Unexpected Relationship between Plasma Homocysteine and Intrauterine Growth Restriction Claire Infante-Rivard, 1,2* Georges-Etienne Rivard, 2,3 Robert Gauthier, 4 and Yves The ´ore ˆt 2,3 Background: Moderate hyperhomocysteinemia is con- sidered a risk factor for thrombosis and atherosclerosis. We hypothesized that higher maternal and newborn homocysteine concentrations in plasma would increase the risk of intrauterine growth restriction through pla- cental thrombosis. Methods: We carried out a case-control study that in- cluded all cases born at our institution over a 2-year period whose birthweight was below the 10th percen- tiles for gestational age and sex according to Canadian norms; controls were born at the same period and institution at or above the 10th percentiles and were matched on gestational age, race, and sex. Homocysteine was measured in cord and maternal blood. The analysis included 483 case and 468 control mothers and 409 case and 438 control newborns. Results: Homocysteine values were largely <15 mol/L. Contrary to expectation, within that range of values, increased plasma homocysteine, particularly in the mother, was protective against intrauterine growth re- striction. With the case/control status as the outcome, the estimated odds ratio was 0.37 (95% confidence interval, 0.24 – 0.58) for a 5 mol/L unit difference on the maternal homocysteine scale. With birthweight as the outcome, the estimated increase was 178.1 g (95% confidence interval, 92.5–263.7 g) for every 5 mol/L unit increase in maternal homocysteine. Results were similar using newborn homocysteine concentrations. Conclusions: The data suggest that, in contrast to the proposed hypothesis, mothers with small babies have lower homocysteine concentrations than those giving birth to larger ones. © 2003 American Association for Clinical Chemistry Intrauterine growth restriction (IUGR) 5 describes a fetus whose weight is less than expected based on gestational age and sex, as determined by population standards; frequently chosen cutoffs point are below the 10th per- centiles on these curves (1). Causes for IUGR are still unknown, although several determinants have been iden- tified (1). On the basis that thrombophilic polymorphisms could affect placental circulation and thus fetal growth, we recently investigated the role of such maternal and newborn polymorphisms on IUGR. Results for the C677T and A1298C polymorphisms in the 5,10-methylenetetra- hydrofolate reductase (MTHFR) gene showed that IUGR risk did not increase with these variants except among women who were homozygous carriers for the C677T variant and who were not taking vitamin supplements during pregnancy (2). We had also hypothesized that higher plasma homocysteine concentrations would be associated with a greater risk of IUGR or a reduction in birthweight through a thrombotic placental effect, regard- less of the relative contribution of thrombophilic poly- morphisms on maternal and newborn homocysteine con- centrations. Mild hyperhomocysteinemia has been associated with pregnancy outcomes such as abruptio placentae, pre- eclampsia, and fetal loss (3, 4). However, results on the 1 Department of Epidemiology, Biostatistics, and Occupational Health, Faculty of Medicine, McGill University, Montre ´al, Province of Que ´bec, H3A 1A3 Canada. 2 Research Centre, 3 Division of Hematology and Oncology, Department of Pediatrics, and 4 Department of Obstetrics, Centre Hospitalier Universitaire Me `re-Enfant (CHUME), Ho ˆ pital Sainte-Justine, Universite ´ de Montre ´al, Mon- tre ´al, H3T 1C5 Canada. *Address correspondence to this author at: Department of Epidemiology, Biostatistics, and Occupational Health, Faculty of Medicine, McGill University, 1130 Pine Ave. West, Montre ´al, Province of Que ´bec, H3A 1A3 Canada. Fax 514-398-7435; e-mail claire.infante-rivard@mcgill.ca. Received March 4, 2003; accepted May 15, 2003. 5 Nonstandard abbreviations: IUGR, intrauterine growth restriction; MTHFR, 5,10-methylenetetrahydrofolate reductase; tHcy, total homocysteine; OR, odds ratio; and 95% CI, 95% confidence interval. Clinical Chemistry 49:9 1476 –1482 (2003) Hemostasis and Thrombosis 1476