CC BY-NC-ND 4.0 · J Lab Physicians 2023; 15(04): 475-487
DOI: 10.1055/s-0043-1764485
Review Article

Stillbirth Investigations: An Iconographic and Concise Diagnostic Workup in Perinatal Pathology

1   Department of Anatomic Pathology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
,
Deborah Spencer
2   Department of Pathology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States
,
Taher Al-Jishi
3   Department of Obstetrics and Gynecology University of Ottawa, Ottawa, Ontario, Canada
› Author Affiliations

Abstract

Introduction Stillbirth is a dramatic event for the parents, health care team, and anyone close to the expectant parents. Multidisciplinary team (MDT) meetings are essential to improve communication in health care. We review the most frequent findings discussed at MDT meetings.

Methods A PubMed search was conducted through December 2021 since the inception (1965) using clinical queries with the key terms “stillbirth” AND “investigation” AND “pathology” AND “human.” The search strategy included reviews, meta-analyses, randomized controlled trials, clinical trials, and observational studies. This systematic review is based on, but not limited to, the search results. It is the experience of more than 30 years of pediatrics, obstetrics, and pathology staff.

Results Two hundred and six articles were screened and complemented through the perusal of congressional activities and personal communications. Pathological findings following perinatal death can be divided into macroscopic, histologic, and placental findings. The placenta is crucial in fetal medicine and is key in determining the cause of stillbirth in a substantial number of events. Perinatal lung disease is essential to evaluate the response of newborns to extrauterine life and address newborns' outcomes appropriately.

Conclusions Stillbirth remains one of the less explored areas of medicine, and we can determine the cause in a limited number of cases. Nevertheless, placental pathology is critical in the etiology discovery pathway. Accurate investigations and discussion of photography-supported findings are vital in promoting communication at MDT meetings.

Author Contribution

C.M.S. was responsible for project development, data collection, and manuscript writing. D.S. and T.A.J. were responsible for data collection and manuscript writing. All the authors reviewed the manuscript and approved it before submission.




Publication History

Received: 24 August 2022

Accepted: 23 January 2023

Article published online:
18 April 2023

© 2023. The Indian Association of Laboratory Physicians. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Corabian P, Scott NA, Lane C, Guyon G. Guidelines for investigating stillbirths: an update of a systematic review. J Obstet Gynaecol Can 2007; 29 (07) 560-567
  • 2 Pinar H. Postmortem findings in term neonates. Semin Neonatol 2004; 9 (04) 289-302
  • 3 Sergi CM, Mullur T. Communication in reporting the autopsy results is utmost. Arch Gynecol Obstet 2022; 1-2
  • 4 Sergi CM, Mullur T. Life and death sometimes coincide, and pastoral response is crucial to the brokenhearted. J Pastoral Care Counsel 2022; 76 (04) 281-284
  • 5 Sergi CM. Implementing epic beaker laboratory information system for diagnostics in anatomic pathology. Risk Manag Healthc Policy 2022; 15: 323-330
  • 6 Allen L, Lenton S, Fraser J, Sidebotham P. Improving the practice of child death overview panels: a paediatric perspective. Arch Dis Child 2014; 99 (03) 193-196
  • 7 Pearson JF, Weaver JB. Fetal activity and fetal wellbeing: an evaluation. BMJ 1976; 1 (6021): 1305-1307
  • 8 Wigglesworth JS. Perinatal Pathology. 2nd ed.. Vol. 15. Major Problems in Pathology. Philadelphia, PA: W.B. Saunders Company; 1996
  • 9 Strachan GI. The pathology of foetal maceration: a study of 24 cases. BMJ 1922; 2 (3211): 80-82
  • 10 Sergi CM. Pathology of Childhood and Adolescence: An Illustrated Guide. Berlin: Springer; 2020
  • 11 Schiesser M, Sergi C, Enders M, Maul H, Schnitzler P. Discordant outcomes in a case of parvovirus b19 transmission into both dichorionic twins. Twin Res Hum Genet 2009; 12 (02) 175-179
  • 12 Jones KL. Smith's Recognizable Patterns of Human Malformation. 4th ed.. Philadelphia, PA: W.B. Saunders; 1988
  • 13 Cunningham FG, Leveno KJ, Bloom SL. et al. Williams Obstetrics. 25th ed.. New York, NY: McGraw-Hill; 2018
  • 14 Khan A, Sergi C. Sialidosis: A Review of Morphology and Molecular Biology of a Rare Pediatric Disorder. Diagnostics (Basel) 2018; 8 (02) 29
  • 15 Sergi C, Penzel R, Uhl J. et al. Prenatal diagnosis and fetal pathology in a Turkish family harboring a novel nonsense mutation in the lysosomal alpha-N-acetyl-neuraminidase (sialidase) gene. Hum Genet 2001; 109 (04) 421-428
  • 16 Sergi C, Beedgen B, Kopitz J. et al. Refractory congenital ascites as a manifestation of neonatal sialidosis: clinical, biochemical and morphological studies in a newborn Syrian male infant. Am J Perinatol 1999; 16 (03) 133-141
  • 17 Schiffer C, Schiesser M, Lehr J. et al. Unique occurrence of Brachmann-de Lange syndrome in a fetus whose mother presented with a diffuse large B-cell lymphoma. Pathol Oncol Res 2007; 13 (03) 255-259
  • 18 Kurdi W. Non-immune fetal hydrops: are we doing the appropriate tests each time?. J Prenat Med 2007; 1 (01) 26-28
  • 19 Bianchi DW, Crombleholme TM, D'Alton ME. Fetology: Diagnosis and management of the fetal patient. New York, NY: McGraw-Hill; 2000
  • 20 Mangione R, Guyon F, Taine L. et al. Pregnancy outcome and prognosis in fetuses with increased first-trimester nuchal translucency. Fetal Diagn Ther 2001; 16 (06) 360-363
  • 21 Hardwick DF, Dimmick JE, Kalousek DK, Baldwin VJ, Lockitch G. Concepts of intrauterine development and embryofetal pathology. In: Dimmick JE, Kalousek DK. eds. Developmental Pathology of the Embryo and Fetus. Philadelphia, PA: JB Lippincott; 1992: 38-43
  • 22 Bourque DK, Cloutier M, Kernohan KD. et al; Care4Rare Canada Consortium. Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis. Am J Med Genet A 2019; 179 (05) 813-816
  • 23 Edwards L, Hui L. First and second trimester screening for fetal structural anomalies. Semin Fetal Neonatal Med 2018; 23 (02) 102-111
  • 24 Gaudineau A, Doray B, Schaefer E. et al. Postnatal phenotype according to prenatal ultrasound features of Noonan syndrome: a retrospective study of 28 cases. Prenat Diagn 2013; 33 (03) 238-241
  • 25 Chen CP. Prenatal diagnosis and genetic analysis of fetal akinesia deformation sequence and multiple pterygium syndrome associated with neuromuscular junction disorders: a review. Taiwan J Obstet Gynecol 2012; 51 (01) 12-17
  • 26 Scholl J, Durfee SM, Russell MA. et al. First-trimester cystic hygroma: relationship of nuchal translucency thickness and outcomes. Obstet Gynecol 2012; 120 (03) 551-559
  • 27 Chen CP, Su YN, Lin SY. et al. Rapid aneuploidy diagnosis by multiplex ligation-dependent probe amplification and array comparative genomic hybridization in pregnancy with major congenital malformations. Taiwan J Obstet Gynecol 2011; 50 (01) 85-94
  • 28 Sparks TN, Thao K, Lianoglou BR. et al; University of California Fetal–Maternal Consortium (UCfC). Nonimmune hydrops fetalis: identifying the underlying genetic etiology. Genet Med 2019; 21 (06) 1339-1344
  • 29 Phibbs RH. Hydrops fetalis and other causes of neonatal edema and ascites. In: Polin RA, Fox WW. eds. Fetal and Neonatal Physiology. 2nd ed.. Philadelphia, PA: W.B. Saunders; 1998: 1730-1735
  • 30 Bendon RW. Review of some causes of stillbirth. Pediatr Dev Pathol 2001; 4 (06) 517-531
  • 31 Chen JY. Etiology and outcome of hydrops fetalis. Pediatr Neonatol 2014; 55 (02) 77
  • 32 Takci S, Gharibzadeh M, Yurdakok M. et al. Etiology and outcome of hydrops fetalis: report of 62 cases. Pediatr Neonatol 2014; 55 (02) 108-113
  • 33 Ismail KM, Martin WL, Ghosh S, Whittle MJ, Kilby MD. Etiology and outcome of hydrops fetalis. J Matern Fetal Med 2001; 10 (03) 175-181
  • 34 Yang YH, Teng RJ, Tang JR, Yau KI, Huang LH, Hsieh FJ. Etiology and outcome of hydrops fetalis. J Formos Med Assoc 1998; 97 (01) 16-20
  • 35 Rodríguez MM, Bruce JH, Jiménez XF. et al. Nonimmune hydrops fetalis in the liveborn: series of 32 autopsies. Pediatr Dev Pathol 2005; 8 (03) 369-378
  • 36 Rodríguez MM, Chaves F, Romaguera RL, Ferrer PL, de la Guardia C, Bruce JH. Value of autopsy in nonimmune hydrops fetalis: series of 51 stillborn fetuses. Pediatr Dev Pathol 2002; 5 (04) 365-374
  • 37 Wigglesworth JS, Husemeyer RP. Intracranial birth trauma in vaginal breech delivery: the continued importance of injury to the occipital bone. Br J Obstet Gynaecol 1977; 84 (09) 684-691
  • 38 Caird MS, Reddy S, Ganley TJ, Drummond DS. Cervical spine fracture-dislocation birth injury: prevention, recognition, and implications for the orthopaedic surgeon. J Pediatr Orthop 2005; 25 (04) 484-486
  • 39 Nurses fail to object to Dr.'s mid-forceps delivery. Daniels v Durham County Hospital Corp. Nurs Law Regan Rep 2005; 46 (04) 2
  • 40 Lehner C, Harry A, Pelecanos A, Wilson L, Pink K, Sekar R. The feasibility of a clinical audit tool to investigate stillbirth in Australia: a single centre experience. Aust N Z J Obstet Gynaecol 2019; 59 (01) 59-65
  • 41 Lewis C, Hill M, Arthurs OJ, Hutchinson C, Chitty LS, Sebire NJ. Factors affecting uptake of postmortem examination in the prenatal, perinatal and paediatric setting. BJOG 2018; 125 (02) 172-181
  • 42 Kunjachen Maducolil M, Abid H, Lobo RM. et al. Risk factors and classification of stillbirth in a Middle Eastern population: a retrospective study. J Perinat Med 2018; 46 (09) 1022-1027
  • 43 Nijkamp JW, Sebire NJ, Bouman K, Korteweg FJ, Erwich JJHM, Gordijn SJ. Perinatal death investigations: what is current practice?. Semin Fetal Neonatal Med 2017; 22 (03) 167-175
  • 44 Fatima U, Sherwani R, Khan T, Zaheer S. Foetal autopsy-categories and causes of death. J Clin Diagn Res 2014; 8 (10) FC05-FC08
  • 45 Meaney S, Gallagher S, Lutomski JE, O'Donoghue K. Parental decision making around perinatal autopsy: a qualitative investigation. Health Expect 2015; 18 (06) 3160-3171
  • 46 Attwood HD. The histological diagnosis of amniotic-fluid embolism. J Pathol Bacteriol 1958; 76 (01) 211-215
  • 47 Attwood HD. Fatal pulmonary embolism by amniotic fluid. J Clin Pathol 1956; 9 (01) 38-46
  • 48 Naeye RL. Acute bacterial chorioamnionitis. Prog Clin Biol Res 1988; 281: 73-86
  • 49 Naeye RL, Kissane JM. Perinatal diseases, a neglected area of the medical sciences. Monogr Pathol 1981; (22) 1-4
  • 50 Naeye RL, Dellinger WS, Blanc WA. Fetal and maternal features of antenatal bacterial infections. J Pediatr 1971; 79 (05) 733-739
  • 51 Behrman RE, Lees MH, Peterson EN, De Lannoy CW, Seeds AE. Distribution of the circulation in the normal and asphyxiated fetal primate. Am J Obstet Gynecol 1970; 108 (06) 956-969
  • 52 Cohn HE, Sacks EJ, Heymann MA, Rudolph AM. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol 1974; 120 (06) 817-824
  • 53 Dawes GS. Foetal and neonatal Physiology. Chicago, IL: Year Book Medical Publisher; 1968
  • 54 Sergi C, Daum E, Pedal I, Hauröder B, Schnitzler P. Fatal circumstances of human herpesvirus 6 infection: transcriptosome data analysis suggests caution in implicating HHV-6 in the cause of death. J Clin Pathol 2007; 60 (10) 1173-1177
  • 55 Wigglesworth JS. Pathology of intrapartum and early neonatal death in the normally formed infant. In: Wigglesworth JS, Singer DB. eds. Textbook of Fetal and Perinatal Pathology. 2nd ed.. Boston, MA: Blackwell Science Publisher; 1998: 251-268
  • 56 Sergi C, Shen F, Lim DW. et al. Cardiovascular dysfunction in sepsis at the dawn of emerging mediators. Biomed Pharmacother 2017; 95: 153-160
  • 57 Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Artificial surfactant therapy in hyaline-membrane disease. Lancet 1980; 1 (8159): 55-59
  • 58 Dekowski SA, Holtzman RB. Surfactant replacement therapy. An update on applications. Pediatr Clin North Am 1998; 45 (03) 549-572
  • 59 Singer DB, Klish W. Morphometric studies of the renal glomerulogenic zone. Am J Pathol 1970;59(32a)
  • 60 Young NA, Mondestin MA, Bowman RL. Ischemic changes in fetal myocardium. An autopsy series. Arch Pathol Lab Med 1994; 118 (03) 289-292
  • 61 Oyer CE, Ongcapin EH, Ni J, Bowles NE, Towbin JA. Fatal intrauterine adenoviral endomyocarditis with aortic and pulmonary valve stenosis: diagnosis by polymerase chain reaction. Hum Pathol 2000; 31 (11) 1433-1435
  • 62 van Baarlen J, Schuurman HJ, Huber J. Acute thymus involution in infancy and childhood: a reliable marker for duration of acute illness. Hum Pathol 1988; 19 (10) 1155-1160
  • 63 Dorn L, Menezes LF, Mikuz G, Otto HF, Onuchic LF, Sergi C. Immunohistochemical detection of polyductin and co-localization with liver progenitor cell markers during normal and abnormal development of the intrahepatic biliary system and in adult hepatobiliary carcinomas. J Cell Mol Med 2009; 13 (07) 1279-1290
  • 64 Sergi C, Benstz J, Feist D, Nutzenadel W, Otto HF, Hofmann WJ. Bile duct to portal space ratio and ductal plate remnants in liver disease of infants aged less than 1 year. Pathology 2008; 40 (03) 260-267
  • 65 Sergi C, Kahl P, Otto HF. Contribution of apoptosis and apoptosis-related proteins to the malformation of the primitive intrahepatic biliary system in Meckel syndrome. Am J Pathol 2000; 156 (05) 1589-1598
  • 66 Sergi C, Adam S, Kahl P, Otto HF. Study of the malformation of ductal plate of the liver in Meckel syndrome and review of other syndromes presenting with this anomaly. Pediatr Dev Pathol 2000; 3 (06) 568-583
  • 67 Sergi C, Adam S, Kahl P, Otto HF. The remodeling of the primitive human biliary system. Early Hum Dev 2000; 58 (03) 167-178
  • 68 Johnson CA, Gissen P, Sergi C. Molecular pathology and genetics of congenital hepatorenal fibrocystic syndromes. J Med Genet 2003; 40 (05) 311-319
  • 69 Stallmach T, Karolyi L. Augmentation of fetal granulopoiesis with chorioamnionitis during the second trimester of gestation. Hum Pathol 1994; 25 (03) 244-247
  • 70 D'Arcy C, Hazrati LN, Chiasson DA. Histopathologic analysis in sudden infant and child deaths: a practical approach. Acad Forensic Pathol 2018; 8 (03) 492-538
  • 71 Becker MJ, Becker AE. Fat distribution in the adrenal cortex as an indication of the mode of intrauterine death. Hum Pathol 1976; 7 (05) 495-504
  • 72 de Sa DJ. Stress response and its relationship to cystic (pseudofollicular) change in the definitive cortex of the adrenal gland in stillborn infants. Arch Dis Child 1978; 53 (10) 769-776
  • 73 Oppenheimer EH. Cyst formation in the outer adrenal cortex. Studies in the human fetus and newborn. Arch Pathol 1969; 87 (06) 653-659
  • 74 Ersch J, Stallmach T. Assessing gestational age from histology of fetal skin: an autopsy study of 379 fetuses. Obstet Gynecol 1999; 94 (5, Pt 1): 753-757
  • 75 Squier M, Keeling JW. The incidence of prenatal brain injury. Neuropathol Appl Neurobiol 1991; 17 (01) 29-38
  • 76 Hargitai B, Szabó V, Cziniel M. et al. Human brain of preterm infants after hypoxic-ischaemic injuries: no evidence of a substantial role for apoptosis by using a fine-tuned ultrasound-guided neuropathological analysis. Brain Dev 2004; 26 (01) 30-36
  • 77 Sergi C, Schmitt HP. The vesicular forebrain (pseudo-aprosencephaly): a missing link in the teratogenetic spectrum of the defective brain anlage and its discrimination from aprosencephaly. Acta Neuropathol 2000; 99 (03) 277-284
  • 78 Stahlman MT, Gray ME, Whitsett JA. Expression of thyroid transcription factor-1(TTF-1) in fetal and neonatal human lung. J Histochem Cytochem 1996; 44 (07) 673-678
  • 79 Mahieu-Caputo D, Dommergues M, Delezoide AL. et al. Twin-to-twin transfusion syndrome. Role of the fetal renin-angiotensin system. Am J Pathol 2000; 156 (02) 629-636
  • 80 Yu VY. Neonatal consequences of placental and membrane dysfunction. Reprod Fertil Dev 1991; 3 (04) 431-437
  • 81 Langston C, Kaplan C, Macpherson T. et al. Practice guideline for examination of the placenta: developed by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists. Arch Pathol Lab Med 1997; 121 (05) 449-476
  • 82 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 (05) 632-638
  • 83 Parveen Z, Tongson-Ignacio JE, Fraser CR, Killeen JL, Thompson KS. Placental mesenchymal dysplasia. Arch Pathol Lab Med 2007; 131 (01) 131-137
  • 84 Nuovo G. The utility of immunohistochemistry and in situ hybridization in placental pathology. Arch Pathol Lab Med 2006; 130 (07) 979-983
  • 85 Khong TY, Mooney EE, Ariel I. et al. Sampling and definitions of placental lesions: Amsterdam Placental Workshop Group consensus statement. Arch Pathol Lab Med 2016; 140 (07) 698-713
  • 86 Fritsch MK. Placental pathology notes. Paper presented at: Aspen Annual Conference, 2014; June 19–10, 2014. Prague, Czech Republic:
  • 87 Wright C, Hinchliffe SA, Taylor C. Fetal pathology in intrauterine death due to parvovirus B19 infection. Br J Obstet Gynaecol 1996; 103 (02) 133-136
  • 88 Singer DB, Macpherson TA. Fetal death and the macerated stillborn fetus. In: Wigglesworth JS, Singer DB. eds. Textbook of Fetal and Perinatal Pathology. 2nd ed.. Boston, MA: Blackwell Science Publisher; 1998: 233-250
  • 89 Vujanić GM, Cartlidge PH, Stewart JH. Improving the quality of perinatal and infant necropsy examinations: a follow up study. J Clin Pathol 1998; 51 (11) 850-853
  • 90 Katzman PJ, Genest DR. Maternal floor infarction and massive perivillous fibrin deposition: histological definitions, association with intrauterine fetal growth restriction, and risk of recurrence. Pediatr Dev Pathol 2002; 5 (02) 159-164
  • 91 Denzer UW, von Renteln D, Lübke A. et al. Minimally invasive autopsy by using postmortem endoluminal and transluminal endoscopy and EUS. Gastrointest Endosc 2013; 78 (05) 774-780
  • 92 Shelmerdine SC, Hutchinson JC, Lewis C. et al. A pragmatic evidence-based approach to post-mortem perinatal imaging. Insights Imaging 2021; 12 (01) 101
  • 93 Shelmerdine SC, Sebire NJ, Arthurs OJ. Perinatal post mortem ultrasound (PMUS): a practical approach. Insights Imaging 2019; 10 (01) 35
  • 94 Shelmerdine SC, Sebire NJ, Arthurs OJ. Diagnostic accuracy of postmortem ultrasound vs postmortem 1.5-T MRI for non-invasive perinatal autopsy. Ultrasound Obstet Gynecol 2021; 57 (03) 449-458
  • 95 Simcock IC, Shelmerdine SC, Langan D, Anna G, Sebire NJ, Arthurs OJ. Micro-CT yields high image quality in human fetal post-mortem imaging despite maceration. BMC Med Imaging 2021; 21 (01) 128
  • 96 Tumanova UN, Lyapin VM, Bychenko VG, Shchegolev AI, Sukhikh GT. Postmortem MRI evaluation of maceration degree of deceased fetus. Bull Exp Biol Med 2020; 170 (01) 106-111
  • 97 Yousef GM. Workload assessment in pathology. Can J Pathol 2022; 14 (03) 5-7
  • 98 Sergi CM. Pediatrics: an evolving concept for the 21st century. Diagnostics (Basel) 2019; 9 (04) 201