Stillbirth case: umbilical cord “accident”

20 Nov

Case of stillbirth

This stillborn infant was delivered vaginally at 35 weeks five days gestation to a G2 P1 mother with a previous fetal demise. The female infant weighed 2,090 g. Mother smoked occasionally during pregnancy. Based on an ultrasound examination at 11 menstrual weeks of gestation, her expected delivery date was moved forward 2 weeks. She had fetal heart tones 2 weeks before an exam that had no fetal beat. She was delivered 24-48 hours later. Her prenatal care was otherwise unremarkable. There are no previous specimens in the pathology database for this patient.
Her placental examination showed a 390 g placenta with a pale area 5 cm in diameter that histologically showed hemorrhagic endovasculosis, but no thrombi in fetal vessels. The diagnosis was evidence of fetal vascular occlusion but no thrombi were seen in the sample. There was also mild erythroblastosis.
The gross examination of her autopsy demonstrated pleural petechiae, and small (10-20 ml) pleural and pericardial serous infusions. An unusual finding was subcutaneous petechial hemorrhages over the anterior chest. Microscopically, beside confirming the petechiae and using the criteria of Genest for histologic dating, nothing in the body was remarkable. The findings were consistent with 24-48 hours of postmortem retention.
The brain notably demonstrated very extensive karyorhexsis of nuclei in the basis pontis and in the subiculum.
A relook at the gross placenta failed to find the pale area and could find no tell-tale hemoglobin staining of surface vessels or palpably firm thrombi in those vessels.       However after several days of fixation in formalin, there were small suspicious pale areas. The placenta was resampled extensively including the insertion of the umbilical cord and the large surface vessel branches.
Microscopically, the pale areas were small areas of avascular villi (fig 1), but the volume of involved villi was small probably less than 1 percent of the placenta, and since these were fibrotic would have been likely days or more in duration. The real surprise was that almost all of the large vessels including the insertion showed non-occlusive mural thrombi sometimes with early organization(fig 2).

  

Fig 2: Mural thrombus in a surface vessel

Fig 1: Avascular villi on the right, slightly hypervascular villi on the left

 

 
So how does a pathologist interpret these findings to explain the fetal death?

First, I have argued elsewhere, the intrathoracic petechiae are evidence of fetal gasping to initiate respiration in response to acute asphyxia. This was likely the terminal event. The asphyxia may not have been sudden and complete, since the effusions suggest heart failure secondary to hypoxia/acidosis. The minimal increase in nucleated red blood cells in the circulation is most likely due to asphyxia with injury to the endothelium of the liver sinsusoids, the site of red cell production, and release into the circulation. This apparently can happen quickly (placenta: nucleated red cells on our web site), but may have been present for an unknown number of hours. Finally, there is the ponto subicular necrosis which can be induced in animal models with very mild intermittent hypoxia and must be at least hours in duration[1]. The pontosubicular necrosis is an apoptotic response to fetal hypoxia. This is a topic for either the web site or another blog. Clearly, the evidence points to a hypoxic/ischemic event that occurred over a period of at least hours prior to death, likely an intermittent or partial asphyxia of the infant that was at some point sufficiently acute to lead to gasping.
Not long ago, I would have relied on the exclusion argument that this was most likely due to an umbilical cord “accident”, that is a physical reduction in umbilical cord blood flow, specific cause unknown. Now thanks to the work of Mana Parast and Theonia Boyd and colleagues, I have perhaps a stronger argument to point to the umbilical cord.
The presence of avascular villi in the placenta is evidence of prior occlusion of fetal blood flow. It is reasonable to assume that the occlusion was a thrombotic event related to the proximal mural thrombi in larger vessels from which distal emboli could arise. Based on the fibrosis in some avascular villi and the more recent hemorrhagic endovasculosis in other areas this thrombotic fetal vasculopathy started more than one week ago and was continuing until the point of fetal death.
The key to understanding the cause of death to understand the likely mechanism of the vascular wall thrombosis in the large surface vessels of the placenta. We start the analysis with Virchow’s observation that thrombosis occurs with stasis, vascular injury and/or hypercoagulability. Indeed any compromise of umbilical cord blood flow would not only cause stasis but because the large vessels of the cord and placental surface do not have a capillary bed, ischemia of their own blood flow is likely to lead to ischemia of the vascular wall and endothelial injury. Indeed the association of fetal thrombotic vasculopathy with various abnormalities of the umbilical cord has been published. Another perhaps inescapable conclusion is that it is not the focal loss of perfusion of placental parenchyma evidenced by avascular villi that accounts for the association of fetal thrombotic vasculopathy with complications in live born infants, but the fact that the avascular villi are a marker for a precarious umbilical cord blood flow.
That said, of course the other etiology in Virchow’s triad, hypercoagulopathy can also lead to extensive fetal thrombotic vasculopathy including thrombi in the fetus not just the placenta, In this case there were no fetal thrombi and no maternal history of thrombophilia. Finally, any cause of a large thrombus on the venous side of the umbilical circulation can lead to emboli in the fetus with a special danger that the fetal circulation favors embolization to the fetal brain across the foramen ovale. Again there was no evidence of such emboli in this fetus.
The newer observation by Dr. Parast and colleagues was that the placentas from stillborn infants of unknown cause had known an excess of vascular thrombi, avascular villi and dilated villous stem vessels compared to those of known cause[2, 3]. The importance of this observation is not just to compete a loop that umbilical cord induced asphyxia is an overlooked and understudies cause of stillbirth, but just as importantly umbilical cord occlusion is frequently is not a sudden event, but an ongoing at least intermittent process of days or more duration. The presence of avascular villi in stillborn infants is evidence that the enabling conditions of umbilical cord occlusion are present long before the coup de grace and be ameliorated if identified, We don’t usually know the exact compromise of the cord such as a short distance between the placenta and the beginning of an umbilical cord wrapping, a long cord which I argued in a previous blog is the same as a functionally short cord earlier in gestation, a trapped cord or a weak insertion of the cord into the placenta, but we can certainly imagine how fetal movement or uterine contractures or perhaps even maternal sleep apnea could exacerbate fetal ischemia producing fetal hypoxia/acidosis

So I am back to my major complaint with obstetrical research. Research needs to be done on the natural causes of fetal asphyxia, not just its consequences.

As a pathologist I learned an important lesson from this case. I do sometimes overcome my inertia and grossly reexamine placentas with avascular villi for proximal vessel thrombi which if occlusive show some hemoglobin staining of the vascular wall on the surface. I completely failed to see grossly these extensive, mural, non-occlusive thrombi. Only more extensive histologic sampling revealed them. If I have a suspicion of fetal thrombotic vasculopathy, more extensive sampling of surface vessels including the umbilical insertion is indicated.

1. Falkowski, A., et al., Apoptosis in the preterm and near term ovine fetal brain and the effect of intermittent umbilical cord occlusion. Brain Res Dev Brain Res, 2002. 136(2): p. 165-73.
2. Parast, M.M., C.P. Crum, and T.K. Boyd, Placental histologic criteria for umbilical blood flow restriction in unexplained stillbirth. Hum Pathol, 2008. 39(6): p. 948-53.
3. Ryan, W.D., et al., Placental histologic criteria for diagnosis of cord accident: sensitivity and specificity. Pediatr Dev Pathol, 2012. 15(4): p. 275-80.

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