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Measurement of maternal serum alphafetoprotein (ms AFP), human chorionic gonadotrophin (ms hCG), and unconjugated oestriol (uE3) at the beginning of the second trimester of pregnancy is a well established screening test for Down syndrome (trisomy 21). Previous studies have described the association of abnormal levels of ms AFP and ms hCG with a variety of problems and complications of pregnancy, such as preterm delivery, fetal growth retardation, and fetal death,1-5 and severe hypertensive disorders in pregnancy.6-10
Over the past years, we have noted in the genetic clinic that several children with syndromic and non-syndromic forms of MCA-MR were born after a pregnancy with a positive maternal serum triple screening test and a normal prenatal karyotype.
Therefore, we decided to perform the present study and collected data on the pregnancy outcome and the physical and psychomotor development of 868 children born after second trimester amniocentesis for positive maternal serum triple screening test with a normal prenatal karyotype. We found a significantly increased incidence of complex multiple congenital anomalies syndromes (17, 1.95%) in the children.
Material and methods
During the period from 1 January 1993 to 31 December 1995, 995 women had amniotic fluid analysed for aneuploidy based on a positive maternal serum triple test (trisomy 21 ⩾1/250).These samples were analysed at the Leuven Centre for Human Genetics and showed normal chromosome results and normal amniotic fluid AFP.
Maternal serum triple tests and amniocenteses were performed in different centres. In October 1998, a questionnaire (available on request) was mailed to the 995 women with a list of questions about the outcome of pregnancy, the perinatal history, and the physical and psychomotor development of their children.
A total of 870 patients (87.5%) answered the questionnaire. They gave birth to 868 children (864 singletons, six twin pregnancies, four spontaneous abortions, and four intrauterine deaths). Further medical information was also obtained from the relevant obstetricians and paediatricians. All children with a major congenital malformation, as an isolated finding or as part of a multiple congenital malformation (MCA) syndrome or sequence, were examined by the same clinical geneticist (JPF) and/or the same fetal pathologist (PM).
Isolated (minor and major) congenital anomalies were present in 28 children (3.23%) (table 1). Twelve children (1.38%) had an isolated major congenital malformation and half of these (0.69%) were isolated congenital cardiac defects. The most interesting result of the study is the high incidence of so called multiple congenital anomalies (MCA) syndromes. In 17 children (1.95%), a complex MCA syndrome was diagnosed in the neonatal period: six MCA syndromes with monogenic inheritance, two chromosomal syndromes not diagnosed in the prenatal period (one 22q11 deletion, one 16q deletion mosaic), and nine children with MCA-(MR) syndromes/sequences of hitherto unknown aetiology (table2). Two of these 17 children died in the perinatal period (a patient with Coffin-Siris syndrome and one with Fryns syndrome); two others (a child with 16q deletion mosaicism and one with MCA/MR syndrome and complex cardiopathy) died at the age of 18 months and 1 year, respectively. Of the 13 surviving MCA children, seven are moderately to severely mentally retarded (table 2, children 1 (3), 3 (4), 3 (6), 3 (7), and 3 (8)) and two mildly to moderately mentally retarded (table2, children 2 (2) and 3 (2)). Only the two children with Pierre-Robin sequence, one child with Bartter syndrome, and one child with Wiedemann-Beckwith syndrome are mentally normal.
The general incidence in liveborns of most of the complex malformation syndromes diagnosed in this study, for example, Fryns syndrome, Coffin-Siris syndrome, and Wiedemann-Beckwith syndrome, is very low (less than 1 in 10 000 to 1 in 20 000 live births). So far, only a few case studies have been reported on positive maternal serum triple test screening and the occurrence of a MCA/MR syndrome, for example, Rubinstein-Taybi syndrome, in the liveborn child.11
The findings in the present study show that the incidence of rare so called MCA/MR syndromes, diagnosed at birth, is significantly increased in children born after maternal serum positive triple test screening (with a normal karyotype after amniocentesis).
The number of MCA/MR syndromes (17 out of 868 children = 1.95%) found in our study group compares well with the number of autosomal unbalanced structural or numerical anomalies found in a control group of 1316 women referred to our centre for maternal serum positive triple test (29 of 1316 = 2.20%) (unpublished data) (table 3). This indicates that triple test screening for Down syndrome with the evaluation of ms hCG, μE3, and AFP in the second trimester of pregnancy selects a broader group of pregnancies at risk for serious MCA (MR) syndromes.
We conclude that a positive triple screening test result selects a group of pregnancies at risk for serious multiple congenital anomaly syndromes with the same efficiency as for numerical chromosomal abnormalities. These data need confirmation by further studies.
We thank the families for their collaboration and are much indebted to the following colleagues for their generous contribution of follow up data: J Aerts, Turnhout; G Albertyn, Antwerpen; S Bafort, Oostende; E Bailleul, Wilrijk; V Ballegeer, Assebroek-Brugge; G Benyts, Lanaken; J Berben, Turnhout; P Berteloot, Duffel; A Beuselinck, Leuven; P Bex, Bilzen; P Boelens, Dendermonde; S Boes, Hasselt; E Boone, Tielt; J Bosteels, Bonheiden; P Braet, Turnhout; P Broeckmans, Lier; A Brouwers, Diest; L Buekenhout, Beringen; K Buyse, Kortrijk; K Buysse, Kortrijk; P Buytaert, Antwerpen; R Campo, Leuven; U Cartrysse, Oostende; J Caudron, Dendermonde; A Charles, Brussel; L Clabout, Mechelen; J Claeys, Waregem; H Coppens, Geel; P Corveleyn, Duffel; N D'Hondt, Geraardsbergen; M C Dallequin, Oudenaarde; L Danneels, Roeselare; L De Baene, Brugge; P Debois, Brasschaat; A De Boodt, Sint-Truiden; M Debrock, Ukkel; A De Bruyn, Lokeren; M De Bruyn, Bonheiden; L Declerck, Roeselare; J De Groeve, Kortrijk; B De Gryse, Ieper; P Delattin, Bonheiden; J De Maeyer, Antwerpen; S Demeyere, Assebroek-Brugge; E Demot, Sint-Niklaas; B De Myttenaere, Menen; M Depierre, Maaseik; J Deprest, Leuven; H De Roo, Lommel; C De Rop, Bonheiden; P Deschilder, Diest; D De Schrijver, Mortsel; D De Schrijver, Wilrijk; E Desmedt, Mortsel; L De Sonnaville, Sint-Truiden; F Dewolf, Brussel; V Deyaert, Leuven; S Dobbelaere, Lier; G Donders, Tienen; A Dupon, Hasselt; P Duvivier, HerkDe-Stad; C Eelen, Wilrijk; M Faict, Knokke-Heist; K Geerinckx, Kortrijk; J Gielen, Genk; L Goessens, Brugge; C Goffart, Ukkel (Brussel); S Gordts, Leuven; W Gyselaers, Genk; M Hanssens, Leuven; T Hendrix, Knokke-Heist 1; M Henskens, Tongeren; F Herman, Hasselt; M Hindryckx, Knokke-Heist; J Hoeterickx, Lier; R Hooghe, Herk De Stad; E Huysmans, Torhout; V Huysmans, Waterschei; P Ide, Hasselt; F Jadoul, Hasselt; E Jankelevitch, Hasselt; S Jankie, Malle; G Janssens, Temse; J Kemps, Diest; P Koninckx Leuven; J Lacocque, Tongeren; H Lamiroy, Brugge; J Landuyt, Deinze; L Laridon, Roeselare; D Lauwagie, Bree; M Lesage, Kortrijk; L Londers, Dendermonde; L Meeuwis, Antwerpen; F Mestdach, Knokke; G Mestdagh, Aalst; C Meuleman, Leuven; P Meulijzer, Wilrijk; N Minten, Bilzen; K Muyldermans, Mol; M Muyldermans, Hasselt; H Nagels, Dendermonde; R Natens, Diest; M Nelis, Boom; S Nuradi, St Niklaas; W Ombelet, Genk; D Oosterlynck, Dendermonde; G Orye, Hasselt; G Page, Poperinge; G Pannemans, Lier; A Pecceu, Turnhout; P Peeters, St Niklaas; T Peeters, Asse; E Persyn, Lier; W Poppe, Leuven; P Puttemans, Brussel; G Quintelier, Veurne; J Quintelier, Ieper; P Ramaekers, Heusden-Zolder; I Riphagen, Tienen; R Rombaut, Oostende; B Rombaut, Oostende; G Romelart, Roosdaal; E Schatteman, Wilrijk; N Schockaert, Assebroek-Brugge 4; R Schollaert, Wilrijk; J Schreurs, Heusden; J Schreurs, Heusden; B Schrurs, Bruxelles; W Schuerwegh, Antwerpen; P Sieprath, Genk; D Smet, Beveren; B Smis, Brugge; D Spinnewijn, St Niklaas; B Spitz, Leuven; G Staelens, Kortrijk; G Stuyven, Herentals; J Thys, Kortrijk; D Timmerman, Leuven; B Timmermans, Oostende; W Traen, Ieper; H Trappeniers, Veurne; F Ulens, Neerpelt; M Ulens, Leuven; P Van Baelen, Oudenaarde; P Van Ballaer, Mol; E Van Bogaert, Antwerpen; J P Van Boxelaer, Mechelen; R Van Braekel, Waregem; R Vandaele, Brugge; T Van Den Bosch, Tienen; W Vandeneede, Vilvoorde; H Van den Driessche, Heusden-Zolder; J Van Den Haute, Aalst; D Vandenweghe, Roeselare; E Van de Poel, Deurne; H Vandeput, Genk; E Vandeputte, Roeselare; G Van De Putte, Genk; I Van De Putte, Leuven; J Vanderheyden, Antwerpen; R Vanderhoydonck, Mol; H Van Der Pas, Turnhout; L Van Der Voort, Roeselare; R Van Dijck, Leuven; J Vanginderachter, Gent; F Van Kelecom, Duffel; M Vanlancker, Turnhout; I Van Mellaert, Leuven; J Van Mohlem, Diest; G Vanneste, Kortrijk; M Vansteenkiste, I Herentals; L Van Steelant, Hasselt; G Van Tendeloo, Kortrijk; J Van Wiemeersch, Wilrijk; K Verbeke, Lommel; V Verboven, St Truiden; J Verbruggen, Vilvoorde; R Vercamer, Oostende; J Vercruysse, Kortrijk; P Vercruysse, Kortrijk; L Verguts, Geel; J Verhaeghe, Leuven; N Verhoeven, Aalst; L Verkinderen, Antwerpen; J Verkinderen, Antwerpen; M Vermeerbergen, Turnhout; P Vermylen, Bonheiden; J Vervliet, Geel; P Viaene, Tongeren; G Vlaemynck, Torhout; J Vlasselaer, Genk; J Voets, Tongeren; L Voorhoof, Brugge; M Vrijens, Gent; J Wajer, Vilvoorde; R Walckiers, St Niklaas; A Waterschoot, Zottegem; R Weckhuysen, St Niklaas; P Wijnants, Hasselt; K Witters, St Niklaas; I Wittevronghel, Duffel.