Uteroplacental ischemia in early- and late-onset pre-eclampsia: a role for the fetus?

Ultrasound Obstet Gynecol 2012; 40: 373–382Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12280

Opinion

Uteroplacental ischemia in early- and late-onset pre-eclampsia: a role for the fetus?

Introduction

Pre-eclampsia is still considered a ‘disease of theories’.However, recent evidence provides important insightinto the role of chronic uteroplacental ischemia andangiogenic imbalances in the mechanism of injury ofthis obstetric syndrome. This Opinion reevaluates theassociation between chronic uteroplacental ischemia andpre-eclampsia using Hill’s criteria of causation in thelight of recent developments. A possible role of the fetusin the pathogenesis of pre-eclampsia and the possibilitythat relative uteroplacental ischemia may be operative inlate-onset pre-eclampsia are also discussed.

Between 1938 and 1940, Ernest W. Page published theresults of a series of experiments providing transcendentalinsight into the understanding of the pathogenesis ofpre-eclampsia. Ogden, Hildebrand and Page describedone of the earliest reports of experimental uteroplacentalischemia in pregnant animals1. They reported thatplacement of a clamp in the aorta below the renal arteriesin pregnant animals, aiming to reduce the femoral pressureby half, produced a gradual increase in the carotid bloodpressure. Of note, this effect was not observed in non-pregnant animals or in pregnant animals that underwenthysterectomy following placement of the aortic clamp.These observations indicate that ischemia below the renalarteries is not sufficient to lead to systemic hypertensionand that, for this to occur, the presence of the fetusand the uteroplacental unit is required. Using teleologicalreasoning, Dr Page wrote2: ‘if the placenta should beunable to obtain a sufficient maternal circulation for itsdemands, it might be capable of increasing this supplyby raising the systemic blood pressure. Since there areno nervous connections by which the placenta couldaccomplish this, such a postulate necessitates the conceptof a placental pressor substance.’ This revolutionaryconcept described in 1939 has been proved correct, asdemonstrated by recent experimental3,4 and clinical3,5

evidence suggesting the identity of the ‘pressor substance’proposed by Dr Page to include antiangiogenic factors ofplacental origin (see below). In 1938, Dr Page reported6

that transfusion of 100 mL blood from a woman withpostpartum eclampsia into a woman who was 7 monthspregnant led to ‘a severe chill, pulmonary edema andcyanosis with marked tachycardia. A chest plate showedscattered patchy areas of consolidation. . . The symptomspersisted for 36 hours then slowly subsided. . . Theblood pressure rose during the chill, but returned toa normal level.’ He interpreted the response in thepregnant recipient as a transfusion reaction; however,

according to the author, ‘blood was again obtained fromboth patients and cross-matched without agglutination.’Thus, it is unlikely that the signs and symptoms in thepregnant recipient were due to a transfusion reaction. Incontrast, transfusion of 400–435 mL blood from patientswith severe pre-eclampsia or eclampsia into four anemicpatients with incomplete abortion or in the postpartumperiod did not significantly increase their blood pressure6.These observations suggest that pregnant women aremore susceptible than are non-pregnant women to theeffects of the circulating pressor substance proposed byDr Page. Moreover, the transient nature of these signs andsymptoms in the recipients of blood transfusion from pre-eclamptic or eclamptic women suggest that a continuoussource of the pressor substance (such as the placenta)is required for the hypertension to persist. The evidencereviewed in this Opinion provides support for the validityof Dr Page’s postulates and for the association betweenuteroplacental ischemia and pre-eclampsia.

Several mechanisms of injury have been proposedin pre-eclampsia7–9, including: 1) chronic uteroplacen-tal ischemia10; 2) immune maladaptation10; 3) very low-density lipoprotein toxicity10; 4) genetic imprinting10;5) increased trophoblast apoptosis/necrosis11,12; and6) an exaggerated maternal inflammatory response todeported trophoblast13,14. Recent observations indicatethat angiogenic imbalances, characterized by an excessof antiangiogenic factors including the soluble form ofvascular endothelial growth factor (VEGF) receptor 1(sFlt-1) and soluble endoglin (s-Eng) as well as low cir-culating maternal concentrations of VEGF and placentalgrowth factor (PlGF)3,5, are implicated in the mechanismsof disease in pre-eclampsia. Novel observations suggestthat a combination of some of the proposed mechanismsof injury may be responsible for the manifestations of theclinical spectrum of pre-eclampsia. For example, clinicaland experimental evidence indicates that uteroplacen-tal ischemia leads to increased circulating concentrationsof antiangiogenic factors and angiogenic imbalances15.Another example is the recent report that deported tro-phoblast, specifically syncytial knot aggregates detachedfrom the placenta, may account for 25% of measurablecirculating sFlt-1 in women with pre-eclampsia16. sFlt-1 isan antiangiogenic factor of placental origin that appearsto play a central role in the mechanisms of injury inpre-eclampsia15.

Hill’s criteria of causation were originally describedby Austin Bradford Hill, a medical statistician, as a wayof determining the causal link between a specific factorand disease17. These criteria form the basis of modern

Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. OPINION

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epidemiological research, which attempts to establish sci-entifically valid causal connections between agents anddiseases, and include the following: 1) strength of associa-tion; 2) biological gradient (dose–response relationship);3) specificity; 4) temporal relationship; 5) consistency;6) biological plausibility; 7) coherence; 8) experiment(reversibility); and 9) analogy (consideration of alternateexplanations). A recent review used some of these criteriato evaluate a possible link between antiangiogenic factorsand pre-eclampsia18. This Opinion uses all of Hill’s cri-teria to reevaluate a possible causal association betweenchronic uteroplacental ischemia and pre-eclampsia.

Hill’s criteria

Strength of association

There is a solid body of evidence indicating that abnor-mal uterine artery Doppler velocimetry (UtADV) in thesecond trimester of pregnancy is a risk factor for the devel-opment of pre-eclampsia in the index pregnancy19–24.Experimental evidence indicates that abnormal UtADVis a surrogate marker of uteroplacental ischemia. Indeed,studies in which gelfoam was used to embolize the uterinecirculation in pregnant animals showed that progressiveembolization of the uterine arteries was associated witha linear increase in the uterine artery pulsatility index(PI)25,26, a Doppler parameter commonly use in ultra-sonography to measure impedance to blood flow. Anotherparameter is the presence of bilateral uterine artery dias-tolic notches27–29. Ochi et al. reported that embolizationof the spiral arteries in pregnant sheep produced a dias-tolic notch only when the uterine blood flow was reducedto approximately one third, and the vascular resistancewas increased to three to four times the normal value25,26.This experimental evidence indicates that high mean uter-ine artery PI and/or the presence of uterine artery notchingare associated with reduced uteroplacental blood flow,and is consistent with the results of a large longitudinalstudy indicating that both high mean uterine artery PIas well as bilateral uterine artery notching in the secondtrimester are independent risk factors for the developmentof pre-eclampsia in the index pregnancy29.

In the latter cohort study29, 4190 singleton womenunderwent UtADV between 23 and 25 weeks of gestation.Patients with chronic hypertension, multiple pregnancy,fetal anomalies, pregestational diabetes mellitus or car-diac disease were excluded from this study. AbnormalUtADV was defined as the presence of bilateral uterineartery notches and/or a mean uterine artery PI > 95th

percentile for gestational age. A multivariable logisticregression analysis determined that abnormal UtADV wasan independent factor for the identification of patients atincreased risk of developing early-onset pre-eclampsiaat less than 34 weeks of gestation (odds ratio (OR),25.7 (95% CI, 9.01–73.31)) and late-onset pre-eclampsia(OR, 2.9 (95% CI, 1.85–4.40)) after adjusting for mater-nal age > 35 years, previous pre-eclampsia, nulliparity,first-trimester body mass index (BMI) > 30 kg/m2 and

smoking status. These results are consistent with previousreports which were summarized in a recent systematicreview30. However, the former study29 estimated therisk conferred by abnormal UtADV while controllingfor other risk factors for pre-eclampsia. Of note, theodds for developing pre-eclampsia conferred by abnor-mal UtADV (OR, 4.0 (95% CI, 2.71–5.83)) was similarto that conferred by other known risk factors, includingnulliparity (OR, 4.8 (95% CI, 3.11–7.42)) and prior pre-eclampsia (OR, 5.77 (95% CI, 2.49–13.31)), and washigher than that conferred by maternal obesity (OR, 2.1(95% CI, 1.30–3.31)). These observations indicate thatsonographic evidence of chronic uteroplacental ischemiain the second trimester is an important risk factor forthe development of pre-eclampsia. In the first trimesterof pregnancy it has been reported that the combina-tion of high mean uterine artery PI, low maternal serumconcentrations of PlGF and other maternal parametersidentified 93.1% of patients who would develop pre-eclampsia requiring delivery before 34 weeks31.

Collectively, this evidence indicates that abnormalUtADV during pregnancy is a surrogate marker of chronicuteroplacental ischemia and is an important risk factor forthe development of pre-eclampsia. Chronic uteroplacentalischemia appears to be more relevant in the pathogenesisof early-onset pre-eclampsia than in term or postterm pre-eclampsia32,33. This view is supported by the observationthat high impedance to blood flow in both uterine arteriesin the second trimester is associated with a higher riskfor pre-eclampsia at ≤ 34 weeks than at > 34 weeks ofgestation19–22. This is important, because early-onset pre-eclampsia is more severe34 and is associated with a higherproportion of growth-restricted fetuses34, a higher riskof maternal death35 and a higher frequency of placentalpathology36 than is late-onset pre-eclampsia.

Biological gradient (dose–response relationship)

During pregnancy the uterus and placenta form ananatomic and functional uteroplacental unit. Absoluteuteroplacental ischemia may result from: 1) placentalbed disorders; 2) vascular insults to the placenta; or3) abnormal fetoplacental circulation. Recent reportsindicate not only that pre-eclampsia is associated withplacental vascular lesions consistent with ‘maternal under-perfusion’, but also that the earlier the gestational ageat which pre-eclampsia develops, the higher the preva-lence of lesions consistent with placental ischemia36,37.For example, a retrospective nested case–control studythat included 743 patients with pre-eclampsia and 167patients with chronic hypertension with superimposedpre-eclampsia indicated that the frequency of placen-tal histological lesions consistent with underperfusion ishigher at earlier gestational ages and gradually decreaseswith advancing gestational age. The frequency of placentalhistological lesions consistent with maternal underperfu-sion ranges from 75–100% in pre-eclampsia that developsbefore 27 weeks to 13% in pre-eclampsia that devel-ops at more than 41 weeks37. Of note, the authors

Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2012; 40: 373–382.

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indicated that there was not an abrupt change in thefrequency of placental lesions consistent with maternalunderperfusion between early-onset and late-onset pre-eclampsia, indicating that the frequency of histologicallesions consistent with chronic uteroplacental ischemia isa continuum, and that the proposed cut-off of 34 weeksto sub-classify pre-eclampsia into early and late onset mayhave clinical value but does not correlate with the resultsof placental pathology. Thus, any other cut-off, such as32 weeks or 35 weeks, could also be used to sub-classifypre-eclampsia.

Collectively, these observations suggest that there isa dose–response relationship between the magnitude ofuteroplacental ischemia and the timing of onset of pre-eclampsia. A striking example of this is the developmentof pre-eclampsia before 20 weeks of gestation in patientswith mole or partial mole. The conventional view is thatplacental villi in partial and complete mole are ‘avas-cular’ or limited to villous capillary remnants15. Thus,molar pregnancies may represent an extreme in the spec-trum of ischemic disease of the trophoblast (see below).The dose–response relationship between the magnitudeof uteroplacental ischemia and the timing of developmentof pre-eclampsia suggests that there is an absolute orrelative ‘trophoblast ischemic threshold’ beyond whichpre-eclampsia develops. It is possible that the responseto this threshold may be modified by gene–environmentinteraction, the magnitude of angiogenic imbalances andfetal signaling in response to uteroplacental ischemia15.

Specificity

Fetal strategies to cope with chronic uteroplacentalischemia may include growth restriction, fetal signalingto increase the maternal systemic blood pressure lead-ing to pre-eclampsia, or preterm parturition to exit aninadequate intrauterine environment. Since the pathogen-esis of these pregnancy complications may overlap, it isnot unusual to observe a combination of these obstetricsyndromes. Indeed, pre-eclampsia and gestational hyper-tension are frequently associated with fetal growth restric-tion; similarly, preterm parturition is commonly asso-ciated with fetal growth abnormalities38–40. Moreover,gestational hypertension and gestational proteinuria15 areconsidered part of the spectrum of pre-eclampsia becausebetween 25% and 50% of patients with gestational hyper-tension develop pre-eclampsia41. Thus, not surprisingly,abnormal UtADV in the second trimester is also animportant risk factor for the development of gestationalhypertension (OR, 1.6 (95% CI, 1.18–2.25)) and forthe delivery of a small-for-gestational age neonate in theabsence of pre-eclampsia (OR, 2.3 (95% CI, 1.72–2.97))after adjusting for maternal age, previous pre-eclampsia,nulliparity, maternal obesity and smoking status29.

Abnormalities in the placental bed and subsequent fail-ure of physiologic transformation of the spiral arteries inthe first or early second trimester limit the blood flow tothe uteroplacental unit42,43. Indeed, high impedance toblood flow in both uterine arteries, a surrogate marker

of uteroplacental ischemia44,45, is associated withfailure of physiologic transformation of the spi-ral arteries in placental bed biopsies from patientswith pre-eclampsia46–49 and those with fetal growthrestriction46,48–50. However, not all patients with thesepregnancy complications have evidence of failure of phys-iologic transformation of the spiral arteries46,47,49,50.Moreover, this pathological finding is not limited topatients with pre-eclampsia or fetal growth restriction; ithas also been described in a subset of patients with pretermparturition51, and fetal death52. Thus, abnormal UtADVin the first or second trimester as well as failure of physio-logic transformation of the spiral arteries are not limited topatients with pre-eclampsia. Therefore, the application ofHill’s criterion of specificity to sonographic or patholog-ical evidence is inadequate because the abovementionedpregnancy complications tend to coexist or overlap.

Temporal relationship

Sonographic evidence of reduced uteroplacental perfu-sion in the first and second trimester is a risk factorfor the development of pre-eclampsia in the index preg-nancy. Thus, by definition, abnormal UtADV precedesthe clinical manifestation of pre-eclampsia. However, thepositive predictive value of abnormal UtADV in the sec-ond trimester for the development of pre-eclampsia is onlybetween 8% and 33%53, indicating that the vast major-ity of patients with second-trimester abnormal UtADVwill not develop this pregnancy complication. Therefore,abnormal UtADV has a limited value in the screeningof patients for pre-eclampsia. In spite of this, a studycomparing second-trimester abnormal UtADV with otherbiochemical parameters, including angiogenic-related fac-tors, markers of oxidative stress and markers of endothe-lial dysfunction, indicated that second-trimester abnormalUtADV performed better than did all the other parametersin the identification of patients at risk for pre-eclampsia54.We believe that the actual value of second-trimesterUtADV is in the assessment of risk for the develop-ment of pre-eclampsia in individual patients, particularlyin combination with other biochemical markers55,56. Thishas important clinical implications, because the typicalpractitioner provides health services to individual patientsand is not involved in population screening.

The conventional view is that physiological transfor-mation of the spiral artery occurs in the first and earlysecond trimester of pregnancy42,43. Thus, the observationsthat a higher proportion of spiral arteries have failureof physiologic transformation in placental bed biopsiesfrom patients with pre-eclampsia than do those from nor-mal pregnancies46–49 suggest that reduced uteroplacentalflow precedes the clinical manifestations of pre-eclampsia.Collectively, this sonographic and pathological evidencesuggests that uteroplacental ischemia in pre-eclampsia ischronic in nature.

Consistency

This Hill’s criterion requires that the observation of anassociation between chronic uteroplacental ischemia and


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pre-eclampsia has been replicated in different settingsusing different methods. The evidence reviewed aboveindicates that abnormal UtADV is a surrogate marker forchronic uteroplacental ischemia, and that it is an impor-tant risk factor for the development of pre-eclampsiain the index pregnancy. Other methods used to provideadditional evidence of chronic uteroplacental ischemiain pre-eclamptic women include studies with functionalplacental scintigraphy with Iridium-113m57, demonstrat-ing that patients with pre-eclampsia have reduced bloodflow in the uteroplacental circulation, as well as morerecent studies using magnetic resonance imaging (MRI)and intravoxel incoherent motion, demonstrating thatpre-eclamptic patients have lower blood flow in the basalplate of the placenta compared with normal controls58.

Animal models of pre-eclampsia provide additional evi-dence of the association between uteroplacental ischemiaand this pregnancy complication. These models weredesigned to reduce the blood flow in the aorta and/orboth uterine arteries in an attempt to mimic the reducedblood flow due to abnormal physiological transforma-tion of the spiral arteries, and include the following:1) placement of a clamp in the aorta below the renalarteries in pregnant animals, aiming to reduce the femoralpressure by half, led to a gradual increase in the carotidblood pressure1; 2) partial occlusion of both uterine arter-ies in baboons, before pregnancy or in the mid-trimester,induced hypertension and proteinuria and renal lesionsthat resemble glomerular endotheliosis59; 3) partial occlu-sion of the aorta below the renal arteries in 11 Rhesusmonkeys produced hypertension and proteinuria in fourof the seven animals who continued pregnancy to term60;4) more recently, unilateral uterine artery ligation in preg-nant baboons resulted in hypertension, proteinuria andrenal histological changes, including endotheliosis anddeposition of fibrin and fibrinoid, as well as, a reducedplatelet count and increased circulating concentrations ofsFlt-161; 5) perhaps one of the most reproducible animalmodels of pre-eclampsia, the reduced uterine perfusion(RUPP) model in pregnant rats62–66, in which uteropla-cental perfusion is reduced by 40% by placement ofsilver clips in the aorta and both right and left uterinearteries; this leads to increased mean arterial blood pres-sure, proteinuria and fetal growth restriction as well asangiogenic imbalances characterized by an increase in theplacental expression of sFlt-1 and sEng as well as reducedexpression of VEGF and PlGF67,68.

Additional evidence of the consistency of the associa-tion between uteroplacental ischemia and pre-eclampsiais provided by the observations that different placentallesions may lead to chronic trophoblast ischemia andangiogenic imbalances15. For example, decidual arteri-olopathy, central villi infarction and hypermaturity ofvilli are frequently seen in ‘classical’ pre-eclampsia, par-ticularly at early gestational ages36. Whereas in mirrorsyndrome associated with pre-eclampsia, the main his-tological feature of the placenta is severe villous edema,the placental villi in molar pregnancies are consideredavascular15. In mirror syndrome, the impaired oxygen

exchange in the fetal–maternal interface is most likelydue to compression of the villous blood vessels and/or athicker interface. However, swollen edematous villi mayalso reduce the intervillous space and the intervillousblood flow, with subsequent reduction in the fetal oxygensupply15. Thus, severe villous edema in hydropic fetusesmay be associated with trophoblast ischemia leadingto placental overexpression and release of antiangio-genic factors. It is possible that chronic uteroplacentalischemia and subsequent angiogenic imbalance may rep-resent a common pathway in the mechanisms of diseaseof pre-eclampsia associated with partial mole and mirrorsyndrome as well as that of classical pre-eclampsia15.

Collectively, the observations reviewed above indicatethat animal models of uteroplacental ischemia andnon-invasive imaging techniques in humans as well asstudies of placental pathology in patients with pre-eclampsia are supportive of the association betweenchronic uteroplacental ischemia and pre-eclampsia.

Biological plausibility

This Hill’s criterion of causation refers to the need forsome theoretical basis for positing an association betweenchronic uteroplacental ischemia and pre-eclampsia andfor this association to agree with the currently acceptedunderstanding of pathological processes. Recent evidenceindicates that a combination of different mechanisms ofdisease may be operative in pre-eclampsia. For example,uteroplacental ischemia may lead to increased circulatingconcentrations of antiangiogenic factors, as demonstratedby the following observations: 1) reduced uterine perfu-sion in non-human primates61 and rats67 is associatedwith hypertension and increased placental expressionof antiangiogenic factors; 2) cytotrophoblasts culturedunder hypoxic conditions upregulate mRNA expressionand production of sFlt-1 in the supernatant69; 3) increasedexpression of sFlt-1 in the human placenta is medi-ated by hypoxia inducible factor-1 (HIF-1)70; 4) amongpatients with pre-eclampsia, the higher the impedance toblood flow in the uterine arteries (a surrogate marker ofchronic uteroplacental ischemia), the higher the mater-nal plasma concentration of antiangiogenic factors71; and5) histological lesions suggestive of chronic trophoblastischemia have been associated with hypertension, pro-teinuria and angiogenic imbalances, including lesionsconsistent with maternal underperfusion in classic pre-eclampsia72, severe villous edema in mirror syndromeand avascular villi in mole and partial mole15. Thus, theevidence reviewed herein provides theoretical support forthe association between chronic uteroplacental ischemiaand pre-eclampsia.

One of the main limitations of in-vitro studies tryingto simulate trophoblast ischemia in the laboratory is thecommon misconception that tissue ischemia equates totissue hypoxia. Ischemia can be defined as a decrease inthe blood supply to a bodily organ, tissue or part causedby constriction or obstruction of the blood vessels, whilehypoxia is defined as a deficiency in the amount of oxygen


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reaching body tissues. The conventional view is that thedegree of tissue ischemia is what determines the presenceor absence of tissue hypoxia. Yet, many in-vitro studiesused hypoxia or hypoxemia as a surrogate marker oftissue ischemia; not surprisingly, these studies reportedconflicting results, indicating an association of tissuehypoxia73–77 or even hyperoxia78–84 with pre-eclampsia.Many of these studies used changes in the expression ofHIF as a surrogate indicator of tissue hypoxia. However,recent evidence indicates that non-hypoxic stimuli canlead to increased expression of HIF in the placenta76,85,86

and other tissues87,88. For example, normoxic inductionof HIF can be mediated by adenosine A2a receptor inmacrophages87. Improvements in non-invasive methodsto evaluate tissue ischemia in animal models and bettermethods to evaluate tissue ischemia in-vitro, apart fromthe evaluation of oxygen content, may provide importantinsight into the mechanisms of injury in pre-eclampsia.

Coherence

This Hill’s criterion refers to the idea that ‘a cause-and-effect interpretation should not seriously conflict with thegenerally known facts of the natural history and biologyof the disease.’17 Some attempts have been made to assessin vivo the changes in blood flow secondary to failureof physiological transformation of the spiral arteries,indicating that this failure leads to placental rheologicalconsequences rather than chronic hypoxia89. However,this idea is based on mathematical modeling and has notbeen confirmed by empirical data. Moreover, these resultsare not consistent with studies using functional MRIwhich found reduced blood flow in the basal plate ofpre-eclamptic women, an anatomic area that correspondsto the spiral arteries58, compared with that of normalcontrols. The evidence reviewed thus far indicates thatchronic uteroplacental ischemia plays a central role inthe pathogenesis of pre-eclampsia and that this possiblecause-and-effect association does not conflict with thenatural history and biology of the disease.

Experiment (reversibility)

In the experimental uteroplacental ischemia describedby Ogden, Hildebrand and Page in 19401, the authorsreported that placement of a clamp in the aorta belowthe renal arteries in pregnant dogs produced a gradualincrease in the carotid blood pressure and that releaseof the aortic clamp was followed by a return to theprevious blood pressure ‘sometimes immediately, some-times gradually during 20 minutes.’1 The observation thatthis effect was prevented when a pregnant animal under-went hysterectomy indicates that uteroplacental ischemiais not sufficient to lead to systemic hypertension, butthat it requires the presence of the fetus (or fetal sig-naling) and the uteroplacental unit; in the words of theauthors: ‘Since in our 4 control animals. . . compressionof the aorta below the renal artery produces no suchprolonged rise as we have here described, we are forced

to conclude that the products of conception (i.e. fetus,placenta, or gravid uterus) are fundamentally responsiblefor these slow blood pressure rises.’ This observation isconsistent with the notion that a combination of utero-placental ischemia and some of the other mechanismsof injury discussed in the introduction of this Opinionmay be operative in pre-eclampsia. For example, accu-mulating clinical15,72 and experimental61,67,69,70 evidenceindicates that uteroplacental ischemia leads to angiogenicimbalances15, which appears to play a central role in thepathogenesis of pre-eclampsia.

In their original report, Ogden, Hildebrand and Pagewrote: ‘These rises of blood pressure could be producedrepeatedly in the same animal except after a long periodon unduly severe constriction when it may be supposedthat prolonged anoxemia had caused irreversible changesin the uterus or its contents.’1 This observation hastranscendental implications, because, if fetal signaling, inresponse to uteroplacental ischemia, leads to an elevationin the maternal systemic blood pressure, initial increasesin the maternal blood pressure might compensate forthe reduced blood flow to the fetal and placentaltissues. However, because of its chronic nature, persistentischemia to the uteroplacental unit may lead to furtherincrease in maternal blood pressure even if the reducedblood supply to the uteroplacental unit was initiallycompensated by an elevation in the maternal systemicblood pressure. Thus, there is a tendency for pre-eclampsiato become more severe if the patient remains pregnant.Moreover, a hypothetical intervention that could correctreduced uteroplacental flow may not be able to reverse thedisease process if the ‘irreversible changes in the uterus orits contents’1 are already in place.

Analogy (consideration of alternate explanations)

Other animal models of pre-eclampsia have beendescribed90, based on: 1) genetic manipulation of enzymesand pathways involved in the pathogenesis of pre-eclampsia; 2) administration of various agents, includ-ing N-omega-nitro-L-arginine (L-NAME), insulin, Adria-mycin (a nephrotoxin agent) and autoantibodies againstangiotensin II type 1a receptors (AT1) obtained fromwomen with pre-eclampsia; of note, in this latter model,coadministration of AT1 and Losartan prevented man-ifestation of pre-eclamptic features; 3) manipulation ofinnate or adaptive immunity; 4) manipulation of pro-and anti-inflammatory cytokines; 5) ultra-low-dose endo-toxin infusion; 5) chronic stress; and 6) sympathetichyperactivity90. A detailed description of these models isbeyond the scope of this Opinion and the reader is referredto a recent review on the topic90. All of these models arebased on the manipulation of different pathways involvedin the pathogenesis of pre-eclampsia; they do not disprovethe possible causal association between chronic uteropla-cental ischemia and pre-eclampsia, because they simplydemonstrate that different pathways may be operative inthe pathogenesis of this pregnancy complication. This isconsistent with the results of a proteomic study indicating


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divergent molecular mechanisms in pre-eclampsia, includ-ing: 1) angiogenesis; 2) mitogen-activated protein kinases(MAPK) signaling; and 3) hormone biosynthesis andmetabolism91. Future studies will determine if there isan association between chronic uteroplacental ischemiaand these molecular pathways.

A possible role of the fetus in the pathogenesis ofpre-eclampsia

Clinical and sonographic observations in patients withpre-eclampsia suggest that the fetus may play arole in the maternal manifestations of this pregnancycomplication92,93. A striking example of the role of thefetus is remission of pre-eclampsia following the deathof the growth-restricted fetus in discordant twins, orafter correction of fetal hydrops in mirror syndromeassociated with parvovirus infection15. In the lattercase, improvement in the fetal status and presumablysubsequent improvement in fetal perfusion of the placentaled to the resolution of pre-eclampsia without the needfor placental delivery.

The fetal endothelium is continuous with that of thevillous capillaries and it is possible that, in responseto ischemia, endothelial signaling in villous capillariesmay lead to placental overexpression and secretion ofan excess of antiangiogenic factors. This is supportedby studies using placental explants, in which the fetalcompartment and the intervillous space are perfusedunder controlled conditions. In one study the authorsdetermined the adenosine concentrations in fetal venousperfusates using isolated dual-perfused human placentalcotyledons. They reported that cessation of ‘maternal’perfusion was associated with a two- to six-fold increase infetal venous perfusate concentrations of adenosine and aconcomitant increase in fetoplacental perfusion pressure.Furthermore, perfusate pressure and the concentration ofadenosine in the fetal compartment returned to baselinelevels on reperfusion of the ‘maternal’ circuit94. Thus,even in the absence of a fetus, the fetal endothelium in theplacental villi is capable of increasing the concentrationof adenosine in response to reduced perfusion. Adenosineis a nucleoside that has been implicated in the placentalexpression of sFlt-1 under both normoxic and hypoxicconditions95. Moreover, recent reports suggest that thefetus may use adenosine signaling in an attempt to improvethe uteroplacental circulation in pre-eclamptic womenwith sonographic evidence of chronic uteroplacentalischemia93.

Abnormal fetoplacental circulation may also lead touteroplacental ischemia and pre-eclampsia. A strikingexample of this is the development of pre-eclampsiabefore 20 weeks of gestation in patients with mole orpartial mole. The conventional view is that placental villiin partial and complete mole are avascular or limitedto villous capillary remnants15. However, this notionwas recently challenged by the observation that vascularendothelial cells are present in the villous stroma ofcomplete mole15. By definition, these vascular endothelial

cells are of fetal origin. Thus, it is possible that the lack offetoplacental circulation in complete mole leads to severeischemia of endothelial and trophoblast cells and excessiveplacental production of antiangiogenic factors. In molarpregnancies, the prevalence of pre-eclampsia is muchhigher when a fetus is present, suggesting a role for thefetus in pre-eclampsia. Indeed, pre-eclampsia is present in41.9% of pregnancies with partial mole15. In contrast, theprevalence of pre-eclampsia in complete mole significantlydecreased, from 12% (41/347) in the period 1966–1972to 1.3% (1/74) in the period 1988–1993, presumablydue to earlier diagnosis and uterine evacuation, whichmay have prevented the subsequent development of pre-eclampsia15. The absence of a fetus in complete moledoes not disprove the fetal role in pre-eclampsia96.On the contrary, the lack of fetal perfusion of theplacenta in complete mole may represent an extremein the spectrum of ischemic disease of the uteroplacenta,leading to angiogenic imbalances and early-onset pre-eclampsia. This is supported by the observation thatthe serum concentration of sFlt-1 in the first trimesteramong patients with complete mole is significantly higherthan that of patients with normal pregnancies and thatof patients who develop pre-eclampsia in the indexpregnancy97.

Late-onset pre-eclampsia: relative uteroplacentalischemia?

Late-onset pre-eclampsia (> 34 weeks) accounts for thevast majority of pre-eclamptic cases. However, absoluteuteroplacental ischemia appears to be less relevant in thepathogenesis of late-onset compared with early-onset pre-eclampsia15. Evidence in support of this view includes therecent observation that more than half of patients withlate-onset pre-eclampsia do not have placental histologicallesions consistent with maternal underperfusion72. Inaddition, among patients with late-onset pre-eclampsia,those without placental lesions consistent with maternalunderperfusion have evidence of angiogenic imbalanceswhen compared with women with normal pregnanciesbut of a lower magnitude than in pre-eclamptic womenwith vascular placental lesions72. Furthermore, late-onsetpre-eclampsia is frequently associated with fetuses thatare appropriate- or large-for-gestational age15. Thus, inthese cases an increased fetal demand for substrates thatsurpasses the placental ability to sustain fetal growthmay induce fetal signaling for placental overproductionof antiangiogenic factors and subsequent ‘compensatory’maternal hypertension. It is possible that relativeuteroplacental ischemia due to a mismatch betweenlimited uteroplacental blood flow and increased fetaldemand for nutrients may be central to the development oflate-onset pre-eclampsia. Not surprisingly, the predictionof late-onset pre-eclampsia using first- and second-trimester biochemical or biophysical (UtADV) parametersor a combination of them has been less effective thanhas the prediction of early-onset pre-eclampsia15. This isprobably because a trophoblast ischemic threshold leading


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to pre-eclampsia is crossed late in pregnancy or due toa more acute nature of the insults to the fetal supplyline in late-onset pre-eclampsia. The latter suggestion issupported by the results of a longitudinal study reportingthat there is a subset of patients who have sonographicevidence of limited uteroplacental blood flow in thethird but not in the second trimester, presumably dueto early regression of the physiologic transformation ofthe spiral arteries. These patients have a higher frequencyof pre-eclampsia than do patients without sonographicevidence of uteroplacental ischemia in the second or thirdtrimester29.

A recent population-based study indicated that gesta-tional diabetes (GDM) is an independent factor for thedevelopment of pre-eclampsia after controlling for con-founding factors including maternal age, parity, BMI,smoking as well as chronic hypertension or renal disease(adjusted OR, 1.61 (95% CI, 1.39–1.86))98. Moreover,a large retrospective study demonstrated that the rateof pre-eclampsia among women with GDM with poorglycemic control was twice as high as that among womenwith better glycemic control (18% vs 9.8%; OR, 2.56(95% CI, 1.5–4.3))99. However, there is limited literatureregarding the timing of onset of pre-eclampsia amongwomen with GDM. Of note, a recent study involving45 consecutive patients with GDM demonstrated normalplacental histology in 80% of them100; thus, placentalvascular lesions are not common in women with GDM.Since this pregnancy complication is associated with large-for-gestational age neonates, it is possible that, in womenwith GDM who develop pre-eclampsia, an increased fetaldemand for substrates that surpass the placental abilityto sustain fetal growth may induce fetal signaling forplacental overproduction of antiangiogenic factors andsubsequent ‘compensatory’ maternal hypertension. How-ever, additional studies are required to explore the role ofangiogenic imbalances in these patients. To the extent thatthese studies confirm angiogenic imbalances in GMD, rel-ative uteroplacental ischemia due to a mismatch betweenuteroplacental blood flow and increased fetal demandfor nutrients may be central to the development of pre-eclampsia associated with GDM. Thus, better methodsto identify large-for-gestational age neonates may pro-vide important insight into the pathogenesis of late-onsetpre-eclampsia.

In view of the limited pathological and sonographicevidence of uteroplacental ischemia in late-onset pre-eclampsia, fetal signaling may provide a unifyingconceptual framework in the pathogenesis of both early-and late-onset pre-eclampsia.

Summary

Pre-eclampsia101 and eclampsia102 are a leading causeof maternal morbidity and mortality. Understandingthe subjacent mechanisms of injury in this pregnancycomplication may help in the design of new prophy-lactic and therapeutic interventions. Absolute uteropla-cental ischemia appears to be more relevant in early-onset pre-eclampsia. In contrast, relative uteroplacental

ischemia due to a mismatch between uteroplacental bloodflow and increased fetal demand for nutrients may be cen-tral to the development of late-onset pre-eclampsia. Hill’scriteria are still widely accepted as a logical structurefor investigating and defining causality in epidemiolog-ical studies. However, their method of application isdebated. For example, some authors propose using acounterfactual consideration as the basis to apply eachcriterion. Moreover, a revision of the criteria was recentlyproposed in the context of evidence-based medicine, sub-dividing them into three categories: direct, mechanisticand parallel evidence103. Also, some authors argue thatthe basic mechanism of proving causality is in scientificcommon sense deduction104. However, it is importantto remember that Sir Austin Bradford Hill himself indi-cated that ‘none of these nine criteria of causality canbring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine quanon.’17 While recognizing these limitations, the balance ofobservations reviewed herein indicate that Hill’s criteriasuggest a causal association between chronic uteropla-cental ischemia and pre-eclampsia. The conventionaldefinition of pre-eclampsia has important limitations105,and recent modifications continue to be based on conven-tion rather than on maternal and/or perinatal outcome.Novel conceptual frameworks may contribute to a moreobjective definition of this obstetric syndrome.

J. EspinozaDepartment of Obstetrics and Gynecology,

Texas Children’s Hospital Pavilion for Women,Baylor College of Medicine,

6651 Main Street, Suite 1020,Houston, TX 77030, USA

(e-mail: [email protected])

REFERENCES

1. Ogden HG, Hildebrand GJ, Page EW. Rise in blood pressureduring ischaemia of the gravid uterus. Proc Soc Exp Biol Med1940; 43: 49–51.

2. Page EW. The relation between hydatid moles, relativeischemia of the gravid uterus, and the placental origin ofeclampsia. Am J Obstet Gynecol 1939; 37: 291–293.

3. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mon-dal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE,Epstein FH, Sukhatme VP, Karumanchi SA. Excess placen-tal soluble fms-like tyrosine kinase 1 (sFlt1) may contributeto endothelial dysfunction, hypertension, and proteinuria inpreeclampsia. J Clin Invest 2003; 111: 649–658.

4. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T,Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA,Stillman IE, Roberts D, D’Amore PA, Epstein FH, Sellke FW,Romero R, Sukhatme VP, Letarte M, Karumanchi SA. Solubleendoglin contributes to the pathogenesis of preeclampsia. NatMed 2006; 12: 642–649.

5. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP,Sibai BM, Epstein FH, Romero R, Thadhani R, KarumanchiSA; CPEP Study Group. Soluble endoglin and other circulatingantiangiogenic factors in preeclampsia. N Engl J Med 2006;355: 992–1005.

6. Page EW. The effect of eclamptic blood upon the urinaryoutput and blood pressure of human recipients. J Clin Invest1938; 17: 207–218.


380 Espinoza

7. Redman CW, Sargent IL. Latest advances in understandingpreeclampsia. Science 2005; 308: 1592–1594.

8. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010; 376: 631–644.

9. von Dadelszen P, Magee LA, Roberts JM. Subclassification ofpreeclampsia. Hypertens Preg 2003; 22: 143–148.

10. Dekker GA, Sibai BM. Etiology and pathogenesis ofpreeclampsia: current concepts. Am J Obstet Gynecol 1998;179: 1359–1375.

11. Crocker IP, Cooper S, Ong SC, Baker PN. Differences inapoptotic susceptibility of cytotrophoblasts and syncytiotro-phoblasts in normal pregnancy to those complicated withpreeclampsia and intrauterine growth restriction. Am J Pathol2003; 162: 637–643.

12. Leung DN, Smith SC, To KF, Sahota DS, Baker PN. Increasedplacental apoptosis in pregnancies complicated by preeclamp-sia. Am J Obstet Gynecol 2001; 184: 1249–1250.

13. Sargent IL, Germain SJ, Sacks GP, Kumar S, Redman CW.Trophoblast deportation and the maternal inflammatoryresponse in pre-eclampsia. J Reprod Immunol 2003; 59:153–160.

14. Chua S, Wilkins T, Sargent I, Redman C. Trophoblast depor-tation in pre-eclamptic pregnancy. Br J Obstet Gynaecol 1991;98: 973–979.

15. Espinoza J, Uckele JE, Starr RA, Seubert DE, Espinoza AF,Berry SM. Angiogenic imbalances: the obstetric perspective.Am J Obstet Gynecol 2010; 203: 17–18.

16. Rajakumar A, Cerdeira AS, Rana S, Zsengeller Z, Edmunds L,Jeyabalan A, Hubel CA, Stillman IE, Parikh SM, Karu-manchi SA. Transcriptionally active syncytial aggregates inthe maternal circulation may contribute to circulating solublefms-like tyrosine kinase 1 in preeclampsia. Hypertension 2012;59: 256–264.

17. Hill AB. The environment and disease: association orcausation? Proc R Soc Med 1965; 58: 295–300.

18. Ramma W, Ahmed A. Is inflammation the cause of pre-eclampsia? Biochem Soc Trans 2011; 39: 1619–1627.

19. Harrington K, Cooper D, Lees C, Hecher K, Campbell S.Doppler ultrasound of the uterine arteries: the importance ofbilateral notching in the prediction of pre-eclampsia, placentalabruption or delivery of a small-for-gestational-age baby.Ultrasound Obstet Gynecol 1996; 7: 182–188.

20. Albaiges G, Missfelder-Lobos H, Lees C, Parra M, Nico-laides KH. One-stage screening for pregnancy complicationsby color Doppler assessment of the uterine arteries at 23 weeks’gestation. Obstet Gynecol 2000; 96: 559–564.

21. Papageorghiou AT, Yu CK, Cicero S, Bower S, Nicolaides KH.Second-trimester uterine artery Doppler screening in unselectedpopulations: a review. J Matern Fetal Neonatal Med 2002; 12:78–88.

22. Papageorghiou AT, Yu CK, Bindra R, Pandis G, Nico-laides KH. Multicenter screening for pre-eclampsia and fetalgrowth restriction by transvaginal uterine artery Doppler at23 weeks of gestation. Ultrasound Obstet Gynecol 2001; 18:441–449.

23. Campbell DM, MacGillivray I, Carr-Hill R. Pre-eclampsia insecond pregnancy. Br J Obstet Gynaecol 1985; 92: 131–140.

24. Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R.Risk factors and clinical manifestations of pre-eclampsia.BJOG 2000; 107: 1410–1416.

25. Ochi H, Suginami H, Matsubara K, Taniguchi H, Yano J,Matsuura S. Micro-bead embolization of uterine spiral arteriesand changes in uterine arterial flow velocity waveforms in thepregnant ewe. Ultrasound Obstet Gynecol 1995; 6: 272–276.

26. Ochi H, Matsubara K, Kusanagi Y, Taniguchi H, Ito M.Significance of a diastolic notch in the uterine artery flowvelocity waveform induced by uterine embolisation in thepregnant ewe. Br J Obstet Gynaecol 1998; 105: 1118–1121.

27. Bower S, Bewley S, Campbell S. Improved prediction ofpreeclampsia by two-stage screening of uterine arteries using

the early diastolic notch and color Doppler imaging. ObstetGynecol 1993; 82: 78–83.

28. Campbell S. The uteroplacental circulation–why computermodelling makes sense. Ultrasound Obstet Gynecol 1995;6: 237–239.

29. Espinoza J, Kusanovic JP, Bahado-Singh R, Gervasi MT,Romero R, Lee W, Vaisbuch E, Mazaki-Tovi S, Mittal P,Gotsch F, Erez O, Gomez R, Yeo L, Hassan SS. Should bilat-eral uterine artery notching be used in the risk assessmentfor preeclampsia, small-for-gestational-age, and gestationalhypertension? J Ultrasound Med 2010; 29: 1103–1115.

30. Duckitt K, Harrington D. Risk factors for pre-eclampsia atantenatal booking: systematic review of controlled studies.BMJ 2005; 330: 565.

31. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH.First-trimester prediction of hypertensive disorders in preg-nancy. Hypertension 2009; 53: 812–818.

32. Rasmussen S, Irgens LM. Fetal growth and body proportionin preeclampsia. Obstet Gynecol 2003; 101: 575–583.

33. Aardema MW, Saro MC, Lander M, De Wolf BT, Ooster-hof H, Aarnoudse JG. Second trimester Doppler ultrasoundscreening of the uterine arteries differentiates between subse-quent normal and poor outcomes of hypertensive pregnancy:two different pathophysiological entities? Clin Sci (Lond)2004; 106: 377–382.

34. Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R.Preeclampsia and fetal growth. Obstet Gynecol 2000; 96:950–955.

35. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortalityfrom preeclampsia and eclampsia. Obstet Gynecol 2001; 97:533–538.

36. Moldenhauer JS, Stanek J, Warshak C, Khoury J, Sibai B. Thefrequency and severity of placental findings in women withpreeclampsia are gestational age dependent. Am J ObstetGynecol 2003; 189: 1173–1177.

37. Ogge G, Chaiworapongsa T, Romero R, Hussein Y, KusanovicJP, Yeo L, Kim CJ, Hassan SS. Placental lesions associated withmaternal underperfusion are more frequent in early-onset thanin late-onset preeclampsia. J Perinat Med 2011; 39: 641–652.

38. Deter RL, Rossavik IK, Harrist RB. Development of individualgrowth curve standards for estimated fetal weight: I. Weightestimation procedure. J Clin Ultrasound 1988; 16: 215–225.

39. Ott WJ. Intrauterine growth retardation and preterm delivery.Am J Obstet Gynecol 1993; 168: 1710–1715.

40. Lampl M, Gotsch F, Kusanovic JP, Espinoza J, Goncalves L,Gomez R, Nien JK, Frongillo EA, Romero R. Downwardpercentile crossing as an indicator of an adverse prenatalenvironment. Ann Hum Biol 2008; 35: 462–474.

41. Sibai BM, Stella CL. Diagnosis and management of atypicalpreeclampsia-eclampsia. Am J Obstet Gynecol 2009; 200:481–487.

42. Espinoza J, Romero R, Mee KY, Kusanovic JP, Hassan S,Erez O, Gotsch F, Than NG, Papp Z, Jai Kim C. Normaland abnormal transformation of the spiral arteries duringpregnancy. J Perinat Med 2006; 34: 447–458.

43. Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiralarteries in human pregnancy: facts and controversies. Placenta2006; 27: 939–958.

44. Kuzmina IY, Hubina-Vakulik GI, Burton GJ. Placental mor-phometry and Doppler flow velocimetry in cases of chronichuman fetal hypoxia. Eur J Obstet Gynecol Reprod Biol 2005;120: 139–145.

45. Prefumo F, Sebire NJ, Thilaganathan B. Decreased endovas-cular trophoblast invasion in first trimester pregnancies withhigh-resistance uterine artery Doppler indices. Hum Reprod2004; 19: 206–209.

46. Olofsson P, Laurini RN, Marsal K. A high uterine arterypulsatility index reflects a defective development of placentalbed spiral arteries in pregnancies complicated by hypertensionand fetal growth retardation. Eur J Obstet Gynecol ReprodBiol 1993; 49: 161–168.


Opinion 381

47. Voigt HJ, Becker V. Doppler flow measurements and histo-morphology of the placental bed in uteroplacental insuffi-ciency. J Perinat Med 1992; 20: 139–147.

48. Lin S, Shimizu I, Suehara N, Nakayama M, Aono T. Uterineartery Doppler velocimetry in relation to trophoblast migrationinto the myometrium of the placental bed. Obstet Gynecol1995; 85: 760–765.

49. Aardema MW, Oosterhof H, Timmer A, van Rooy I,Aarnoudse JG. Uterine artery Doppler flow and uteroplacentalvascular pathology in normal pregnancies and pregnanciescomplicated by pre-eclampsia and small for gestational agefetuses. Placenta 2001; 22: 405–411.

50. Madazli R, Somunkiran A, Calay Z, Ilvan S, Aksu MF. Histo-morphology of the placenta and the placental bed of growthrestricted foetuses and correlation with the Doppler velocime-tries of the uterine and umbilical arteries. Placenta 2003; 24:510–516.

51. Kim YM, Chaiworapongsa T, Gomez R, Bujold E, Yoon BH,Rotmensch S, Thaler HT, Romero R. Failure of physiologictransformation of the spiral arteries in the placental bedin preterm premature rupture of membranes. Am J ObstetGynecol 2002; 187: 1137–1142.

52. Avagliano L, Bulfamante GP, Morabito A, Marconi AM.Abnormal spiral artery remodelling in the decidual segmentduring pregnancy: from histology to clinical correlation. J ClinPathol 2011; 64: 1064–1068.

53. Papageorghiou AT, Yu CK, Nicolaides KH. The role of uterineartery Doppler in predicting adverse pregnancy outcome. BestPract Res Clin Obstet Gynaecol 2004; 18: 383–396.

54. Parra M, Rodrigo R, Barja P, Bosco C, Fernandez V, MunozH, Soto-Chacon E. Screening test for preeclampsia throughassessment of uteroplacental blood flow and biochemicalmarkers of oxidative stress and endothelial dysfunction. Am JObstet Gynecol 2005; 193: 1486–1491.

55. Espinoza J. Recent biomarkers for the identification of patientsat risk for preeclampsia: the role of uteroplacental ischemia.Expert Opin Med Diagn 2012; 6: 109–120.

56. Espinoza J, Romero R, Nien JK, Gomez R, Kusanovic JP,Goncalves LF, Medina L, Edwin S, Hassan S, Carstens M,Gonzalez R. Identification of patients at risk for early onsetand/or severe preeclampsia with the use of uterine arteryDoppler velocimetry and placental growth factor. Am J ObstetGynecol 2007; 196: 326.e1–13.

57. Lunell NO, Nylund LE, Lewander R, Sarby B. Uteroplacentalblood flow in pre-eclampsia measurements with indium-113mand a computer-linked gamma camera. Clin Exp Hypertens B1982; 1: 105–117.

58. Moore RJ, Ong SS, Tyler DJ, Duckett R, Baker PN, DunnWR, Johnson IR, Gowland PA. Spiral artery blood volume innormal pregnancies and those compromised by pre-eclampsia.NMR Biomed 2008; 21: 376–380.

59. Cavanagh D, Rao PS, Knuppel RA, Desai U, Balis JU.Pregnancy-induced hypertension: development of a model inthe pregnant primate (Papio anubis). Am J Obstet Gynecol1985; 151: 987–999.

60. Combs CA, Katz MA, Kitzmiller JL, Brescia RJ. Experimentalpreeclampsia produced by chronic constriction of thelower aorta: validation with longitudinal blood pressuremeasurements in conscious rhesus monkeys. Am J ObstetGynecol 1993; 169: 215–223.

61. Makris A, Thornton C, Thompson J, Thomson S, Martin R,Ogle R, Waugh R, McKenzie P, Kirwan P, Hennessy A. Utero-placental ischemia results in proteinuric hypertension andelevated sFLT-1. Kidney Int 2007; 71: 977–984.

62. Llinas MT, Alexander BT, Seedek M, Abram SR, Crell A,Granger JP. Enhanced thromboxane synthesis during chronicreductions in uterine perfusion pressure in pregnant rats. AmJ Hypertens 2002; 15: 793–797.

63. Granger JP, LaMarca BB, Cockrell K, Sedeek M, Balzi C,Chandler D, Bennett W. Reduced uterine perfusion pressure(RUPP) model for studying cardiovascular-renal dysfunction

in response to placental ischemia. Methods Mol Med 2006;122: 383–392.

64. Sedeek M, Gilbert JS, LaMarca BB, Sholook M, Chandler DL,Wang Y, Granger JP. Role of reactive oxygen species inhypertension produced by reduced uterine perfusion inpregnant rats. Am J Hypertens 2008; 21: 1152–1156.

65. Gilbert J, Dukes M, Lamarca B, Cockrell K, Babcock S,Granger J. Effects of reduced uterine perfusion pressure onblood pressure and metabolic factors in pregnant rats. Am JHypertens 2007; 20: 686–691.

66. George EM, Cockrell K, Aranay M, Csongradi E, Stec DE,Granger JP. Induction of heme oxygenase 1 attenuatesplacental ischemia-induced hypertension. Hypertension 2011;57: 941–948.

67. Gilbert JS, Babcock SA, Granger JP. Hypertension producedby reduced uterine perfusion in pregnant rats is associatedwith increased soluble fms-like tyrosine kinase-1 expression.Hypertension 2007; 50: 1142–1147.

68. Gilbert JS, Gilbert SA, Arany M, Granger JP. Hypertensionproduced by placental ischemia in pregnant rats is associatedwith increased soluble endoglin expression. Hypertension2009; 53: 399–403.

69. Nagamatsu T, Fujii T, Kusumi M, Zou L, Yamashita T,Osuga Y, Momoeda M, Kozuma S, Taketani Y. Cytotro-phoblasts up-regulate soluble fms-like tyrosine kinase-1expression under reduced oxygen: an implication for theplacental vascular development and the pathophysiology ofpreeclampsia. Endocrinology 2004; 145: 4838–4845.

70. Nevo O, Soleymanlou N, Wu Y, Xu J, Kingdom J, Many A,Zamudio S, Caniggia I. Increased expression of sFlt-1 inin vivo and in vitro models of human placental hypoxia ismediated by HIF-1. Am J Physiol Regul Integr Comp Physiol2006; 291: R1085–R1093.

71. Chaiworapongsa T, Espinoza J, Gotsch F, Kim YM, Kim GJ,Goncalves LF, Edwin S, Kusanovic JP, Erez O, Than NG,Hassan SS, Romero R. The maternal plasma soluble vascularendothelial growth factor receptor-1 concentration is elevatedin SGA and the magnitude of the increase relates to Dopplerabnormalities in the maternal and fetal circulation. J MaternFetal Neonatal Med 2008; 21: 25–40.

72. Soto E, Romero R, Kusanovic JP, Ogge G, Hussein Y, Yeo L,Hassan SS, Kim CJ, Chaiworapongsa T. Late-onset preeclamp-sia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placentallesions consistent with maternal underperfusion. J MaternFetal Neonatal Med 2012; 25: 498–507.

73. Howard RB, Hosokawa T, Maguire MH. Hypoxia-inducedfetoplacental vasoconstriction in perfused human placentalcotyledons. Am J Obstet Gynecol 1987; 157: 1261–1266.

74. Alvarez H, Medrano CV, Sala MA, Benedetti WL. Tro-phoblast development gradient and its relationship to placentalhemodynamics. II. Study of fetal cotyledons from the toxemicplacenta. Am J Obstet Gynecol 1972; 114: 873–878.

75. Rajakumar A, Whitelock KA, Weissfeld LA, Daftary AR,Markovic N, Conrad KP. Selective overexpression of thehypoxia-inducible transcription factor, HIF-2alpha, in pla-centas from women with preeclampsia. Biol Reprod 2001; 64:499–506.

76. Qian D, Lin HY, Wang HM, Zhang X, Liu DL, Li QL, Zhu C.Normoxic induction of the hypoxic-inducible factor-1 alphaby interleukin-1 beta involves the extracellular signal-regulatedkinase 1/2 pathway in normal human cytotrophoblast cells.Biol Reprod 2004; 70: 1822–1827.

77. Sharma S, Norris WE, Kalkunte S. Beyond the threshold:an etiological bridge between hypoxia and immunity inpreeclampsia. J Reprod Immunol 2010; 85: 112–116.

78. Heazell AE, Moll SJ, Jones CJ, Baker PN, Crocker IP. Forma-tion of syncytial knots is increased by hyperoxia, hypoxia andreactive oxygen species. Placenta 2007; 28: Suppl A: S33–S40.

79. Jarvenpaa J, Vuoristo JT, Ukkola O, Hirvikoski P, SavolainenER, Raudaskoski T, Ryynanen M. Cord compression may


382 Espinoza

rapidly influence the expression of placental angiogenic genesin pre-eclampsia. Placenta 2008; 29: 436–438.

80. Robinson NJ, Wareing M, Hudson NK, Blankley RT, BakerPN, Aplin JD, Crocker IP. Oxygen and the liberation ofplacental factors responsible for vascular compromise. LabInvest 2008; 88: 293–305.

81. Kingdom JC, Kaufmann P. Oxygen and placental vasculardevelopment. Adv Exp Med Biol 1999; 474: 259–275.

82. Kingdom JC, Kaufmann P. Oxygen and placental villousdevelopment: origins of fetal hypoxia. Placenta 1997; 18:613–621.

83. Lyall F, Young A, Boswell F, Kingdom JC, Greer IA. Placentalexpression of vascular endothelial growth factor in placentaefrom pregnancies complicated by pre-eclampsia and intrauter-ine growth restriction does not support placental hypoxia atdelivery. Placenta 1997; 18: 269–276.

84. Hung TH, Burton GJ. Hypoxia and reoxygenation: a possiblemechanism for placental oxidative stress in preeclampsia.Taiwan J Obstet Gynecol 2006; 45: 189–200.

85. Fukushima K, Murata M, Hachisuga M, Tsukimori K, Seki H,Takeda S, Asanoma K, Wake N. Hypoxia inducible factor 1alpha regulates matrigel-induced endovascular differentiationunder normoxia in a human extravillous trophoblast cell line.Placenta 2008; 29: 324–331.

86. Ietta F, Wu Y, Winter J, Xu J, Wang J, Post M, Caniggia I.Dynamic HIF1A regulation during human placental develop-ment. Biol Reprod 2006; 75: 112–121.

87. De Ponti C, Carini R, Alchera E, Nitti MP, Locati M,Albano E, Cairo G, Tacchini L. Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC andPI-3K-dependent pathways in macrophages. J Leukoc Biol2007; 82: 392–402.

88. Haeberle HA, Durrstein C, Rosenberger P, Hosakote YM,Kuhlicke J, Kempf VA, Garofalo RP, Eltzschig HK. Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1during RSV infection. PLoS One 2008; 3: e3352.

89. Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheologicaland physiological consequences of conversion of the maternalspiral arteries for uteroplacental blood flow during humanpregnancy. Placenta 2009; 30: 473–482.

90. McCarthy FP, Kingdom JC, Kenny LC, Walsh SK. Animalmodels of preeclampsia; uses and limitations. Placenta 2011;32: 413–419.

91. Cox B, Sharma P, Evangelou AI, Whiteley K, Ignatchenko V,Ignatchenko A, Baczyk D, Czikk M, Kingdom J, Rossant J,Gramolini AO, Adamson SL, Kislinger T. Translational anal-ysis of mouse and human placental protein and mRNA reveals

distinct molecular pathologies in human preeclampsia. MolCell Proteomics 2011; 10: M111.012526.

92. Espinoza J, Espinoza AF. Pre-eclampsia: a maternal manifesta-tion of a fetal adaptive response? Ultrasound Obstet Gynecol2011; 38: 367–370.

93. Espinoza J, Espinoza AF, Power GG. High fetal plasmaadenosine concentration: a role for the fetus in preeclampsia?Am J Obstet Gynecol 2011; 205: 485.e24–27.

94. Slegel P, Kitagawa H, Maguire MH. Determination of adeno-sine in fetal perfusates of human placental cotyledons usingfluorescence derivatization and reversed-phase high-perfor-mance liquid chromatography. Anal Biochem 1988; 171:124–134.

95. George EM, Cockrell K, Adair TH, Granger JP. Regulationof sFlt-1 and VEGF secretion by adenosine under hypoxicconditions in rat placental villous explants. Am J PhysiolRegul Integr Comp Physiol 2010; 299: R1629–R1633.

96. Jank A, Kratzsch J, Stepan H. Effect of terminated fetalcirculation on maternal angiogenic factors in severe earlypreeclampsia. Hypertens Pregnancy 2012; 31: 201–206.

97. Koga K, Osuga Y, Tajima T, Hirota Y, Igarashi T, Fujii T,Yano T, Taketani Y. Elevated serum soluble fms-like tyrosinekinase 1 (sFlt1) level in women with hydatidiform mole. FertilSteril 2010; 94: 305–308.

98. Ostlund I, Haglund B, Hanson U. Gestational diabetes andpreeclampsia. Eur J Obstet Gynecol Reprod Biol 2004; 113:12–16.

99. Yogev Y, Xenakis EM, Langer O. The association betweenpreeclampsia and the severity of gestational diabetes: theimpact of glycemic control. Am J Obstet Gynecol 2004; 191:1655–1660.

100. Pathak S, Lees CC, Hackett G, Jessop F, Sebire NJ. Frequencyand clinical significance of placental histological lesions in anunselected population at or near term. Virchows Arch 2011;459: 565–572.

101. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet2005; 365: 785–799.

102. Belfort MA, Anthony J, Saade GR. Prevention of eclampsia.Semin Perinatol 1999; 23: 65–78.

103. Howick J, Glasziou P, Aronson JK. The evolution of evidencehierarchies: what can Bradford Hill’s ‘guidelines for causation’contribute? J R Soc Med 2009; 102: 186–194.

104. Phillips CV, Goodman KJ. Causal criteria and counterfactuals;nothing more (or less) than scientific common sense. EmergThemes Epidemiol 2006; 3: 5.

105. Espinoza J. The need to redefine preeclampsia. Expert OpinMed Diagn 2012; 6: 347–357.


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Uteroplacental ischemia in early- and late-onset pre-eclampsia: a role for the fetus?