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Deaths: Pregnancy-Related Deaths – Pathology
Deaths: Pregnancy-Related Deaths – Pathology CT Buschmann and M Tsokos, Institut für Rechtsmedizin der Charité - Universitätsmedizin Berlinm r 2016 Elsevier Ltd. All rights reserved.
Abstract Maternal deaths during pregnancy, both from pregnancy-related and other causes, are rare in Western industrialized countries. Pregnancy-induced hypertension and amniotic fluid embolism (AFE) are the main contributors to directly gestation-related maternal death in pregnancy. The forensic evaluation of such a case should include autopsy, clinical details, and microscopic and toxicological investigations, noting that autopsy findings are often nonspecific. Even if the cause of death is apparently obvious after autopsy, histopathological examination should be performed in suspected pregnancy-related fatalities. In cases of suspected AFE, representative histological specimens from different areas of each organ, in particular from pulmonary tissue, should be collected and examined.
Introduction Maternal deaths in pregnancy, in particular pregnancyrelated maternal deaths, are rare in the Western world. In 2008, according to the World Health Organization (WHO), the maternal mortality ratio (MMR, maternal deaths per 100 000 live births per year), as a measurement of the quality of medical care for pregnant women, amounted to approximately 14 deaths per 100 000 live births for Western industrial nations, which corresponds to approximately 1700 deaths of pregnant women. There were 358 000 maternal deaths during pregnancy in 2008 worldwide, approximately 99% of which occurred in the so-called ‘developing’ countries. For the Federal Republic of Germany, the estimated MMR in 2008 was 7 deaths per 100 000 live births (49 maternal deaths) (WHO, 2010). The distinction between maternal deaths in pregnancy and pregnancy-related maternal deaths is not always clear (ICD-10): if maternal death occurs during or within 42 days after termination of pregnancy, the criterion of ‘gestational death’ is met. However, actual ‘maternal deaths during pregnancy’ are only those deaths that can be traced back directly to gestational circumstances, and nonnatural causes of death of pregnant women (i.e., accidents, suicides, or other, nonpregnancy-associated fatal events) are not counted among them. Furthermore, ‘maternal deaths’ can again be divided into two subcategories: ‘direct gestational deaths’ are causally due to complications of gestation (pregnancy, delivery, and postpartum) or by gestationrelated medical interventions, omissions, and improper handling (i.e., fatal gestational hypertension or fatal delivery complications). ‘Indirect gestational deaths’ are caused by preexisting cardiovascular diseases with nonobstetric origin which decompensate by the physiological effects of pregnancy, birth, and postpartum: the heart rate increases by 10–30 bpm, and the cardiac output up to the 32nd week of gestation by 30–50%;
Encyclopedia of Forensic and Legal Medicine, Volume 2
there is vasodilatation, an increased tendency to coagulation, an increase of serum lipids, and a reversible increase of the size of the heart of up to 30%. Systolic blood pressure drops toward the middle of pregnancy and returns toward baseline at the end of pregnancy. Maternal oxygen consumption increases up to threefold during vaginal delivery, and systolic pressure spikes up to 200 mmHg are possible in the expulsion period (Regitz-Zagrosek et al., 2011). Owing to the high medical standards in the Western world, ‘maternal deaths’ might occur well after delivery/ postabortion. Maternal deaths of both direct and indirect gestational cause occurring later than 42 days, but within 1 year after termination of pregnancy, are classified as ‘late maternal deaths.’ An overview of current definitions and terms of causes of death in pregnancy is given in Table 1. The autopsy of a deceased pregnant woman is currently rare in routine forensic practice, and representative statements about characteristic pathophysiological or pathomorphological changes in pregnancy-related maternal deaths remain difficult. In a retrospective review of the medicolegal autopsy files (n ¼11 270) in 5 years, we identified a total of 13 autopsies of maternal deaths in pregnancy (0.12%) (Buschmann et al., 2013). According to the WHO classification, three cases met the category of ‘nongestational death.’ In one case the cause of death could not be clarified morphologically, histologically, or toxicologically. Toxicological examinations were performed in every case. Except for one case, the findings were unremarkable. In this case, death resulted from fatal narcotic intoxication. Of the remaining 9 cases, 8 deaths were ‘maternal deaths,’ of which, in turn, 6 were directly and 2 indirectly attributable to gestation. One case of delayed death 2 years after abortion and eclampsia was not to technically a ‘late maternal death,’ but the cause of death appeared to be directly due to former pregnancy and abortion. The case was given the auxiliary term ‘(very)
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Table 1
Deaths: Pregnancy-Related Deaths – Pathology Causes of pregnancy-related deaths
Classification Gestational (maternal) death Direct gestational death
Indirect gestational death
Death due to any (direct/indirect) gestational cause between 42 days and 1 year after delivery/ abortion (‘late maternal deaths’) Death due to any (direct/indirect) gestational cause 41 year after delivery/abortion Nongestational (maternal) death
Definition
Death as a result of complications of gestation (pregnancy, childbirth, and postpartum), as a result of interventions, omissions, and improper handling, or as a result of a causal chain that starts from one of these states Death as a result of a preexisting disease or a disease that developed during gestation and is not due to direct gestational causes, but due to physiological effects of gestation
Death during gestation as a result of external violence, suicide, and/or other random events
Death during gestation from further nonspecified causes
late maternal death.’ In the heterogeneous group of deaths, we identified two diseases directly related to gestation: pregnancy-induced hypertension (PIH) and amniotic fluid embolism (AFE). The distribution of causes of maternal deaths in pregnancy in our study was not surprising and was broadly in line with the 2006 WHO analysis: hypertensive diseases in developed countries account for up to 16.1% of all maternal deaths, being the most frequent cause of death in pregnant women (Khan et al., 2006). The real number of deceased pregnant women may be significantly higher as not every fatality will undergo a forensic autopsy. A thorough investigation of such deaths by performing a forensic autopsy seems appropriate, especially regarding pathomorphological features and additional investigations. Histological examinations are always useful in clarifying the cause of death in pregnancy, as important information about pathophysiological changes can be provided. The lack of histological investigations in pregnancy-related maternal fatalities is not atypical and has been criticized in former studies (Rushton and Dawson, 1982; Jashnani et al., 2009). Histopathological examination should become an integral part of forensic investigations in suspected
pregnancy-related fatalities, even if the cause of death already seems to be clarified by macroscopic autopsy findings (Simic et al., 2004). In accordance with the guidelines published in 2010 by the Royal College of Pathologists, Table 2 gives important histopathological findings and clinical evidence (Royal College of Pathologists, 2010). The main contributors to maternal deaths in pregnancy are PIH, AFE, and postpartum hemorrhage (PPH). Pregnancy-Induced Hypertension
The prevalence of preeclampsia as the mildest form of PIH is reported to be 3–7%, this being seen mainly in primiparae, typically from the 20th week of gestation (Prahlow and Barnard, 2004; Young et al., 2010; Hladunewich et al., 2007). Characteristic symptoms include hypertension with systolic blood pressures of at least 140 mmHg and/or diastolic blood pressures of at least 90 mmHg, and also proteinuria of more than 300 mg per 24 h. Subsequent severe eclampsia is reported to occur in only 0.5–2% of all pregnancies, but the mortality rate increases to 20%. The patients also suffer from severe cephalgia and neurological deficits, i.e., visual disturbances. A syndrome known as hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, the most serious form of PIH, is reported to be found in 4–12% of all (pre-)eclampsia deaths. If HELLP syndrome develops postpartum, an increased mortality rate of 32% is reported. PIH may manifest itself in various degrees of severity, presenting as fulminant HELLP syndrome or preliminary stages of PIH (preeclampsia/eclampsia). Macroscopic autopsy findings will generally yield no distinct cause of death, and the final diagnosis of the cause of death is based on the results of histological examinations. PIH is most pronounced in the kidneys, with pathological changes limited to the glomeruli and correlating with the severity of PIH (Young et al., 2010; Tribe et al., 1979; Moran and Davison, 1999; Gaber et al., 1987). Light microscopy shows a general glomerular increase and also swelling of the glomerular endothelial cells, which are characterized by not only the increase in volume, but also their vacuolization. These lipid- and fluid-filled vacuoles may occupy the entire cytoplasm, resulting in a ‘foamy’ appearance. Glomerular hypertrophy leads to compression of the renal capillaries with subsequent anemia, described as ‘glomerular endotheliosis.’ In addition, hypertrophy of mesangial cells is observed, spreading through their volume expansion even into the periphery of the capillary loops, edging themselves between endothelial cells and the basal membrane. This mechanism not only reinforces the lack of blood to the capillary loops, but also results in compression and a correspondingly elongated appearance of
Deaths: Pregnancy-Related Deaths – Pathology
the vessels (‘cigar-shaped’) (Gaber et al., 1987; Tsokos et al., 2002; Tsokos, 2004) and split capillary loops (‘tramlining’ effect) (Tribe et al., 1979). A further consequence is an apparent thickening of the endothelial basal membrane, which is reinforced by subendothelial fibrin deposits. In addition, as an effect of the increased glomerular cell elements, the so-called ‘pounting’ appears (up to 200 mm wide extension of some capillary loops at the beginning of the proximal tubule in up to 50% of glomeruli). The regression of these morphological changes begins 48 h after birth and might take up to 6 months to resolve. During this period, a pearlnecklace-like appearance of the capillary loops (‘beading’), may be observed, indicating a healing process. While these renal tissue changes can be present in all degrees of PIH, a fulminate HELLP syndrome additionally consists of a characteristic pathology of the liver with typical periportal necrosis in zone 1 and intraparenchymal hemorrhage (Prahlow and Barnard, 2004; Tsokos et al., 2002; Tsokos, 2004; Amsin et al., 1996; Schneider, 1994). Subcapsular liver hematomas are not uncommon and may rupture. Fibrin deposits in the liver sinusoids are found, but evidence of inflammatory response is typically not present. Macroscopic autopsy findings in fatal PIH cases typically include cerebral edema, vasogenic infarcts, and hypoxic damage, particularly in posterior parietal-occipital brain areas (Prahlow and Barnard, 2004; Young et al., 2010). Since PIH originates from the placenta, uterine vessels present distinct changes in terms of fibrinoid necrosis of the entire wall of both basal and spiral arteries, with considerable amounts of lipoid foam cells. In severe cases swelling of the blood vessels, loss of plasma, and uterine vessel rupture may be fatal (Brosens et al., 1967; Robertson et al., 1967; Huppertz and Peeters, 2005; Schmidt and Kimmig, 2007). Disseminated intravascular coagulopathy (DIC) is a further complication associated with PIH, occurring in 5% of deaths from PIH (Montagnana et al., 2010). Excessive activation of the coagulation cascade leads to formation of numerous microthrombi consisting of fibrin and platelet aggregates, and hence to the infarction of particularly small capillaries and arterioles. The increased consumption of coagulation factors ultimately results in an increased tendency to bleed. Interestingly, DIC is frequently observed not only in PIH, but also in AFE (50%), intrauterine death, and septic abortion or abruptio placentae (Montagnana et al., 2010; Thachil and Toh, 2009). Amniotic Fluid Embolism
Amniotic and thromboembolic events are the second most common cause of maternal death in pregnancy (14.9%). Data are sparse, and the exact incidence is difficult to determine, ranging from 1:8000 to 1:80 000 (Harun, 2009). For Europe, an incidence of 1:53 800 with a mortality rate between 37% and 86% has been
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calculated (Harun, 2009; Conde-Agudelo and Romero, 2009; Gist et al., 2009). AFE typically occurs during birth (vaginal delivery 70%, cesarean section 19%) or immediately after birth (11%) via damage to fetal membranes by enhanced or drug-induced uterine contractions, placental separation/rupture, fetal death, or cesarean section. Apart from subsequent PPH as a significant contributor to maternal morbidity, an influx of amniotic fluid components into the maternal circulation system results in pulmonary embolism and cardiopulmonary failure (Harun, 2009; Montagnana et al., 2010). Moreover, amniotic fluid contains numerous mediators that can cause shock or an anaphylactic reaction in the mother (Kretzschmar et al., 2003; Gürke et al., 2001). Histological changes in AFE are initially nonspecific, corresponding to the histological findings in cases of shock. Diagnosis of AFE depends on proof of amniotic fluid components in the maternal circulation system, especially in pulmonary arteries. Epithelial skin cells of the fetus, lanugo hairs, vernix caseosa, meconial mucin, or bile pigments can be determined by different investigation methods (Brosens et al., 1967; Rushton and Dawson, 1982; Attwood, 1958; Steiner and Lushbaugh, 1941; Sinicina et al., 2010). Although all potential ingredients of amniotic fluid become visible via the routinely used hematoxylin-eosin staining, the particles are very small and might easily be overlooked. Visualization techniques with a higher detection rate should be used, for example, Attwood’s phloxine-tartrazine staining, which is a combination of phloxine and Alice Green that uses the selective affinity of mucin to Alice Green or epithelial cells to phloxine. Accurate detection of amniotic fluid components is established by the red color of the epithelial cells and green color of the mucin contrast (Attwood, 1958). Immunohistochemical methods for identifying AFE use cytokeratins, which serve as intermediate filaments in epithelial cells. These cytokeratins are specifically targeted by monoclonal antibodies, thus confirming the presence of epithelial cells. A suitable pan-cytokeratin antibody is A1-/A3 which targets the cytokeratins 1, 2, 9, and 10, detecting cells from the multilayered, cornified epidermal epithelium, while the monoclonal antibody TKH-2 identifies fetal mucin in maternal vessels. The maternal plasma level of zinccoproporphyrin I, as a component of meconium, serves as a noninvasive method of AFE detection (Aguilera et al., 2002; Gürke et al., 2001). Neither method is, however, yet established in practice (Table 2). Detection of AFE remains difficult, and even if there is no proof of amniotic fluid particles, AFE cannot be excluded. The usually small amounts of amniotic fluid are easy to miss and are also irregularly distributed. Representative histological specimens from different areas of each organ, in particular from the pulmonary tissue, should be collected. Moreover, the exact pathophysiology of AFE is still unclear. Current studies are
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Table 2
Deaths: Pregnancy-Related Deaths – Pathology Microscopic findings in cases of direct gestational maternal death
Histopathology Pregnancy-induced hypertension
Amniotic fluid embolism
Relevant clinical information 1. Kidneys (depending on severity): ‘Glomerular endotheliosis’ with hypertrophy of endothelial and mesangial cells. Bloodless, elongated capillaries, subendothelial fibrinous deposits, and ‘pounting’ 2. Liver: periportal necrosis and bleedings (hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome) 3. Brain: edema and hypoxic damage 4. Disseminated intravascular coagulation (DIC) 5. (Uterus: vessel changes) 6. DIC 1. Amniotic fluid and/or fetal particles in maternal circulatory system 2. Right heart failure and shock 3. Uterus: trauma and venous vessel leakage 4. Disseminated intravascular coagulation
based mainly on case series, and animal studies with direct injection of fetal tissue particles to establish AFE remain unsatisfactory (Gist et al., 2009); it is not fully understood to what extent or which amniotic fluid components have to penetrate the maternal circulation system to provoke a reaction in the mother. Thus, the diagnosis of suspected cases of AFE is based not only on the histopathological findings, but also on the clinical findings (Conde-Agudelo and Romero, 2009; Kretzschmar et al., 2003; Gürke et al., 2001). Postpartum Hemorrhage
Damage to fetal membranes by the mechanisms mentioned above may not only result in AFE, but the subsequent pressure gradient from lacerated uterine veins and those near the cervix may result in potentially serious PPH. Generally PPH, especially during delivery (various disorders of the placenta, uterine atony, and injuries to the genital tract) occurs in up to 13.4% and thus also represents a significant complication (The German Federal Health Monitoring). Autopsy findings are similar to autopsy findings in fatal exsanguinations from other causes (pale body, sparse lividity, pale inner organs, and subendocardial bleeding).
Conclusions The forensic evaluation of a (suspected) pregnancy-related death must include autopsy, clinical details, and microscopic and toxicological investigations, since autopsy findings are often nonspecific. Histopathological examination is mandatory in such cases, even if the cause of death is apparently obvious after autopsy. The main contributors to maternal deaths in pregnancy are PIH, AFE, and PPH.
Proteinuria? Hypertension? Headache? Neurologic disorders? Visual disturbances? Seizures? Right-sided abdominal pain? Hemorrhage?
Abortion? Delivery?
In cases of suspected PIH, the extent of pathological changes in the glomeruli of the kidneys correlate with the severity of PIH. Transitions to HELLP syndrome are sudden and severe. In cases of suspected AFE, representative histological specimens from different areas of each organ, in particular from the lungs, should be collected and examined. In cases of suspected PPH, macroscopic autopsy findings are similar to those in fatal exsanguinations from other causes. Sources of bleeding are fetal membranes.
See also: Autopsy Findings: Organic Toxins. Autopsy: Medicolegal Considerations, Including Organ Retention and Handling. Histopathology. Medical Ethics: Abortion. Mortality: Statistics
References Aguilera, L.G., Fernandez, C., Plaza, A., Gracia, J., Gomar, C., 2002. Fatal amniotic fluid embolism diagnosed histologically. Acta Anaesthesiologica Scandinavica 46, 334–337. Amsin, T., Nox, A.K., Olans, L.B., 1996. Liver disease in pregnancy. New England Journal of Medicine 335, 569–576. Attwood, H.D., 1958. The histological diagnosis of amniotic-fluid embolism. Journal of Pathology and Bacteriology 76, 211–215. Brosens, I., Robertson, W.B., Dixon, H.G., 1967. The physiological response of the vessels of the placental bed to normal pregnancy. Journal of Pathology and Bacteriology 93, 569–579. Buschmann, C., Schmidbauer, M., Tsokos, M., 2013. Maternal and pregnancyrelated death: Causes and frequencies in an autopsy study population. Forensic Science, Medicine, and Patholology 9, 296–307. Conde-Agudelo, A., Romero, R., 2009. Amniotic fluid embolism: An evidencebased review. American Journal of Obstetrics and Gynecology 201 (445), e1–13. Gaber, L.W., Spargo, B.H., Lindheimer, M.D., 1987. Renal pathology in preeclampsia. Baillière's Clinical Obstetrics and Gynaecology 1, 971–975. Gist, R.S., Stafford, I.P., Leibowitz, A.B., Beilin, Y., 2009. Amniotic fluid embolism. Anesthesia and Analgesia 108, 1599–1602.
Deaths: Pregnancy-Related Deaths – Pathology Gürke, B., Bremerich, D.H., Engels, K., Ahr, A., Kaufmann, M., 2001. Die Fruchtwasserembolie als geburtshilflicher Notfall − Darstellung des Syndroms anhand eines Falles mit fatalem Ausgang. Anästhesiologie Intensivmedizin NotfallmedizinSchmerztherapie 36, 247–249. Harun, T., 2009. Amniotic fluid embolism. European Journal of General Medicine 6, 108–115. Hladunewich, M., Karumanchi, S.A., Lafayette, R., 2007. Pathophysiology of the clinical manifestations of preeclampsia. Clinical Journal of the American Society of Nephrology 2, 543–549. Huppertz, B., Peeters, L.L.H., 2005. Vascular biology in implantation and placentation. Angiogenesis 8, 157–167. Jashnani, K., Rupani, A., Wani, R., 2009. Maternal mortality: An autopsy audit. Journal of Postgraduate Medicine 55, 12–16. Khan, K.S., Wojdyla, D., Say, L., Gülmezoglu, A.M., Van Look, P.F., 2006. WHO analysis of causes of maternal death: A systematic review. Lancet 367, 1066–1074. Kretzschmar, M., Zahm, D.M., Remmler, K., et al., 2003. Anaphylactoid syndrome of pregnancy. Der Anaesthesist 52, 419–426. Montagnana, M., Franchi, M., Danese, E., Gotsch, F., Guidi, G.C., 2010. Disseminated intravascular coagulation in obstetric and gynecologic disorders. Seminars in Thrombosis and Hemostasis 36, 404–418. Moran, P., Davison, J.M., 1999. The kidney and the pathogenesis of pre-eclampsia. Current Obstetrics and Gynaecology 9, 196–202. Prahlow, J.A., Barnard, J.J., 2004. Pregnancy-related maternal deaths. American Journal of Forensic Medicine and Pathology 25, 220–236. Regitz-Zagrosek, V., Seeland, U., Geibel-Zehender, A., et al., 2011. Cardiovascular diseases in pregnancy. Deutsches Ärzteblatt International 108, 267–273. Robertson, W.B., Brosens, I., Dixon, H.G., 1967. The pathological response of the vessels of the placental bed to hypertensive pregnancy. Journal of Pathology and Bacteriology 93, 581–592. Rushton, D.I., Dawson, I.M., 1982. The maternal autopsy. Journal of Clinical Pathology 35, 909–921. Schmidt, M., Kimmig, R., 2007. Pathophysiologie der Präeklampsie. Gynäkologischgeburtshilfliche Rundschau 47, 199–204. Schneider, H., 1994. Leberpathologie im Rahmen des HELLP-Syndroms. Archives of Gynecology and Obstetrics 255, 245–254. Simic, M., Tasic, M., Stojiljkovic, G., Draskovic, D., Vukovic, R., 2004. HELLP syndrome as a cause of unexpected rapid maternal death − A case report and review of the literature. International Journal of Legal Medicine 119, 103–106.
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Sinicina, I., Pankratz, H., Bise, K., Matevossian, E., 2010. Forensic aspects of postmortem histological detection of amniotic fluid embolism. International Journal of Legal Medicine 124, 55–62. Steiner, P.E., Lushbaugh, C.C., 1941. Maternal pulmonary embolism by amniotic fluid as a cause of obstretic shock and unexpected deaths in obstetrics. Journal of the American Medical Association 117, 1245–1254. Thachil, J., Toh, C.H., 2009. Disseminated intravascular coagulation in obstetric disorders and its acute haematological management. Blood Reviews 23, 167–176. The German Federal Health Monitoring. Deaths per 100 000 inhabitants (as of 1998). Classification: Years, region, age, sex, nationality, ICD-10. Available at: http://www.gbe-bund.de (accessed 10.10.14). The Royal College of Pathologists, 2010. Guidelines on Autopsy Practice, Scenario 5: Maternal death. Available at: http://www.rcpath.org/index.aspPageID=687 (accessed 06.09.14). Tribe, C.R., Smart, G.E., Davies, D.R., Mackenzie, J.C., 1979. A renal biopsy study in toxaemia of pregnancy. Journal of Clinical Pathology 32, 681–692. Tsokos, M., 2004. Pathological features of maternal death from HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. In: Tsokos, M. (Ed.), Forensic Pathology Reviews, first ed., vol. 1. Totowa, NJ: Humana Press lnc, pp. 275–290. Tsokos, M., Longauer, F., Kardošová, V., et al., 2002. Maternal death in pregnancy from HELLP syndrome. A report of three medico-legal autopsy cases with special reference to distinctive histopathological alterations. International Journal of Legal Medicine 116, 50–53. World Health Organization (WHO), 2010. Trends in maternal mortality 1990 − 2008. Estimates developed by WHO, UNICEF, UNFPA and the World Bank. Available at: http://whqlibdoc.who.int/publications/2010/9789241500265_eng.pdf (accessed 06.09.14). Young, B.C., Levine, R.J., Karumanchi, S.A., 2010. Pathogenesis of preeclampsia. Annual Review in Pathology 5, 173–192.
Further Reading World Health Organization (WHO), 2004. International Classification of Diseases and Related Health Problems, 10th Revision. Available at: http://apps.who.int/iris/ bitstream/10665/42980/1/9241546530_eng.pdf (accessed 10.10.14).
Abstract Maternal deaths during pregnancy, both from pregnancy-related and other causes, are rare in Western industrialized countries. Pregnancy-induced hypertension and amniotic fluid embolism (AFE) are the main contributors to directly gestation-related maternal death in pregnancy. The forensic evaluation of such a case should include autopsy, clinical details, and microscopic and toxicological investigations, noting that autopsy findings are often nonspecific. Even if the cause of death is apparently obvious after autopsy, histopathological examination should be performed in suspected pregnancy-related fatalities. In cases of suspected AFE, representative histological specimens from different areas of each organ, in particular from pulmonary tissue, should be collected and examined.
Introduction Maternal deaths in pregnancy, in particular pregnancyrelated maternal deaths, are rare in the Western world. In 2008, according to the World Health Organization (WHO), the maternal mortality ratio (MMR, maternal deaths per 100 000 live births per year), as a measurement of the quality of medical care for pregnant women, amounted to approximately 14 deaths per 100 000 live births for Western industrial nations, which corresponds to approximately 1700 deaths of pregnant women. There were 358 000 maternal deaths during pregnancy in 2008 worldwide, approximately 99% of which occurred in the so-called ‘developing’ countries. For the Federal Republic of Germany, the estimated MMR in 2008 was 7 deaths per 100 000 live births (49 maternal deaths) (WHO, 2010). The distinction between maternal deaths in pregnancy and pregnancy-related maternal deaths is not always clear (ICD-10): if maternal death occurs during or within 42 days after termination of pregnancy, the criterion of ‘gestational death’ is met. However, actual ‘maternal deaths during pregnancy’ are only those deaths that can be traced back directly to gestational circumstances, and nonnatural causes of death of pregnant women (i.e., accidents, suicides, or other, nonpregnancy-associated fatal events) are not counted among them. Furthermore, ‘maternal deaths’ can again be divided into two subcategories: ‘direct gestational deaths’ are causally due to complications of gestation (pregnancy, delivery, and postpartum) or by gestationrelated medical interventions, omissions, and improper handling (i.e., fatal gestational hypertension or fatal delivery complications). ‘Indirect gestational deaths’ are caused by preexisting cardiovascular diseases with nonobstetric origin which decompensate by the physiological effects of pregnancy, birth, and postpartum: the heart rate increases by 10–30 bpm, and the cardiac output up to the 32nd week of gestation by 30–50%;
Encyclopedia of Forensic and Legal Medicine, Volume 2
there is vasodilatation, an increased tendency to coagulation, an increase of serum lipids, and a reversible increase of the size of the heart of up to 30%. Systolic blood pressure drops toward the middle of pregnancy and returns toward baseline at the end of pregnancy. Maternal oxygen consumption increases up to threefold during vaginal delivery, and systolic pressure spikes up to 200 mmHg are possible in the expulsion period (Regitz-Zagrosek et al., 2011). Owing to the high medical standards in the Western world, ‘maternal deaths’ might occur well after delivery/ postabortion. Maternal deaths of both direct and indirect gestational cause occurring later than 42 days, but within 1 year after termination of pregnancy, are classified as ‘late maternal deaths.’ An overview of current definitions and terms of causes of death in pregnancy is given in Table 1. The autopsy of a deceased pregnant woman is currently rare in routine forensic practice, and representative statements about characteristic pathophysiological or pathomorphological changes in pregnancy-related maternal deaths remain difficult. In a retrospective review of the medicolegal autopsy files (n ¼11 270) in 5 years, we identified a total of 13 autopsies of maternal deaths in pregnancy (0.12%) (Buschmann et al., 2013). According to the WHO classification, three cases met the category of ‘nongestational death.’ In one case the cause of death could not be clarified morphologically, histologically, or toxicologically. Toxicological examinations were performed in every case. Except for one case, the findings were unremarkable. In this case, death resulted from fatal narcotic intoxication. Of the remaining 9 cases, 8 deaths were ‘maternal deaths,’ of which, in turn, 6 were directly and 2 indirectly attributable to gestation. One case of delayed death 2 years after abortion and eclampsia was not to technically a ‘late maternal death,’ but the cause of death appeared to be directly due to former pregnancy and abortion. The case was given the auxiliary term ‘(very)
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Table 1
Deaths: Pregnancy-Related Deaths – Pathology Causes of pregnancy-related deaths
Classification Gestational (maternal) death Direct gestational death
Indirect gestational death
Death due to any (direct/indirect) gestational cause between 42 days and 1 year after delivery/ abortion (‘late maternal deaths’) Death due to any (direct/indirect) gestational cause 41 year after delivery/abortion Nongestational (maternal) death
Definition
Death as a result of complications of gestation (pregnancy, childbirth, and postpartum), as a result of interventions, omissions, and improper handling, or as a result of a causal chain that starts from one of these states Death as a result of a preexisting disease or a disease that developed during gestation and is not due to direct gestational causes, but due to physiological effects of gestation
Death during gestation as a result of external violence, suicide, and/or other random events
Death during gestation from further nonspecified causes
late maternal death.’ In the heterogeneous group of deaths, we identified two diseases directly related to gestation: pregnancy-induced hypertension (PIH) and amniotic fluid embolism (AFE). The distribution of causes of maternal deaths in pregnancy in our study was not surprising and was broadly in line with the 2006 WHO analysis: hypertensive diseases in developed countries account for up to 16.1% of all maternal deaths, being the most frequent cause of death in pregnant women (Khan et al., 2006). The real number of deceased pregnant women may be significantly higher as not every fatality will undergo a forensic autopsy. A thorough investigation of such deaths by performing a forensic autopsy seems appropriate, especially regarding pathomorphological features and additional investigations. Histological examinations are always useful in clarifying the cause of death in pregnancy, as important information about pathophysiological changes can be provided. The lack of histological investigations in pregnancy-related maternal fatalities is not atypical and has been criticized in former studies (Rushton and Dawson, 1982; Jashnani et al., 2009). Histopathological examination should become an integral part of forensic investigations in suspected
pregnancy-related fatalities, even if the cause of death already seems to be clarified by macroscopic autopsy findings (Simic et al., 2004). In accordance with the guidelines published in 2010 by the Royal College of Pathologists, Table 2 gives important histopathological findings and clinical evidence (Royal College of Pathologists, 2010). The main contributors to maternal deaths in pregnancy are PIH, AFE, and postpartum hemorrhage (PPH). Pregnancy-Induced Hypertension
The prevalence of preeclampsia as the mildest form of PIH is reported to be 3–7%, this being seen mainly in primiparae, typically from the 20th week of gestation (Prahlow and Barnard, 2004; Young et al., 2010; Hladunewich et al., 2007). Characteristic symptoms include hypertension with systolic blood pressures of at least 140 mmHg and/or diastolic blood pressures of at least 90 mmHg, and also proteinuria of more than 300 mg per 24 h. Subsequent severe eclampsia is reported to occur in only 0.5–2% of all pregnancies, but the mortality rate increases to 20%. The patients also suffer from severe cephalgia and neurological deficits, i.e., visual disturbances. A syndrome known as hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, the most serious form of PIH, is reported to be found in 4–12% of all (pre-)eclampsia deaths. If HELLP syndrome develops postpartum, an increased mortality rate of 32% is reported. PIH may manifest itself in various degrees of severity, presenting as fulminant HELLP syndrome or preliminary stages of PIH (preeclampsia/eclampsia). Macroscopic autopsy findings will generally yield no distinct cause of death, and the final diagnosis of the cause of death is based on the results of histological examinations. PIH is most pronounced in the kidneys, with pathological changes limited to the glomeruli and correlating with the severity of PIH (Young et al., 2010; Tribe et al., 1979; Moran and Davison, 1999; Gaber et al., 1987). Light microscopy shows a general glomerular increase and also swelling of the glomerular endothelial cells, which are characterized by not only the increase in volume, but also their vacuolization. These lipid- and fluid-filled vacuoles may occupy the entire cytoplasm, resulting in a ‘foamy’ appearance. Glomerular hypertrophy leads to compression of the renal capillaries with subsequent anemia, described as ‘glomerular endotheliosis.’ In addition, hypertrophy of mesangial cells is observed, spreading through their volume expansion even into the periphery of the capillary loops, edging themselves between endothelial cells and the basal membrane. This mechanism not only reinforces the lack of blood to the capillary loops, but also results in compression and a correspondingly elongated appearance of
Deaths: Pregnancy-Related Deaths – Pathology
the vessels (‘cigar-shaped’) (Gaber et al., 1987; Tsokos et al., 2002; Tsokos, 2004) and split capillary loops (‘tramlining’ effect) (Tribe et al., 1979). A further consequence is an apparent thickening of the endothelial basal membrane, which is reinforced by subendothelial fibrin deposits. In addition, as an effect of the increased glomerular cell elements, the so-called ‘pounting’ appears (up to 200 mm wide extension of some capillary loops at the beginning of the proximal tubule in up to 50% of glomeruli). The regression of these morphological changes begins 48 h after birth and might take up to 6 months to resolve. During this period, a pearlnecklace-like appearance of the capillary loops (‘beading’), may be observed, indicating a healing process. While these renal tissue changes can be present in all degrees of PIH, a fulminate HELLP syndrome additionally consists of a characteristic pathology of the liver with typical periportal necrosis in zone 1 and intraparenchymal hemorrhage (Prahlow and Barnard, 2004; Tsokos et al., 2002; Tsokos, 2004; Amsin et al., 1996; Schneider, 1994). Subcapsular liver hematomas are not uncommon and may rupture. Fibrin deposits in the liver sinusoids are found, but evidence of inflammatory response is typically not present. Macroscopic autopsy findings in fatal PIH cases typically include cerebral edema, vasogenic infarcts, and hypoxic damage, particularly in posterior parietal-occipital brain areas (Prahlow and Barnard, 2004; Young et al., 2010). Since PIH originates from the placenta, uterine vessels present distinct changes in terms of fibrinoid necrosis of the entire wall of both basal and spiral arteries, with considerable amounts of lipoid foam cells. In severe cases swelling of the blood vessels, loss of plasma, and uterine vessel rupture may be fatal (Brosens et al., 1967; Robertson et al., 1967; Huppertz and Peeters, 2005; Schmidt and Kimmig, 2007). Disseminated intravascular coagulopathy (DIC) is a further complication associated with PIH, occurring in 5% of deaths from PIH (Montagnana et al., 2010). Excessive activation of the coagulation cascade leads to formation of numerous microthrombi consisting of fibrin and platelet aggregates, and hence to the infarction of particularly small capillaries and arterioles. The increased consumption of coagulation factors ultimately results in an increased tendency to bleed. Interestingly, DIC is frequently observed not only in PIH, but also in AFE (50%), intrauterine death, and septic abortion or abruptio placentae (Montagnana et al., 2010; Thachil and Toh, 2009). Amniotic Fluid Embolism
Amniotic and thromboembolic events are the second most common cause of maternal death in pregnancy (14.9%). Data are sparse, and the exact incidence is difficult to determine, ranging from 1:8000 to 1:80 000 (Harun, 2009). For Europe, an incidence of 1:53 800 with a mortality rate between 37% and 86% has been
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calculated (Harun, 2009; Conde-Agudelo and Romero, 2009; Gist et al., 2009). AFE typically occurs during birth (vaginal delivery 70%, cesarean section 19%) or immediately after birth (11%) via damage to fetal membranes by enhanced or drug-induced uterine contractions, placental separation/rupture, fetal death, or cesarean section. Apart from subsequent PPH as a significant contributor to maternal morbidity, an influx of amniotic fluid components into the maternal circulation system results in pulmonary embolism and cardiopulmonary failure (Harun, 2009; Montagnana et al., 2010). Moreover, amniotic fluid contains numerous mediators that can cause shock or an anaphylactic reaction in the mother (Kretzschmar et al., 2003; Gürke et al., 2001). Histological changes in AFE are initially nonspecific, corresponding to the histological findings in cases of shock. Diagnosis of AFE depends on proof of amniotic fluid components in the maternal circulation system, especially in pulmonary arteries. Epithelial skin cells of the fetus, lanugo hairs, vernix caseosa, meconial mucin, or bile pigments can be determined by different investigation methods (Brosens et al., 1967; Rushton and Dawson, 1982; Attwood, 1958; Steiner and Lushbaugh, 1941; Sinicina et al., 2010). Although all potential ingredients of amniotic fluid become visible via the routinely used hematoxylin-eosin staining, the particles are very small and might easily be overlooked. Visualization techniques with a higher detection rate should be used, for example, Attwood’s phloxine-tartrazine staining, which is a combination of phloxine and Alice Green that uses the selective affinity of mucin to Alice Green or epithelial cells to phloxine. Accurate detection of amniotic fluid components is established by the red color of the epithelial cells and green color of the mucin contrast (Attwood, 1958). Immunohistochemical methods for identifying AFE use cytokeratins, which serve as intermediate filaments in epithelial cells. These cytokeratins are specifically targeted by monoclonal antibodies, thus confirming the presence of epithelial cells. A suitable pan-cytokeratin antibody is A1-/A3 which targets the cytokeratins 1, 2, 9, and 10, detecting cells from the multilayered, cornified epidermal epithelium, while the monoclonal antibody TKH-2 identifies fetal mucin in maternal vessels. The maternal plasma level of zinccoproporphyrin I, as a component of meconium, serves as a noninvasive method of AFE detection (Aguilera et al., 2002; Gürke et al., 2001). Neither method is, however, yet established in practice (Table 2). Detection of AFE remains difficult, and even if there is no proof of amniotic fluid particles, AFE cannot be excluded. The usually small amounts of amniotic fluid are easy to miss and are also irregularly distributed. Representative histological specimens from different areas of each organ, in particular from the pulmonary tissue, should be collected. Moreover, the exact pathophysiology of AFE is still unclear. Current studies are
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Table 2
Deaths: Pregnancy-Related Deaths – Pathology Microscopic findings in cases of direct gestational maternal death
Histopathology Pregnancy-induced hypertension
Amniotic fluid embolism
Relevant clinical information 1. Kidneys (depending on severity): ‘Glomerular endotheliosis’ with hypertrophy of endothelial and mesangial cells. Bloodless, elongated capillaries, subendothelial fibrinous deposits, and ‘pounting’ 2. Liver: periportal necrosis and bleedings (hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome) 3. Brain: edema and hypoxic damage 4. Disseminated intravascular coagulation (DIC) 5. (Uterus: vessel changes) 6. DIC 1. Amniotic fluid and/or fetal particles in maternal circulatory system 2. Right heart failure and shock 3. Uterus: trauma and venous vessel leakage 4. Disseminated intravascular coagulation
based mainly on case series, and animal studies with direct injection of fetal tissue particles to establish AFE remain unsatisfactory (Gist et al., 2009); it is not fully understood to what extent or which amniotic fluid components have to penetrate the maternal circulation system to provoke a reaction in the mother. Thus, the diagnosis of suspected cases of AFE is based not only on the histopathological findings, but also on the clinical findings (Conde-Agudelo and Romero, 2009; Kretzschmar et al., 2003; Gürke et al., 2001). Postpartum Hemorrhage
Damage to fetal membranes by the mechanisms mentioned above may not only result in AFE, but the subsequent pressure gradient from lacerated uterine veins and those near the cervix may result in potentially serious PPH. Generally PPH, especially during delivery (various disorders of the placenta, uterine atony, and injuries to the genital tract) occurs in up to 13.4% and thus also represents a significant complication (The German Federal Health Monitoring). Autopsy findings are similar to autopsy findings in fatal exsanguinations from other causes (pale body, sparse lividity, pale inner organs, and subendocardial bleeding).
Conclusions The forensic evaluation of a (suspected) pregnancy-related death must include autopsy, clinical details, and microscopic and toxicological investigations, since autopsy findings are often nonspecific. Histopathological examination is mandatory in such cases, even if the cause of death is apparently obvious after autopsy. The main contributors to maternal deaths in pregnancy are PIH, AFE, and PPH.
Proteinuria? Hypertension? Headache? Neurologic disorders? Visual disturbances? Seizures? Right-sided abdominal pain? Hemorrhage?
Abortion? Delivery?
In cases of suspected PIH, the extent of pathological changes in the glomeruli of the kidneys correlate with the severity of PIH. Transitions to HELLP syndrome are sudden and severe. In cases of suspected AFE, representative histological specimens from different areas of each organ, in particular from the lungs, should be collected and examined. In cases of suspected PPH, macroscopic autopsy findings are similar to those in fatal exsanguinations from other causes. Sources of bleeding are fetal membranes.
See also: Autopsy Findings: Organic Toxins. Autopsy: Medicolegal Considerations, Including Organ Retention and Handling. Histopathology. Medical Ethics: Abortion. Mortality: Statistics
References Aguilera, L.G., Fernandez, C., Plaza, A., Gracia, J., Gomar, C., 2002. Fatal amniotic fluid embolism diagnosed histologically. Acta Anaesthesiologica Scandinavica 46, 334–337. Amsin, T., Nox, A.K., Olans, L.B., 1996. Liver disease in pregnancy. New England Journal of Medicine 335, 569–576. Attwood, H.D., 1958. The histological diagnosis of amniotic-fluid embolism. Journal of Pathology and Bacteriology 76, 211–215. Brosens, I., Robertson, W.B., Dixon, H.G., 1967. The physiological response of the vessels of the placental bed to normal pregnancy. Journal of Pathology and Bacteriology 93, 569–579. Buschmann, C., Schmidbauer, M., Tsokos, M., 2013. Maternal and pregnancyrelated death: Causes and frequencies in an autopsy study population. Forensic Science, Medicine, and Patholology 9, 296–307. Conde-Agudelo, A., Romero, R., 2009. Amniotic fluid embolism: An evidencebased review. American Journal of Obstetrics and Gynecology 201 (445), e1–13. Gaber, L.W., Spargo, B.H., Lindheimer, M.D., 1987. Renal pathology in preeclampsia. Baillière's Clinical Obstetrics and Gynaecology 1, 971–975. Gist, R.S., Stafford, I.P., Leibowitz, A.B., Beilin, Y., 2009. Amniotic fluid embolism. Anesthesia and Analgesia 108, 1599–1602.
Deaths: Pregnancy-Related Deaths – Pathology Gürke, B., Bremerich, D.H., Engels, K., Ahr, A., Kaufmann, M., 2001. Die Fruchtwasserembolie als geburtshilflicher Notfall − Darstellung des Syndroms anhand eines Falles mit fatalem Ausgang. Anästhesiologie Intensivmedizin NotfallmedizinSchmerztherapie 36, 247–249. Harun, T., 2009. Amniotic fluid embolism. European Journal of General Medicine 6, 108–115. Hladunewich, M., Karumanchi, S.A., Lafayette, R., 2007. Pathophysiology of the clinical manifestations of preeclampsia. Clinical Journal of the American Society of Nephrology 2, 543–549. Huppertz, B., Peeters, L.L.H., 2005. Vascular biology in implantation and placentation. Angiogenesis 8, 157–167. Jashnani, K., Rupani, A., Wani, R., 2009. Maternal mortality: An autopsy audit. Journal of Postgraduate Medicine 55, 12–16. Khan, K.S., Wojdyla, D., Say, L., Gülmezoglu, A.M., Van Look, P.F., 2006. WHO analysis of causes of maternal death: A systematic review. Lancet 367, 1066–1074. Kretzschmar, M., Zahm, D.M., Remmler, K., et al., 2003. Anaphylactoid syndrome of pregnancy. Der Anaesthesist 52, 419–426. Montagnana, M., Franchi, M., Danese, E., Gotsch, F., Guidi, G.C., 2010. Disseminated intravascular coagulation in obstetric and gynecologic disorders. Seminars in Thrombosis and Hemostasis 36, 404–418. Moran, P., Davison, J.M., 1999. The kidney and the pathogenesis of pre-eclampsia. Current Obstetrics and Gynaecology 9, 196–202. Prahlow, J.A., Barnard, J.J., 2004. Pregnancy-related maternal deaths. American Journal of Forensic Medicine and Pathology 25, 220–236. Regitz-Zagrosek, V., Seeland, U., Geibel-Zehender, A., et al., 2011. Cardiovascular diseases in pregnancy. Deutsches Ärzteblatt International 108, 267–273. Robertson, W.B., Brosens, I., Dixon, H.G., 1967. The pathological response of the vessels of the placental bed to hypertensive pregnancy. Journal of Pathology and Bacteriology 93, 581–592. Rushton, D.I., Dawson, I.M., 1982. The maternal autopsy. Journal of Clinical Pathology 35, 909–921. Schmidt, M., Kimmig, R., 2007. Pathophysiologie der Präeklampsie. Gynäkologischgeburtshilfliche Rundschau 47, 199–204. Schneider, H., 1994. Leberpathologie im Rahmen des HELLP-Syndroms. Archives of Gynecology and Obstetrics 255, 245–254. Simic, M., Tasic, M., Stojiljkovic, G., Draskovic, D., Vukovic, R., 2004. HELLP syndrome as a cause of unexpected rapid maternal death − A case report and review of the literature. International Journal of Legal Medicine 119, 103–106.
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Sinicina, I., Pankratz, H., Bise, K., Matevossian, E., 2010. Forensic aspects of postmortem histological detection of amniotic fluid embolism. International Journal of Legal Medicine 124, 55–62. Steiner, P.E., Lushbaugh, C.C., 1941. Maternal pulmonary embolism by amniotic fluid as a cause of obstretic shock and unexpected deaths in obstetrics. Journal of the American Medical Association 117, 1245–1254. Thachil, J., Toh, C.H., 2009. Disseminated intravascular coagulation in obstetric disorders and its acute haematological management. Blood Reviews 23, 167–176. The German Federal Health Monitoring. Deaths per 100 000 inhabitants (as of 1998). Classification: Years, region, age, sex, nationality, ICD-10. Available at: http://www.gbe-bund.de (accessed 10.10.14). The Royal College of Pathologists, 2010. Guidelines on Autopsy Practice, Scenario 5: Maternal death. Available at: http://www.rcpath.org/index.aspPageID=687 (accessed 06.09.14). Tribe, C.R., Smart, G.E., Davies, D.R., Mackenzie, J.C., 1979. A renal biopsy study in toxaemia of pregnancy. Journal of Clinical Pathology 32, 681–692. Tsokos, M., 2004. Pathological features of maternal death from HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. In: Tsokos, M. (Ed.), Forensic Pathology Reviews, first ed., vol. 1. Totowa, NJ: Humana Press lnc, pp. 275–290. Tsokos, M., Longauer, F., Kardošová, V., et al., 2002. Maternal death in pregnancy from HELLP syndrome. A report of three medico-legal autopsy cases with special reference to distinctive histopathological alterations. International Journal of Legal Medicine 116, 50–53. World Health Organization (WHO), 2010. Trends in maternal mortality 1990 − 2008. Estimates developed by WHO, UNICEF, UNFPA and the World Bank. Available at: http://whqlibdoc.who.int/publications/2010/9789241500265_eng.pdf (accessed 06.09.14). Young, B.C., Levine, R.J., Karumanchi, S.A., 2010. Pathogenesis of preeclampsia. Annual Review in Pathology 5, 173–192.
Further Reading World Health Organization (WHO), 2004. International Classification of Diseases and Related Health Problems, 10th Revision. Available at: http://apps.who.int/iris/ bitstream/10665/42980/1/9241546530_eng.pdf (accessed 10.10.14).