Associations Between Inherited Thrombophilias, Gestational Age, and Cerebral Palsy

Abstract

The incidence of cerebral palsy (CP) has not decreased over the past 4 decades. A number of small studies have suggested a possible association between CP and thrombophilia. Both inherited and acquired thrombophilias affecting the mother and/or the fetus may lead to thrombosis and adverse pregnancy outcomes, including CP. This population-based case-control study sampled genome DNA from 443 newborn infants with CP and 883 control infants. The study population included all children with CP born in South Australia in the years 1986-1999. Participants were screened for 4 common polymorphisms associated with thrombophilia: factor V Leiden (FVL, G1691A), prothrombin gene mutation (PGM, G20210A), methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C. Compound heterozygosity for MTHFR C677T and MTHFR A1298C was also evaluated. First, infants of all gestational ages at birth were grouped together for analysis. There was an association between homozygous or heterozygous MTHFR C677T and diplegia (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.09-2.46), but no other statistically significant positive association between any of the thrombophilias and CP. For infants with quadriplegia, homozygosity for MTHFR A1298C was negatively associated with CP (OR, 0.33; 95% CI, 0.1-0.87). When only children born at 37 weeks gestation or later were analyzed, no significant relationship was evident between thrombophilias and CP. However, when only infants born preterm were evaluated, several strong associations were found. In infants born at 32 to 26 weeks gestation, the MTHFR C677T polymorphism was associated with all types of CP combined: the OR for heterozygotes was 1.91 (95% CI, 1.01-3.66), and for homozygotes, it was 2.55 (95% CI, 1.12-5.74). The MTHFR A1298C mutation was negatively associated with diplegia in the same infants (OR, 0.16; 95% CI, 0.02-0.70). In 405 infants with CP born at a gestational age less than 32 weeks, homozygosity for MTHFR C677T correlated with diplegic CP (OR, 2.76; 95% CI, 1.21-6.12), and homozygosity for FVL correlated with quadriplegic CP (OR, 9.12; 95% CI, 0.86-57.71). Homozygosity for FVL increased the risk of diplegic CP 26 times more than heterozygosity (OR, 26; 95% CI, 1.09-1551.59). Compound thrombophilias were also considered. The combination of heterozygosity for PGM and homozygosity for MTHFR C677T was associated with quadriplegia at all gestational ages (OR, 5.33; 95% CI, 1.06-23.25).