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- Material and methods
Ultrasound scans for the detection of congenital malformations are now a routine part of prenatal care in most European countries. As technology and skill improve more fetal malformations are recognized1–4. There are many reports of prenatal detection of malformation in high-risk groups but few studies have been reported on the effectiveness of routine anomaly testing in unselected populations5. For example, many cardiac malformations are amenable to prenatal diagnosis but general screening of low-risk populations shows a low detection rate, from 14 to 45%6–9. Some dysmorphic syndromes affecting face or skull and/or hands, feet, ears, and external genitalia can be diagnosed prenatally by ultrasound examination, for example, trisomy 13, trisomy 18 and thanatophoric dwarfism, but others with milder features are more difficult to detect prenatally, for example, 22q11 deletion (Di George syndrome)10 and Crouzon syndrome.
The objective of this study was to evaluate the prenatal diagnosis of dysmorphic syndromes across Europe by routine fetal ultrasound examination.
Material and methods
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- Material and methods
Data were provided by 20 congenital malformation registries, 18 of which are population-based, from 12 European countries (Table 1). Sixteen of them collaborate in the EUROCAT program, use the same epidemiological methodologies, and their general characteristics have been previously described11. The remaining registries used the same coding system with multiple sources of ascertainment and active case finding11. Included in this study were all live births, still births and terminations of pregnancy with a major malformation, defined as a structural abnormality detectable by ultrasound, diagnosed prenatally or within 7 days of birth. Routine prenatal ultrasound screening for congenital malformations was performed in all registry areas except in Denmark and in The Netherlands. In countries with more than one ultrasound screening offered (Table 2), the additional scan performed in the first and/or third trimesters of pregnancy was mainly for biometric purposes. The sonography was performed by trained operators. Cases with prenatally suspected malformations detected in a district hospital were referred for confirmation to a specialist center.
Table 1. Details of registries participating in the study
|Registry||Study period (months)||Births (n)||Malformed (n)||Prenatal detection rate (n (%))|
|Funen County, Odense, Denmark||18|| 8788|| 89||25 (28.1)|
|Groningen, N Netherlands||30|| 34 085|| 438||100 (22.8)|
|Rotterdam, SW Netherlands||18|| 47 895|| 186||50 (26.9)|
|Paris, France|| 9|| 27 550|| 592||399 (67.4)|
|Strasbourg, France||30|| 33 155|| 648||335 (51.7)|
|Lausanne, Switzerland||30|| 18 907|| 351||202 (57.5)|
|Croatia||30|| 10 718|| 115||22 (19.1)|
|Basque Country, Spain||24|| 32 429|| 405||220 (54.3)|
|Barcelona, Spain||18|| 19 357|| 206||135 (65.5)|
|El Valles, Spain||30|| 5737|| 108||68 (63.0)|
|Styria, Austria||30|| 29 026|| 246||129 (52.4)|
|Lithuania||30|| 95 469|| 807||193 (23.9)|
|SW Ukraine||30|| 44 761|| 342||115 (33.6)|
|NE Italy, Italy||30||111 719|| 818||305 (37.3)|
|Sicily, Italy||30|| 25 339|| 280||100 (35.7)|
|Tuscany, Italy||30|| 67 120||1044||332 (31.8)|
|Mainz, Germany||30|| 9535|| 274||141 (51.5)|
|Leipzig, Germany||30|| 8745|| 71||61 (85.9)|
|Wessex, UK||30|| 65 559|| 859||482 (56.1)|
|Oxford, UK||30|| 13 136|| 247||187 (75.7)|
|Total|| ||709 030||8126||3601 (44.3)|
Table 2. Current practice in the participating registries
|Number of ultrasound examinations|
| One examination|
| 18–22 weeks||Oxford, Wessex (UK)|
| Two examinations|
| E + 20–22 weeks||Lausanne (Switzerland)|
| L + 16–20 weeks||Styria (Austria), SW Ukraine|
| E + 16–18 weeks||Lithuania|
| Three examinations|
| E + L + 18–22 weeks||Sicily, Tuscany, NE Italy (Italy), Mainz, Leipzig (Germany)|
| E + L + 18–20 weeks||Basque Country, Barcelona, El Valles (Spain), Croatia|
| E + L + 18–24 weeks||Strasbourg, Paris (France)|
| Not routine||Funen County (Denmark), Groningen, Rotterdam (The Netherlands)|
|TOP: upper gestational age limit|
| None||France, Germany, UK|
| 22–24 weeks||Spain, Lithuania, Croatia, Italy, Denmark, The Netherlands, Switzerland, Austria|
| 28 weeks||Ukraine|
Termination of pregnancy after prenatal diagnosis of major congenital malformation has no upper gestational age limit in France, Germany and the UK. In the other countries it was allowed in the second trimester of pregnancy in all registry areas, with upper gestational age limits ranging between 22 and 28 weeks.
The ICD/BPA 9 coding system12 was used by all participating registries for diagnosis. For the purpose of this study all forms coded 74 000 to 75 999 were included in the analysis. Validation was performed at local and at central database levels11. Protection of privacy was assured, so confidentiality is preserved.
The malformations were classified as isolated when only one malformation was present and as non-isolated when one or more additional malformations were diagnosed. Non-isolated anomalies were subdivided into chromosomal if associated with a chromosomal anomaly, syndromic if the malformation was part of a non-chromosomal malformation syndrome, or multiple if at least one other major malformation was present in non-syndromic cases.
The study period was 1 July 1996 to 31 December 1998 but not all registries covered the whole time period. The total number of births in the registry areas was 709 030, including 8126 malformed children (Table 1).
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- Material and methods
Most birth defects occur in an unpredictable way in couples having no prior risk. Routine ultrasound screening offered to all women provides a potential means for their detection13.
There have been many studies on prenatal diagnosis by ultrasound examination in high-risk groups1–3, 5, 14, but few studies have been done on routine prenatal screening at the population level15–17. Due to widely different levels of expertise and equipment, there is a large discrepancy in the results of such screening13, with prenatal detection rates ranging from 0 to 60% for congenital heart disease16. An overview of the European experience shows a detection rate of about 28% for major congenital anomalies18. The purpose of the Eurofetus study, which was performed in 61 obstetric units over a 3-year period (1990–1993) was to evaluate the prenatal detection of malformations by routine ultrasound examination in unselected populations3. Overall 55% of the major abnormalities were detected in 3685 fetuses. The detection rate varied from 88.3% for the central nervous system to 38.8% for the heart and great vessels. However, the Eurofetus study was not population-based and so cannot be compared with the current study. In this report 709 030 fetuses were screened. Our calculations for detection rate of structural defects by routine ultrasound examination used data from congenital anomalies registers, 18/20 of which were population-based. Several studies involving most or all 20 of the registries have already been published which indicate that the detection rate varies widely between registries: 62–97% for neural tube defects19, 11–48% for congenital heart disease20, 21, 0–64% for limb reduction defects22, 7–55% for cleft lip and palate23, 16–45% for chromosomal anomalies24, 38–72% for gastrointestinal anomalies25, 46–100% for omphalocele and 50–100% for gastroschisis26, and 36–96% for renal anomalies (unpubl. data) despite the fact that the participating registries used the same methodology. How can such a large variation be explained? Variations in detection rate may result from differences in operator skill, equipment used, or the gestational age at which examinations are done8.
As the policies regarding prenatal scanning were country-specific (Table 2), it is possible to assess the diverse policies in Europe. As can be seen in Table 1, those registries in countries with no routine scanning policy (The Netherlands and Denmark) had some of the lowest detection rates. The highest detection rates were found in the registries of three European countries with three routine scans (France, Germany and Spain) and in the UK registries, where there is only one routine anomaly scan between 18 and 22 weeks of gestation. In the five other European countries there is also only one anomaly scan to search for congenital anomalies between 16 and 22 weeks of gestation and one or two scans for biometric purposes, in early and/or in late pregnancy.
Detection rate varies with the type of syndrome and increases with increasing numbers of abnormalities in the fetus. For all categories of congenital anomalies apart from renal ones, the detection rate is much higher for associated anomalies, (when the fetus has two or more congenital anomalies) than it is for isolated anomalies27.
The reason for adopting a routine scanning policy is not to increase the termination of pregnancy rate but to provide information and the best care for the fetus and for the mother. In some cases prenatal diagnosis may provide optimum care for the delivery of the liveborn infant and may help prepare the parents for the birth of an affected infant.
This study focused on the prenatal detection of syndromes. It is therefore difficult to compare these results with those of studies which studied the overall outcome of liveborn infants over a long period after birth. For example, concerning the most frequent congenital anomalies, cardiac defects, Meberg et al.28 studied the main outcomes of congenital heart defects in an unselected population of 35 218 liveborn infants over the 15-year period 1982–1996, 3–18 years after birth. Of 360 children with congenital heart defects, 72 (20%) had congenital heart defects associated with chromosomal disorders, other recognizable syndromes or extracardiac malformations. Trisomy 21 accounted for 15 (20.8%) of these. In our series, 479 of 2454 cases with congenital heart defects had recognized syndromes including 375 chromosomal anomalies of which 239 were trisomy 21 (49.9% of those with recognized syndromes), twice as many as in the study of Meberg et al.28. This difference is due to the fact that in our series many cases were diagnosed prenatally and the pregnancy was terminated; 86 of 375 cases with chromosomal anomalies were terminated (22.9%).
In the series of Meberg et al.28 non-isolated disorders occurred significantly less often in children with ventricular septal defects (24/211 = 11.4%) than they did in children with other types of congenital heart defect. In our series, 276 (36.2%) of 761 cases of non-isolated congenital heart defect had ventricular septal defect.
In interpreting these results one should take into consideration the limitations and strengths of the study. The registries participating in this study are selected registries from each country. For example, in France only two of four congenital anomalies registries participated in this study, similarly for Germany, Spain and Italy. Some of the variations seen in types of malformation and their detection rates may have been due to the fact that some of the participating registries cover a small population. The sensitivity of prenatal diagnosis depends on when, where, by whom and on whom the screening is performed. Higher detection rates may be obtained by trained sonographers using the most recent equipment and working on women at high risk for birth defects. The timing of screening is an important factor to take into consideration as screening in early pregnancy may miss the detection of certain malformations that become apparent later in pregnancy and may thus reduce the overall sensitivity of sonographic screening. Some congenital anomalies, for example congenital heart disease and intestinal and renal malformations, are not apparent at birth or during the first week of postnatal life. Therefore, their detection rates may be overestimated. The gestational age at the time of ultrasound examination was not the same for all the registries participating in this study. This may account for some of the discrepancies between countries.
Major strengths of this study are that it evaluated large numbers of births, that it was population-based and that participating registries used the same epidemiological methods. Case fetuses/infants were actively ascertained through multiple sources from geographically defined residential populations. The same definitions and coding system for the malformations were used by all participants. The validation was performed at a local and at a central database level, and analysis of the data was performed centrally.
In conclusion, this study categorized different types of anomaly (e.g. cardiac, renal, gastrointestinal) and identified those with a syndrome to determine the number identified prenatally by ultrasound examination. Some syndromes will not have been identified because they will not have been diagnosed until after the first week of postnatal life. However, it is clear that prenatal ultrasound screening allows diagnosis of a large proportion of chromosomal syndromes and recognized syndromes without chromosomal anomalies. In fetuses with associated congenital anomalies the main purpose of prenatal diagnosis is to give parents as much information about the likely outcome and prognosis as possible.