Background: Preterm birth (PTB) is a multifactorial syndrome occurring before the 37th week of fullterm
pregnancy . Babies delivered preterm experience short-term and long-term complications affecting multiple
organ systems, and serious maternal complications include hemorrhage and infection. Each year, an estimated
15 million babies are born preterm, and complications from prematurity are the leading cause of death among
children up to 5 years of age . With another increase in PTB rates over the last several years, the United States
continues to have the highest incidence of any industrialized country . Makena (a progesterone analog) is the
only FDA approved medication available in the United States to reduce the risk of PTB. Its use is only indicated
in women who are currently pregnant with one fetus and have unexpectedly delivered a baby preterm in the past
. Furthermore, Makena is very expensive and not used in mothers with multiple gestations or other risk factors,
such as infection, preeclampsia and obesity. Consequently, physicians commonly prescribe supportive therapies,
such as magnesium sulfate, to slow uterine contractions, and glucocorticoids to stimulate fetal lung maturity.
Methods: In this article, we review the full spectrum of in vivo models that investigators have developed to study
PTB, including rodent, ruminant and non-human primate models. We evaluate the discrepancies among various
models, the shortcomings of individual models and how well these models reflect various causes of PTB in humans.
Results: Recent studies reveal that infection is unessential in reproductive disorders linked to inflammation, and
that infection and inflammation are two of many triggers of PTB [1, 5-6]. Despite such findings, many investigators
continue recycling infectious- (using bacterium) and non-infectious-based models (using products of bacteria
or individual cytokines). These models are inconsistent across laboratories, and produce variable degrees of maternal
morbidity (inconsistent with human PTB).
Conclusion: The aim of this review is to encourage the reproductive science community to rethink the design of
non-infectious PTB animal studies. While these models have strengthened our understanding of the mediators and
triggers of PTB, we must develop improved models that are more consistent with the various factors associated
with human PTB (Fig. 1). If we continue viewing PTB through one lens or dimension, Makena will remain the
only FDA approved medication. In vivo PTB research requires multi-model, multifactorial approaches that account
for the complexity of living animals within and between species.