A Method to Evaluate Fetal Erythropoiesis from Postnatal Survival of Fetal RBCs

Abstract

Abstract. Fetal RBCs are produced during a period of very rapid growth and stimulated erythropoiesis under hypoxic intrauterine conditions. Fetal RBC life span varies with gestational age (GA) and is shorter than that in healthy adults. Due to the special kinetic properties of life span-based survival of human RBCs, a mathematical model-based kinetic analysis of the survival of fetal RBCs shortly after birth provides a unique opportunity to Blook backward in time^to evaluate fetal erythropoiesis. This work introduces a novel method that utilizes postnatal in vivo RBC survival data collected within 2 days after birth to study both nonsteady-state (non-SS) in utero RBC production and changing fetal RBC life span over time. The effect of changes in erythropoiesis rate and RBC life span and the effect of multiple postnatal phlebotomies on the RBC survival curves were investigated using model-based simulations. This mathematical model, which considers both changes in the rate of erythropoiesis and RBC life span and which accurately accounts for the confounding effect of multiple phlebotomies, was applied to survival curves for biotin-labeled RBCs from ten anemic very low birth weight preterm infants. The estimated mean fetal RBC production rate scaled by body weight was 1.07×107 RBCs/day g, and the mean RBC life span at birth was 52.1 days; these values are consistent with reported values. The in utero RBC life span increased at a rate of 0.51 days per day of gestation. We conclude that the proposed mathematical model and its implementation provide a flexible framework to study in utero non-SS fetal erythropoiesis in newborn infants.

Estimation of adult and neonatal RBC lifespans in anemic neonates using RBCs labeled at several discrete biotin densities

“…To accurately model the survival of neonatal RBCs, a model that accounts for non-SS RBC production is required. Such a model has been derived by us previously (12) and was employed in this study. In brief, in utero growth was estimated using the birth weight as a function of GA (13) and can be expressed as follows: $$BWfalse(GAfalse)=\{\begin{array}{cc}A·G{A}^4+B·G{A}^3+C·G{A}^2+D·GA+E& GA>154\\ M·false(e^{\gamma ·GA}-1false)& 0<GA\le 154\end{array}$$where GA is the gestational age at birth measured in days and A, B, C, D, E, M and γ are fixed parameters that were set to values previously validated for VLBW infants (Table 1) (12).…”

A Mass Balance-Based Semiparametric Approach to Evaluate Neonatal Erythropoiesis

“…In addition, RBC lifespan varies with gestational age (GA) at birth (i.e., the time between last menstrual period and day of delivery of an infant) and is less than that in healthy adults (16,17). The mathematical model that accounts for both the non-steady state (non-SS) in utero RBC production and changing fetal RBC lifespan over time has been detailed in our previous work (18). In brief, the in utero body weight, BW(GA), which increases rapidly over time, can be expressed as:…”

“…where GA is the gestational age at birth of the infant measured in days and A, B, C, D, E, M, and γ are the fixed parameters that were set equal to previously reported values (Table I) (18). The in utero erythropoiesis rate, R(t), is considered to be proportional to the in utero body weight and is expressed as:…”

“…The final model (derivation detailed in our previous work (18)) used in calculating the amount of Hb present in RBCs produced in utero and remaining in circulation after birth at time t can be given as:…”

“…5 must be corrected to accurately account for the perturbations in Hb levels caused by the phlebotomies. The loss of fetal RBCs from infant's circulation was accounted for by introducing a phlebotomy correction factor as previously described (11,12,18). Details of the phlebotomy correction are described in the Appendix.…”