Mechanisms of death in structurally normal stillbirths

Abstract

Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered "raised". Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results There were 60 cases and 60 controls. Hypoxia was present in 88% (53/60), myocardial damage in 70% (42/60) and brain injury in 45% (27/60) of fetal deaths. Hypoxic fetuses had evidence of myocardial injury, brain injury or both in 77% (41/53), 49% (26/53) and 13% (7/53) of cases, respectively. Histopathological evidence for placental dysfunction was found in 74% (43/58) of these cases. Conclusion Hypoxia, secondary to placental dysfunction, was found to be the mechanism of death in the majority of fetal deaths among structurally normal fetuses. Ninety-one percent of hypoxic fetal deaths sustained brain, myocardial or both brain and myocardial injuries in utero. Hypoxic myocardial injury was an attributable mechanism of death in 70% of the cases. Non-hypoxic cases may be caused by cardiac arrhythmia secondary to a cardiac conduction defect.

Keywords: CD15; amniotic fluid; brain injury; cardiac troponin I; delayed villous maturation; erythropoietin; fetal hypoxia; glial fibrillary acidic protein; myocardial damage; placental dysfunction.

Conflict of interest statement

Disclosure: The authors report no conflicts of interest.

Figures

Figure 1.. Frequency of risk factors in cases of fetal death.

A: Frequency of different risk factors. B: Frequency of none, one, or more than one risk factor.

Figure 2.. Percentile distribution of birthweight in cases of fetal death and the controls.

A: There was no significant difference in the percentile distribution of birthweight between cases of fetal death and the controls (p=0.05). B: Distribution of birthweight centiles by gestational age for cases of fetal deaths. There was a significant correlation between birthweight centile and gestational age (Spearman’s rho = 0.3, p = 0.03): earlier fetal deaths had lower birthweight centiles than later fetal deaths.

Figure 3.. Amniotic fluid concentration of erythropoietin (EPO), cardiac troponin I (cTnI), and glial fibrillary acidic protein (GFAP) in controls and cases of fetal death.

A: The median amniotic fluid concentration of EPO in fetal death was significantly higher compared to controls [median (interquartile range): 17.33 mIU/mL (9.89–77.08) versus 1.27 mIU/mL (1.27–4.03), p<0.0001]. The concentration at the 90th centile in amniotic fluid EPO for controls was 6.44 mIU/ml (dashed line). B: The median amniotic fluid concentration of cTnI in fetal death was significantly higher compared to controls [median (interquartile range): 172.8 pg/mL (97.51–326.30) versus 52.29 pg/mL (21.07–85.60), p<0.0001)]. The concentration at the 90th centile in amniotic fluid of cTnI for controls was 111.11 pg/mL (dashed line). C: The median amniotic fluid concentration of cTnI in fetal death was significantly higher compared to controls [median (interquartile range): 2.56 ng/mL (1.21–3.65) versus 1.92 ng/mL (1.32–2.56), p=0.01)]. The concentration at the 90th centile in amniotic fluid of GFAP for controls was 2.84 ng/ml (dashed line).