Current Challenges to Appropriate Clinical Use of New Genetic Knowledge in Different Countries.

Objective: To describe the challenges facing countries all over the world regarding the appropriate clinical use of genetics in their health care systems. Methods and Results: Aspects of the economic and social contexts in different countries which are of particular relevance to shaping the existing challenges are outlined. Issues which are relevant (but of different prominence) in all countries in providing genetic services are discussed. Conclusions: The challenges facing the provision of appropriate genetic services differ markedly in four major groups of countries. These challenges range from controlling inappropriate commercialization and the overuse of genetic approaches to putting in place even minimal basic community genetics services in countries where the infant mortality rate has fallen to a range where genetic and congenital disorders contribute substantially to ongoing handicap and early mortality. Copyright 2001 S. Karger AG, Basel

Genetic technologies and achieving health for populations.

The remarkable progress in genetics over the last 50 years has led to the development of genetic technologies to identify or alter genes in living organisms, and these technologies can be applied to people. This article presents background information on the role of genetics in human disease, outlines the technologies, and discusses the sources of the strong push for a genetic approach to ill-health and some implications and harmful consequences of using these genetic technologies. The determinants of most diseases are complex and are embedded in a social context. To focus on only one strand of this web--the genetic strand--because it is one that may be amenable to biological/pharmaceutical treatment, although profitable for industry, does not address other important determinants of health and may lead to a harmful overemphasis on genetic approaches. The author outlines some limitations to the potential contribution of genetic technologies to population health across the globe and the need for policy development if these technologies are to have an appropriate place in health care.

Prenatal screening and the reduction of birth defects in populations.

OBJECTIVES: Birth defects occur in populations in 3-5% of births. This paper assesses whether population-wide screening programmes for pregnant women would be likely to result in major decreases in the prevalence of birth defects. METHOD: Relevant literature on this question is reviewed and synthesized. RESULTS: Given certain assumptions, a decrease from 3-5 to 2-4% in the prevalence of defects at birth may be possible. The resources required to put in place an appropriately delivered programme to achieve this are substantial. CONCLUSIONS: As well as the potential benefit of a decrease, there are opportunity costs, and potential serious harms. Unless undertaken in a carefully planned and monitored way, a population-based birth defects reduction programme is likely to bring harm and anxiety rather than benefit.

Funding medical and health-related research in the public interest.

Public funding for medical and health-related research in Canada is declining. At the same time, the pharmaceutical industry is directing increasing amounts of money to publicly funded agencies such as universities and the Medical Research Council of Canada. However, the kinds of research most valuable to commercial firms may not be those most valuable to the Canadian public. There is a danger that research priorities and activities in public institutions may become skewed as a result of increased drug-industry funding. Mechanisms need to be found to ensure an appropriate balance between the research that is most valuable to the public interest and to the long-term advancement of knowledge, and the research that is likely to lead to marketable products. One such mechanism is the direction of a proportion of the money from drug companies to a "no-strings-attached" fund specifically to support types of research that are in the public interest but not likely to lead to marketable products.

Sex ratios in fetuses and liveborn infants with autosomal aneuploidy.

Ten data sources were used substantially to increase the available data for estimating fetal and livebirth sex ratios for Patau (trisomy 13), Edwards (trisomy 18), and Down (trisomy 21) syndromes and controls. The fetal sex ratio estimate was 0.88 (N = 584) for trisomy 13, 0.90 (N = 1702) for trisomy 18, and 1.16 (N = 3154) for trisomy 21. All were significantly different from prenatal controls (1.07). The estimated ratios in prenatal controls were 1.28 (N = 1409) for CVSs and 1.06 (N = 49427) for amniocenteses, indicating a clear differential selection against males, mostly during the first half of fetal development. By contrast, there were no sex ratio differences for any of the trisomies when comparing gestational ages < 16 and > 16 weeks. The livebirth sex ratio estimate was 0.90 (N = 293) for trisomy 13, 0.63 (N = 497) for trisomy 18, and 1.15 (N = 6424) for trisomy 21, the latter two being statistically different than controls (1.05) (N = 3660707). These ratios for trisomies 13 and 18 were also statistically different than the ratio for trisomy 21. Only in trisomy 18 did the sex ratios in fetuses and livebirths differ, indicating a prenatal selection against males > 16 weeks. No effects of maternal age or race were found on these estimates for any of the fetal or livebirth trisomies. Sex ratios for translocations and mosaics were also estimated for these aneuploids. Compared to previous estimates, these results are less extreme, most likely because of larger sample sizes and less sample bias. They support the hypothesis that these trisomy sex ratios are skewed at conception, or become so during embryonic development through differential intrauterine selection. The estimate for Down syndrome livebirths is also consistent with the hypothesis that its higher sex ratio is associated with paternal nondisjunction.

Ethical issues of fertility and reproduction.

How reproductive technologies are used has consequences not just for immediate users but for others as well. This article discusses issues that should be taken into consideration in coming to decisions about whether or not it is appropriate to use a particular reproductive technology, or whether to use a technology in a particular way.

Sibling risks of abdominal aortic aneurysm.

There is evidence that the risk of abdominal aortic aneurysm (AAA) is greater in first-degree relatives of patients with the disorder than in the same age group of the general population. We conducted a 3-year study of siblings of AAA probands and siblings of a control group (cataract surgery patients) of the same age. Genetic information was obtained by interview from 126 probands and 100 controls; another family member was present at the interview. Medical records were obtained and further information verified before a sibling (over age 50) was assigned affected status. Of 427 siblings of probands, 19 (4.4%) had probable or definite AAA, compared with five (1.1%) of 451 siblings of controls. The lifetime cumulative risks of AAA at age 83 were 11.7% (SD 3.1) and 7.5% (4.1), respectively. The risk of AAA began at an earlier age and increased more rapidly for probands' siblings than for controls' siblings (p < 0.01, log-rank test). A risk comparison, based on the results of ultrasound screening of 54 geographically accessible siblings of probands and the 100 controls showed a similar pattern. Ten (19%) siblings of probands and eight (8%) controls had AAA on ultrasound (lifetime cumulative risk 60.8% [18.9] vs 14.9% [5.1], p = 0.01). These results show that familial factors influence the age of onset of AAA. We recommend routine ultrasound examination of siblings of patients with AAA.

Paternal age and the risk of birth defects in offspring.

Previous studies have shown that advanced paternal age is associated with an increase in new dominant mutations that may result in some rare congenital anomalies or syndromes in the offspring. Nevertheless, few epidemiologic studies have evaluated the effect of paternal age on the risk of more common birth defects. We examined data from the British Columbia Health Surveillance Registry, which included a total of 9,660 cases of birth defects (22 specific defect groups). We chose matched controls from the birth files of British Columbia (1952-1973). With the exception of an unusual change in direction in the 45-49 years age category, we found a general pattern of increasing relative risk estimates (adjusted for maternal age and other factors) with increasing paternal age for neural tube defects, congenital cataracts, reduction defects of the upper limb, and Down syndrome. For example, the adjusted relative risk estimates for neural tube defects in the offspring were 1.2 (for fathers age 30-34 years relative to 25-29 years); 1.3 (35-39); 1.6 (40-44); 0.6 (45-49); and 2.3 (men 50 years and older). Men under 20 years of age were also at increased risk for fathering children with birth defects such as neural tube defects, hypospadias, cystic kidney, and Down syndrome. We hypothesize that among certain commonly observed birth defects a subgroup of cases may be due to new, unrecognized dominant mutations.

Population-based study of long-term outcomes after amniocentesis.

Amniocentesis is now commonly used in many countries; it is important to know whether there are any long-term adverse effects on children born after this procedure, in particular disabilities that may emerge during childhood or adolescence. We studied consecutive liveborn offspring of women who had had amniocentesis and compared them with matched controls whose mothers had not had amniocentesis. The controls were matched for age of mother, residence by geographic health unit, sex, and when the birth occurred. 1296 cases and 3704 controls were studied. With the exception of one disorder, the offspring of women who had had amniocentesis were no more likely than controls to have a registrable disability (such as hearing disabilities, learning difficulties, visual problems, and limb anomalies) during childhood and adolescence. The follow-up period was 7-18 years. Children of women who had amniocentesis had a significantly higher rate of haemolytic disease due to ABO isoimmunisation than matched controls. The results of this study should therefore be reassuring to women having amniocentesis, and be useful to women making decisions about having this procedure.

Paternal age and the risk of congenital heart defects.

The effect of paternal age on the risk of birth defects among offspring is less well studied than the effect of maternal age, with few comprehensive epidemiologic studies having been conducted. Advanced paternal age has been shown to be associated with an increase in new dominant mutations that result in particular congenital anomalies. The relationship between paternal age and more common birth defects, for example, cardiac defects, has not been as extensively evaluated. Therefore, a total of 4,110 cases of congenital heart defects was identified from the British Columbia Health Surveillance Registry. Matched controls were obtained from the birth files of British Columbia for the years 1952-1973. Prevalence odds ratios for paternal age, adjusted for maternal age and other factors, were estimated for 8 cardiac defect groups. A suggestive general pattern of increasing risk with increasing age among cases (excluding chromosomal anomalies) relative to controls was found for ventricular septal defects (VSD), atrial septal defects (ASD), and patent ductus arteriosus (PDA). In addition, an increased risk among men younger than 20 yr was found for VSD and ASD. These findings are consistent with the results of some previous epidemiologic studies. Based on the results of this study it is estimated that for cardiac defects such as VSD, approximately 5% of cases may be due to advanced paternal age (> 35 yr), possibly through dominant mutations.

Maternal age and oral cleft malformations: data from a population-based series of 576,815 consecutive livebirths.

It has been suggested that older mothers are more likely to have a child with isolated cleft palate (CP) or cleft lip +/- cleft palate (CL +/- CP), but most of these studies have been based on fairly small sample sizes. Data from a population-based registry with multiple sources of case ascertainment were used to examine any association of maternal age with the incidence of these defects in infants without other congenital anomalies. The study group consisted of all cases with CP or CL +/- CP without other congenital anomalies from a series of over half a million consecutive livebirths during the period 1966 to 1981 inclusive in British Columbia. During the study period, the overall incidences of isolated CP and isolated CL +/- CP per 10,000 livebirths were 3.9 and 8.2, respectively. No association with maternal age was found when either isolated CP or isolated CL +/- CP was analyzed as a group. When analyzed by sex, and by CP or CL +/- CP, no significant maternal-age effect was observed for males and females with CP or CL +/- CP. Our population-based data, therefore, do not show that older mothers are more likely to have a child with cleft palate, or cleft lip +/- cleft palate.

Mood Disorder Service Genetic Database: morbidity risks for mood disorders in 3,942 first-degree relatives of 671 index cases with single depression, recurrent depression, bipolar I, or bipolar II.

There is increasing evidence that genetic factors play a role in the etiology of mood disorders. As a result, relatives of affected individuals are more often asking about their own risks to develop a mood disorder. From 1988 to 1990, all consecutive, unrelated inpatients and outpatients (index cases) presenting to the Mood Disorders Service, Department of Psychiatry, University of British Columbia, had detailed family histories taken, thus creating the Mood Disorders Service Genetic Database. Diagnoses for index cases and their first-degree relatives were made according to Research Diagnostic Criteria and Family History Research Diagnostic Criteria respectively. Morbidity risks for mood disorders were calculated for first-degree relatives (parents, siblings, children--aged 10 and above) of all index cases with a diagnosis of single depression, recurrent depression, bipolar I, or bipolar II disorder. Morbidity risks were calculated using the maximum likelihood approach. Morbidity risk data are presented according to the sex and diagnosis for the index case in an easy reference format for risk counselling. The risks are presented twice, including and excluding data for "high-risk" families whose genetic pedigree is suggestive of "autosomal dominant" inheritance.

Maternal factors, medications, and drug exposure in congenital limb reduction defects.

As part of an ongoing study on all limb reduction defects occurring among 1,213,913 consecutive live births in the province of British Columbia, Canada, during 1952-1984, cases with documented maternal drug exposure and chronic maternal diseases were analyzed separately. This population-based study was made possible through the existence of an ongoing Health Surveillance Registry, which documents all infants born with congenital, genetic, or chronically handicapping conditions in the province of British Columbia. Strict rules of confidentiality are obeyed. For this part of the analysis of limb reduction defects, cases with documented maternal illness, drug abuse, and exposure to environmental hazards early in pregnancy were analyzed as a separate group to identify specific, recurring patterns of anomalies. A total of 51 cases with possibly related maternal factors were identified. Among them were five cases with maternal epilepsy, four cases with documented maternal diabetes, and three cases with uterine anomalies. Three infants, all born in 1962, had documented thalidomide exposure. It is rarely possible to identify particular teratogenic factors or specific maternal factors as etiologically related to the pattern of limb reduction defects or a spectrum of congenital malformations. Exposure to environmental factors during pregnancy is not reliably registered and can thus only occasionally be ascertained in retrospective studies. This means that very large numbers of cases and cross-referencing to other family members are required to assess whether a potential teratogen is related to limb defects or not.

Congenital defects of the limbs in stillbirths: data from a population-based study.

We analyzed limb deficiencies occurring in stillbirths with congenital anomalies registered in the Health Surveillance Registry of British Columbia between the years 1964 and 1984. Thirty stillborn infants presenting with various defects of the limbs were found during this time, giving an incidence of 39.52 in 10,000 stillbirths (1:253). This incidence is significantly higher than the incidence among liveborn individuals in the Province (5.97 in 10,000 livebirths or 1:1,842). Most cases involved the upper limbs, and most frequently the radius. Additional anomalies were present in 77% of cases, compared to 48% in liveborns. The study of stillbirths with congenital anomalies provides important information regarding the spectrum of birth defects seen in this group. This may be of relevance because of improved survival possibilities due to advances in perinatal care.

Amniotic band sequence and limb defects: data from a population-based study.

Cases with amniotic bands were analysed separately as part of an ongoing study of limb defects occurring among 1,213,913 liveborn infants in British Columbia during the years 1952 to 1984. A total of 24 cases with this specific condition was identified among 659 cases with limb defects. The calculated incidence for amniotic band sequence with significant limb involvement was 0.19 in 10,000 livebirths. This is a minimal incidence, as cases without defects of the limbs, but with constriction rings were not identified with this approach. Familial cases and cases with additional anomalies were found.

Congenital defects of lower limbs and associated malformations: a population based study.

As part of a detailed study of limb defects and associated patterns of congenital malformations, cases with lower limb deficiencies were analysed separately. We identified a total of 130 cases with deficiencies of the lower limbs without defects of the upper limbs. This gives an incidence of 1.07/10,000 livebirths, or 1/9,337 for this group of limb defects. Most common were femur deficiencies and deficiencies of the foot. A preponderance of males was found in the group of transverse defects of the leg (fibula/tibia deficiencies) and central axis deficiencies, while females had significantly more often longitudinal tibia defects and preaxial ray defects.