First-trimester screening: dealing with the fall-out

The articles collected together in this issue describe first-trimester screening for a variety of complications. With the advance of both technology and research, early pregnancy screening is becoming ever more sophisticated and complex. While there are clear benefits to most women receiving early reassurance that their baby is developing as expected, there is no evidence to suggest that an earlier prenatal diagnosis has less long-term emotional impact than at later gestations. The poignancy of ultrasound images for many parents means that it can be especially difficult to manage the anxiety when an ultrasound marker is highlighted as potential cause for concern. They can then face a journey of anxiety-laden uncertainty, which can extend through much of the pregnancy, and even beyond. Professionals involved in screening need to recognise and acknowledge such adverse side-effects and develop the skills necessary to help parents understand and cope with the uncertainties inherent in the process. Copyright © 2011 John Wiley & Sons, Ltd.     

International perspectives on the implementation of reproductive carrier screening

Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay-Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X-linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions. Different programs target different groups (high school, premarital, couples before conception, couples attending fertility clinics, and pregnant women) as does the governance structure (public health initiative and user pays). Ancestry-based offers of screening are being replaced by expanded carrier screening panels with multiple genes that is independent of ancestry. This review describes screening in Australia, Cyprus, Israel, Italy, Malaysia, the Netherlands, Saudi Arabia, the United Kingdom, and the United States. It provides an insight into the enormous variability in how reproductive carrier screening is offered across the globe. This largely relates to geographical variation in carrier frequencies of genetic conditions and local health care, financial, cultural, and religious factors.     

Cell-free DNA screening in twin pregnancies: A more accurate and reliable screening tool

Objective

Outcome data from cell-free DNA (cfDNA) screening in twin gestations are limited. This study adds an appreciable number of confirmed outcomes to the literature, and assesses performance of cfDNA screening in twins over a 4.5-year period at one large clinical laboratory.

Method

Prenatal cytogenetic and SNP microarray results were cross-referenced with cfDNA results for twin pregnancies, yielding 422 matched cases. Using diagnostic results as truth, performance of cfDNA screening in this population was assessed.

Results

Of the 422 twin pregnancies with both cfDNA and diagnostic results, 3 specimens failed amniocyte analysis, and 48 samples (11.5%) were nonreportable from the initial cfDNA draw. Analysis of the 371 reportable samples demonstrated a collective sensitivity of 98.7% and specificity of 93.2% for trisomies 21/18/13. Positive predictive values (PPVs) in this study population, which is enriched for aneuploidy, were 78.7%, 84.6%, and 66.7% for trisomy 21, 18, and 13, respectively.

Conclusion

CfDNA screening in a cohort of twin pregnancies with matched diagnostic results showed superior performance compared to traditional serum biochemical screening in twins. This study adds to a growing body of evidence suggesting that cfDNA is an accurate and reliable screening tool for the major trisomies in twin pregnancies.

     

Prenatal screening for haemoglobin disorders

The technology has been available to detect carriers of haemoglobin disorders since the late 1960s. Prenatal diagnosis has been available since 1978. First trimester diagnosis by chorionic villus sampling and DNA analysis was introduced in 1982, and subsequent simplifications in DNA technology have made screening, counselling and prenatal diagnosis cost-effective at the community level, in countries at all levels of development. Audit of prenatal diagnosis for haemoglobin disorders in countries which have the resources and infrastructure necessary for genetic population screening (such as the UK and other European countries), has shown that the number of prenatal diagnoses actually performed fall far short of expectation. The demonstration that this reflects failures in delivering information, screening and counselling to the populations at risk, rather than rejection of prenatal diagnosis, shows the importance of placing more emphasis on the organisational and social requirements for genetic population screening. In some countries current attitudes towards abortion exclude provision of prenatal diagnosis within the health service, but in many such cases it has been set up in the private sector. It is also being introduced through combined private and charitable efforts in an increasing number of developing countries, including some with extremely limited health resources: such centres are likely to act as nuclei for emergence of genetics services in these communities. A particularly notable recent achievement is the introduction of prenatal diagnosis in Nigeria, where 1–2% of all children born suffer from sickling disorders.     

Ultrasound screening for fetal abnormalities

Ultrasound screening for fetal abnormalities is increasingly becoming part of routine antenatal care in Europe and the UK. However, there has been very little formal evaluation of this practice. In this article reports of routine ultrasound screening are reviewed and the advantages and disadvantages discussed. The majority of routine anomaly scanning is done in the second trimester but there may be a case for screening at other times in pregnancy and alternative anomaly screening policies are discussed.     

Carrier screening for cystic fibrosis

A number of different models of CF carrier screening have now been tested in pilot trials. Apart from opportunistic and cascade testing (which are strictly speaking not true forms of screening), the major programmes have been directed either to young adults in primary care or to pregnant women in antenatal clinics. Only in the latter form of screening has sufficient data been collected to allow conclusions to be reached on the optimum mode of delivery. It seems very probable that when CF carrier screening passes into routine service, it will be the antenatal couple model that is used.     

Cystic fibrosis: selecting the prenatal screening strategy of choice

Cystic fibrosis is a serious disorder. Research into the treatment of affected individuals is in progress, but a cure is not expected in the near future. In this review, we demonstrate that prenatal screening for cystic fibrosis meets the requirements for a worthwhile screening programme. We explain the reasons that have led us to conclude that one approach (‘couple screening’) is the method of choice. The couple-based approach calls for reporting results to the couple as a unit. Only if both parents are found to be carriers is the result designated screen-positive and an amniocentesis or chorionic villus sampling offered. This offers a substantial reduction in the proportion of women with unaffected pregnancies with positive results (the false-positive rate) compared with other methods without reducing the detection of affected pregnancies. It also avoids creating a screen-positive group for which no definitive diagnosis is available. This is a problem with other screening methods. The couple method can achieve a 72% detection rate for a 0.1% false-positive rate. The screening method is simple, non-invasive, reliable, safe and reasonably cost effective. Existing programmes have shown that screening using this method is acceptable to health care professionals and patients. Setting up a national prenatal screening programme for cystic fibrosis is timely and should be implemented using the couple screening method. Copyright © 2003 John Wiley & Sons, Ltd.     

Pilot study for the neonatal screening of fragile X syndrome

An Erratum has been published for this article in Prenatal Diagnosis 23 (9), 2003, 771. Fragile X syndrome (SFX) is the commonest form of inherited mental retardation. Due to the highly variable phenotype clinical diagnosis is complicated. In nearly all cases, the disorder is caused by expansion of a CGG-repeat in the 5′-untranslated region of the FMR1 (fragile X mental retardation-1) gene. We have evaluated the feasibility, efficiency and costs of two methodologies in order to develop a simple test to screen large populations: PCR and fragile X mental retardation-1 protein (FMRP) immunodetection. We studied 100 newborn males using PCR and immunodetection (26.91 Euro). All but one amplified the CGG repeat of the FMR1 gene within the normal size range. The sample that failed to amplify showed only 28% of FMRP expression by immunodetection study; both results indicated an affected male. A further 100 males were studied only by polymerase chain reaction (PCR) (7.8 Euro); all of them amplified within the normal size range. Both methodologies, PCR and immunodetection, are feasible for screening large populations, PCR being the most suitable, economical and less time-consuming. However, it is advisable to keep slides for immunodetection when PCR fails or the external control shows no amplification. Early detection of SFX-affected individuals would represent a great benefit for their maximum social integration, due to appropriate treatment and early stimulation and would permit a cascade screening in their pedigree. Copyright © 2002 John Wiley & Sons, Ltd.     

Ultrasound screening for chromosomal anomalies in the first trimester of pregnancy

For the last 6 years, sonographic signs for excessive fluid accumulation in the backs of 10- to 12-week-old fetuses have been looked for prior to transabdominal chorionic biopsy. In 1400 pregnancies, subsequent karyotype analyses revealed 28 cases of Down syndrome. In 15 ( = 54 per cent), a large fluid cushion over most of the back had been documented at the time of biopsy. Only a few chromosomally normal fetuses with the same peculiarity were observed. The cushion was also present in fetuses with trisomies 18 and 13 , and in Turner syndrome. Systematic first-trimester screening for nuchal fluid accumulation seems to be a recommended method for the detection of Down syndrome and other chromosome anomalies in young pregnant women at low risk. It compares favourably with current methods of maternal serum screening performed at 16–18 weeks which require a higher number of invasive procedures.