Short communicationIncreased trophoblast inclusions in placentas from prematurely born infants: A potential marker of risk for preterm neurodevelopmental outcomes
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)
- et al.
A computational model of the mechanics of growth of the villous trophoblast bilayer
Bull. Math. Biol.
(2004) - et al.
The placenta may predict the baby
J. Theor. Biol.
(2003) Placental trophoblast inclusions in autism spectrum disorder
Biol. Psychiatry
(2007)Trophoblast inclusions are significantly increased in the placentas of children in families at risk for autism
Biol. Psychiatry
(2013)Increased placental trophoblast inclusions in placenta accreta
Placenta
(2014)Accreta placentation: a systematic review of prenatal ultrasound imaging and grading of villous invasiveness
Am. J. Obstet. Gynecol.
(2016)Long-term deficits of preterm birth: evidence for arousal and attentional disturbances
Clin. Neurophysiol.
(2008)Placental implantation abnormalities and risk of preterm delivery: a systematic review and metaanalysis
Am. J. Obstet. Gynecol.
(2015)Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae
Endocrinology
(1986)Regional brain volume abnormalities and long-term cognitive outcome in preterm infants
JAMA
(2000)
Cited by (6)
Genetics, not the uterine environment, drive the formation of trophoblast inclusions: Insights from a twin study
2021, PlacentaCitation Excerpt :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].
Trophoblast inclusions in the human placenta: Identification, characterization, quantification, and interrelations of subtypes
2021, PlacentaCitation Excerpt :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].
Placental Pathology Findings in Unexplained Pregnancy Losses
2024, Reproductive SciencesTrophoblast inclusions and adverse birth outcomes
2022, PLoS ONEThe placenta-brain-axis
2021, Journal of Neuroscience ResearchPatterns of Placental Injury in Congenital Anomalies in Second Half of Pregnancy
2019, Pediatric and Developmental Pathology