OBSTETRICS

The role of shed plac sinflammatory syndroJames D. R. Hartley, BA; Brian J. Ferguso

P reeclampsia is a syndrome occur-ring only in human pregnancycharacterized clinically by persistent

into the maternal circulation.10

Circumstantial evidence forplacental DNA as the linkingfactorThree pieces of circumstantial evidencesuggest placental DNA could be oneof the inammatory triggers inpreeclampsia:

(1) DNA itself is an immunostimula-tory molecule when present outside

endosomes,13 and various sensors ofdouble-stranded DNA in the cytoplasm(Figure 2).TLR9 is preferentially expressed in

plasmacytoid dendritic cells, trafcs toendosomes and becomes maturefollowing cleavage of its exodomain.Though much DNA binds TLR9 withlittle specicity, only unmethylated CpGDNA is able to cause a conformationalchange in TLR9 homodimers resultingin the close apposition of the TIR

lytthsiatee

pr

Review ajog.orgthe nucleus or mitochondria.(2) In preeclamptic pregnancies the

quantity of free DNA shed into thematernal circulation by the placentais greatly increased.

(3) Placental DNA derived from syn-cytiotrophoblast may be in a moreimmunostimulatory state than

signaling domains and downstreamactivation of interferon regulatory fac-tors (IRFs) and expression of inam-matory cytokines.14 Although initiallydiscovered because of its ability to detectbacterial DNA, subsequent studiesfound TLR9 also detects self-DNAwhenpresent in endosomes in sufcient

ReceivedDec. 23, 2014; revisedMarch 2, 2015;accepted March 12, 2015.

The authors report no conict of interest.

Corresponding author: Ashley Moffett, MD.am485@cam.ac.uk

0002-9378/$36.00 2015 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2015.03.026From the Department of Pathology, University ofCambridge, Cambridge, United Kingdom.maternal hypertension (systolic bloodpressure >140 mm Hg or diastolic >90mm Hg) accompanied by 1 of a rangeof other symptoms and/or signs in-cluding severe proteinuria, decreasedplatelets, or decreased kidney or liverfunction.1 Preeclampsia causes consid-erable mortality and morbidity world-wide, affecting 2-8% of pregnancies2 andcontributes, along with other hyper-tensive disorders of pregnancy (theseinclude hypertension but no proteinuriaand women with preceding chronic hy-pertension), to at least a quarter of ma-ternal deaths.3 In addition, preeclampsiais associated with considerable fetal andneonatal mortality due to preterm birthand fetal growth restriction.4,5

Despite the importance of this dis-ease, the pathogenesis of preeclampsiais still somewhat mysterious.6,7 Animportant model postulates that pre-eclampsia should be considered as a 2-stage disorder.8 The rst stage isreduced placental perfusion and thesecond stage the maternal systemicinammatory syndrome, where endo-thelial cell decompensation is particu-larly important in triggering maternalhypertension.9 An extension of thismodel now includes a stage 0etheinitial problem with placentation, theroot of the majority of cases ofpreeclampsiaeand a second stage 2,describing the effects on the fetus(Figure 1). Although it may requiresome adaptation, this model is sup-ported by many of the key observationsin preeclampsia research, summarizedin Table 1. One of the challenges inunderstanding preeclampsia is explainingthe link between a local effect generatedat the level of the stressed placenta andthe systemic maternal syndrome. Thevarious hypotheses proposed are sum-marized in Table 2. The focus of thisreview is on DNA shed from the placentaental DNA in the syme of preeclampsian, PhD; Ashley Moffett, MD

Preeclampsia is a syndrome occurring onmaternal inflammation and associated withaspects of the disease are linked has beenRecently, there has been increasing interematernal circulation as a potential agent initwill discuss the current evidence and futurfactor in preeclampsia in the context of oth

Key words: inflammation, placental DNA,from somatic cells.

MONTH 2015temic

Immune sensors for free DNAThe immunostimulatory properties offree DNA have been known for >50years.11 Although DNA in the nucleus ofcells is generally considered to be safefrom detection, cytoplasmic or extracel-lularDNAcan act as a pathogen or dangerassociated molecular pattern (PAMP orDAMP). PAMPs activate pattern recog-nition receptors (PRRs) of the innateimmune system and initiate immune re-sponses.12 There are many PRRs in-cluding Toll-like receptor 9 (TLR9),which senses unmethylated Cytosine-phosphate-Guanine (CpG) islands in

in pregnancy characterized by systemiche presence of the placenta. How these 2e subject of numerous theories and ideas.t in DNA shed from the placenta into theing the inflammatory response. This reviewdirections for placental DNA as the linkingr hypotheses.

eeclampsiaquantity.15 This raises the possibility of

American Journal of Obstetrics& Gynecology 1

FIGURE 1Preeclampsia model

Adaptation of Redmans 2 stages for preeclampsia, and factors that have been suggested to contribute to each stage.6,9,71,92-101

KIR, killer-cell immunoglobulin-like receptor.

Hartley. Shed placental DNA and preeclampsia. Am J Obstet Gynecol 2015.

Review Obstetrics ajog.org

2 American Journal of Obstetrics& Gynecology MONTH 2015

pesviruses,17 it has also been linked tomany autoimmune and autoinammatoryconditions, including systemic lupus ery-thematosus (SLE), Aicardi-Goutiere syn-drome, and chronic heart failure.18,19 Inthese conditions, sterile inammation oftenassociated with genetic variations in DNAdisposal enzymes such as the lysosomaldeoxyribonuclease II and cytoplasmicTREX1 can drive pathology. Indeed, loss ofTREX1 inmice is sufcient to cause inuterodeath fromDNA-driven inammation thatdepends on the cytoplasmic detection ofDNA as shown by rescue upon STINGknockout.20 Thus, there are precedents forthe involvement of fetal DNA as the factordriving inammation in preeclampsia.

Shedding of placental DNA inpregnancyFetal DNAwas rst detected in maternalplasma in 1997.21 This DNA originates

nancy, respectively.24 This accounts foraround 3.5% and 6.2% of the DNApresent in maternal plasma in the 2stages of pregnancy.Importantly, in preeclampsia, fetal

DNA reaches concentrations up to 5-fold higher than this and can be detec-ted in early pregnancy before the onset ofpreeclampsia.25-28 There is also a gradedresponse between the quantity of fetalDNA and the risk of developing pre-eclampsia,29 with levels highest inwomen with HELLP (hemolysis,elevated liver enzymes, and low plateletcount) syndrome (Figure 3).30

The increase in shed DNA in pre-eclampsia reects the increased cell deathdue to hypoxia. Levels of DNA releasedinto supernatants from placental ex-plants are increased when exposed toreduced oxygenation.31 Thus, themagnitude of the placental stress (stage 1

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ajog.org Obstetrics ReviewTLR9 stimulation by placental DNA,particularly because of the unique char-acteristics of DNA derived fromtrophoblast cells (see below).The cytoplasmic DNA sensors belong

to a broad range of protein families.Earlier discoveries focused on thePYHIN family, a group of proteins thatcontain DNA-binding HIN domains aswell as signaling PYR domains.12 ThePRR absent inmelanoma protein (AIM)2 that belongs to this class is thefounding member of a group of AIM2-like receptors, including the PRR IFI16.AIM2 signals by assembling ASC andcaspase-1 containing inammasomes,thus resulting in the production of theinammatory cytokine interleukin(IL)-1b whereas IFI16 activates IRFsand nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)via stimulator of interferon genes(STING) (see below) inducing theproduction of a broad range of inam-matory mediators. Another group ofDNA sensors are the DExD/H-box hel-icases, including RIG-I and DDX41.Counterintuitively, RIG-I actuallydirectly detects RNA, but can alsoindirectly detect DNA through theconverting action of cytoplasmicRNA polymerase III. Further STING-activating DNA sensors such as DNA-dependant protein kinase, cyclicGMP-AMP synthetase, and meioticrecombination 1 also exist in the cyto-plasm. A common question is how thedetection of DNA by these factors sig-nals to produce transcriptional changeswithin a cell. One protein of importanceis STING, which forms a commonadaptor in many of these signaling path-ways.16 STING is an endoplasmicreticulum-bound protein with a cyto-plasmic C-terminal domain that uponactivation by upstream elements forms ascaffold for assembly of the kinase TANK-binding kinase 1 and transcription factorIRF3, allowing phosphorylation ofTANK-binding kinase 1 and IRF3 activa-tion. This process occurs simultaneouslywith the relocation of STING from theendoplasmic reticulum to mysteriouspunctate foci closer to the cell membrane.How exactly STING becomes active re-

mains an area of intensive research, butbecause STING is responsive to thesignaling molecule cyclic guanosinemonophosphate-adenosine mono-phosphate, formed by the DNA-sensingenzyme cyclic GMP-AMP synthetase,other DNA-sensing proteins may affectSTING through alterations in the level ofthis second messenger.12

Although DNA sensing has beenshown to be essential in our defenseagainst certain pathogens such as her-

TABLE 1Two-stage model of preeclampsiaAspect of model Supporting

Placenta is key initiator Fetus andepreeclamhydatidiforpregnancy

Delivery oftreatment

Role of placental hypoperfusion Indirect meblood flow

Doppler ult

Systemic inflammatory nature ofmaternal syndrome

Multiple maggregatioactivation

Effects on fetus Multiple msurvival

Hartley. Shed placental DNA and preeclampsia. Am J Obfrom the placenta, and placental-specic

MONTH 2015messenger RNAmolecules are also easilydetected in maternal plasma.22 Thesource of the placental DNA is mainlyfrom the syncytiotrophoblast coveringthe villous tree that is in contact with thematernal blood in the intervillousspace.23 Fetal DNA inmaternal plasma isdetectable from the seventh week ofgestation onwards and can reach highconcentrations: 25.4 and 292.2 genomeequivalents/mL in early and late preg-

vidence Reference

rus are unnecessarysia can occur inmole and abdominal

67,68

e placenta is the only effective 6

urements of uteroplacental 69

sound studies 70

sures including plateletcytokine levels, endothelial

7,9

sures including birthweight, 71

t Gynecol 2015.of preeclampsia) can be correlated with

American Journal of Obstetrics& Gynecology 3

em

In a

Review Obstetrics ajog.orgTABLE 2Suggestions for linking factor in prHypothesis for linking factor Su

Direct products of placenta

Cytokinesthe levels of DNA (the putative linkingfactor) and hence to initiation of thesystemic inammatory syndrome (stage2). Moreover, although fetal DNA inwomen with preeclampsia is increasedcompared to controls as early as 17weeksof gestation, there is a sharp rise 3 weeksbefore the appearance of signs of pre-eclampsia,32 also suggesting a role for

In

C

H

s-Flt and other angiogenesis-regulatingfactors

s

It

In

S

Leptin L

L

H

Direct effects of hypoxia

Effects of oxidative stresson cells passing throughplacenta and release ofmetabolites such asuric acid

A

M

In

In

Release of placental debris

Syncytiotrophoblast microparticles M

T

S

Placental DNA R

R

C

F

CpG, cytosine-phosphate-guanine; s-Flt, soluble fms-like tyrosin

Hartley. Shed placental DNA and preeclampsia. Am J Obst

4 American Journal of Obstetrics& Gynecology Meclampsiamary of evidence

creased concentrations of tumor necrosis factor-preeclampsia;DNA in the precipitation of the systemicsyndrome (Figure 4). However, 1 studyfound that increases in plasma C-reativeprotein levels did not mirror the in-creases in fetal DNA, arguing against adirect link between DNA levels and sys-temic inammation.32 Nonetheless,these studies do provide circumstantialevidence that increased circulating fetal

flammatory cytokines rise early in pregnancy with

ytokine production can be induced from placental e

owever, 1 study found no increase in cytokine proteof women with compared to without preeclampsi

-Flt is produced by placenta;

s levels are raised 3-fold in women with preeclamp

jection of s-Flt into pregnant rats induces preeclam

imilar results have been obtained with another placesoluble endoglin.

eptin is abundantly produced by placenta;

eptin production by placenta is up-regulated by hypaugmented in women with preeclampsia;

owever, maternal leptin levels are not increased inrestriction.

bundant markers of increased oxidative stress in w

arkers of oxidative stress and DNA damage in pree

creased expression of activation markers in cells isowith preeclampsia but not in controls;

creased expression of xanthine oxidase in preeclam

icroparticles shed from placenta are increased in p

hese microparticles have activating effects on humcells in vitro;

hedding occurs in greater amounts in early-onset cpreeclampsia.

ise in placental DNA seen in pregnancy is exacerbatcorrelates with time of onset and severity;

ise in fetal DNA also correlates with intrauterine groabnormal uterine artery Doppler;

pG DNA can induce preterm birth or fetal resorptionpregnant mice

etal DNA can induce inflammation in vitro and inflamto greater extent than adult.

e kinase.

et Gynecol 2015.

ONTH 2015References

in blood of women with 72-75(trophoblast) DNA may play a role indriving the systemic symptoms and signsof preeclampsia.

Characteristics of shedplacental DNAAs well as being shed in large quantitiesfrom preeclamptic placentas, one char-acteristic of fetaleand particularly

hydatidiform mole;

xplants by hypoxia in vitro;

in or messenger RNA in placentasa.

sia compared to controls;

psia-like syndrome.

ntally derived angiogenesis factor,

76-79

oxia and leptin levels are

cases of intrauterine growth

80-83

omen with preeclampsia;

clamptic placenta itself;

lated from uterine veins in women

ptic placenta.

80,84-86

reeclampsia;

an peripheral blood mononuclear

ompared to late-onset

87-89

ed in preeclampsia to degree that

wth restriction and variably with

in interleukin-10-deficient

mation or fetal resorption in mice

41,90,91

eajog.org Obstetrics ReviewFIGURE 2Detection of intracellular and extractrophoblasteDNA is that it is hypo-methylated,33,34 related to epigeneticstates important for early development.35

This distinct methylation pattern is pre-sent throughout gestation, though it maybe inuenced by fetal sex.36 Hypo-methylation at CpG motifs could maketrophoblast DNA a ligand for TLR9,13,37

increasing its immunostimulatory abilityin preeclampsia. Furthermore, tropho-blast DNA is hypomethylated to a greaterextent in the preeclamptic placentacompared to controls, and to a greaterextent in early- compared to late-onsetdisease.38,39 Indeed, methylome prolingof placental DNA in maternal blood has

DNA-sensing systems.12 From left to right: (1) pos

dead cells, or as result of invasion by vesicle-dwell

DNA species from nucleus. In addition, certain bac

acts as TLR9 ligand, and double-stranded DNA can

rich DNA such as that of Plasmodium parasites, an

molecules. Color-coded such that purple molecules

to act through inflammasomes, and green to potent

bottom: inflammasome-forming sensors act to pro

cytoplasmic sensors are thought to act through ST

Casp, caspase; CpG, Cytosine-phosphate-Guanine; DAMP, danger asprimary response gene 88; NF-kB, nuclear factor kappa-light-chain-eTANK-binding kinase 1; TLR9, Toll-like receptor 9.

Hartley. Shed placental DNA and preeclampsia. Am J Obstet Gllular DNA by the immune systembeen proposed as a way of assessing therisk of early- or late-onset preeclampsia.40

This is attributed to a secondary effectof hypoxia altering gene expression.Increased hypomethylation characteristicof trophoblast could also have a primaryrole in the pathogenesis of preeclampsiathrough increased activation of innateDNA sensors.

Direct evidence for placental DNAas the linking factorIn addition to the above circumstantialevidence, placental DNA can act as aninammatory agent with associatedpregnancy disruption in mice.41 Human

sible sources of intracellular DNA. DNA can enter ve

ing pathogens. DNA can enter cytoplasm as result o

teria actively secrete their DNA into cytoplasm (not

act as PAMP in cytoplasm. In addition, recent studie

d in some circumstances foreign DNA in nucleus ca

are proposed to monitor DNA in endosomes, red to a

ially detect DNA PAMPs in nucleus. (4) Signaling pat

cess prointerleukin-1b, TLR9 acts to activate NF-ING, which in complex with TBK1 links DNA detect

sociated molecular pattern; DAI, DNA-dependent activator of interferonnhancer of activated B cells; PAMP, pathogen associated molecular pa

ynecol 2015.

MONTH 2015fetal DNA triggers in vitro activation ofNF-kB (a transcription factor with amajor role in the inammatoryresponse) with resultant IL-6 productionin both a human B-cell line and pe-ripheral blood mononuclear cells fromboth pregnant and nonpregnant donors.Injection of human fetal (but not adult)DNA into pregnant BALB/c mice causesfetal resorption with increased levels oftumor necrosis factor-a and IL-6 andinltration by inammatory cells in theplacental bed. Fetal but not adult DNA isalso susceptible to cleavage by HPAII, anenzyme that cleaves DNA at unmethy-lated CpG islands. Deletion or inhibition

sicles as result of phagocytosis of pathogens or

f vesicle lysis, entry of viruses, or leak of certain

shown). (2) DNA PAMPs/DAMPs. CpG-rich DNA

s suggest single-stranded DNA in cytoplasm, AT-

n also act as PAMPs. (3) Proposed DNA-sensing

ctivate interferon response from cytoplasm, blue

hways and effects of host responses. From top to

kB and interferon regulatory factors, and manyion to transcriptional responses.

regulatory factor; DHX, DEAH box;MyD88, myeloid differentiationttern; STAT, signal transducer and activator of transcription; TBK1,

American Journal of Obstetrics& Gynecology 5

Review Obstetrics ajog.orgof TLR9 in pregnant mice blocked fetalloss and the accompanying inamma-tion. Thus, fetal DNA can initiateinammation through TLR9 activationand this affects pregnancy outcome in

FIGURE 3Cell-free fetal DNA in maternalblood in different conditions

Blood was drawn at time of diagnosis for cases

and at routine appointment between 30-36th

weeks of pregnancy in control group. As shown,

amount of placental DNA shed into maternal

blood is greatly increased in preeclampsia (PCL)

and similar syndromes.30

c-f, cell-free.

Hartley. Shed placental DNA and preeclampsia. Am J ObstetGynecol 2015.mice, supporting the hypothesis thatfetal DNA may contribute to inamma-tion in preeclampsia. This model is notwithout its problems however. Althoughinjection of control CpG DNA intopregnant mice induced systemic pro-duction of a range of inammatory cy-tokines (interferon-g, IL-12p70, tumornecrosis factor-a, IL-10), histologicalevidence of inammation was restrictedto the placenta and endometrium. Thisargues against placental DNA as a creatorof systemic inammation. The fetal DNAin this study was derived from umbilicalcord tissue (Dr Sinad Corr, PhD, writ-ten personal communication receivedMarch 19, 2014), and not from tropho-blast so is not representative of theplacental DNA liberated into maternalblood. Moreover, mice do not naturallyexperience preeclampsia, limiting theirusefulness as a representative model.

Future directionsCircumstantial evidence shows thatplacental DNA is in the right place at the

6 American Journal of Obstetrics& Gynecology Mright time and possesses the appropriateimmunostimulatory capacities to beconsidered a strong candidate for one ofthe linking factors in preeclampsia.However, as yet, sufcient direct evi-dence to implicate placental DNAbeyond reasonable doubt is still lacking.To do this, several questions need to beaddressed.

Does placental trophoblast DNA shedinto the maternal blood duringpreeclampsia have the capacity toinduce inammation in vivo?Human fetal DNA failed to induce sys-temic inammation in pregnant micebut only 1 dose of cord blood DNA wastested, and that may not be the appro-priate DNA to use.41 DNA shed by syn-cytiotrophoblast in its unique epigeneticstate and fragment size should be testedby using placental DNA extracted fromhuman maternal plasma, or from su-pernatants of placental explants culturedunder hypoxic conditions. To test thehypothesis more directly a range of dosesof trophoblast DNA infused into preg-nant mice to mimic the high levels offetal DNA seen in preeclamptic womencould be used. Importantly, the readoutsshould not only look for disruption ofpregnancy but also for markers ofendothelial activation. An in vitro com-parison of the immunostimulatoryability of fetal DNA from the blood ofhealthy vs preeclamptic women couldalso address the question of whe-ther the hypomethylation of placentaltrophoblast DNA in preeclampsia hasany impact on its inammatory capacity.

How does placental DNA acts as aninammatory agent?The hypomethylated state of trophoblastDNA indicates TLR9 activation is theprime inammatory trigger. TLR9 de-tects unmethylated CpG islands in DNAthat enters the endosomes of cells byprocesses such as endocytosis. Such DNAuptake occurs constitutively in somedendritic cells. Inhibitors of vesicle acid-ication such as antimalarials can blockthis, perhaps explaining their efcacy inthe treatment of diseases in which DNAsensing occurs such as SLE.42 Moreover,

such uptake is enhanced by certain

ONTH 2015endogenous proteins such as the cath-elicidin LL3743 and antinuclear anti-bodies, characteristic of SLE. Preeclampsiais 3-5 times more likely in patients withSLE possibly because of a higher baselineinammatory state (so-called maternalpreeclampsia). Increased uptake ofplacental DNA into TLR9-containingendosomes because of antinuclear anti-bodies could also contribute. Thus, TLR9seems the best candidate PRR to detectextracellular DNA. Plasmacytoid dendriticcells express TLR9 in human beings44 aswell as B cells and monocytes. Of notethough is that TLR9 is also constitutivelyexpressed and functional in the cells acti-vated in preeclampsia, human endothelialcells. TLR9 stimulated NF-kB activationand IL-8 production in response to ligandssuch as CpG-rich DNA in endothelialcells. Exposure of leukocytes and endo-thelial cells to placental DNA will deter-mine whether TLR9 activation contributesto systemic proinammatory responses. Asearch for TLR9 genetic variants that areassociatedwith preeclampsiamight also bea fruitful approach.41

TLR9 is only one ofmanyDNA sensorsand all the others reside not in endo-somes but in the cytoplasm. Underexperimental conditions activation ofthese receptors will therefore require atransfection agent. However, there arearticial situations such as DNA vacci-nationwhere extracellularDNAcan reachthe cytoplasm and even nuclei withoutsuch agents by unknown mechanisms.Furthermore, STING knockout mice areinsensitive to diseases driven by auto-inammation created by extracellularDNA, even though STING is essential tomany intracellular DNA-sensing path-ways.20 Although this process remainsunexplained, there is precedent for theidea that placental DNA could enter thecell cytoplasm, implicating intracellularDNA detectors in preeclampsia.

Are there other potential factorslinking placental stress with thesystemic syndrome of preeclampsia?As shown in Table 1, placental DNA isonly one of many placental products anddebris with the potential to stimulate asystemic inammatory state. Future

research could focus on interactions

FIGURE 4Fetal DNA in maternal blood changes over course of pregnancy anddevelopment of signs

Changes in levels of fetal DNA in maternal blood.32 A, Mean concentrations of fetal DNA in serum

women who went on to be diagnosed with preeclampsia (cases), women who had normal preg-

nancies (controls), and women after diagnosis with preeclampsia (endpoints) at various stages of

gestation, given in genome equivalents (GE)/mL. Bars indicate SEM. Asterisks indicate significant

differences with reference to controls matched for gestational age (GA). Longitudinal analysis of

samples reveals that cases have significantly greater fetal DNA concentrations before onset of

preeclampsia than controls. B, Fetal DNA in cases by weeks before preeclampsia in GE/mL. Bar

labeled PE represents mean concentration from number of samples taken from women on or after

onset of preeclampsia. Dotted line indicates start of second rise in fetal DNA occurring

cation,63 but in addition hypertensive

ling enough to stimulate further

Review Obstetrics ajog.orgresearch. Understanding the linkingfactor in preeclampsia could enhanceour ability both to predict and treat thedisease. Along these lines, it has alreadybeen demonstrated that the blocking ofTLR9 in mice with chloroquine is suf-cient to prevent fetal DNA mediatedinammation and pregnancy loss.41

Thus, the impact on our understandingand management of preeclampsia couldbe considerable. -

REFERENCES

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Whether the increased DNA released inpreeclampsia might have a divergent rolein raising early delivery risk as well ascausing the systemic effects of the diseaseare interesting questions.

SummaryThe correlation between increased levelsof hypomethylated circulating tropho-blast DNA in the maternal circulationand preeclampsia is based on robust andreproducible observations. There is alsodirect evidence that human fetal DNAinduces inammation in pregnant micewith an impact on pregnancy outcome.Placental DNA released into thematernal circulation could therefore playa key role in driving the systemic in-ammatory response of preeclampsia.Although this model needs furtherstudies, the current evidence is compel-induction of inammation via TLR9activation. Preeclampsia and other dis-orders of hypertension in pregnancy arealso associated with an increase in pre-term birth.62 This is due to iatrogenicdelivery with preeclampsia as an indi-Pregnancy Hypertens An Int J Womens Car-diovasc Heal 2014;4:105-45.

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Review Obstetrics ajog.org10 American Journal of Obstetrics& Gynecology MONTH 2015

The role of shed placental DNA in the systemic inflammatory syndrome of preeclampsiaOutline placeholderCircumstantial evidence for placental DNA as the linking factorImmune sensors for free DNAShedding of placental DNA in pregnancyCharacteristics of shed placental DNA

Direct evidence for placental DNA as the linking factorFuture directionsDoes placental trophoblast DNA shed into the maternal blood during preeclampsia have the capacity to induce inflammation in ...How does placental DNA acts as an inflammatory agent?Are there other potential factors linking placental stress with the systemic syndrome of preeclampsia?

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