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Home The Goal of Placental Analytics, LLC
The goal of Placental Analytics, LLC, is to develop the basis for the translating of placental pathology methods into instruments that can be implemented in epidemiologic practices, and to begin the exploration of placental measures of fetal exposures in large-scale epidemiologic research. Placental pathology evidence has contributed to current understanding of causes of low birth weight 1-14, preeclampsia 15-28 and preterm birth, 26,27,29-32 each of which have been linked to increased risk of later neurodevelopmental and neuropsychiatric disorders. 3,5, 33-50 However, placental data have rarely been analyzed in epidemiologic samples due in large part to the paucity of validated measurement indices. 51-55

Converging lines of evidence, from human epidemiologic and case-control studies 3,5, 7,33,35-50,56-64 and from animal models, 65-76 suggest that the fetal environment plays a significant role in the etiology of neurodevelopmental and neuropsychiatric disorders. The further development of this field of research is limited, however, by the difficulty of measuring the human fetal environment in population-based research. Until recently, most studies depended upon relatively crude indices of fetal experience, such as “obstetric complications” (including the gamut from preterm birth, post-term birth, preeclampsia, bleeding during pregnancy, premature rupture of membranes, prolonged labor, to inertia of labor), and fetal characteristics ranging from fetal growth restriction, low BW, abnormal fetal presentation at delivery, umbilical cord complications, fetal distress, hypoxia, asphyxia, anoxia, cyanosis, to low Apgar scores. 61,77-86 These have often been summed to a clinical “optimality scale”, from which inference has been drawn regarding a specific pathophysiologic process (fetal hypoxia). 68,79,87-93 Prenatal maternal serum samples, stored and frozen, have been used on a large scale in the National Collaborative Perinatal Project (NCPP) and in the Child Health and Development Study (CHDS), two very large birth cohorts assembled in the United States in the 1960s. Prenatal sera have been thawed and used in research on schizophrenia in the NCPP 94, and in the CHDS. 95-97 Prenatal maternal serum samples greatly extend the precision of fetal exposure measurements, but also have serious limitations. First, they directly measure exposures only in the mother. Other maternal serum measures, such as cytokines, may have less direct relationship to the fetal environment, 55, 98-100 as the placenta also limits transport of large molecules into the fetal circulation. 101 Second, their window on maternal exposures is obtained at isolated time points, and can only inform on intervals of gestation.

Another complementary window on fetal development is placental pathology. Prenatal insults originating outside the conceptus (i.e., in the mother) are commonly mediated by the placenta 101 and are very often reflected in abnormalities of placental growth and development. An important advantage of measuring placental growth and development is that it reflects cumulative fetal experience, whereas a maternal serum sample reflects the state of the mother (rather than the fetus) at one moment in time.

Distinguishing among intrauterine pathophysiologic processes has the potential to clarify the pathways underlying associations of neurodevelopmental and neuropsychiatric disorders with clinical markers. The obstetric and fetal characteristics that have been linked to ND/NP outcomes share associations with three distinct types of intrauterine pathophysiology: vascular pathology, and acute or chronic inflammation. 1-32,102-112 Vascular pathologies impair placental functions of nutrient and oxygen transfer, 115 and affect fetal cardiovascular homeostasis. 36,37,101 Intrauterine inflammation represents an abnormal fetal-placental environment characterized by exposure to products of activated maternal and fetal immune systems that potentially alter placental growth, function and fetal integrity. 101,113,114 The distinction between acute and chronic inflammation lies in the different agents (acute- bacterial, chronic- viral) and route of fetal exposure (acute- intraamniotic, chronic-hematogenous). 101,116 Gross placental evidence of abnormal growth and development is limited in its ability to mark these specific underlying processes; histologic features are necessary to their full characterization. Histologic evaluation is complementary, identifying subclinical preeclampsia0type pathologies in clinically “spontaneous” prematurity 117,118, creating often the only clear understanding of the full range of types and severities of intrauterine pathology. This is important as “lesion multiplicity” (i.e., having multiple types of pathologic insults, or multiple pathologic events) is correlated with increased risk of poor neurodevelopmental outcome.

The optimal placental measurement instrument would identify, quantify and time-point the major pathology types the have been proposed to involve critical fetal exposures with ND/NP consequences (acute inflammation, chronic inflammation and vascular pathology). Gross placental measures can best assess the time of onset and cumulative placental effects of a suboptimal intrauterine environment. The underlying pathology types can be best identified by clearly defined histology features but often co-occur; such lesion “multiplicity” an important risk factor for neurodevelopmental and neuropsychiatric compromise. 5, 10,117 Individual histology features, and by inference the pathology types that cause them, have been correlated with clinical markers of fetal dysfunction or damage. cf 8,10,25,27,118,119

However, reliance on single histology features has limited the ability to understand the fetal-placental environment; no single histologic feature can be expected to capture and characterize a multifaceted process such as acute or chronic inflammation. Identification, quantitation and timing the onset of the pathology types, acute inflammation, chronic inflammation and vascular pathology, would translate placental pathology measures into a measurement index of fetal physiologic exposure. From this, biologically plausible causal pathways could be proposed, tested and the field of fetal antecedents of adult disease could most efficiently move forward to illuminate the critical mechanisms of intrauterine “programming”. No instrument has proven able to capture the key pathology processes across populations differing by GA, socioeconomic or race/ethnicity. This is necessary to fully capitalize on the power of placental measures to translate fetal exposures into indices suitable for epidemiologic analyses.

A crucial advance in research modalities on developmental disabilities generally would be provided by more effective and biologically valid use of placental data.

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2. Hansen AR, Collins MH, Genest D, Heller D, Schwarz S, Banagon P, Allred EN, Leviton A. Very low birthweight Infant's placenta and its relation to pregnancy and fetal characteristics. Pediatr Dev Pathol. 2000;3(5):419-30.

3. Redline RW, Wilson-Costello D, Borawski E, Fanaroff AA, Hack M. The relationship between placental and other perinatal risk factors for neurologic impairment in very low birth weight children. Pediatr Res. 2000;47(6):721-6.

4. Lao TT, Wong W. The neonatal implications of a high placental ratio in small-for-gestational age infants. Placenta. 1999;20(8):723-6.

5. Redline RW, Wilson-Costello D, Borawski E, Fanaroff AA, Hack M. Placental lesions associated with neurologic impairment and cerebral palsy in very low-birth-weight infants. Arch Pathol Lab Med. 1998;122(12):1091-8.

6. Bortolus R, Chatenoud L, Di Cintio E, Rossi P, Benzi G, Surace M, Parazzini F. Placental ratio in pregnancies at different risk for intrauterine growth. Eur J Obstet Gynecol Reprod Biol. 1998;80(2):157-8.

7. O'Shea TM, Kothadia JM, Roberts DD, Dillard RG. Perinatal events and the risk of intraparenchymal echodensity in very-low-birthweight neonates. Paediatr Perinat Epidemiol. 1998;12(4):408-21.

8. Salafia CM, Pezzullo JC, Minior VK, Divon MY. Placental pathology of absent and reversed end-diastolic flow in growth-restricted fetuses. Obstet Gynecol. 1997;90(5):830-6.

9. Morssink LP, de Wolf BT, Kornman LH, Beekhuis JR, van der Hall TP, Mantingh A. The relation between serum markers in the second trimester and placental pathology. A study on extremely small for gestational age fetuses. Br J Obstet Gynaecol. 1996;103(8):779-83.

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12. Laurini R, Laurin J, Marsal K. Placental histology and fetal blood flow in intrauterine growth retardation. Acta Obstet Gynecol Scand. 1994;73(7):529-34.

13. Krohn MA, Hillier SL, Kiviat NB, Eschenbach DA. The severity of fetal membrane infection and pregnancy complications. Ann Epidemiol. 1993;3(1):78-85.

14. 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(10):1049-59.

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16. Aardema MW, Oosterhof H, Timmer A, van Rooy I, Aarnoudse JG. Uterine artery Doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by pre-eclampsia and small for gestational age fetuses. Placenta. 2001;22(5):405-11.

17. Redman CW, Sargent IL Placental debris, oxidative stress and pre-eclampsia. Placenta. 2000;21(7):597-602.

18. DiFederico E, Genbacev O, Fisher SJ. Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall. Am J Pathol. 1999;155(1):293-301.

19. Gabinskaya T, Salafia CM, Gulle VE, Holzman IR, Weintraub AS. Gestational age-dependent extravillous cytotrophoblast osteopontin immunolocalization differentiates between normal and preeclamptic pregnancies. Am J Reprod Immunol. 1998;40(5):339-46.

20. Salafia CM, Pezzullo JC, Ghidini A, Lopez-Zeno JA, Whittington SS. Clinical correlations of patterns of placental pathology in preterm pre-eclampsia. Placenta. 1998;19(1):67-72.

21. Balducci J, Weiss PM, Atlas RO, Pajarillo MF, Dupree WB, Klasko SK. Preeclampsia: immunologic alteration of Nitabuch's membrane? Clinical sequelae. J Matern Fetal Med. 1997;6(6):324-8.

22. Starzyk KA, Salafia CM, Pezzullo JC, Lage JM, Parkash V, Vercruysse L, Hanssens M, Pijnenborg R. Quantitative differences in arterial morphometry define the placental bed in preeclampsia. Hum Pathol. 1997;28(3):353-8.

23. Kos M, Latin V, Hodzic D, Ilic-Forko J, Babic D, Nola M, Jukic S. Histopathologic findings of placenta and arcuate artery Doppler velociometry in preeclampsia and intrauterine growth retardation. Acta Med Croatica. 1997;51(3):151-4.

24. Mayhew TM. Patterns of villous and intervillous space growth in human placentas from normal and abnormal pregnancies. Eur J Obstet Gynecol Reprod Biol. 1996;68(1-2):75-82.

25. Salafia CM, Pezzullo JC, Lopez-Zeno JA, Simmens S, Minior VK, Vintzileos AM. Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol. 1995;173(4):1097-105.

26. Salafia CM, Lopez-Zeno JA, Sherer DM, Whittington SS, Minior VK, Vintzileos AM. Histologic evidence of old intrauterine bleeding is more frequent in prematurity. Am J Obstet Gynecol. 1995;173(4):1065-70.

27. Salafia CM, Minior VK, Pezzullo JC, Popek EJ, Rosenkrantz TS, Vintzileos AM. Intrauterine growth restriction in infants of less than thirty-two weeks' gestation: associated placental pathologic features. Am J Obstet Gynecol. 1995;173(4):1049-57.

28. Redline RW, Patterson P. Pre-eclampsia is associated with an excess of proliferative immature intermediate trophoblast. Hum Pathol. 1995;26(6):594-600.

29. Salafia CM, Ghidini A, Lopez-Zeno JA, Pezzullo JC. Uteroplacental pathology and maternal arterial mean blood pressure in spontaneous prematurity. J Soc Gynecol Investig. 1998;5(2):68-71.

30. van Hoeven KH, Anyaegbunam A, Hochster H, Whitty JE, Distant J, Crawford C, Factor SM. Clinical significance of increasing histologic severity of acute inflammation in the fetal membranes and umbilical cord. Pediatr Pathol Lab Med. 1996;16(5):731-44

31. Jacques SM, Qureshi F Chronic intervillositis of the placenta. Arch Pathol Lab Med. 1993;117(10):1032-5.

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33. Vermeulen GM, Bruinse HW, de Vries LS. Perinatal risk factors for adverse neurodevelopmental outcome after spontaneous preterm birth. Eur J Obstet Gynecol Reprod Biol. 2001;99(2):207-12.

34. Lorenz JM. The outcome of extreme prematurity. Semin Perinatol. 2001;25(5):348-59

35. Gaillard EA, Cooke RW, Shaw NJ. Improved survival and neurodevelopmental outcome after prolonged ventilation in preterm neonates who have received antenatal steroids and surfactant. Arch Dis Child Fetal Neonatal Ed. 2001;84(3):F194-6.

36. Vossbeck S, de Camargo OK, Grab D, Bode H, Pohlandt F. Neonatal and neurodevelopmental outcome in infants born before 30 weeks of gestation with absent or reversed end-diastolic flow velocities in the umbilical artery. Eur J Pediatr. 2001;160(2):128-34.

37. Fouron JC, Gosselin J, Amiel-Tison C, Infante-Rivard C, Fouron C, Skoll A, Veilleux A . Correlation between prenatal velocity waveforms in the aortic isthmus and neurodevelopmental outcome between the ages of 2 and 4 years. Am J Obstet Gynecol. 2001 Mar;184(4):630-6.

38. Jacobs SE, O'Brien K, Inwood S, Kelly EN, Whyte HE. Outcome of infants 23-26 weeks' gestation pre and post surfactant. Acta Paediatr. 2000;89(8):959-65.

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43. Stewart AL, Rifkin L, Amess PN, Kirkbride V, Townsend JP, Miller DH, Lewis SW, Kingsley DP, Moseley IF, Foster O, Murray RM. Brain structure and neurocognitive and behavioural function in adolescents who were born very preterm. Lancet. 1999;353(9165):1653-7.

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45. Battin M, Ling EW, Whitfield MF, Mackinnon M, Effer SB. Has the outcome for extremely low gestational age (ELGA) infants improved following recent advances in neonatal intensive care? Am J Perinatol. 1998;15(8):469-77.

46. Gray PH, Hurley TM, Rogers YM, O'Callaghan MJ, Tudehope DI, Burns YR, Phty M, Mohay HA. Survival and neonatal and neurodevelopmental outcome of 24-29 week gestation infants according to primary cause of preterm delivery. Aust N Z J Obstet Gynaecol. 1997;37(2):161-8.

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51. Grether JK, Eaton A, Redline R, Bendon R, Benirschke K, Nelson K. Reliability of placental histology using archived specimens. Paediatr Perinat Epidemiol. 1999;13(4):489-95.

52. Khong TY, Bendon RW, Qureshi F, Redline RW, Gould S, Stallmach T, Lipsett J, Staples A. Chronic deciduitis in the placental basal plate: definition and interobserver reliability. Hum Pathol. 2000;31(3):292-5.

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