Prevalence of neural tube defects in South Australia, 1966-91: effectiveness and impact of prenatal diagnosis.

OBJECTIVE--To determine trends in total prevalence of neural tube defects in South Australia during 1966-91, the impact of prenatal diagnosis on birth prevalence, and the effectiveness of prenatal screening for neural tube defects in 1986-91. DESIGN--All births and terminations of pregnancy affected by neural tube defects and information on prenatal screening were ascertained from multiple sources including the South Australian perinatal and abortion statistics collections, birth defects register, and state maternal serum alpha fetoprotein screening programme. SETTING--Southern Australia. SUBJECTS--All 1058 births and terminations of pregnancy affected by neural tube defects in 1966-91. MAIN OUTCOME MEASURES--Total prevalence and birth prevalence of individual and all neural tube defects. The proportion of screened cases detected prenatally. RESULTS--Total prevalence of neural tube defects during 1966-91 was 2.01/1000 births with no upward or downward trend. However, birth prevalence fell significantly (by 5.1% a year), with an 84% reduction from 2.29/1000 births in 1966 to 0.35/1000 in 1991 (relative risk = 0.16, 95% confidence interval 0.07 to 0.34). The fall was 96% for anencephaly and 82% for spina bifida. 85% of defects, both open and closed, were detected before 28 weeks'' gestation in women screened by serum alpha fetoprotein or mid-trimester ultrasonography, or both, in 1986-91 (99.0% for anencephaly and 75.7% for spina bifida). CONCLUSIONS--While the total prevalence of neural tube defects in South Australia remained stable, prenatal diagnosis and termination of pregnancy resulted in an 84% fall in birth prevalence during 1966-91. Screening detected over four fifths of cases in 1986-91.     

Activity of enzymes in amniotic fluid in prenatal diagnosis of cystic fibrosis

The activity of microvillar enzymes--gamma-glutamyltranspeptidase, aminopeptidase, general and intestinal forms of alkalyne phosphotases was studied in amniotic fluid (AF) of 33 women with 25% risk of cystic fibrosis (CF) (mucoviscidoses) in their progeny. The figures obtained in this group were compared with corresponding values of the same enzymes in 100 AF samples from normal pregnancies (negative control) and with 9 AF samples from women which were known to give birth to the children with CF (positive control). CF has been predicted in 5 cases, pregnancies were artificially terminated in 4 women. Biochemical CF prediction was proved by immunochemical assay of albumin contents in meconium of fetal ileum. One woman from the high risk group refused abortion and gave birth to a CF child. Among 26 cases of low CF prediction, 13 resulted in birth of a child without a sign of CF, one - in a child with clear-cut diagnosis of CF and 12 other pregnancies still proceed. The efficiency of complex biochemical, pathomorphological and molecular approaches for verification of intrauterine CF diagnosis in aborted fetuses as well as for detection of heterozygous carriers of CF gene and prenatal diagnosis of CF is discussed.     

Audit of prenatal diagnosis for haemoglobin disorders in the United Kingdom: the first 20 years.

OBJECTIVES: To audit services for prenatal diagnosis for haemoglobin disorders in the United Kingdom. DESIGN: Comparison of the annual number of cases recorded in a United Kingdom register of prenatal diagnoses for haemoglobin disorders, with the annual number of pregnancies at risk of these disorders, by ethnic group and regional health authority. The number of pregnancies at risk was estimated using data on ethnic group from the 1991 census and data from the United Kingdom thalassaemia register, which records the number of babies born with thalassaemia. SETTING: The three national prenatal diagnosis centres for haemoglobin disorders. SUBJECTS: 2068 cases of prenatal diagnosis for haemoglobin disorders in the United Kingdom from 1974 to 1994. MAIN OUTCOME MEASURES: Utilisation of prenatal diagnosis by risk, ethnic group, and regional health authority. Proportion of referrals in the first trimester and before the birth of any affected child. RESULTS: National utilisation of prenatal diagnosis for haemoglobin disorders was around 20%. During the past 10 years it has remained steady at about 50% for thalassaemias and risen from 7% to 13% for sickle cell disorders. Utilisation for sickle cell disorders varies regionally from 2% to 20%. Utilisation for thalassaemias varies by ethnic group. It is almost 90% for Cypriots and ranges regionally for British Pakistanis from 0% to over 60%. About 60% of first prenatal diagnoses are done for couples without an affected child. Less than 50% of first referrals are in the first trimester. CONCLUSIONS: National utilisation of prenatal diagnosis for haemoglobin disorders is far lower than expected, and there are wide regional variations. A high proportion of referrals are still in the second trimester and after the birth of an affected child. The findings point to serious shortcomings in present antenatal screening practice and in local screening policies and to inadequate counselling resources, especially for British Pakistanis.     

Prenatal diagnosis for recessive dystrophic epidermolysis bullosa in 10 families by mutation and haplotype analysis in the type VII collagen gene (COL7A1).

BACKGROUND: Epidermolysis bullosa (EB) is a group of heritable diseases that manifest as blistering and erosions of the skin and mucous membranes. In the dystrophic forms of EB (DEB), the diagnostic hallmark is abnormalities in the anchoring fibrils, attachment structures beneath the cutaneous basement membrane zone. The major component of anchoring fibrils is type VII collagen, and DEB has been linked to the type VII collagen gene (COL7A1) at 3p21, with no evidence for locus heterogeneity. Due to life-threatening complications and significant long-term morbidity associated with the severe, mutilating form of recessive dystrophic EB (RDEB), there has been a demand for prenatal diagnosis from families with affected offspring. MATERIALS AND METHODS: Intragenic polymorphisms in COL7A1 and flanking microsatellite markers on chromosome 3p21, as well as detection of pathogenetic mutations in families, were used to perform PCR-based prenatal diagnosis from DNA obtained by chorionic villus sampling at 10-15 weeks or amniocentesis at 12-15 weeks gestation in 10 families at risk for recurrence of RDEB. RESULTS: In nine cases, the fetus was predicted to be normal or a clinically unaffected carrier of a mutation in one allele. These predictions have been validated in nine cases by the birth of a healthy child. In one case, an affected fetus was predicted, and the diagnosis was confirmed by fetal skin biopsy. CONCLUSIONS: DNA-based prenatal diagnosis of RDEB offers an early, expedient method of testing which will largely replace the previously available invasive fetal skin biopsy at 18-20 weeks gestation.     

High incidence of profound deafness in an isolated community

In a Muslim Israeli Arab village, different types of hearing loss affect some 2% of the inhabitants. Most cases of profound deafness are due to recessive mutations in the Connexin-26 gene. Since in this community, marriages are by preference within the family (consanguineous), for many of the couples from the village the risk for an affected child is high. There are 30 families living in the village in which both parents have normal hearing and at least one child has a profound hearing defect. In these families, the birth of a child with profound deafness did not change family planning. The rate of marriage was similar for the siblings of deaf children as for other individuals in the village. The major problems were encountered by the deaf individuals themselves; in particular, most of the women were not married. Because of the distinctive nature of this particular problem, different types of screening programs were envisaged. However, all of them are problematic. Therefore, as a first step it was decided to begin a program including individual genetic counseling together with education of the entire population on practical aspects of human genetics.     

Prenatal diagnosis of spinal muscular atrophy in Macedonian families

Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disorder of childhood, affecting approximately 1 in 6,000-10,000 births, with a carrier frequency of 1 in 40-60. There is no effective cure or treatment for this disease. Thus, the availability of prenatal testing is important. The aim of this study was to establish an efficient and rapid method for prenatal diagnosis of SMA and genetic counseling in families with risk for having a child with SMA. In this paper we present the results from prenatal diagnosis in Macedonian SMA families using direct analysis of fetal DNA. The probands of these families were previously found to be homozygous for a deletion of exons 7 and 8 of SMN1 gene. DNA obtained from chorionic villas samples and amniocytes was analyzed for deletions in SMN gene. SMN exon 7 and 8 deletion analysis was performed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Of the 12 prenatal diagnoses, DNA analysis showed normal results in eight fetuses. Four of the fetuses were homozygote for a deletion of exons 7 and 8 of SMN1. After genetic counseling, the parents of the eight normal fetuses decided to continue the pregnancy, while in the four families with affected fetuses, the pregnancy was terminated. The results were confirmed after birth.     

Prenatal diagnosis and characteristics of chromosome aberrations in families with genetic risk

Characteristics of the chromosomal aberrations diagnosed in 959 prenatal tests in the II trimester of pregnancy is presented. Chromosomal aberrations were diagnosed in 33 tests (3.4%). Twenty one out of these aberrations (2.2%) were of labile character. Six aberrations resulted from the parental segregation, translocation or chromosomal inversion. In 12 cases fetus inherited stable aberration from one of parents. It amounted to 1.2% of all tested cases. Chromosomal aberrations were diagnosed in 2.7% cases tested due to the risk related to the mother's age. Half of them was trisomy of chromosome 21. Chromosomal aneuploidy in the progeny of families with a child with the same abnormality was diagnosed in 1.6% of cases. Chromosomal mosaicism was diagnosed in 2.2% of cases including 0.2% of cases with true mosaicism and 1.98% of cases with pseudomosaicism. Incidence and type of the diagnosed chromosomal aberrations coincided with foreseen aberrations for each group of the genetic risk.     

Stillbirth pattern in an isolated mediterranean population: La Alpujarra, Spain

This study attempted to analyze the effect of several factors on the stillbirth pattern in a relatively isolated rural population, La Alpujarra (Spain), during the first half of the 20th century. The study was a retrospective analysis from a total sample of 2199 births to 525 mothers, allowing for birth year of mother, maternal age, parental inbreeding, family size, birth order, sex, single/twin delivery, and birth interval. Binomial probability distribution of stillbirths provided no evidence for any significantly increased risk in relation to family size. Analysis of covariance (ANCOVA) of stillbirth risk in affected families indicated a significant effect for sex of the child, parental consanguinity, and birth year of mother. Logistic regression showed increased risk in twin delivery and pregnancy order one, but not for birth order other than one. Multivariate analysis of variance (MANOVA) testing for differences between affected and unaffected families supported a temporal decrease of stillbirths during the period studied. Although the birth interval average was significantly shorter in affected families (p < 0.0001), this association did not hold, in a more detailed analysis, for individual intervals in these families (p = 0.20). There was no significant effect of maternal age on stillbirths in the whole sample or limited to first pregnancies. These results suggest that birth order one and twin delivery were the main determinants of the stillbirth pattern in La Alpujarra. Furthermore, our data indicate that the decline in stillbirth rate began before medical facilities for perinatal care became available, which was not until after 1950. The temporal decrease in stillbirth rates may therefore be related to an increasing social attention to deliveries rather than to prenatal care medical facilities.     

Impact of public health strategies on the birth prevalence of cystic fibrosis in Brittany,France

Taking into account the situation of Brittany, a region of western France where cystic fibrosis (CF) is common and where a neonatal screening program was set up 14 years ago, the aim of this study was to determine the way in which the birth prevalence of CF has been influenced by the various public health strategies implemented in the region (neonatal screening, prenatal diagnosis, ultrasound examination and family testing). This study used the results of the neonatal screening program, which enabled a precise measure of the prevalence of CF at birth to be obtained. Over the same period, we collected data from prenatal diagnoses carried out in the region, first in families related to a CF child and also those made following the detection of an echogenic bowel upon routine ultrasound examination performed during pregnancy. The prevalence of CF at birth was estimated to be 1/2838 in the region over a 10-year period (1992-2001). By including the 54 CF-affected pregnancies that were terminated during these 10 years, the corrected birth prevalence of CF was 1/1972. Prenatal diagnosis was therefore responsible for a global decrease in CF prevalence at birth of 30.5%. This work constitutes the first study able to provide a precise measure of CF birth prevalence and of its evolution through the combined effects of neonatal screening, prenatal diagnosis, ultrasound examination and family testing.     

Fertility in couples heterozygous for the tyrosinemia gene in Saguenay Lac-St-Jean

A case-control study of 84 couples from Saguenay-Lac-St-Jean, jointly heterozygous for the tyrosinemia gene, was done to determine whether the birth of an homozygous child affected their fertility rates. The mean number of children born to tyrosinemia and control couples between 1940 and 1986 was not different (p greater than 0.05). The knowledge that tyrosinemia was an autosomal recessive disorder, with risk of recurrence in these families, did not appear to modify reproductive behaviour. Fertility fell significantly in both the tyrosinemia and control families in the period of observation. This change reflects the decline in fertility of French Canadians in general during this period.     

Prenatal diagnosis of sickle hemoglobinopathies: The experience of the Columbia university comprehensive center for sickle cell disease

We report here an evaluation of 55 pregnancies at risk for a sickle hemoglobinopathy prenatally diagnosed by restriction-endonuclease analysis, with the endonucleases MstII and HpaI, of amniocyte DNA. The diagnosis was completed in all cases. Eleven fetuses were predicted to be affected, of which six were terminated. Forty-one of the 55 cases were confirmed. One false-negative was reported in a case predicted to be hemoglobin AS but that was determined to be hemoglobin SS at birth. We estimate that the 55 cases represent only 5% of the pregnancies at risk for a sickle hemoglobinopathy in the New York metropolitan area during the study period. We conclude that the prenatal diagnosis of sickle hemoglobinopathies by molecular methods is reliable. However, the efficiency of utilization and effectiveness of prenatal testing is dependent on the early prospective identification of couples at risk and on the education of communities concerning the significant morbidity of the sickle hemoglobinopathies and the reproductive choices now available to them.     

Reproductive patterns and thalassaemia major

This study investigated the effect of the diagnosis of transfusion-dependent homozygous beta-thalassemia on subsequent parental reproductive patterns in 44 families in New South Wales. The results indicate a shift over time from parental risk-taking (either consciously or in ignorance of the implications of the diagnosis) to premature curtailment of reproduction to the likelihood of attaining birth expectations through antenatal diagnosis. 67% of families with both of their 1st 2 children affected by thalassemia major had additional children, compared with 38% of those where the 1st child was affected and the 2nd child was unaffected and 37% of families where the 1st child was unaffected and the 2nd child was affected. Overall, 48% of mothers of children with thalassemia major had as many children as they had expected at the time of marriage, 13% had more, and 39% had fewer children. The mothers of older children were less likely to have had the planned number of births than those of children born more recently. The value of antenatal diagnosis to couples at risk of thalassemia appears to have been to enable them to meet or almost meet their birth expectations.     

Molecular genetic characteristics of Duchenne-Becker muscular dystrophy in the Republic of Moldova

Solution to some problems of clinical genealogical and molecular genetic study of Duchenne muscular dystrophy (DMD) in the Republic of Moldova and prenatal diagnosis aimed at preventing the birth of infants with this disease is proposed. An integrated clinical and molecular genetic study of families with a high risk of DMD has allowed its specific characteristics in the Moldovan population to be identified. The spectrum of mutations at the gene level in DMD patients and their role in prenatal and clinical diagnosis has been determined. RFLP analysis and PCR have been used to estimate the informativeness of families with a high DMD risk; prenatal diagnosis has been performed in some of them. Population analysis of the frequencies of polymorphic restriction sites have been carried out for loci pERT87-8/Tag1, pERT87-15/BamH1, and 16intron/Tag1. The results of analysis of deletion frequencies in the dystrophin gene and the frequencies of the pERT87-8, pERT87-15, and 16intron intragenic polymorphic loci have served as a basis for a strategy of molecular diagnosis. The new strategy allows the informativeness to be evaluated and, hence, clinical, preclinical, and prenatal diagnosis to be performed in approximately 94% of cases. A modified PCR method (MPCR) using the system of primers pERT87-8/Tag1 and 16intron/Tag1 has been developed for direct search for deletions. The method makes it possible to avoid diagnostic errors and decrease both the duration and the cost of the analysis.     

Intrauterine exposure to diagnostic X rays and risk of childhood leukemia subtypes.

The relationship between childhood leukemia and prenatal exposure to low-dose ionizing radiation remains debatable. This population-based case-control study investigated the association between prenatal exposure to diagnostic X-ray examinations (for different types of examinations and at different stages of pregnancy) and the risk of childhood lymphatic and myeloid leukemia. All children born and diagnosed with leukemia between 1973-1989 in Sweden (578 lymphatic and 74 myeloid) were selected as cases, and each was matched (by sex and year of birth) to a healthy control child (excluding Down's syndrome). Exposure data were abstracted blindly from all available medical records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by conditional logistic regression. It was found that prenatal X-ray examinations resulting in direct fetal exposure were not associated with a significant overall increased risk for childhood leukemia (OR = 1.11, 95% CI 0.83-1.47), for lymphatic leukemia (OR = 1.04, 95% CI 0.77-1.40), or for myeloid leukemia (OR = 1.49, 95% CI 0.48-4.72). There was little evidence of a dose response or variation in risk by trimester of exposure or age at diagnosis. Thus X-ray examinations performed during pregnancy in the 1970s and 1980s in Sweden did not affect the risk of childhood leukemia discernibly.     

Attitudes toward the prenatal diagnosis of cystic fibrosis: factors in decision making among affected families.

The objective of this study was to explore psychosocial factors underlying decisions about use of prenatal diagnosis for cystic fibrosis (CF), among parents of affected children. Anonymous survey questionnaires, supplemented by voluntary interviews, were used at 12 CF centers in six New England states, for a consecutive sample of families of minor children visiting CF centers during a 4-mo period. In all, 227 (71%) of 318 families responded. We hypothesized that attitudes toward utilization would be affected by (a) intentions to have children, (b) knowledge, (c) perception of risk, (d) the health of the child with CF, (e) expectations about the child's future, (f) attitudes toward abortion, (g) insurance, (h) genetic counseling, and (i) sociodemographic factors (including attendance at religious services). Of the 227 couples who responded, 69% were surgically sterile, over 45 years of age, widowed, or divorced, and 31% were at risk. Of 70 at-risk couples, 44% intended to have more children; of these, 77% had had or were considering CF prenatal diagnosis. Most families knew CF could be diagnosed prenatally; 20% would terminate for CF. Among intended prenatal diagnosis users, 44% would carry a fetus with CF to term, 28% would abort, and 28% were undecided. Stepwise logistic regression showed three variables significantly related to intentions to use prenatal diagnosis: (1) respondent's willingness to abort for CF (P less than .02, odds ratio 3.36), (2) respondent's siblings' approval of abortion for CF (P less than .03, odds ratio 2.99), and (3) respondent listed no accomplishments for the child with CF (P less than .09, odds ratio 3.01). The majority of affected families reject selective abortion for CF; many will curtail childbearing rather than use prenatal diagnosis.     

Risk factors for gastroschisis

The prevalence at birth of gastroschisis, a rare abnormality of the abdominal wall, appears to have increased over the past decade. To characterize risk factors that might explain this increase, birth certificates for Washington State residents were compared for 62 infants born with gastroschisis during the years 1984 to 1987 and 617 randomly selected unaffected infants matched for birth year. After simultaneously adjusting for 14 potential risk factors, 4 factors stood out. Infants born during January, February, or March were at greater risk than infants born in any other months (odds ratio 2.2, 95% confidence interval 1.1, 4.1). Mothers less than 25 years old were at greater risk than mothers 25 years and older, with the highest risk to mothers less than 20 years old (odds ratio 4.1, 95% confidence interval 1.4, 12.0). Women who smoked during pregnancy were at greater risk than women who did not smoke (odds ratio 2.0, 95% confidence interval 1.03, 3.8). Finally, mothers receiving inadequate prenatal care were at greater risk than mothers receiving adequate prenatal care (odds ratio 2.1, 95% confidence interval 0.99, 4.6). Unidentified behavioral and environmental exposures may explain the associations with month of birth, maternal age, and prenatal care. However, smoking during pregnancy is a plausible risk factor that should be examined further as an explanation of the apparently increasing prevalence at birth of gastroschisis in developed nations.     

Prenatal screening for hemoglobinopathies. I. A prospective regional trial.

Prenatal hemoglobinopathy screening was chosen as a model system for the study of patient receptivity to unsolicited genetic information. Providers of prenatal care in Rochester, NY, were offered free testing of all their prenatal patients and genetic counseling of women found positive. The 18,907 prenatal samples tested in a 5-year period represented 35.1% of the pregnancies in the Rochester metropolitan region. A hemoglobinopathy was found in 810 pregnancies (4.3%). Of the 21 different types of hemoglobinopathies detected, the most common were sickle cell trait (59%), hemoglobin C trait (19%), beta-thalassemia trait (11%), and hemoglobin E trait (5%). At the time of phlebotomy, 75% of the pregnancies were of less than 18 wk duration. Sixty-six percent of the pregnancies occurred in patients unaware of their diagnosis, and 80% occurred in patients unaware that they might be at risk for a child with a serious blood disorder. Of the 810 positive pregnancies, 551 (68%) occurred in patients who came for counseling. Of 453 women counseled during their first screened pregnancy, 390 (86%) said they wanted their partners tested and 254 (55%) had their partner tested. In the 77 pregnancies thus found to be at risk, the couple was too late for prenatal diagnosis in 12 cases, and the condition for which the fetus was at risk was too mild in 12 cases. Prenatal diagnosis was offered in the remaining 53 pregnancies and was accepted by 25 couples (47%). These results indicate that unselected patients in the primary care setting in this region, even though pregnant, are receptive to and utilize genetic information.     

What genetic risk should suggest prenatal diagnosis for cystic fibrosis?

Prenatal diagnosis of cystic fibrosis is today possible by chemical study of amniotic fluid during the 18th week of pregnancy. We have, among 90 families seen for genetic counseling between 1972 and 1985, estimated the risk of recurrence; it was of 0.25 in 55 cases; between 0.05 and 0.16 in 30 cases, greater than 0.01 in 16 cases. Before suggesting a prenatal diagnosis, it is necessary to take as basis the risk of abortion and the reliability of the method. The first risk is well known, less 0.005, in these young women; reliability can be estimated: almost 0.01 of false wrong negative, and this number is probably overvalued if all technical conditions are perfect. In front of these risks, it seems possible to propose a prenatal diagnosis from a risk of 0.01, the families being informed of all risks. We think so to hearten some families and to make possible for them to live quietly these pregnancies, probably non undertaken without our help.     

NAT2 slow acetylation genotypes contribute to asthma risk among Caucasians: evidence from 946 cases and 1,091 controls

NAT2 plays a critical role in external chemical detoxification. Thus, polymorphism of NAT2 has been suggested to associate with several disorders. A number of studies have been devoted to the relationship between NAT2 polymorphism and asthma risk. However, the results were inconclusive. In this study we aimed to derive a more precise estimation of the association. A literature search in the common databases was conducted and then meta-analyses evaluating the association of NAT2 polymorphism and asthma risk were performed. Eligible studies were identified for the period up to May 2013. A total of five case–control studies containing 946 cases and 1,091 controls were lastly included for analysis. The overall data showed that slow acetylators of NAT2 might have an association with increased asthma risk (OR 2.20; 95 % CI 1.31–3.72). The pooled data suggest that slow acetylators of NAT2 might contribute to asthma risk among Caucasians. Future studies are needed to confirm this conclusion.     

Breast-feeding, birth interval and child mortality in Bangladesh

The 1975-76 Bangladesh Fertility Survey data show little evidence that breast-feeding is the intermediate factor through which birth intervals influence child survival in Bangladesh. Preceding birth interval, subsequent pregnancy and breast-feeding duration each have an independent influence on early mortality risk. Within a specific interval the risk of dying decreases with increase in duration of breast-feeding, and also with an increase in the time between the index birth and the next pregnancy. The death of the immediately preceding child in infancy has a significant negative effect on the survival chance of the index child at ages 1-5 months. However, death of the preceding child appears to have a significantly positive effect on the survival chance of the index child between ages 9 months and 5 years; this may be related to competition between siblings.