Empirical Models for Anatomical and Physiological Changes in a Human Mother and Fetus During Pregnancy and Gestation

Abstract

12Many parameters treated as constants in traditional physiologically based pharmacokinetic models must 13 be formulated as time-varying quantities when modeling pregnancy and gestation due to the dramatic 14 physiological and anatomical changes that occur during this period. While several collections of 15 empirical models for such parameters have been published, each has shortcomings. We sought to create 16 a repository of empirical models for tissue volumes, blood flow rates, and other quantities that undergo 17 substantial changes in a human mother and her fetus during the time between conception and birth, 18 and to address deficiencies with similar, previously published repositories. We used maximum likelihood 19 estimation to calibrate various models for the time-varying quantities of interest, and then used the 20 Akaike information criterion to select an optimal model for each quantity. For quantities of interest for 42 physiological changes that occur in a human mother and fetus during pregnancy and gestation. We 43 evaluated and selected models by applying a consistent statistical technique, and where possible, we 44 compared results produced by our models to those produced by previously-published models. The 45 collection of pregnancy parameter models presented here represents the most comprehensive such 46 collection to date. 48Human health chemical risk assessments frequently consider pregnant women as a subpopulation of 49 interest based on the relatively high exposure rates and/or susceptibility of this group to various 50 compounds [1,2]. Unfortunately, pregnant women are generally underrepresented in pharmaceutical 51 clinical studies [3] and non-therapeutic chemicals are rarely studied in humans at any life-stage [4][5][6]. In 52 order to assess the risk posed by a chemical, pharmacokinetic (PK) modeling can be used to relate 53 chemical exposure to potential toxicity in tissues [7]. PK models describe chemical absorption, 54 distribution, metabolism, and elimination by the body [8,9]. Furthermore, such models allow one to 55 quantify the tissue concentrations resulting from external doses, whether they are controlled (e.g., 56doses administered in a clinical trial or animal toxicity study [10]) or uncontrolled (e.g., through complex 57 environmental exposures [11]). 58During gestation there are windows of toxic susceptibility during which chemical insults may induce life-59 long adverse effects [2,9,[12][13][14]. Mathematical PK models provide a means for predicting fetal tissue 60 exposures to chemicals [12,15]. Given that PK data in pregnant women and in utero infants are 61 unavailable for most chemicals, models are needed to estimate doses of concern based on data 62 collected for non-pregnant adults or from animals [12]. Physiologically based PK (PBPK) models offer an 63 attractive option for extrapolating information in applications such as human health risk assessments 64 [16-18]. Furthermore, PBPK models can be used to understand and potentially replace some of the 65 default uncertain...

Assessing the impacts on fetal dosimetry of the modelling of the placental transfers of xenobiotics in a pregnancy physiologically based pharmacokinetic model

“…The umbilical vein blood flow (F placf ) was assumed to start at GW = 3.6 weeks, when the uteroplacental circulation is established (Kapraun et al 2019). Several equations were tested in the model Kapraun et al 2019), but for the five first FW, either the computed F placf were above the fetal blood cardiac output or presented negative values. F placf was then assumed to be proportional to the placenta volume during pregnancy with the value at the end of pregnancy set to the value obtained by .…”