Assoziationsstudien von Polymorphismen zur Risikoevaluierung in der Schwangerschaft - Literaturübersicht und Metaanalyse

Zusammenfassung

Ein potenziell wirksames Instrument zur Erkennung der individuellen Physiologie und individueller Risikoprofile von Schwangeren stellt die Kenntnis von Polymorphismen dar. Mittlerweile wurden in über 70 Assoziationsstudien die Effekte der Trägerschaft bestimmter Polymorphismen auf die Schwangerschaft und schwangerschaftsassoziierte Erkrankungen wie Präeklampsie und Thrombose untersucht. Eine Metaanalyse von 22, 11 und 10 Studien weist die Trägerschaft des F-V-Leiden G1691A- (OR 1,9; 95 %-KI 1,6 - 2,5), des F II G20210A- (OR 1,8; 95 %-KI 1,1 - 2,9) und des AGT Met235Thr-Polymorphismus (OR 1,6; 95 %-KI 1,4 - 1,8) als signifikante Risikofaktoren für Präeklampsie aus, während die Trägerschaft des MTHFR C677T-Polymorphismus in einer Metaanalyse von 24 Assoziationsstudien nicht mit einem erhöhten Präeklampsierisiko assoziiert ist (OR 1,1; 95 %-KI 0,9 - 1,3).

Des Weiteren kann die Trägerschaft des F-V-Leiden G1691A- und F II G20210A-Polymorphismus zur Risikoevaluierung einer schwangerschaftsassoziierten Thrombose herangezogen werden. In absoluten Zahlen wird die Häufigkeit einer schwangerschaftsassoziierten Thrombose bei heterozygoten und homozygoten Trägerinnen des F-V-Leiden G1691A-Polymorphismus in der Literatur mit 6,4 % bzw. 8,9 - 16,7 % angegeben. 6,2 % aller Frauen mit F II G20210A-Polymorphismus und 17,8 % aller Frauen mit kombinierter F-V-Leiden G1691A- und F II G20210A-Trägerschaft entwickeln eine schwangerschaftsassoziierte Thrombose.

Die beiden thrombophilen Polymorphismen F-V-Leiden G1691A und F II G20210A können aufgrund einer Metaanalyse von 31 Studien weiters als Risikofaktoren für frühe wiederholte, späte wiederholte und späte sporadische Fehlgeburten angesehen werden. In sechs in der Literatur publizierten Fallkontroll- und Kohortenstudien von 687 Trägerinnen dieser Polymorphismen wird insgesamt unter niedrigmolekularem Heparin oder fraktioniertem Heparin (40 - 80 mg/d) eine Lebendgeburtrate von 82 % (181/221) im Vergleich zu 20 % (95/466) ohne Therapie beschrieben (p < 0,001, OR 17,7; 95 %-KI 12,2 - 25,5).

Die Daten in der Literatur sowie eine Metaanalyse 67 publizierter Assoziationsstudien weisen die Polymorphismen F-V-Leiden G1691A, F II G20210A und AGT Met235Thr als signifikante Risikofaktoren für die Entwicklung einer Präeklampsie, einer schwangerschaftsassoziierten Thrombose und für Früh- und Spätaborte aus.

Abstract

Polymorphisms are a potentially useful tool for assessing the individual physiology and risk profile of pregnancy-associated disorders. Associations between selected polymorphisms and preeclampsia and thrombosis have been evaluated in over 60 studies. We performed a meta-analysis of 22, 11, and 10 association studies and demonstrated that presence of the F-V-Leiden G1691A (OR 1.9; 95 % CI 1.6 - 2.5), the F II G20210A (OR 1.8; 95 % CI 1.1 - 2.9), and the AGT Met235Thr polymorphism (OR 1.6; 95 % CI 1.4 - 1.8), respectively, is significantly associated with preeclampsia. Presence of the MTHFR C677T polymorphism, however, is not associated with preeclampsia in a meta-analysis of 24 association studies (OR 1.1; 95 % CI 0.9 - 1.3).

Besides preeclampsia, genotyping for the F-V-Leiden G1691A and the F II G20210A polymorphisms is useful for individual risk assessment regarding pregnancy-associated thrombosis. Heterozygous and homozygous carriers of the F-V-Leiden G1691A polymorphism will develop this condition in 6.4 % and 8.9 % to 16.7 % of cases, respectively. 6.2 % of women with the F II G20210A polymorphism and 17.8 % of women with simultaneous carriage of the F-V-Leiden G1691A and F II G20210A polymorphisms will develop pregnancy-associated thrombosis.

The thrombophilic polymorphisms F-V-Leiden G1691A and F II G20210A are also risk factors of early recurrent, late recurrent, and late spontaneous miscarriage based on a published meta-analysis of 31 studies. Six case-control and cohort studies of 687 women with thrombophilic polymorphisms demonstrate live birth rates of 82 % (181/221) using low molecular weight heparin or fractionated heparin compared to 20 % (95/466) without therapy (p < 0.001, OR 17.7; 95 %-KI 12.2 - 25.5).

Based on the data in the literature and a meta-analysis of 67 association studies, we conclude that the F-V-Leiden G1691A, F II G20210A, and AGT Met235Thr polymorphisms are significant risk factors for preeclampsia, pregnancy-associated thrombosis, and early and late miscarriages.

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