Trophoblast inclusions and adverse birth outcomes

Abstract

Objective Trophoblast inclusions—cross sections of abnormal trophoblast bilayer infoldings—have previously been associated with aneuploidy, placenta accreta, and prematurity. This study was conducted to establish the relationship between trophoblast inclusions and a range of placental, pregnancy, and birth outcomes in a patient population with high smoking and alcohol exposure. Specifically, we sought to evaluate the association between the presence of trophoblast inclusions and 1) three primary birth outcomes: full-term birth, preterm birth, and stillbirth; 2) gestational age at delivery; and 3) specific placental pathologies. Methods Two slides containing chorionic villi were evaluated from 589 placentas that were collected from Stellenbosch University in Cape Town, South Africa as part of the prospective, multicenter cohort Safe Passage Study of the Prenatal Alcohol and SIDS and Stillbirth Network. The subsample included 307 full-term live births, 212 preterm live births, and 70 stillbirths. Results We found that the odds of identifying at least one trophoblast inclusion across two slides of chorionic villi was significantly higher for placentas from preterm compared to term liveborn deliveries (OR = 1.74; 95% CI: 1.22, 2.49, p = 0.002), with an even greater odds ratio for placentas from stillborn compared to term liveborn deliveries (OR = 4.95; 95% CI: 2.78, 8.80, p < 0.001). Gestational age at delivery was inversely associated with trophoblast inclusion frequency. Trophoblast inclusions were significantly associated with small for gestational age birthweight, induction of labor, villous edema, placental infarction, and inflammation of the chorionic plate. Conclusions The novel associations that we report warrant further investigation in order to understand the complex network of biological mechanisms through which the factors that lead to trophoblast inclusions may influence or reflect the trajectory and health of a pregnancy. Ultimately, this line of research may provide critical insights that could inform both clinical and research applications.

Placental Pathology Findings in Unexplained Pregnancy Losses

“…TIs and invaginations have been shown to be associated with abnormal genetics, including cases of triploidy, trisomies, and other genetic conditions [ 27 – 30 , 47 , 49 ]. Therefore, the identification of TIs in most miscarriages suggests a genetic mechanism for these losses [ 20 , 25 ]. Support for the strong association of developmental anomalies [ 102 ] and genetic abnormalities as the basis of pregnancy loss also comes from detailed genetic studies of loss cases [ 103 – 110 ].…”

“…An increased frequency of TIs and invaginations have been observed in cases of placenta accreta, increta, and percreta [ 18 ] and intrauterine growth restriction [ 20 ], but not in cases of gestational diabetes, gestational hypertension, or preeclampsia [ 51 ]. There is no data relating TI frequencies to other common obstetrical pathologies, such as placenta previa, or to the method of conception.…”

“…TIs were first described by Boyd and Hamilton in 1964 [ 46 ], and later linked specifically to placentas from triploid losses in 1969 [ 47 , 48 ]. Over time other investigators found that TIs were not a specific marker of triploidy but rather were seen in a wide range of karyotypic and non-karyotypic genetic abnormalities [ 25 , 27 – 30 , 49 , 50 ], and adverse pregnancy outcomes, including stillbirth [ 20 ]. Importantly, the frequency of TIs in normal control placentas is very low [ 51 – 53 ].…”

“…The key may be the placenta, as placental abnormalities are commonly detected in adverse pregnancy outcomes [ 11 , 17 – 20 ], and have been associated with potentially preventable types of losses [ 21 – 23 ]. One systemic review reported that up to 65% of stillbirths are attributable to placental abnormalities [ 24 ].…”

“…One systemic review reported that up to 65% of stillbirths are attributable to placental abnormalities [ 24 ]. However, absent in these abovementioned classification systems are the categories of dysmorphic chorionic villi, represented by trophoblast inclusions [ 20 , 25 – 37 ], and the consistent inclusion of the category of a small placenta, which is clearly associated with pregnancy loss [ 38 – 41 ]. We thus hypothesized that expanding the placental pathology diagnostic categories to include the two explicit categories of dysmorphic chorionic villi and small placenta in examining previously unexplained losses could decrease the number of cases that remained “Unspecified” [ 16 ].…”