaging variants shared between the proband and her mother were identified in 47 genes. Variants in genes coding for proteins implicated in oocyte maturation, oocyte activation or polar body extrusion were then prioritized. Eight of the most promising candidate variants were confirmed by Sanger sequencing. These included a novel change in the PLCD4 gene, and a rare variant in the OSBPL5 gene, which have been implicated in oocyte activation upon fertilization and completion of MII. Several variants in genes coding proteins playing a role in oocyte maturation and early embryonic development were also identified. The genes identified may be candidates for the study in other women experiencing recurrent triploidy or recurrent IVF failure.

Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.

Incidental findings from clinical genome-wide sequencing: a review.

There are several unresolved challenges associated with the clinical application of genome-wide sequencing technologies. One of the most discussed issues is incidental findings (IF), which are defined as discoveries made as a result of genetic testing that are unrelated to the indication for the test. The discussion surrounding IF began in the context of research, which we have used to frame consideration of IF in the clinical context. There is growing consensus that analytically valid and medically actionable IF should be offered to patients, but whether and to what extent clinicians should disclose other kinds of IF is debated. While others have systematically reviewed the literature concerning genetic IF, previous reviews focus on ethical and research-related issues and do not consider the implications for the genetic counseling profession specifically. This review discusses the practical considerations, ethical concerns and genetic counseling issues related to IF, with a particular focus on clinical genome-wide sequencing. To date, the bulk of the literature with respect to IF in the clinical context consists of commentaries, reviews and case reports. There is a need for more empirical studies to provide a foundation for institutional protocols and evidence-based clinical practice standards.

The generalized bone phenotype in children with neurofibromatosis 1: a sibling matched case-control study.

People with neurofibromatosis 1 (NF1) have low bone mineralization, but the natural history and pathogenesis are poorly understood. We performed a sibling-matched case-control study of bone mineral status, morphology, and metabolism. Eighteen children with NF1 without focal bony lesions were compared to unaffected siblings and local population controls. Bone mineral content at the lumbar spine and proximal femur (dual energy X-ray absorptiometry (DXA)) was lower in children with NF1; this difference persisted after adjusting for height and weight. Peripheral quantitative computed tomography (pQCT) of the distal tibia showed that trabecular density was more severely compromised than cortical. Peripheral QCT-derived estimates of bone strength and resistance to bending and stress were poorer among children with NF1 although there was no difference in fracture frequencies. There were no differences in the size or shape of bones after adjusting for height. Differences in markers of bone turnover between cases and controls were in the directions predicted by animal studies, but did not reach statistical significance. Average serum calcium concentration was higher (although within the normal range) in children with NF1; serum 25-OH vitamin D, and PTH levels did not differ significantly between cases and controls. Children with NF1 were less mature (assessed by pubertal stage) than unaffected siblings or population controls. Children with NF1 have a generalized difference of bone metabolism that predominantly affects trabecular bone. Effects of decreased neurofibromin on bone turnover, calcium homeostasis, and pubertal development may contribute to the differences in bone mineral content observed among people with NF1.

Hospitalizations among people with Down syndrome: a nationwide population-based study in Denmark.

Most persons with Down syndrome (DS) now survive to adulthood, but their health care needs beyond childhood are not well described. We followed a national cohort of 3,212 persons with DS and a reference cohort of persons without DS through the Danish National Hospital Register from January 1, 1977, to May 31, 2008. Poisson regression was used to calculate rate ratios for numbers of overnight hospital admissions and hospital days. During the study period, persons with DS had more than twice the rate of hospital admissions and nearly three times as many bed-days as the population as a whole. Malformations, diseases of the respiratory system, and diseases of the nervous system or sensory organs were the principal indications for hospital admissions. The higher rate ratios for hospital admissions were seen especially among persons less than 20 years of age. Hospitalizations for neoplasms or for diseases of the musculoskeletal system or connective tissue were much less frequent among adults with DS. As survival among persons with DS continues to improve, these findings are likely to be useful for health care planning, although the potential utility may be different for different health care systems.

Cardiac characterization of 16 patients with large NF1 gene deletions.

The aim of this study was to characterize cardiac features of patients with neurofibromatosis 1 (NF1) and large deletions of the NF1 gene region. The study participants were 16 patients with large NF1 deletions and 16 age- and sex-matched NF1 patients without such deletions. All the patients were comprehensively characterized clinically and by echocardiography. Six of 16 NF1 deletion patients but none of 16 non-deletion NF1 patients have major cardiac abnormalities (p = 0.041). Congenital heart defects (CHDs) include mitral insufficiency in two patients and ventricular septal defect, aortic stenosis, and aortic insufficiency in one patient each. Three deletion patients have hypertrophic cardiomyopathy. Two patients have intracardiac tumors. NF1 patients without large deletions have increased left ventricular (LV) diastolic posterior wall thickness (p < 0.001) and increased intraventricular diastolic septal thickness (p = 0.001) compared with a healthy reference population without NF1, suggestive of eccentric LV hypertrophy. CHDs and other cardiovascular anomalies are more frequent among patients with large NF1 deletion and may cause serious clinical complications. Eccentric LV hypertrophy may occur in NF1 patients without whole gene deletions, but the clinical significance of this finding is uncertain. All patients with clinical suspicion for NF1 should be referred to a cardiologist for evaluation and surveillance.

Striatal dopamine release in schizophrenia comorbid with substance dependence.

Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies have indicated that striatal DA release is increased in schizophrenia, predominantly in the precommissural caudate (preDCA), and blunted in addiction, mostly in the ventral striatum (VST). Therefore, we aimed to measure striatal DA release in patients with comorbid schizophrenia and substance dependence. We used [(11)C]raclopride positron emission tomography and an amphetamine challenge to measure baseline DA D2-receptor availability (BPND) and its percent change post-amphetamine (ΔBPND, to index amphetamine-induced DA release) in striatal subregions in 11 unmedicated, drug-free patients with both schizophrenia and substance dependence, and 15 healthy controls. There were no significant group differences in baseline BPND. Linear mixed modeling using ΔBPND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1,24)=8.38, P=0.008, with significantly smaller ΔBPND in patients in all striatal subregions (all P ≤ 0.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with ΔBPND in the preDCA (rs=0.69, P=0.03) and VST (rs=0.64, P=0.05). In conclusion, patients with comorbid schizophrenia and substance dependence showed significant blunting of striatal DA release, in contrast to what has been found in schizophrenia without substance dependence. Despite this blunting, DA release was associated with the transient amphetamine-induced positive-symptom change, as observed in schizophrenia. This is the first description of a group of patients with schizophrenia who display low presynaptic DA release, yet show a psychotic reaction to increases in D2 stimulation, suggesting abnormal postsynaptic D2 function.

Survival among people with Down syndrome: a nationwide population-based study in Denmark.

PURPOSE: Several studies have shown substantially longer survival among persons with Down syndrome in recent decades. We examined survival patterns among Danish persons with Down syndrome by karyotype. METHODS: A national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population were followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System. RESULTS: Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% confidence interval 3.51-7.08), 8.94 (8.32-9.60), and 10.23 (7.50-13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects. CONCLUSION: Recent birth cohorts of persons with Down syndrome experienced declining mortality, likely due to treatment for congenital heart defects, and persons with mosaic trisomy 21 had better survival than persons with other Down syndrome karyotypes.

Low-pass genome-wide sequencing and variant inference using identity-by-descent in an isolated human population.

Whole-genome sequencing in an isolated population with few founders directly ascertains variants from the population bottleneck that may be rare elsewhere. In such populations, shared haplotypes allow imputation of variants in unsequenced samples without resorting to complex statistical methods as in studies of outbred cohorts. We focus on an isolated population cohort from the Pacific Island of Kosrae, Micronesia, where we previously collected SNP array and rich phenotype data for the majority of the population. We report identification of long regions with haplotypes co-inherited between pairs of individuals and methodology to leverage such shared genetic content for imputation. Our estimates show that sequencing as few as 40 personal genomes allows for inference in up to 60% of the 3000-person cohort at the average locus. We ascertained a pilot data set of whole-genome sequences from seven Kosraean individuals, with average 5× coverage. This assay identified 5,735,306 unique sites of which 1,212,831 were previously unknown. Additionally, these variants are unusually enriched for alleles that are rare in other populations when compared to geographic neighbors (published Korean genome SJK). We used the presence of shared haplotypes between the seven Kosraen individuals to estimate expected imputation accuracy of known and novel homozygous variants at 99.6% and 97.3%, respectively. This study presents whole-genome analysis of a homogenous isolate population with emphasis on optimal rare variant inference.

Valuing gene testing in children with possible neurofibromatosis 1.

With the growing number of clinical guidelines recommending genetics tests in routine clinical care, the value of these tests should be evaluated. We examined the economic value of offering genetic testing to children with possible neurofibromatosis 1 (NF1) in British Columbia. Diagnosis of NF1 is usually made based on diagnostic clinical criteria, but molecular diagnostic testing, currently offered on a case-by-case basis in BC, now reliably diagnoses NF1 in 95% of cases. Children who present with some clinical features but whose findings are insufficient to meet the diagnostic criteria are labelled as having 'possible NF1'. Current guidelines call for these children to be followed as they have NF1, leading to annual ophthalmologic examinations and screening for complications; thus, there are increased costs to health care system. We created a model to account for these costs to the health care system, comparing the current protocol with one that would offer all children diagnosed with possible NF1 with genetic testing. Focusing on the incremental cost allowed us to determine that genetic testing provides good value, and patient interviews provided insight into the qualitative benefits of an earlier firm diagnosis. These findings may be helpful in guiding health policy decision-making.

How do we know if an exposure is actually teratogenic in humans?

The only way we can be certain that an exposure is teratogenic in humans is to recognize that it causes birth defects in babies. The goal of clinical teratology research is, therefore, to identify when a teratogenic exposure has harmed babies as quickly and effectively as possible. We use several kinds of human data to characterize teratogenic effects-case reports, case series, pregnancy registries, cohort studies, case-control studies, and record linkage studies. Each approach can be helpful, but each has limitations as well. Drawing a causal inference requires analysis of all available data, their consistency, and their biological plausibility.

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.