Reduced uterine perfusion pressure as a model for preeclampsia and fetal growth restriction in murine: a systematic review and meta-analysis

Abstract

The reduced uterine perfusion pressure (RUPP) model is frequently used to study preeclampsia and fetal growth restriction. An improved understanding of influential factors might improve reproducibility and reduce animal use considering the variability in RUPP phenotype. We performed a systematic review and meta-analysis by searching Medline and Embase (until 28 March, 2023) for RUPP studies in murine. Primary outcomes included maternal blood pressure (BP) or proteinuria, fetal weight or crown-rump length, fetal reabsorptions, or antiangiogenic factors. We aimed to identify influential factors by meta-regression analysis. We included 155 studies. Our meta-analysis showed that the RUPP procedure results in significantly higher BP (MD = 24.1 mmHg; [22.6; 25.7]; n = 148), proteinuria (SMD = 2.3; [0.9; 3.8]; n = 28), fetal reabsorptions (MD = 50.4%; [45.5; 55.2]; n = 42), circulating soluble FMS-like tyrosine kinase-1 (sFlt-1) (SMD = 2.6; [1.7; 3.4]; n = 34), and lower fetal weight (MD = -0.4 g; [-0.47; -0.34]; n = 113. The heterogeneity (variability between studies) in primary outcomes appeared ≥90%. Our meta-regression identified influential factors in the method and time point of BP measurement, randomization in fetal weight, and type of control group in sFlt-1. The RUPP is a robust model considering the evident differences in maternal and fetal outcomes. The high heterogeneity reflects the observed variability in phenotype. Because of underreporting, we observed reporting bias and a high risk of bias. We recommend standardizing study design by optimal time point and method chosen for readout measures to limit the variability. This contributes to improved reproducibility and thereby eventually improves the translational value of the RUPP model.

Keywords: fetal growth restriction; placental insufficiency; preeclampsia; pregnancy; reduced uterine perfusion pressure.

Figure 1.

Schematic overview of reduced uterine perfusion pressure model. A surgical model induced in most cases (*) placing a clip (as illustrated in the picture) or a ligature around the abdominal aorta of a pregnant mouse or rat, below the renal arteries, during early to midgestation. The placement of a clip or ligature on the right and left ovarian arteries at the uterine arcade just before the first segmental artery prevents an adaptive increase in uterine blood flow via the ovarian artery.

Figure 2.

Flowchart of identification and selection process according to Preferred Reporting Items for systematic reviews and Meta-Analyses (PRISMA). The search strategy retrieved 2,071 unique hits via Embase and MEDLINE using OVID, of which we included 155 studies reporting relevant outcomes in the reduced uterine perfusion pressure (RUPP) model.

Figure 3.

Stratified meta-regressions for the outcome of maternal blood pressure. A: method of blood pressure measurement. B: state of consciousness of animal during blood pressure measurement. C: pairing. D: type of control. E: study design on randomization. Data represent pooled estimates expressed as mean difference (MD) with a 95% confidence interval (CI) using a random effect model; n, number of independent comparisons in the stratum. RUPP, reduced uterine perfusion pressure.

Figure 4.

Time depending on the effect of maternal blood pressure measurement. Regression time-point bubble plot of maternal blood pressure measurement, time-point gestational days (GDs) 17–21. On the time-points GD20 (n = 11) and GD21 (n = 3), effect of blood pressure (BP) is lower and revealed a significant regression R² = 1.53%. P < 0.05.

Figure 5.

Stratified meta-regressions for the outcome of fetal weight. A–C: meta-regression on fetal weight as follows: pairing (A), type of control (B), and study design on randomization (C). Data represent pooled estimates expressed as mean difference (MD) with a 95% confidence interval (CI) using a random effect model; n, number of independent comparisons in the stratum. RUPP, reduced uterine perfusion pressure.

Figure 6.

Stratified meta-regressions for the outcome circulating soluble FMS-like tyrosine kinase-1 (sFlt-1). A: type of control. B: study design on randomization. Data represent pooled estimates expressed as standardized mean difference (SMD) with a 95% confidence interval (CI) using a random effect model; n, number of independent comparisons in the stratum. RUPP, reduced uterine perfusion pressure.

Figure 7.

Risk of bias assessment. A and B: assessment of reporting of key study quality indicators (A) and risks of bias (B), according to SYRCLE’s risk of bias tool.