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The placenta in stillbirth
ARTICLE IN PRESS Current Diagnostic Pathology (2006) 12, 161–172
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MINI SYMPOSIUM: PAEDIATRIC PATHOLOGY
The placenta in stillbirth T. Yee Khong Department of Histopathology, Women’s and Children’s Hospital, 72 King William Road, North Adelaide SA5006, Australia
KEYWORDS Placenta; Medicolegal; Pathology; Stillbirth
Summary Stillbirth is an absolute indication for pathological examination of the placenta. Placental histopathology can shed light on the cause of the stillbirth and help in the management of future pregnancies and in the resolution of medicolegal issues. Placental lesions that are likely causes of stillbirth are discussed. They can be broadly classified into umbilical cord lesions, fetal vascular lesions, maternal uteroplacental insufficiency and placental inflammation. In some of these lesions, the direct contribution to the stillbirth may be obvious; in others, it may be debatable. Medicolegal questions that are frequently posed in placental examination in stillbirths are the timing of fetal demise and whether there was fetal distress. & 2006 Elsevier Ltd. All rights reserved.
Introduction The reasons for examining the placenta in stillbirth are similar to those for other indications: in summary, clarification of the pathophysiology of adverse outcome, management of subsequent pregnancies and assessment of factors for resolving medicolegal issues.1 Of the many indications for a placenta to be examined pathologically,1 stillbirth would seem to be incontrovertible. Nevertheless, for whatever reasons, placentas were not examined in 7.7% of stillbirths in South Australia2 and 11% of stillbirths in northern England.3 On a countrywide basis, the problem of non-examination of the placenta in stillbirth is probably of a larger magnitude. The 4th Confidential Enquiry Tel.: +61 8 8161 6793; fax: +61 8 8161 7022.
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into Stillbirths and Deaths in Infancy showed that placentas were examined in only 44% of intrapartum stillbirths,4 and yet, four Confidential Enquiry reports later, failure to send the placenta for histology remains a problem: ‘there was no histology on the placenta which might have shed light on the cause of this unexplained stillbirth’.5 Standards of reporting of the placenta vary,6 but it has been shown that perinatal/placental pathologists are able to detect clinically significant placental lesions more frequently and more accurately than general anatomical pathologists.7 It is important, therefore, that meticulous gross examination and appropriate sampling should be the prime objectives, supplemented, if necessary, by photography of gross lesions and slices of the placenta. In this way, at the very least, the slides could be reviewed by an expert pathologist.8
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It is not the intention of this review to cover all aspects of placental pathology. There have been recent publications on how placentas should be examined,9–11 and a list of recent texts on placental pathology is appended. This review will focus on those aspects which are pertinent to stillbirth and are topical.
Clinical history The placenta should, like other surgical pathology specimens, be examined with as much clinical information available as possible.12 Many placental findings are not specific to a disease process, and interpretation may be dependent on the clinical context. For example, the placenta responds to reduced uteroplacental blood flow by developing pathological changes that may be attributable to several maternal conditions such as hypertension, diabetes, prolonged pregnancy and maternal autoimmune disease. Information about the maternal obstetric history, antenatal course and delivery is therefore important to allow a correct clinicopathological correlation to be made.13 If permission for an autopsy has been given, the placental findings should be interpreted in the light of those of the autopsy. A history of fetal hydrops and antenatal monitoring indicating increasing heart failure would lead one reasonably to conclude that a sizeable chorangioma found on placental examination could be the cause of the stillbirth: chorangiomas are vascular tumours in the villous stroma, and the vascularity could lead to increased shunted blood flow. On the other hand, in the absence of the history and autopsy findings, the chorangioma may or may not be felt to have been the cause of the stillbirth.
Table 1
Cause of the stillbirth Cord lesions Even where placental examination is performed, there is considerable variation in terms of which gross or histological lesions are accorded significance. A good example of this conundrum is illustrated by the wide variation in the reported incidence of cord pathology as a cause of or related finding in stillbirth (Table 1). Cord complications that have been cited as being related to stillbirth have included a single umbilical artery and a velamentous or marginal insertion. Although these lesions can be identified objectively at gross examination, the interpretation of whether these are sufficient to explain the cause of the stillbirth is subjective and may be biased by past experiences. The incidence of a single umbilical artery varies from 0.2% to 1.1% of births, but has varied from 2.7% to 12% in perinatal autopsy series. A single umbilical artery in itself is clearly insufficient to explain a stillbirth. However, its associations with anatomical malformations and karyotypic anomalies could account for the perinatal loss. Parenthetically, an overcalling of the significance of umbilical cord lesions did not result in a lower unexplained stillbirth rate (Table 1). Another example of where there is a need for close clinicopathological correlation is the issue of cord entanglement and knots. Cord entanglement is frequent and can be present in as many as a third of pregnancies at term.14 Entanglement around a limb or torso is less frequent than entanglement around the neck, but it still has a potential to produce sufficient kinking to affect the fetal circulation, especially if there is looping of the cord around itself. Adverse perinatal
Cord pathology and relation to unexplained stillbirth rate.
Study area
Number of cases with cord pathology (Number of stillbirths)
% Stillbirths with cord pathology
% Cases of unexplained stillbirth in the study
Germany19 Greece20 Denmark21 China22 South Africa23 USA24 Finland25 South Australia
43 42 21 27 8 9 29 0
22.5 25.6 25.0 28.0 5.3 7.8 11.9 0
15 12 Not stated 14 15 Not stated 9 24
(310) (164) (84) (114) (150) (89) (243) (242)
ARTICLE IN PRESS The placenta in stillbirth outcome is related to the number of coils around fetal parts.15 Examination of the placenta alone would not be able to determine whether entanglements were important, but entanglements are more frequent among long cords. True knots are present in between 0.1% and 2.1% of cords at delivery. A higher rate of stillbirth has been described in cords with true knots,16,17 but this is disputed by others.18 Information such as number of body parts involved, cord diameter as a surrogate for the amount of Wharton’s jelly or the presence of growth restriction, and whether the knot has been loosened prior to receipt by the pathologist is needed to ascertain whether or not entanglements and true knots are significant. To overcome wrongly ascribing the significance of a true knot as a cause of stillbirth, we have set a threshold that stipulates the finding of oedema and congestion or thrombosis of the vessels in the vicinity of a knot.
Fetal vascular lesions The possible association of various inherited thrombophilias with placental abruption, intrauterine growth restriction, pre-eclampsia and intrauterine death26 has led to a careful evaluation of the maternal and fetal vasculatures. Thrombotic or occlusive lesions within the fetal circulation can manifest as obvious white plaques of avascular villi
163 or be recognized only on microscopy. The term ‘fetal thrombotic vasculopathy’ has been used to embrace these lesions, which include fetal artery thrombosis, haemorrhagic endovasculitis, fibromuscular sclerosis and fibrinous vasculosis.27 The lesion can be seen easily on a low-power microscopic view, with a clear division between the groups of avascular and normally vascularized villi. There is often a large thrombosed stem artery upstream of the avascular villi (Fig. 1). The thrombus may show organization and recanalization. This ingrowth of fibroblasts or endothelial cells into the lumen creates a pattern of septation within the vessels and is described in stillbirths as well as in liveborns (Fig. 2). Early changes in this lesion, termed haemorrhagic endovasculitis, comprise the organization and recanalization of thrombi with neutrophils or nuclear debris in the vessel walls, i.e. villous stromal-vascular karyorhexis.28 The vessels distal to the occlusion show progressive fibromuscular sclerosis, and the connective tissue is fibrous with a hyalinized appearance. Other larger fetal vessels may show intimal fibrin cushions, which are seen as subendothelial or medial deposition of fibrin or fibrinoid within the walls. Older lesions will show calcification. Fetal thrombotic vasculopathy is seen in about 5% of placentas from uncomplicated, term pregnancies but in about 15% in placentas from stillbirths. Lesions such as haemorrhagic endovasculitis may be recurrent.29 This would implicate
Figure 1 Fetal thrombotic vasculopathy. There is thrombosis (arrowheads) and an intimal fibrin cushion (arrow) in this large chorionic vessel.
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Figure 2 Septation of blood vessels. These are seen increasingly after 24 h in stillbirth and also in fetal thrombotic vasculopathy. It may not be possible to distinguish between the two clinical conditions.
inherited thrombophilia as a likely factor in the pathophysiological pathway. The correlation between histological fetal thrombotic vasculopathy and most of the currently known inherited thrombophilias is, however, poor,30 and other factors, such as umbilical cord pathology, may be important.31
Uteroplacental insufficiency The placentas of some stillbirths are characterized by maternal underperfusion where it is small, with or without infarction, and histologically displays increased syncytial knot formation and distal villous hypoplasia.32 The maternal spiral arteries in the placental bed normally respond to the demands of the growing placenta and fetus by adapting during early pregnancy from being narrow-calibre, vasoresponsive arteries with a musculo-elastic arterial wall to being flaccid, dilated, vaso-non-reactive uteroplacental arteries with a fibrinoid wall (Fig. 3). These changes are completed by mid-pregnancy. Characteristically, in placentas from pregnancies complicated by pre-eclampsia and by intrauterine growth restriction, these physiological changes do not occur, owing to a failure of trophoblast migration from the cytotrophoblastic shell and anchoring villi into the decidua and superficial myometrium in early pregnancy.33 The retention of musculo-elastic tissue within the
arterial wall would render the spiral arteries in the placental bed responsive to vasomotor influences (Fig. 4). This would result in a reduction in the blood flow through the maternal arteries to the placental intervillous space. Further reduction in the blood flow in preeclampsia and in intrauterine growth restriction arises from the development of acute atherosis, where there is fibrinoid necrosis of the vessel wall with lipid-laden macrophages in the wall and lumen, and a perivascular round-cell infiltrate (Fig. 5). Acute atherosis can be detected in the terminations of the spiral arteries in the basal plate, and in the spiral arteries in the decidua parietalis in the amniochorial membranes. Alternatives to traditional sampling by using an en face block of the basal plate and stacking of multiple leaves of the amniochorial membranes can facilitate the improved detection of acute atherosis.34,35 The endothelial integrity and the luminal diameter of the spiral arteries are further compromised in the third trimester by the presence of endovascular trophoblast within the lumen, which is not seen normally at that stage of pregnancy (Fig. 6).36,37 There is a suggestion that the development of the uteroplacental vascular blood supply is also defective in placental abruption.38 The correlation between placental examination and clinical placental abruption is often poor. A retroplacental haematoma that may indent
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Figure 3 Uteroplacental artery in the basal plate showing marked distension and replacement of the muscular and elastic wall by fibrinoid.
Figure 4 A spiral artery without physiological changes in the basal plate showing retention of muscular and elastic tissue in the wall.
the placental parenchyma may form where the placental separation is prolonged. On the other hand, no gross evidence may be evident in an acute placental separation, although there
may be histological evidence with intense congestion and dilatation of the fetal vessels of the affected area with chorionic intravillous haemorrhage.39
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Figure 5 Acute atherosis. There is pronounced fibrinoid necrosis of the vessel wall with lipid-laden macrophages in the lumen and wall, and a perivascular mononuclear cellular infiltrate.
Figure 6 Abnormal placentation. There is intraluminal endovascular trophoblast (arrowed) in the uteroplacental artery.
Placental inflammation Amniotic fluid infection is a frequent cause of perinatal loss and, where there is attendant fetal sepsis, stillbirth. Acute chorioamnionitis is a maternal neutrophilic response to the amniotic fluid
infection, and this may be accompanied by a fetal inflammatory response. The inflammation is seen initially in the decidua parietalis (Fig. 7) and in the roof of the intervillous space in the subchorionic fibrin. This will extend into the chorion and amnion. A fetal inflammatory response can be seen
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Figure 7 Acute chorioamnionitis. Acute inflammation is seen confined to the decidua parietalis and chorion laeve at this stage without a spillover into the amnion.
Figure 8 Non-specific chronic villitis. A cluster of agglutinated villi with a lymphocytic infiltrate is shown.
in the vessels in the chorionic plate and, later, in the umbilical cord vessels. Inflammation in the Wharton’s jelly in the umbilical cord is fetal in origin. I have not found it useful to grade the severity or stage the extent of the inflammation. Some organisms can provoke an intrauterine death,
even in the presence of intact membranes, and yet have no histological chorioamnionitis; a prime example of this is the group B Streptococcus. The corollary is that acute chorioamnionitis alone is rarely the cause of stillbirth unless there is overwhelming fetal sepsis, which would require
ARTICLE IN PRESS 168 corroboration by an autopsy. It is, however, clear that chorioamnionitis leads to vasoreactivity in the umbilical vessels,40 which can lead in turn to impaired fetoplacental blood flow that can possibly result in fetal demise. Chronic villitis is a lymphoplasmacytic inflammation of the villi (Fig. 8). It can be specific to organisms, usually viral, but is more often nonspecific.41 The incidence of non-specific chronic villitis, usually termed villitis of unknown aetiology, varies considerably in the literature, and this may be related to observer reliability. The occasional villus affected by chronic inflammation may be missed, but a low-power microscope scan can often reveal clusters of villi that are agglutinated together. Villitis of unknown aetiology can be seen in placentas of stillbirths, and the association may be recurrent. It is associated with intrauterine growth restriction, the severity of which is correlated with the extent of the villitis. In the absence of an identifiable pathogen, the definition of villitis of unknown aetiology, a possible explanation for the lesion is the infiltration of maternal lymphocytes across the syncytiotrophoblastic barrier into the villous stroma. This would result in an alloimmune reaction from the fetus, and the increasing incidence of villitis of unknown aetiology with increasing gestational age and maturity of the fetal immune system would lend support to this. Massive chronic intervillositis is another relatively recent entity that has been described in
T.Y. Khong stillbirths.42,43 It is defined by the infiltration of the intervillous space by maternal macrophages without an attendant villitis (Fig. 9). The lesion is associated with recurrent pregnancy loss, especially in the first trimester.
Management of subsequent pregnancies The value of placental examination in stillbirth lies in the management of future pregnancies. Some placental findings should prompt further investigations in the fetus and mother (Table 2). Other findings are informative to the obstetrician in suggesting additional surveillance in future pregnancies. Thus, impaired uteroplacental blood supply would indicate that uterine artery and umbilical Table 2 Placental findings in stillbirth that should suggest additional laboratory investigations. Placental finding
Suggested investigation
Chronic villitis Maternal vasculopathy Fetal thrombotic vasculopathy Chorioamnionitis Small placenta for gestational age
TORCH screen Thrombophilia screen Thrombophilia screen High vaginal swab Cytogenetics
TORCH, toxoplasmosis, rubella, cytomegalovirus, herpes.
Figure 9 Massive chronic intervillositis. An extensive infiltrate of macrophages is present within the intervillous space.
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Figure 10 Massive perivillous fibrin deposition. The placental villi are separated from each other by the fibrinoid infiltrate.
artery Doppler flow velocity studies might be beneficial. Findings that corroborate a clinical diagnosis of pre-eclampsia may sway the obstetrician to treat empirically with aspirin; trials have indicated that this is of benefit in early onset preeclampsia and may have a role in later-onset preeclampsia. Some of the placental lesions that can recur in subsequent pregnancies, and that can also be associated with stillbirth, have been described above. Another lesion that has been described in stillbirth is massive perivillous fibrin deposition and the related lesion, maternal floor infarction. This is a problematic lesion that lacks a standard definition. There is an abnormal and excessive increase in intervillous fibrinoid encasing the villi, including but not confined to the maternal floor (Fig. 10). Massive fibrinoid infiltration is a suggested term to keep the acronym, MFI, of maternal floor infraction.44 Its recurrence rate is about 20%, but this is based on small numbers in the literature.45 The association of the recurrence with stillbirths and particularly with early pregnancy losses has led some to speculate that it is a result of the eddying or cessation of maternal perfusion. The frequent finding of massive fibrinoid infiltration in the prolonged retention of the dead fetus in a twin pregnancy in which the other twin survives to term supports this suggestion. Despite the lack of a
standard definition and a clear aetiology, recurrence can be diagnosed antenatally by ultrasound,46 again demonstrating the value of placental examination in stillbirth.
Medicolegal issues The importance of placental examination in the context of litigation in cerebral palsy cases has been highlighted.47 However, litigation concerning stillbirth can also bring the placenta into consideration.48 It is not the place for pathologists, as expert witness, to argue for a plaintiff or a defendant but instead to interpret the pathological findings; findings from a placental examination are as likely to help rule out obstetric negligence as a cause of fetal death as they are to support a negligence claim or cast doubt on an obstetrician’s defence.49 Questions that may be asked of the pathologist include estimates of time of fetal demise or whether there was fetal distress.
When did fetal demise occur? Genest50 provided data suggesting that examination of the placenta might be useful for estimating the time of death of stillbirths. The histological
ARTICLE IN PRESS 170 changes may vary depending on the interval between fetal death and delivery of the placenta. No changes may be apparent if the fetus has been dead for less than 6 h. Intravascular karyorhexis in the villous vessels is an early postmortem change, being present when the time interval is between 6 and 48 h. A striking histological feature is progressive fibromuscular sclerosis of the fetal stem arteries, which eventually leads to their obliteration. The villi appear avascular because of capillary collapse and become increasingly fibrotic. If these features are present in 50% or fewer of the villi, fetal demise most likely occurred between 2 and 14 days before delivery. More marked changes indicate an in utero retention period of over 14 days. The fetal vascular changes can, however, be indistinguishable from fetal thrombotic vasculopathy in the placentas of liveborn infants, although the distribution in fetal thrombotic vasculopathy tends to be regional, as opposed to the diffuse change seen in stillbirth.50 The nexus between fetal and/or maternal thrombophilia and fetal thrombotic vasculopathy placental lesions is disputed, as is the nexus between thrombophilia and pre-eclampsia and intrauterine growth restriction. Yet, preeclampsia and intrauterine growth restriction are risk factors for stillbirth, and it is therefore unclear to what extent they affect estimation of the time of fetal demise.
Was there fetal distress? Fetal haematopoiesis increases in response to hypoxia, and, in the absence of other causes that might cause increased haematopoietic activity, an excess of nucleated red blood cells in the fetal vessels of the placenta is now accepted as a marker of fetal hypoxia.51 It is, however, not possible to time the fetal hypoxia as the response time for erythropoietin production is unknown and it is also unknown whether it differs between acute and chronic hypoxia. In addition, we have found that although nucleated red blood cells were significantly more likely to be present in those placentas from infants with a delivery cord pH of less than 7.1 than in those with a pH of over 7.1, being absent from those without acidosis, there was a high falsepositive rate.52 Meconium staining of the membranes used to be regarded as evidence of intrauterine fetal hypoxia and distress, but it is seen in up to 20% of placentas and many of the infants with meconium staining of the membranes have not been subjected to a chronic hypoxic insult.53 On the other hand, many
T.Y. Khong
Figure 11 Effects of meconium on the amnion. There is columnar metaplasia of the epithelium, and a meconiumladen macrophage (arrow) is seen within the amnion.
infants with severe asphyxia and subsequent intrauterine death do not pass meconium. Timing of the passage of meconium is based on an in vitro study, and many factors may modify those parameters. The meconium-stained placenta is yellow in remote episodes and green in fresh episodes, depending on the age of meconium exposure. Meconium staining can be identified by the uptake of meconium by macrophages in the membranes. There can be necrosis and columnar or pseudopapillary metaplasia of the amniotic epithelium (Fig. 11). A note of caution, however: not all pigments in the membranes or chorionic plate are meconium, and this has to be distinguished from haemosiderin, which would be iron positive.
Conclusion The placenta can provide valuable information regarding the cause of the stillbirth and of possible interventions and strategies for future pregnancies. The loss of such information when the placenta is not submitted for examination or when it is suboptimally reported is a disservice to the parents.
ARTICLE IN PRESS The placenta in stillbirth
Practice points
Obstetric units need to ensure that all placentas from stillbirths are sent for histopathological examination Placental findings in stillbirth should be interpreted in the context of clinical information and, where possible, the autopsy findings Alternative methods of sampling the basal plate and the amniochorial membranes can yield a higher detection of acute atherosis Fetal vascular changes to time fetal demise can be virtually indistinguishable from fetal thrombotic vasculopathy Some placental findings are associated with recurrent stillbirths, and additional laboratory investigations may be suggested
Research agenda
Clarification of the role of umbilical cord lesions is stillbirth through a prospective study of cases and controls Seperation of fetal thrombotic vasculopathy from post-mortem in utero changes
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171 9. Vogler C, Petterchak J, Sotelo-Avila C, Thorpe C. Placental pathology for the surgical pathologist. Adv Anat Pathol 2000;7:214–29. 10. Khong TY. A topographical and clinical approach to examination of the placenta. Pathology 2001;33:174–86. 11. Hargitai B, Marton T, Cox PM. Best Practice no. 178. Examination of the human placenta. J Clin Pathol 2004;57: 785–92. 12. Spencer MK, Khong TY. Conformity to guidelines for pathologic examination of the placenta. Arch Pathol Lab Med 2003;127:205–7. 13. Khong TY. From delivery suite to laboratory: optimizing returns from placental examination in medico-legal defence. Aust N Z J Obstet Gynaecol 1997;37:1–5. 14. Clapp 3rd JF, Stepanchak W, Hashimoto K, Ehrenberg H, Lopez B. The natural history of antenatal nuchal cords. Am J Obstet Gynecol 2003;189:488–93. 15. Spellacy WN, Gravem H, Fisch RO. The umbilical cord complications of true knots, nuchal coils, and cords around the body. Report from the collaborative study of cerebral palsy. Am J Obstet Gynecol 1966;94:1136–42. 16. Airas U, Heinonen S. Clinical significance of true umbilical knots: a population-based analysis. Am J Perinatol 2002; 19:127–32. 17. Hershkovitz R, Silberstein T, Sheiner E, et al. Risk factors associated with true knots of the umbilical cord. Eur J Obstet Gynecol Reprod Biol 2001;98:36–9. 18. Matorras R, Diez J, Pereira JG. True knots in the umbilical cord: clinical findings and fetal consequences. J Obstet Gynaecol 1990;10:383–6. 19. Horn LC, Langner A, Stiehl P, Wittekind C, Faber R. Identification of the causes of intrauterine death during 310 consecutive autopsies. Eur J Obstet Gynecol Reprod Biol 2004;113:134–8. 20. Agapitos E, Papadopoulou C, Kavantzas N, Papoulias J, Antonaki V, Davaris P. The contribution of pathological examination of the placenta in the investigation of the causes of foetal mortality. Arch Anat Cytol Pathol 1996; 44:5–11. 21. Larsen LG, Graem N. Morphological findings and value of placental examination at fetal and perinatal autopsy. APMIS 1999;107:337–45. 22. Tang MY, Zhu YN, Xu H, Gai MY, Ji XC, Zhao SM. Clinicopathological analysis of causes of perinatal death. Chin Med J (Engl) 1989;102:672–8. 23. Woods DL, Draper RR. A clinical assessment of stillborn infants. S Afr Med J 1980;57:441–3. 24. Rayburn W, Sander C, Barr Jr M, Rygiel R. The stillborn fetus: placental histologic examination in determining a cause. Obstet Gynecol 1985;65:637–41. 25. Hovatta O, Lipasti A, Rapola J, Karjalainen O. Causes of stillbirth: a clinicopathological study of 243 patients. Br J Obstet Gynaecol 1983;90:691–6. 26. Brenner B, Kupferminc MJ. Inherited thrombophilia and poor pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2003;17:427–39. 27. Redline RW, Ariel I, Baergen RN, et al. Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004;7:443–52. 28. Sander CH, Kinnane L, Stevens NG, Echt R. Haemorrhagic endovasculitis of the placenta: a review with clinical correlation. Placenta 1986;7:551–74. 29. Sander CM, Gilliland D, Richardson A, Foley KM, Fredericks J. Stillbirths with placental hemorrhagic endovasculitis: a morphologic assessment with clinical implications. Arch Pathol Lab Med 2005;129:632–8.
ARTICLE IN PRESS 172 30. Ariel I, Anteby E, Hamani Y, Redline RW. Placental pathology in fetal thrombophilia. Hum Pathol 2004;35:729–33. 31. Redline RW. Clinical and pathological umbilical cord abnormalities in fetal thrombotic vasculopathy. Hum Pathol 2004;35:1494–8. 32. Redline RW, Boyd T, Campbell V, et al. Maternal vascular underperfusion: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004;7:237–49. 33. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 1986;93:1049–59. 34. Khong TY, Chambers HM. Alternative method of sampling placentas for the assessment of uteroplacental vasculature. J Clin Pathol 1992;45:925–7. 35. Walford N, Htun K, Akhilesh M. Detection of atherosis in preeclamptic placentas: comparison of two gross sampling protocols. Pediatr Dev Pathol 2005;8:61–5. 36. Khong TY, Sawyer IH, Heryet AR. An immunohistologic study of endothelialization of uteroplacental vessels in human pregnancy—evidence that endothelium is focally disrupted by trophoblast in preeclampsia. Am J Obstet Gynecol 1992; 167:751–6. 37. Kos M, Czernobilsky B, Hlupic L, Kunjko K. Pathological changes in placentas from pregnancies with preeclampsia and eclampsia with emphasis on persistence of endovascular trophoblastic plugs. Croat Med J 2005;46:404–9. 38. Dommisse J, Tiltman AJ. Placental bed biopsies in placental abruption. Br J Obstet Gynaecol 1992;99:651–4. 39. Mooney EE, al Shunnar A, O’Regan M, Gillan JE. Chorionic villous haemorrhage is associated with retroplacental haemorrhage. Br J Obstet Gynaecol 1994;101:965–9. 40. Salafia CM, Ghidini A, Sherer DM, Pezzullo JC. Abnormalities of the fetal heart rate in preterm deliveries are associated with acute intra-amniotic infection. J Soc Gynecol Invest 1998;5:188–91. 41. Redline RW. Placental inflammation. Semin Neonatol 2004; 9:265–74. 42. Jacques SM, Qureshi F. Chronic intervillositis of the placenta. Arch Pathol Lab Med 1993;117:1032–5.
T.Y. Khong 43. Gersell DJ. Chronic villitis, chronic chorioamnionitis, and maternal floor infarction. Semin Diagn Pathol 1993;10: 251–66. 44. Bendon RW. Two problems in placental pathology: umbilical cord torsion and massive fibrinoid infiltration. Pathol Int 2004;54(Suppl. 1):S432–4. 45. Khong TY. What’s in fibrin? Pediatr Dev Pathol 2002;5:106–7. 46. Mandsager NT, Bendon R, Mostello D, Rosenn B, Miodovnik M, Siddiqi TA. Maternal floor infarction of the placenta: prenatal diagnosis and clinical significance. Obstet Gynecol 1994;83:750–4. 47. Kraus FT. Perinatal pathology, the placenta, and litigation. Hum Pathol 2003;34:517–21. 48. Kaplan CG. Forensic aspects of the placenta. Perspect Pediatr Pathol 1995;19:20–42. 49. Apfel D. Placental pathology: a tool for obstetrical cases. Trial 1994;30:43–6. 50. Genest DR. Estimating the time of death in stillborn fetuses. II. Histologic evaluation of the placenta; a study of 71 stillborns. Obstet Gynecol 1992;80:585–92. 51. Fox H. The incidence and significance of nucleated erythrocytes in the foetal vessels of the mature human placenta. J Obstet Gynaecol Br Commonw 1967;74:40–3. 52. Spencer MK, Khong TY, Matthews BL, MacLennan AH. Haematopoietic indicators of fetal metabolic acidosis. Aust N Z J Obstet Gynaecol 2000;40:286–9. 53. Houlihan CM, Knuppel RA. Meconium-stained amniotic fluid. Current controversies. J Reprod Med 1994;39:888–98.
Further reading 1. Benirschke K, Kaufmann P. Pathology of the human placenta, 4th ed. New York: Springer; 2000. 2. Faye-Peterson O, Heller D, Joshi V. Handbook of placental pathology. London: Taylor & Francis; 2005. 3. Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Placental pathology. Washington, DC: American Registry of Pathology; 2004.
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MINI SYMPOSIUM: PAEDIATRIC PATHOLOGY
The placenta in stillbirth T. Yee Khong Department of Histopathology, Women’s and Children’s Hospital, 72 King William Road, North Adelaide SA5006, Australia
KEYWORDS Placenta; Medicolegal; Pathology; Stillbirth
Summary Stillbirth is an absolute indication for pathological examination of the placenta. Placental histopathology can shed light on the cause of the stillbirth and help in the management of future pregnancies and in the resolution of medicolegal issues. Placental lesions that are likely causes of stillbirth are discussed. They can be broadly classified into umbilical cord lesions, fetal vascular lesions, maternal uteroplacental insufficiency and placental inflammation. In some of these lesions, the direct contribution to the stillbirth may be obvious; in others, it may be debatable. Medicolegal questions that are frequently posed in placental examination in stillbirths are the timing of fetal demise and whether there was fetal distress. & 2006 Elsevier Ltd. All rights reserved.
Introduction The reasons for examining the placenta in stillbirth are similar to those for other indications: in summary, clarification of the pathophysiology of adverse outcome, management of subsequent pregnancies and assessment of factors for resolving medicolegal issues.1 Of the many indications for a placenta to be examined pathologically,1 stillbirth would seem to be incontrovertible. Nevertheless, for whatever reasons, placentas were not examined in 7.7% of stillbirths in South Australia2 and 11% of stillbirths in northern England.3 On a countrywide basis, the problem of non-examination of the placenta in stillbirth is probably of a larger magnitude. The 4th Confidential Enquiry Tel.: +61 8 8161 6793; fax: +61 8 8161 7022.
E-mail address: [email protected].
into Stillbirths and Deaths in Infancy showed that placentas were examined in only 44% of intrapartum stillbirths,4 and yet, four Confidential Enquiry reports later, failure to send the placenta for histology remains a problem: ‘there was no histology on the placenta which might have shed light on the cause of this unexplained stillbirth’.5 Standards of reporting of the placenta vary,6 but it has been shown that perinatal/placental pathologists are able to detect clinically significant placental lesions more frequently and more accurately than general anatomical pathologists.7 It is important, therefore, that meticulous gross examination and appropriate sampling should be the prime objectives, supplemented, if necessary, by photography of gross lesions and slices of the placenta. In this way, at the very least, the slides could be reviewed by an expert pathologist.8
0968-6053/$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.cdip.2006.03.001
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It is not the intention of this review to cover all aspects of placental pathology. There have been recent publications on how placentas should be examined,9–11 and a list of recent texts on placental pathology is appended. This review will focus on those aspects which are pertinent to stillbirth and are topical.
Clinical history The placenta should, like other surgical pathology specimens, be examined with as much clinical information available as possible.12 Many placental findings are not specific to a disease process, and interpretation may be dependent on the clinical context. For example, the placenta responds to reduced uteroplacental blood flow by developing pathological changes that may be attributable to several maternal conditions such as hypertension, diabetes, prolonged pregnancy and maternal autoimmune disease. Information about the maternal obstetric history, antenatal course and delivery is therefore important to allow a correct clinicopathological correlation to be made.13 If permission for an autopsy has been given, the placental findings should be interpreted in the light of those of the autopsy. A history of fetal hydrops and antenatal monitoring indicating increasing heart failure would lead one reasonably to conclude that a sizeable chorangioma found on placental examination could be the cause of the stillbirth: chorangiomas are vascular tumours in the villous stroma, and the vascularity could lead to increased shunted blood flow. On the other hand, in the absence of the history and autopsy findings, the chorangioma may or may not be felt to have been the cause of the stillbirth.
Table 1
Cause of the stillbirth Cord lesions Even where placental examination is performed, there is considerable variation in terms of which gross or histological lesions are accorded significance. A good example of this conundrum is illustrated by the wide variation in the reported incidence of cord pathology as a cause of or related finding in stillbirth (Table 1). Cord complications that have been cited as being related to stillbirth have included a single umbilical artery and a velamentous or marginal insertion. Although these lesions can be identified objectively at gross examination, the interpretation of whether these are sufficient to explain the cause of the stillbirth is subjective and may be biased by past experiences. The incidence of a single umbilical artery varies from 0.2% to 1.1% of births, but has varied from 2.7% to 12% in perinatal autopsy series. A single umbilical artery in itself is clearly insufficient to explain a stillbirth. However, its associations with anatomical malformations and karyotypic anomalies could account for the perinatal loss. Parenthetically, an overcalling of the significance of umbilical cord lesions did not result in a lower unexplained stillbirth rate (Table 1). Another example of where there is a need for close clinicopathological correlation is the issue of cord entanglement and knots. Cord entanglement is frequent and can be present in as many as a third of pregnancies at term.14 Entanglement around a limb or torso is less frequent than entanglement around the neck, but it still has a potential to produce sufficient kinking to affect the fetal circulation, especially if there is looping of the cord around itself. Adverse perinatal
Cord pathology and relation to unexplained stillbirth rate.
Study area
Number of cases with cord pathology (Number of stillbirths)
% Stillbirths with cord pathology
% Cases of unexplained stillbirth in the study
Germany19 Greece20 Denmark21 China22 South Africa23 USA24 Finland25 South Australia
43 42 21 27 8 9 29 0
22.5 25.6 25.0 28.0 5.3 7.8 11.9 0
15 12 Not stated 14 15 Not stated 9 24
(310) (164) (84) (114) (150) (89) (243) (242)
ARTICLE IN PRESS The placenta in stillbirth outcome is related to the number of coils around fetal parts.15 Examination of the placenta alone would not be able to determine whether entanglements were important, but entanglements are more frequent among long cords. True knots are present in between 0.1% and 2.1% of cords at delivery. A higher rate of stillbirth has been described in cords with true knots,16,17 but this is disputed by others.18 Information such as number of body parts involved, cord diameter as a surrogate for the amount of Wharton’s jelly or the presence of growth restriction, and whether the knot has been loosened prior to receipt by the pathologist is needed to ascertain whether or not entanglements and true knots are significant. To overcome wrongly ascribing the significance of a true knot as a cause of stillbirth, we have set a threshold that stipulates the finding of oedema and congestion or thrombosis of the vessels in the vicinity of a knot.
Fetal vascular lesions The possible association of various inherited thrombophilias with placental abruption, intrauterine growth restriction, pre-eclampsia and intrauterine death26 has led to a careful evaluation of the maternal and fetal vasculatures. Thrombotic or occlusive lesions within the fetal circulation can manifest as obvious white plaques of avascular villi
163 or be recognized only on microscopy. The term ‘fetal thrombotic vasculopathy’ has been used to embrace these lesions, which include fetal artery thrombosis, haemorrhagic endovasculitis, fibromuscular sclerosis and fibrinous vasculosis.27 The lesion can be seen easily on a low-power microscopic view, with a clear division between the groups of avascular and normally vascularized villi. There is often a large thrombosed stem artery upstream of the avascular villi (Fig. 1). The thrombus may show organization and recanalization. This ingrowth of fibroblasts or endothelial cells into the lumen creates a pattern of septation within the vessels and is described in stillbirths as well as in liveborns (Fig. 2). Early changes in this lesion, termed haemorrhagic endovasculitis, comprise the organization and recanalization of thrombi with neutrophils or nuclear debris in the vessel walls, i.e. villous stromal-vascular karyorhexis.28 The vessels distal to the occlusion show progressive fibromuscular sclerosis, and the connective tissue is fibrous with a hyalinized appearance. Other larger fetal vessels may show intimal fibrin cushions, which are seen as subendothelial or medial deposition of fibrin or fibrinoid within the walls. Older lesions will show calcification. Fetal thrombotic vasculopathy is seen in about 5% of placentas from uncomplicated, term pregnancies but in about 15% in placentas from stillbirths. Lesions such as haemorrhagic endovasculitis may be recurrent.29 This would implicate
Figure 1 Fetal thrombotic vasculopathy. There is thrombosis (arrowheads) and an intimal fibrin cushion (arrow) in this large chorionic vessel.
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Figure 2 Septation of blood vessels. These are seen increasingly after 24 h in stillbirth and also in fetal thrombotic vasculopathy. It may not be possible to distinguish between the two clinical conditions.
inherited thrombophilia as a likely factor in the pathophysiological pathway. The correlation between histological fetal thrombotic vasculopathy and most of the currently known inherited thrombophilias is, however, poor,30 and other factors, such as umbilical cord pathology, may be important.31
Uteroplacental insufficiency The placentas of some stillbirths are characterized by maternal underperfusion where it is small, with or without infarction, and histologically displays increased syncytial knot formation and distal villous hypoplasia.32 The maternal spiral arteries in the placental bed normally respond to the demands of the growing placenta and fetus by adapting during early pregnancy from being narrow-calibre, vasoresponsive arteries with a musculo-elastic arterial wall to being flaccid, dilated, vaso-non-reactive uteroplacental arteries with a fibrinoid wall (Fig. 3). These changes are completed by mid-pregnancy. Characteristically, in placentas from pregnancies complicated by pre-eclampsia and by intrauterine growth restriction, these physiological changes do not occur, owing to a failure of trophoblast migration from the cytotrophoblastic shell and anchoring villi into the decidua and superficial myometrium in early pregnancy.33 The retention of musculo-elastic tissue within the
arterial wall would render the spiral arteries in the placental bed responsive to vasomotor influences (Fig. 4). This would result in a reduction in the blood flow through the maternal arteries to the placental intervillous space. Further reduction in the blood flow in preeclampsia and in intrauterine growth restriction arises from the development of acute atherosis, where there is fibrinoid necrosis of the vessel wall with lipid-laden macrophages in the wall and lumen, and a perivascular round-cell infiltrate (Fig. 5). Acute atherosis can be detected in the terminations of the spiral arteries in the basal plate, and in the spiral arteries in the decidua parietalis in the amniochorial membranes. Alternatives to traditional sampling by using an en face block of the basal plate and stacking of multiple leaves of the amniochorial membranes can facilitate the improved detection of acute atherosis.34,35 The endothelial integrity and the luminal diameter of the spiral arteries are further compromised in the third trimester by the presence of endovascular trophoblast within the lumen, which is not seen normally at that stage of pregnancy (Fig. 6).36,37 There is a suggestion that the development of the uteroplacental vascular blood supply is also defective in placental abruption.38 The correlation between placental examination and clinical placental abruption is often poor. A retroplacental haematoma that may indent
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Figure 3 Uteroplacental artery in the basal plate showing marked distension and replacement of the muscular and elastic wall by fibrinoid.
Figure 4 A spiral artery without physiological changes in the basal plate showing retention of muscular and elastic tissue in the wall.
the placental parenchyma may form where the placental separation is prolonged. On the other hand, no gross evidence may be evident in an acute placental separation, although there
may be histological evidence with intense congestion and dilatation of the fetal vessels of the affected area with chorionic intravillous haemorrhage.39
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Figure 5 Acute atherosis. There is pronounced fibrinoid necrosis of the vessel wall with lipid-laden macrophages in the lumen and wall, and a perivascular mononuclear cellular infiltrate.
Figure 6 Abnormal placentation. There is intraluminal endovascular trophoblast (arrowed) in the uteroplacental artery.
Placental inflammation Amniotic fluid infection is a frequent cause of perinatal loss and, where there is attendant fetal sepsis, stillbirth. Acute chorioamnionitis is a maternal neutrophilic response to the amniotic fluid
infection, and this may be accompanied by a fetal inflammatory response. The inflammation is seen initially in the decidua parietalis (Fig. 7) and in the roof of the intervillous space in the subchorionic fibrin. This will extend into the chorion and amnion. A fetal inflammatory response can be seen
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Figure 7 Acute chorioamnionitis. Acute inflammation is seen confined to the decidua parietalis and chorion laeve at this stage without a spillover into the amnion.
Figure 8 Non-specific chronic villitis. A cluster of agglutinated villi with a lymphocytic infiltrate is shown.
in the vessels in the chorionic plate and, later, in the umbilical cord vessels. Inflammation in the Wharton’s jelly in the umbilical cord is fetal in origin. I have not found it useful to grade the severity or stage the extent of the inflammation. Some organisms can provoke an intrauterine death,
even in the presence of intact membranes, and yet have no histological chorioamnionitis; a prime example of this is the group B Streptococcus. The corollary is that acute chorioamnionitis alone is rarely the cause of stillbirth unless there is overwhelming fetal sepsis, which would require
ARTICLE IN PRESS 168 corroboration by an autopsy. It is, however, clear that chorioamnionitis leads to vasoreactivity in the umbilical vessels,40 which can lead in turn to impaired fetoplacental blood flow that can possibly result in fetal demise. Chronic villitis is a lymphoplasmacytic inflammation of the villi (Fig. 8). It can be specific to organisms, usually viral, but is more often nonspecific.41 The incidence of non-specific chronic villitis, usually termed villitis of unknown aetiology, varies considerably in the literature, and this may be related to observer reliability. The occasional villus affected by chronic inflammation may be missed, but a low-power microscope scan can often reveal clusters of villi that are agglutinated together. Villitis of unknown aetiology can be seen in placentas of stillbirths, and the association may be recurrent. It is associated with intrauterine growth restriction, the severity of which is correlated with the extent of the villitis. In the absence of an identifiable pathogen, the definition of villitis of unknown aetiology, a possible explanation for the lesion is the infiltration of maternal lymphocytes across the syncytiotrophoblastic barrier into the villous stroma. This would result in an alloimmune reaction from the fetus, and the increasing incidence of villitis of unknown aetiology with increasing gestational age and maturity of the fetal immune system would lend support to this. Massive chronic intervillositis is another relatively recent entity that has been described in
T.Y. Khong stillbirths.42,43 It is defined by the infiltration of the intervillous space by maternal macrophages without an attendant villitis (Fig. 9). The lesion is associated with recurrent pregnancy loss, especially in the first trimester.
Management of subsequent pregnancies The value of placental examination in stillbirth lies in the management of future pregnancies. Some placental findings should prompt further investigations in the fetus and mother (Table 2). Other findings are informative to the obstetrician in suggesting additional surveillance in future pregnancies. Thus, impaired uteroplacental blood supply would indicate that uterine artery and umbilical Table 2 Placental findings in stillbirth that should suggest additional laboratory investigations. Placental finding
Suggested investigation
Chronic villitis Maternal vasculopathy Fetal thrombotic vasculopathy Chorioamnionitis Small placenta for gestational age
TORCH screen Thrombophilia screen Thrombophilia screen High vaginal swab Cytogenetics
TORCH, toxoplasmosis, rubella, cytomegalovirus, herpes.
Figure 9 Massive chronic intervillositis. An extensive infiltrate of macrophages is present within the intervillous space.
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Figure 10 Massive perivillous fibrin deposition. The placental villi are separated from each other by the fibrinoid infiltrate.
artery Doppler flow velocity studies might be beneficial. Findings that corroborate a clinical diagnosis of pre-eclampsia may sway the obstetrician to treat empirically with aspirin; trials have indicated that this is of benefit in early onset preeclampsia and may have a role in later-onset preeclampsia. Some of the placental lesions that can recur in subsequent pregnancies, and that can also be associated with stillbirth, have been described above. Another lesion that has been described in stillbirth is massive perivillous fibrin deposition and the related lesion, maternal floor infarction. This is a problematic lesion that lacks a standard definition. There is an abnormal and excessive increase in intervillous fibrinoid encasing the villi, including but not confined to the maternal floor (Fig. 10). Massive fibrinoid infiltration is a suggested term to keep the acronym, MFI, of maternal floor infraction.44 Its recurrence rate is about 20%, but this is based on small numbers in the literature.45 The association of the recurrence with stillbirths and particularly with early pregnancy losses has led some to speculate that it is a result of the eddying or cessation of maternal perfusion. The frequent finding of massive fibrinoid infiltration in the prolonged retention of the dead fetus in a twin pregnancy in which the other twin survives to term supports this suggestion. Despite the lack of a
standard definition and a clear aetiology, recurrence can be diagnosed antenatally by ultrasound,46 again demonstrating the value of placental examination in stillbirth.
Medicolegal issues The importance of placental examination in the context of litigation in cerebral palsy cases has been highlighted.47 However, litigation concerning stillbirth can also bring the placenta into consideration.48 It is not the place for pathologists, as expert witness, to argue for a plaintiff or a defendant but instead to interpret the pathological findings; findings from a placental examination are as likely to help rule out obstetric negligence as a cause of fetal death as they are to support a negligence claim or cast doubt on an obstetrician’s defence.49 Questions that may be asked of the pathologist include estimates of time of fetal demise or whether there was fetal distress.
When did fetal demise occur? Genest50 provided data suggesting that examination of the placenta might be useful for estimating the time of death of stillbirths. The histological
ARTICLE IN PRESS 170 changes may vary depending on the interval between fetal death and delivery of the placenta. No changes may be apparent if the fetus has been dead for less than 6 h. Intravascular karyorhexis in the villous vessels is an early postmortem change, being present when the time interval is between 6 and 48 h. A striking histological feature is progressive fibromuscular sclerosis of the fetal stem arteries, which eventually leads to their obliteration. The villi appear avascular because of capillary collapse and become increasingly fibrotic. If these features are present in 50% or fewer of the villi, fetal demise most likely occurred between 2 and 14 days before delivery. More marked changes indicate an in utero retention period of over 14 days. The fetal vascular changes can, however, be indistinguishable from fetal thrombotic vasculopathy in the placentas of liveborn infants, although the distribution in fetal thrombotic vasculopathy tends to be regional, as opposed to the diffuse change seen in stillbirth.50 The nexus between fetal and/or maternal thrombophilia and fetal thrombotic vasculopathy placental lesions is disputed, as is the nexus between thrombophilia and pre-eclampsia and intrauterine growth restriction. Yet, preeclampsia and intrauterine growth restriction are risk factors for stillbirth, and it is therefore unclear to what extent they affect estimation of the time of fetal demise.
Was there fetal distress? Fetal haematopoiesis increases in response to hypoxia, and, in the absence of other causes that might cause increased haematopoietic activity, an excess of nucleated red blood cells in the fetal vessels of the placenta is now accepted as a marker of fetal hypoxia.51 It is, however, not possible to time the fetal hypoxia as the response time for erythropoietin production is unknown and it is also unknown whether it differs between acute and chronic hypoxia. In addition, we have found that although nucleated red blood cells were significantly more likely to be present in those placentas from infants with a delivery cord pH of less than 7.1 than in those with a pH of over 7.1, being absent from those without acidosis, there was a high falsepositive rate.52 Meconium staining of the membranes used to be regarded as evidence of intrauterine fetal hypoxia and distress, but it is seen in up to 20% of placentas and many of the infants with meconium staining of the membranes have not been subjected to a chronic hypoxic insult.53 On the other hand, many
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Figure 11 Effects of meconium on the amnion. There is columnar metaplasia of the epithelium, and a meconiumladen macrophage (arrow) is seen within the amnion.
infants with severe asphyxia and subsequent intrauterine death do not pass meconium. Timing of the passage of meconium is based on an in vitro study, and many factors may modify those parameters. The meconium-stained placenta is yellow in remote episodes and green in fresh episodes, depending on the age of meconium exposure. Meconium staining can be identified by the uptake of meconium by macrophages in the membranes. There can be necrosis and columnar or pseudopapillary metaplasia of the amniotic epithelium (Fig. 11). A note of caution, however: not all pigments in the membranes or chorionic plate are meconium, and this has to be distinguished from haemosiderin, which would be iron positive.
Conclusion The placenta can provide valuable information regarding the cause of the stillbirth and of possible interventions and strategies for future pregnancies. The loss of such information when the placenta is not submitted for examination or when it is suboptimally reported is a disservice to the parents.
ARTICLE IN PRESS The placenta in stillbirth
Practice points
Obstetric units need to ensure that all placentas from stillbirths are sent for histopathological examination Placental findings in stillbirth should be interpreted in the context of clinical information and, where possible, the autopsy findings Alternative methods of sampling the basal plate and the amniochorial membranes can yield a higher detection of acute atherosis Fetal vascular changes to time fetal demise can be virtually indistinguishable from fetal thrombotic vasculopathy Some placental findings are associated with recurrent stillbirths, and additional laboratory investigations may be suggested
Research agenda
Clarification of the role of umbilical cord lesions is stillbirth through a prospective study of cases and controls Seperation of fetal thrombotic vasculopathy from post-mortem in utero changes
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T.Y. Khong 43. Gersell DJ. Chronic villitis, chronic chorioamnionitis, and maternal floor infarction. Semin Diagn Pathol 1993;10: 251–66. 44. Bendon RW. Two problems in placental pathology: umbilical cord torsion and massive fibrinoid infiltration. Pathol Int 2004;54(Suppl. 1):S432–4. 45. Khong TY. What’s in fibrin? Pediatr Dev Pathol 2002;5:106–7. 46. Mandsager NT, Bendon R, Mostello D, Rosenn B, Miodovnik M, Siddiqi TA. Maternal floor infarction of the placenta: prenatal diagnosis and clinical significance. Obstet Gynecol 1994;83:750–4. 47. Kraus FT. Perinatal pathology, the placenta, and litigation. Hum Pathol 2003;34:517–21. 48. Kaplan CG. Forensic aspects of the placenta. Perspect Pediatr Pathol 1995;19:20–42. 49. Apfel D. Placental pathology: a tool for obstetrical cases. Trial 1994;30:43–6. 50. Genest DR. Estimating the time of death in stillborn fetuses. II. Histologic evaluation of the placenta; a study of 71 stillborns. Obstet Gynecol 1992;80:585–92. 51. Fox H. The incidence and significance of nucleated erythrocytes in the foetal vessels of the mature human placenta. J Obstet Gynaecol Br Commonw 1967;74:40–3. 52. Spencer MK, Khong TY, Matthews BL, MacLennan AH. Haematopoietic indicators of fetal metabolic acidosis. Aust N Z J Obstet Gynaecol 2000;40:286–9. 53. Houlihan CM, Knuppel RA. Meconium-stained amniotic fluid. Current controversies. J Reprod Med 1994;39:888–98.
Further reading 1. Benirschke K, Kaufmann P. Pathology of the human placenta, 4th ed. New York: Springer; 2000. 2. Faye-Peterson O, Heller D, Joshi V. Handbook of placental pathology. London: Taylor & Francis; 2005. 3. Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Placental pathology. Washington, DC: American Registry of Pathology; 2004.