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?

Abstract

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 ϭ 0.0001) and increased with gestational age (p ϭ 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 [␤ for log 2 EPO: Ϫ0.56 (95% CI, Ϫ0.77 to Ϫ0.36) versus Ϫ0.27 (Ϫ0.42 to Ϫ0.12), respectively; p ϭ 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 pairspecific factors. Size at birth (standardized for sex and gestational age) reflects intrauterine growth. This is determined substantially by maternal acquisition of oxygen and nutrients and their transfer to the fetus via the placenta (1). It is difficult to study the contributions of and interactions between maternal and placental factors, especially in large cohorts, but twin pregnancies may offer such an opportunity, because maternal factors are shared, whereas placental factors can be discordant (2,3).As an indicator of fetal oxygenation (4), cord blood erythropoietin (EPO) reflects adequacy of oxygen delivery to the fetus. It is of fetal origin because maternal EPO does not cross the human placenta (5-7). Raised cord blood EPO indicates fetal hypoxemia and impaired oxygen transfer to the fetus, an impairment that may extend to delivery of other substrates that are essential for fetal growth (8).A number of studies have demonstrated a relationship between EPO in cord blood and size at birth, including studies of twins (4,9 -12). However, there is evidence that EPO level rises within~4 h of an episode of hypoxia, (13) and neonates who are small for gestation may be more likely to sustain perinatal asphyxia (14). Thus, the observed negative association between birth weight and cord blood EPO could primarily

Influence of intrauterine and extrauterine growth on neurodevelopmental outcome of monozygotic twins

“…'Robust' standard errors and confidence intervals for estimates have been produced (28). In the first model, MDI figured as the dependent variable and two terms were estimated: a term representing the growth ratio pair means and a term calculating the difference between the individual value and the twin pair mean value of growth ratio (29).…”

Increased Fetal Plasma and Amniotic Fluid Erythropoietin Concentrations: Markers of Intrauterine Hypoxia

“…In pregnancies complicated by preeclampsia, intrauterine growth restriction is often a result of placental insufficiency and presumed fetal hypoxia. Thus, it is not surprising that amniotic fluid EPO levels correlate inversely with the birth weight adjusted for gestational age in pregnancies with growth-restricted fetuses [29, 65]. In this regard it is noteworthy that, in twins with discordant growth, the smaller, and presumably more hypoxic, twin has higher EPO levels [66, 67].…”

Hypoxia and Oxidative Stress Are Associated with Reduced Fetal Growth in Twin and Undernourished Sheep Pregnancies

“…Evidence suggests that the pathogenesis of fetal growth restriction seems to be related not only to inadequate nutrient supply, but also to reduced oxygen delivery to the fetus and, therefore, hypoxia [ 19 , 20 , 21 ]. Furthermore, hypoxia induces oxidative stress and aggravates the effects of FGR, as found in hypoxic pregnancies [ 22 ].…”