Association between erythropoietin in cord blood of twins and size at birth: does it relate to gestational factors or to factors during labor or delivery?

We hypothesized that cord blood erythropoietin (EPO), a marker of fetal hypoxia, relates to gestational factors and not solely those associated with delivery. We investigated the association between birth weight SD score (SDS) and cord blood EPO in 290 twins (145 pairs), assessing the influence of gestational versus perinatal factors by comparing the association in those who were delivered by elective cesarean (CS) with that in other delivery modes. Blood EPO values were skewed, so geometric means are presented and log EPO values were used in statistical models. The birth size-EPO association was estimated in mixed-effects models that included terms that represented difference in log EPO and mean log EPO for each twin pair. Within-pair estimates of the association were unconfounded by maternal factors (because these were perfectly controlled). Geometric mean EPO was higher in boys versus girls (24.4 versus 17.0 IU/L; p = 0.0001) and increased with gestational age (p = 0.0003) but was similar after elective CS versus other delivery modes. The negative birth size-EPO association was stronger in infants who were delivered by elective CS than by other delivery modes [beta for log(2) EPO: -0.56 (95% CI, -0.77 to -0.36) versus -0.27 (-0.42 to -0.12), respectively; p = 0.02 for interaction). Because the association was seen after elective CS delivery, cord blood EPO must relate to factors during gestation, not just perinatal factors. There was no evidence of an association between birth weight SDS and pair mean log EPO, indicating that the association is entirely due to fetus-specific rather than pair-specific factors.