Methods of Early Prenatal Diagnosis

SBU’s Conclusions

This report presents the scientific evidence for the methods currently used, or in the process of being adopted, to detect fetal chromosomal and structural abnormalities during early pregnancy. Medical, social, psychological, ethical, health economic, quality assurance and safety aspects of early prenatal diagnosis were analysed. This summary reviews the questions addressed and the most important conclusions reached in each chapter of the report.

Conclusions

• A combined test of ultrasound nuchal translucency measurement and maternal serum biochemistry (biochemical screening) in early pregnancy (10–14 gestational weeks), along with maternal age, is the clinically evaluated method of assessing the probability of fetal Down syndrome that gives the best balance between the percentage of detected cases and falsepositive results. (Evidence Grade 1)
• Maternal serum biochemistry with four markers (quadruple test) is the clinically evaluated method of assessing the probability of fetal Down syndrome that in the second trimester gives the best balance between the percentage of detected cases and false-positive results. (Evidence Grade 1)
• All the methods (nuchal translucency measurement, maternal serum biochemistry in the second trimester and the combined test) for assessing the probability of fetal Down syndrome examined by this report and evaluated in clinical practice gives a better balance between the percentage of detected cases and false-positive results than maternal age alone. Thus, the use of these methods requires fewer amniocenteses and chorionic villus samplings per detected cases of Down syndrome than maternal age alone. (Evidence Grade 1)
• Use of the interphase fluorescence in situ hybridization (FISH) test or quantitative fluorescent polymerase chain reaction (QFPCR) is essentially as accurate as full karyotyping for detecting aneuploidies in chromosomes 13, 18, 21, x and y. (Evidence Grade 1)
• Normal results on the rapid FISH test or QF-PCR in prenatal diagnosis leave a residual possibility of fetal chromosomal abnormalities. In approximately 0.9% of all amniocenteses and chorionic villus samplings a full karyotype analysis will detect a chromosomal abnormality missed by the rapid FISH test or QFPCR. For chromosomal abnormalities of clinical significance, the figure is 0.4%. (Evidence Grade 1)
• Fewer congenital abnormalities, including heart defects, appear to be detected when a routine ultrasound examination is performed at 12 instead of 18 gestational weeks. That is the case even if the 12-week examination includes nuchal translucency measurement and if increased nuchal translucency or greater probability of chromosomal abnormalities according to nuchal translucency is an indication for a comprehensive fetal anatomy at 18–22 gestational weeks. However, the scientific evidence is insufficient to draw a reliable conclusion in this regard.
• No detrimental impact of ultrasound exposure during the second trimester has been demonstrated on children’s growth, vision or hearing – or their neurological, cognitive or speech development. No correlation has been demonstrated between prenatal ultrasound exposure and childhood malignancies. (Evidence Grade 1)
• A meta-analysis of randomized trials have not shown any difference with respect to the frequency of non-right handedness (left handedness or no clear preference) between controls and groups assigned to in utero exposure to ultrasound. Analyses of subpopulations and two Swedish registry studies have found a correlation between such exposure and non-right handedness in boys. However, the scientific evidence is insufficient to draw a reliable conclusion.
• Invasive tests (amniocentesis and chorionic villus sampling) increase the risk of fetal loss. The best available estimate, which concerns fetal loss after late amniocentesis (15 or more completed gestational weeks), indicates a 1 percentage point increase in the risk. Most of these losses are miscarriages. (Evidence Grade 2)
• Pregnant women prefer individual to group information. Audio or video information appears to improve their knowledge and understanding somewhat more effectively than letters and brochures. However, most studies reveal inadequacies when it comes to providing information to women prior to prenatal diagnosis. The women are not sufficiently knowledgeable, particularly with respect to the purpose and the potential implications of the results, to make a wellfounded decision about whether or not to undergo testing. It is especially difficult for them to understand that nuchal translucency measurement with ultrasound and an evaluation of markers is part of a probability assessment rather than a final diagnosis. (Evidence Grade 1)
• Most pregnant women want to obtain early information and prefer screening in the first trimester. (Evidence Grade 1)
• Greater knowledge does not make pregnant women more anxious. The information required to minimize their stress and anxiety levels should be communicated in the same way as that which is provided prior to other medical interventions. Increased anxiety prior to prenatal diagnosis, while waiting for the results or after obtaining notification of detected (or of increased probability of) abnormalities is a natural reaction on the part of the woman and/or her partner. (Evidence Grade 1).

Fact Box 1 Study Quality and Relevance, Evidence Grade.

Study quality and relevance refers to the scientific quality of a particular study and its ability to reliably address a specific question.
Evidence Grade refers to the total scientific evidence for a conclusion, ie, how many high-quality studies support the conclusion.

Evidence Grade 1 – Strong Scientific Evidence
A conclusion assigned Evidence Grade 1 is supported by at least two studies with high quality and relevance among the total scientific evidence. If some studies are at variance with the conclusion, the Evidence Grade may be lower.
Evidence Grade 2 – Moderately strong scientific evidence
A conclusion assigned Evidence Grade 2 is supported by at least one study with high quality and relevance, as well as two studies with medium quality and relevance, among the total scientific evidence. If some studies are at variance with the conclusion, the Evidence Grade may be lower.
Evidence Grade 3 – Limited scientific evidence
A conclusion assigned Evidence Grade 3 is supported by at least two studies with medium quality and relevance among the total scientific evidence. If some studies are at variance with the conclusion, the scientific evidence may lower.
Insufficient scientific evidence
If no studies meet the quality and relevance criteria, the scientific evidence is rated as insufficient to draw any conclusions.
Contradictory scientific evidence
If different studies are characterised by equal quality and relevance but generate conflicting results, the scientific evidence is rated as contradictory and no conclusions can be drawn.