The Etiology of
9 June 2009
Presented by Damon T. Cudihy, MD
Mentor: Richard Lee, M.D.
Goals of Project
1. To survey and review recent literature
proposing evidence for theories of
pathogenesis of preeclampsia
2. To distinguish true causes of preeclampsia as
opposed to mere bio-indices and
3. Regarding the etiology of preeclampsia, to
provide a biologically plausible theory
that unifies the essential and validated
findings of past and current scientific
Questions to answer
1. What do we know about the burden of
pre-eclampsia so far?
2. Do we know enough to understand the
cause of pre-eclampsia?
3. With a better understanding of the cause
of pre-eclampsia could we begin to
prevent the disease and develop better
treatments that will minimize the
associated morbidity and mortality ?
– Hypertension: SBP≥140 or DBP≥90
– Proteinuria: ≥0.1g/L (2+) in ≥2 random urine
samples ≥4hrs apart; or ≥0.3g in 24hrs
– Affects 3-14% of all pregnancies worldwide
(5-8% of pregnancies in the U.S.)
Effect on mother and child
– Leading cause of worldwide pregnancy-related
maternal and neonatal mortality and morbidity
Spectrum of Preeclampsia
Early Placental Late Placental
Vascular dificiency Dysfunction
Spontaneous abortion Preeclampsia
Risk Factors for Preeclampsia
Nulliparity Androgen excess
Personal or family history Resistance
(37% in sisters) Dyslipidemia
Twin gestation (20, 70%) Thrombophilias
Molar pregnancy (70%) (Antiphospholipid, Protein C/S
Maternal infection deficiency, Factor V Leiden,
Chronic Hypertension MTHFR)
Renal Disease Condom use
Donor sperm fertilization
Pre-eclampsia as a risk factor:
Current Theories Associated with
Etiology of Preeclampsia
Abnormal trophoblastic invasion
Vascular endothelial damage
Inflammation and oxidative stress
Dietary deficiencies or excesses
Model of Contributing Factors
Maternal factors Paternal factors Gestational factors
Genetic Acquired Genetic Acquired
―Disease of first pregnancy‖
– 3-7% in nulliparas, 1-5% in multiparas
– Primipaternity model
Placental load association
– Increased incidence and severity in multiple
gestations and molar gestation
Global Endothelial dysfunction
Biomarkers for prediciton and
detection of Preeclampsia
the focus of most U.S. studies in past 2
demonstrate preeclampsia as an
antiangiogenic state resulting from over-
production of antiangiogenic factors
Soluble fms-like tyrosine kinase 1
(sFlt-1) and Soluble Endoglin
Circulating placental proteins
– Inhibit angiogenesis and arteriolar
Excessive amounts may lead to systemic
endothelial dysfunction causing
screening test for preeclampsia?
--MAYNARD, SHARON E.; et al. Soluble Fms-like Tyrosine Kinase 1 and Endothelial Dysfunction in the
Pathogenesis of Preeclampsia. Pediatric Research. Review Issue. 57(5 Part 2):1R-7R, May 2005.
--Levine, Richard J.;et al. for the CPEP Study Group Soluble Endoglin and Other Circulating Antiangiogenic
Factors in Preeclampsia. Obstetrical & Gynecological Survey. 62(2):82-83, February 2007.
Pathophysiology of preeclampsia and resulting symptoms; EDFMD,
endothelium-dependent flow-mediated vasodilation.
From: WEISSGERBER: Med Sci Sports Exerc, Volume 36(12).December 2004.2024-2031
Clinical manifestations of
All result from endothelial dysfunction at
the various end organs in the body:
– Systemic Arterial vasculature HTN, edema
– Central Nervous System headache, visual
– Hepatic system RUQ pain, HELLP
– Renal system proteinuria, renal failure
– Placental system IUGR, oligohyrdramnios,
Risk factors for pre-eclampsia
A loosely defined grouping
1. Genetically inherited susceptibilities
(maternal and paternal side)
2. Conditions with known associations with
3. States affecting the immune-modulated
placental cytotrophoblastic cell invasion
of maternal spiral artery endothelium
1. Genetically Inherited Factors
Both men and women who themselves were the
born of a pregnancy complicated by pre-
eclampsia are significantly more likely to be
parents of a child with pre-eclampsia
Baseline ―fitness‖ of maternal endothelial
Maternal immune system function
Particular genotype combinations between
mother and child (or mother and father)
associated with preeclampsia
2. Endothelial Dysfunction
All clinical manifestations can be explained by
Most risk factors associated with endothelial
– all chronic disease risk before and after preeclampsia
– role of infection, diet, exercise, and oxidative stress
Pregnancy and preeclampsia as a physiologic
endothelial stress test
3. Immune-mediated invasion
Accounts for remaining risk factors:
nulliparity, primipaternity, condom use,
IVF, twins, moles, and non-smoking
Maternal immune system facilitates
invasion of fetal extravillous cytophoblastic
cells into the myometrium and arteriolar
Accounts latest findings of anti-angiogenic
factors associated with preeclampsia
Grouping of Risk Factors
1. Genetic 3. Immune-mediated
– Personal or family history invasion
(37% in sisters) and angiogenesis
2. Endothelial dysfunction – Nulliparity
– Maternal infection – Primipaternity
– Chronic Hypertension – Twin gestation (20, 70%)
– Renal Disease – Molar pregnancy (70%)
– Diabetes (50%) – Condom use
– Androgen excess – Donor sperm fertilization
– Obesity/Insulin – Non-smoking
Pathophysiology of Preeclampsia
2 Stage process
1. Preclinical (≤20 weeks):
– inadequate invasion of maternal spiral arterioles
by fetal cytotrophoblasts insufficient maternal
vascular remodeling and angiogenesis
2. Clinical (normally >20 weeks):
– Oxidatively stressed/hypoxic placenta
generalized systemic inflammatory response
with release of anti-angiogenic factors,
inflammatory cytokines, and trophoblast debris
Natural Killer Cells:
Friend or Foe?
Named for their cytotoxic action against virus-
infected and tumor-transformed cells
Paradoxically, NK cells play a key role in
facilitating and stimulating the invasion of
tumor-like fetal trophoblastic cells into the
The dysfunction/dysregulation of decidual NK
cells recocile the two leading theories:
1. Immune maladaptation
2. Insufficient invasion of the maternal spiral arteries
by fetal trophoblasts
Diagram of basic maternal and
Normal vs Abnormal Vascular
Remodeling of Spiral Arteries
Further clarification of the physiologic vs. pathologic
interactions between maternal decidual NK cells and
fetal extravillous trophoblasts
Identification of genes involved with immune
Biomarkers as screening tools to target interventions to
Tx‘s designed to boost extravillous trophoblastic invasion
targeted to high risk women?
Pharmacologic manipulation of NK cells to direct them in
the pro-angiogenic pathway?
1. Early maternal-fetal interface involving
decidual/uterine NK cells and extravillous
2. Healthy pregnancy requires NK cell stimulation of
vascular invasion by fetal trophoblasts
(an immune-mediated process)
3. Inadequate vascular invasion by fetal cells leads to
placental hypoxiaoxidative stressmaternal
endothelial dysfunctionclinical signs and
symptoms of pre-eclampsia
―Therefore, one may state at least
tentatively, that future collaboration
between the obstetrician and
immunologist should produce the needed
diagnostic and therapeutic tools to place
preeclampsia together with Rh
isoimmunization as an interesting, but
eminently treatable immunologic
--John Willems. The Etiology of Preeclampsia: A Hypothesis. Obstetrics
and Gynecology, 50 (4), Oct 1977.
1. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in
Pregnancy. American Journal of Obstetrics and Gynecology.2000;183:S1-S22
2. ACOG Committee on Practice Bulletins--Obstetrics. ACOG practice bulletin. Diagnosis and management of
preeclampsia and eclampsia. Obstetrics and Gynecology 2002; 99:159.
3. Sibai BM; Gordon T, Thom E, Caritis SN, Klebanoff M, McNellis D, Paul RH Risk factors for preeclampsia in
healthy nulliparous women: a prospective multicenter study. The National Institute of Child Health and Human
Development Network of Maternal-Fetal Medicine Units. American Journal of Obstetrics and Gynecology.1995
Feb;172(2 Pt 1):642-8.
4. Saftlas AF, Olson DR, Franks AL, Atrash HK, Pokras R Epidemiology of preeclampsia and eclampsia in the
United States, 1979-1986. American Journal of Obstetrics and Gynecology.1990 Aug;163(2):460-5.
5. Maternal mortality--United States, 1982-1996. Morbidity and Mortality Weekly Report (MMWR) 1998 Sep
6. Cunningham FG, Lindheimer MD. Hypertension in pregnancy. New England Journal of Medicine 1992 Apr
7. Walker J. Pre-eclampsia. Lancet 2000: 356(9237):1260-1265.
8. South Africa Every Death Counts Writing Group. Every death counts: use of mortality audit data for decision
making to save the lives of mothers, babies, and children in South Africa. Lancet 2008; 371:1294-304.
9. Barton J, Sibai B. Prediction and Prevention of Recurrent Preeclampsia. Obstetrics and Gynecology 2008;
10. Harkskamp R, Zeeman G. Preeclampsia: At Risk for Remote Cardiovascular Disease. The American Journal of
the Medical Sciences 2007. 334(4): 291-295.
11. Thadhani R, Solomon C. Preeclampsia—A Glimpse into the Future? New England Journal of Medicine 2008.
12. Wolf M, Hubel C, Lam C, Sampson M, Ecker H, Ness R, Rajakumar A, Daftary A, Shakir A, Seely E, Roberts J,
Sukhatme V, Karumanchi A, Thadhani R. Preeclampsia and Future Cardiovascular Disease: Potential Role of
Altered Angiogenesis and Insulin Resistance. The Journal of Clinical Endocrinology & Metabolism 2004. Vol. 89,
No. 12 6239-6243
13. Vikse B, Irgens L, Leivestad T, Skjærven R, Iversen B. Preeclampsia and Risk of End-Stage Renal Disease. New
England Journal of Medicine 2008. 359(8):800-809.
14. Mogren I, Hogberg U, Winkvist A, Stenlund H. Familial occurrence of preeclampsia. Epidemiology 1999.
15. Esplin M, Fausett M, Fraser A, Kerber R, Mineau G, Carrillo J, Varner M. Paternal and maternal components of
the predisposition to preeclampsia. New England Journal of Medicine 2001. 344:867.
16. Hiby S, Walker J, O‘Shaughnessy K, Redman C, Carrington M, Trowsdale J, Moffett A. Combinations of Maternal
KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success. The Journal of
Experimental Medicine 2004. 200(8):957-965.
17. Saito S, Sakai M, Sasaki Y, Nakashima A, Shiozaki A. Inadequate tolerance induction may induce pre-eclampsia.
Journal of Reproductive Immunology 2007. 76:30-39.
18. Le Bouteiller P, Pizzato N, Barakonyi A, Solier C. HLA-G, pre-eclampsia, immunity and vascular events. Journal of
Reproductive Immunology 2003. 59:219-234.
19. Goldman-Whol D, Ariel I, Greenfield C, Hochner-Celnikier D, Cross J, Fisher S, Yagel S. Lack of human leukocyte
antigen-G expression in extravillous trophoblasts is associated with pre-eclampsia. Molecular Human Reproduction
2000. 6(1): 88-95.
20. Conde-Agudelo A, Villar J, Lindheimer M. Maternal infection and risk of preeclampsia: Systematic review and
metaanlysis. American Journal of Obstetrics and Gynecology 2008. 198(1):7-22
21. Cines D, Pollak E,. Buck C, Loscalzo J, Zimmerman G, McEver R,. Pober J, Wick T, Konkle B, Schwartz B,
Barnathan E, McCrae k, Hug B, Schmidt A, Stern D. Endothelial Cells in Physiology and in the Pathophysiology of
Vascular Disorders. Blood 1998. 91(10): 3527-3561.
22. LaMarca B, Gilbert J, Granger J. Recent Progress Toward the Understanding of the Pathophysiology of
Hypertension During Preeclampsia. Hypertension 2008. 51:982-988.
23. Robillard P, Dekker G, Chaouat G, Hulsey T. Etiology of preeclampsia: maternal vascular predisposition and couple
disease—mutural exclusion or complementarity? Journal of Reproductive Immunology 2007. 76:1-7.
24. Willems J. The Etiology of Preeclampsia. Obstetrics and Gynecology. 50:495, 1977.
25. Shembrey M, Noble A. An instructive case of abdominal pregnancy. The Australian and New Zealand Journal of
Obstetrics and Gynaecology 1995. 35:220-221.
26. Clark J, Niles J. Abdominal Pregnancy Associated with Toxemia of Pregnancy. Journal of the National Medical
Association 1967. 59(1): 22-24.
27. Kopcow H, Karumanchi A. Angiogenic factors and natural killer (NK) cells in the pathogenesis of preeclampsia.
Journal of Reproductive Immunology 2007. 76: 23-29.
28. Pfarrer C, Macara L, Leiser R, Kingdom J. Adaptive angiogenesis in placentas of heavy smokers. The Lancet 1999.
29. Egleton R, Brown K, Dasgupta P, Angiogenic activity of nicotinic acetylcholine receptors: Implications in tobacco-
related vascular diseases. Pharmacology and Therapeutics 2008. Nov 14 [Epub ahead of print].
30. Redman C, Sargent I. Latest Advances in Understanding Preeclampsia. Science 2005. 308(5728):1592-1594.
31. Soundararajan R, Rao A. Trophoblast ‗pseudo-tumorigenesis‘: Significance and contributory factors. Reproductive
Biology and Endocrinology 2004. 2:15
32. Sargent I, Borzychowski A, Redman C. Immunoregulation in normal pregnancy and pre-eclampsia: an overview.
Reproductive Biomedicine Online 2006. 13(5): 680-686.
33. Wiessgerber T, Wolfe L, Davies G. The Role of Regular Phyisical Activity in Preeclampsia Prevention. Medicine &
Science in Sports & Exercise 2004. 36(12):2024-2031.
34. Maynard, Sharon E.; et al. Soluble Fms-like Tyrosine Kinase 1 and Endothelial Dysfunction in the Pathogenesis of
Preeclampsia. Pediatric Research. Review Issue 2005. 57(5 Part 2):1R-7R.
35. Levine R, Lam C, et al. for the CPEP Study Group Soluble Endoglin and Other Circulating Antiangiogenic Factors in
Preeclampsia. Obstetrical & Gynecological Survey. 62(2):82-83, February 2007.
36. Rana S, Karumanchi A, et al. Sequential Changes in Antiangiogenic Factors in Early Pregnancy and Risk of
Developing Preeclampsia. Hypertension 2007. 50:137-142.
37. Scholl T, Leskiw M, Chen X, Sims M, Stein T. Oxidative stress, diet, and the etiology of preeclampsia. American
Journal of Clinical Nutrition 2005. 81:1390-1396.
38. Moffet A, Hiby S. How Dose the Maternal Immune System Contribute to the Development of Pre-eclampsia?
Placenta 2007. 28(21):S51-S56.
39. Sargent L, Borychowski A, Redman C. NK Cells and pre-eclampsia. Journal of Reproductive Immunology 2007.
40. Hanna J, Goldman-Wohl D, et al. Decidiual cells regulate key developmental processes at the human fetal-
maternal interface. Nature Medicine 2006. 12(9): 1065-1074.
41. Chaouat G, Ledee-Bataille N, Dubanchet S. Immune cells in uteroplacental tissues throughout pregnancy: a brief
review. Reproductive BioMedicine Online 2006. 14(20:256-266.
42. Kwak-Kim J, Gilman-Sachs A. Clinical Implication of Natural Killer Cells and Reproduction. American Journal of
Reproductive Immunology 2008. 59:388-400.
43. Hiby S, Regan L, Farrell L, Carrington M, Moffett A. Association of maternal killer-cell immunoglobuline-like
receptors and parental HLA-C genotypes with recurrent miscarriage. Human Reproduction 2008. 23(4):972-976.
44. Miko E, Szereday L, et al. The Role of Invariant NKT Cells in Pre-Eclampsia. American Journal of Reproductive
Immunology 2008. 60:118-126.