Elsevier

Placenta

Volume 60, December 2017, Pages 61-63
Placenta

Short communication
Increased trophoblast inclusions in placentas from prematurely born infants: A potential marker of risk for preterm neurodevelopmental outcomes

https://doi.org/10.1016/j.placenta.2017.10.006Get rights and content

Highlights

  • Trophoblast inclusions are associated with risk for autism.

  • Trophoblast inclusions are increased in placentas of preterm infants.

  • Trophoblast inclusions and preterm birth may share a causative factor.

Abstract

Trophoblast inclusions (TIs) are placental abnormalities of the trophoblast bilayer. Present in 2–8% of full-term placentas, they are associated with poor neurodevelopment, including autism. Although previously unstudied, examination of chorionic villi from 108 preterm births revealed a ∼4 fold increase in the frequency of TIs (30.5%). Frequency of TIs was inversely related to gestational age (GA); 43% of placentas <30 weeks and 20% of placentas ≥32 weeks had TIs (χ2 = 4.41, p = 0.036). This increased prevalence in preterm infants suggests that TIs may indicate adverse intrauterine processes or undetected genetic abnormalities and could identify infants at risk for poor neurodevelopment.

Introduction

Shortly after fertilization, two trophoblast layers of mononuclear cytotrophoblasts and multinucleated syncytiotrophoblasts begin to form the placenta, which serves as the interface between mother and fetus. Observational in vitro studies demonstrate that isolated cytotrophoblast cells fuse together to form multinucleated syncytia [1]. Trophoblast inclusions (TIs) are histologically visible abnormalities in which an outer ring of cytotrophoblasts surrounds a cluster of syncytiotrophoblasts [2]. This atypical infolding of the trophoblast bilayer is due to either an abnormal increase in the rate of cytotrophoblast proliferation or a decrease in the rate of cell fusion [3].

Only 2–8% of full-term pregnancies without known chromosomal abnormalities have TIs [4], [5]. In contrast, 93% of cases with aneuploidy and 37% of cases of placenta accreta have an average of at least 0.5 TIs [2], [6], [7]. TIs are also more common in children with autism and their siblings [4], [5].

Limited information is available regarding the prevalence of TIs in placentas of infants who are born prematurely. Preterm infants are prone to deficits overlapping with symptoms observed in children with autism [8], [9], [10], [11]. Risk factors for preterm birth are also associated with autism, including advanced maternal age [12], assisted reproductive technologies [13], preeclampsia [14], and maternal infection/fever during pregnancy [15]. Indeed, the incidence of autism among preterm infants is higher than in the general population [16], [17], [18].

Since preterm infants are at increased risk for adverse congenital and neurodevelopmental outcomes that have been associated with TIs [19], [20], we sought to determine whether TIs are more prevalent in preterm placentas.

Section snippets

Methods

150 infants were enrolled as part of a postnatal intervention trial in the NICU at Columbia University Medical Center (CUMC) (NCT01439269) that was approved by the CUMC IRB. Histology slides containing placental tissue from the participants were stored by the Pathology Department and mothers consented to retrospective analysis of the tissue.

Mothers were eligible to participate if they gave birth to a singleton or twins without significant congenital defects between 26 and 34 weeks gestational

Results

Of the 108 placentas, 44.4% (n = 48) had at least 1 TI in four slides (Fig. 1). Using the conservative cutoff of 0.5 TIs per slide, we found that 30.5% (n = 33) had at least 2 TIs across the four slides.

GA at birth was negatively correlated with the average number of TIs (r = −0.26, p < 0.01). Twice as many infants born <30 compared to those born ≥32 weeks GA met the 0.5 cutoff (χ2 = 4.41, p = 0.036) (Fig. 2). The severity of an inflammatory response in the membranes – classified by the

Discussion

This is the first report of the prevalence of TIs in placentas from preterm births. Using the 0.5 cutoff, our analysis suggests a 4–15-fold increase in the average number of TIs in preterm placentas (30.5%) compared to rates published previously for placentas from full-term births (2–8%) [2], [5]. One interpretation of this finding is that TIs are a feature of normal gestational development. However, a prior study reported that only 2.8% of placentas from elective terminations have TIs,

Conflicts of interest

The authors confirm that there are no conflicts of interest.

Acknowledgements

We extend our gratitude to the Columbia University Medical Center NICU Staff, the Department of Pathology & Cell Biology, and the families who generously participated in this research. We would also like to thank our colleague Dr. Raymond Stark for his significant intellectual contributions. Additionally, we thank the reviewers for their thoughtful comments and suggestions. This work was supported by Columbia University Grant #GT005491 and the Einhorn Family Charitable Trust.

References (21)

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    Trophoblast inclusions (TIs) are microscopic morphological abnormalities of the placenta due to abnormal infolding of the trophoblast bilayer into the villous core [1–3]. By convention, TIs are characterized by a core of syncytiotrophoblasts surrounded by a layer of cytotrophoblasts [4–8]. Recently, researchers have identified a total of 4 TI subtypes: inclusionoids, inclusions, calcified inclusions, and calcified bodies [3].

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    The primary outcome of interest was the frequency of TIs per slide. TIs are defined as cross sections of invaginations of the trophoblast bilayer, resulting in the appearance of trophoblasts within the villous core characterized by central syncytiotrophoblast nuclei surrounded by one or more cytotrophoblasts, always away from the villus edge [1,2,4,21,22]. In our previous studies, two types of TIs were assessed: inclusions and calcified inclusions [2,4].

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    2021, Journal of Neuroscience Research
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