Table Of ContentRisk Factors for Gestational Diseases
SilviaVannuccini,MichelaTorricelli,FilibertoMariaSeveri,and
Felice Petraglia
Contents Abstract
Pretermbirth(PTB)andpreeclampsia(PE)are
Introduction.......................................... 1
severe pathologies that may affect and com-
PretermBirth........................................ 2 promise the course of pregnancy, with a high
RiskFactorsofPretermBirth......................... 2
perinatalmorbidityandmortality.Theyrepre-
Preeclampsia......................................... 7 sentthemain“obstetricsyndromes,”causedby
RiskFactorsforPreeclampsia........................ 7
multipleconditionsandcharacterizedbycom-
References............................................ 10 plexpathogenesis.Theknowledgeofthepath-
ogenetic mechanisms leading to these
conditionsisveryimportantinordertorecog-
nize women at risk and to perform the strate-
gies for preventing their onset and reducing
associatedmorbidityandmortality.
Introduction
Preterm birth (PTB) and preeclampsia (PE) are
severe pathologies that may affect and compro-
misethecourseofpregnancy,withahighperina-
talmorbidityandmortality(Plunkettetal.2008).
They represent the main “obstetric syndromes,”
caused by multiple conditions and characterized
by complex pathogenesis. Nonetheless, recent
evidences attest that deregulation of the immune
system and exaggeration of inflammatory pro-
cesses,takingplaceinthefetoplacentalunit,rep-
resent common central mechanisms occurring in
bothdiseases(Torricellietal.2012).
S.Vannuccini(cid:129)M.Torricelli(cid:129)F.M.Severi(cid:129) The knowledge of the pathogenetic mecha-
F.Petraglia(*) nisms leading to these conditions is very impor-
ObstetricsandGynecology,DepartmentofMolecularand
tant in order to recognize women at risk and to
DevelopmentalMedicine,UniversityofSiena,Siena,Italy
perform the strategies for reducing perinatal
e-mail:[email protected]
#SpringerInternationalPublishingSwitzerland2016 1
G.Buonocoreetal.(eds.),Neonatology,
DOI10.1007/978-3-319-18159-2_151-1
2 S.Vannuccinietal.
morbidity and mortality. Interventions can be and rupture of the chorioamniotic membranes.
classified as primary (detected in all women The common pathway is activated physiologi-
beforeorduringpregnancytopreventandreduce cally in the case of labor at term, whereas in
risk),secondary(aimedateliminatingorreducing preterm labor several disease processes activate
riskinwomenwithknownriskfactors),ortertiary one or more of the components. In fact, PTB is
(initiatedafterdiseasehasdeveloped,withagoal considered a syndrome initiated by various con-
ofpreventingdeliveryorimprovingoutcomesfor ditions, such as inflammation/infection,
infants).Mostobstetricinterventionsareintended uteroplacental ischemia or hemorrhage, uterine
to reduce the burden of prematurity-related ill- overdistension,cervicaldisease,stress andendo-
ness, but the primary prevention is a desirable crinedisorders,andotherimmunologicallymedi-
goal(Iamsetal.2008). ated processes (Petraglia et al. 2012; Romero
etal.2014a).
Preterm Birth
RiskFactorsofPretermBirth
PTB,definedasbirthbefore37weeks’gestational
age, occurs with an incidence of 5–18 % (Beck Multiple risk factors increase a woman’s risk of
etal.2010),anditistheleadingcauseofneonatal PTB (Rubens et al. 2014; Institute of Medicine
death and the second cause of childhood death (US) Committee on Understanding Premature
below the age of 5 years (Liu et al. 2010). Neo- Birth and Assuring Healthy Outcomes
nates born preterm are at an increased risk of et al. 2007), and they may be identified before
short-termcomplicationsattributedtoimmaturity pregnancy, at conception, or during pregnancy
of multiple organ systems as well as neurodeve- (Iams 2014). These include maternal genetics
lopmentaldisorders,suchascerebralpalsy,intel- anddemography(e.g.,age,ethnicity,poorsocio-
lectual disabilities, and vision and hearing economic status), poor nutritional status, preg-
impairments (Mwaniki et al. 2012). Two-thirds nancy history, external factors (e.g., smoking,
of preterm births occur after the spontaneous alcoholingestion,drugsofabuse),characteristics
onsetoflabor,whereastheremainderismedically of the present pregnancy, and associated condi-
indicated because of maternal or fetal complica- tions(infection,uterinecontractions,andcervical
tions,suchaspreeclampsiaorintrauterinegrowth length shortening) (Table 1). However, the bio-
restriction (Goldenberg et al. 2012). The condi- logicalbasisformanyoftheseriskfactorsandthe
tionmerelydescribesaneventthatoccursbefore underlying mechanisms remain poorly under-
itsduetimeandisnotadiagnosisinitself.There stood. Although some of these risk factors are
are many pathways leading to preterm birth, and not modifiable, others represent potential targets
thepreventionofeachrequiresdifferent typesof for treatment and risk reduction (Goldenberg
scientific inquiry and clinical strategies etal.2005,2008).
(Newnham et al. 2014). Despite the high global
burdenofPTBonchildhoodmortality,morbidity, PreconceptionalFactors
and healthcare expenditure, few strategies are
available to effectively detect women at risk and
preventpretermdelivery(Rubensetal.2014). (cid:129) Genetics: Genetic factors are thought to be
The risk factors associated with spontaneous important causal components (Plunkett and
pretermbirths(sPTB)seemtovarybygestational Muglia 2008), as both maternal and fetal
age, social, and environment factors. However, genomes have been shown to influence the
morethan50 %themhavenocausalfactoriden- risk of sPTB (Haataja et al. 2011). Epidemio-
tified (Menon 2008; Lockwood 2002). Preterm logical analyses of large, population-based
andtermlaborsharedthesameclinicaleventsof cohortshaverevealedincreasedriskofPTBif
increaseduterinecontractility,cervicaldilatation, the mother herself was born preterm or has
RiskFactorsforGestationalDiseases 3
Table1 Riskfactorsforpretermbirth (cid:129) Ethnicity:Womenclassifiedasblack,African-
Preconceptional American,andAfro-Caribbeanarethreetimes
Genetics more likely to have a very early PTB than
Ethnicity women from other ethnic groups. The racial
Age disparity persists after adjustment for social,
Nutritionalstatus educational, economic, and medical risk fac-
Socioeconomicstatus tors(Healyetal.2006;Smithetal.2007a).
Obstetrichistory (cid:129) Age:Lowandhighmaternalageareassociated
Intervalbetweenpregnancies with PTB. Age (cid:1)40is associated withsignif-
Previouspretermbirth icantly higher rates of preterm birth (8 % vs
Maternaldisorders
16 %).Similarly,prematurityismorelikelyin
Systemicdiseases
adolescents(Augeretal.2013).
Hypertension (cid:129) Nutritionalstatus:Alowpregnancybodymass
Diabetes
index (BMI) is associated with high risk of
Asthma
spontaneous PTB. Women with low serum
Thyroiddiseases
concentrations of iron, folate, or zinc have
Localorsystemicinfections
more PTB than those with measurements
Reproductivedisorders
within the normal range (Bloomfield 2011).
PCOS
The risk of PTB is increased in obese and
Endometriosis/adenomyosis
Uterinefibroids overweight women as well (Cnattingius
Previouscervicalsurgery et al. 2013; Lynch et al. 2014; McDonald
Externalfactors etal.2010).
Stress (cid:129) Socioeconomic status: Low socioeconomic
Smoking status is an important risk factor for preterm
Drugsandsubstancesofabuse birth. Socioeconomic disadvantage is associ-
Pregnancy-associatedriskfactors ated with unhealthy or risky behaviors, expo-
ARTconception suretostress,andpsychologicalreactionsthat
Multiplepregnancy influence gestation negatively. Indeed, behav-
Intrauterineinfectionandbacterialvaginosis ioral risk factors, such as cigarette smoking,
Vaginalbleeding
alcohol and drug use, sexually transmitted
Shortcervixandcervicalinsufficiency
infections, poor food intake, and obesity, are
Biochemicalmarkers
all associated with preterm birth (Kramer
fFN,phIGFBP1
etal.2001).
Biophysicalmarkers
(cid:129) Obstetrichistory:
TVScervicallength
– Interval between pregnancies: An
interpregnancy interval of less than
6 months confers a greater than twofold
sisters that have had preterm children (Boyd increased risk of PTB (Smith et al. 2003).
et al. 2009). More formal genetic studies in Indeed,Caesareandeliveryinthefirstpreg-
offspringof twins and segregation analysis of nancy and short interpregnancy interval
traitsinfamiliesconsistentlydemonstratedthat <18 months are significant risk factors for
30–40 %ofthevariationinbirthtimingisdue term-pretermsequence(Wongetal.2015).
to genetic factors (Bezold et al. 2013). How- Furthermore, women whose first birth was
ever, recent evidence showed that a maternal preterm are far more likely to have a short
effect accounts for 15.2 % of the variance of interval than women who had a term first
gestational age at birth, while the remaining birth,thuscompoundingtherisk.
60.3 % is contributed by individual environ- – Previous PTB: The recurrence risk in
mentaleffects(Wuetal.2015). women with a previous PTB ranges from
4 S.Vannuccinietal.
15 % to 50 %, depending on the number including preterm birth (Conti et al. 2013,
and gestational age of previous deliveries 2015;Naveretal.2014;Palombaetal.2015;
(Kazemier et al. 2014). The number, Juang et al. 2007). Inflammatory, endocrine,
sequence, and weeks of gestation of previ- and metabolic aberrations associated with
ous births all affect the risk of recurrence, thesedisordersareimplicatedinthepathogen-
which ranges from less than 15 % among esis of obstetric complications (Vannuccini
women with one preterm birth after et al. 2016). Infertility and subfertility itself
32 weeks of gestation followed by a term are also risk factors for preterm birth
deliverytonearly60 %amongwomenwith (DoPieralaetal.2015;Sternetal.2015).
a history of two or more preterm births – Previous cervicalsurgery:Cervical surgeryis
(Goldenbergetal.2006).Basedontheclin- associated with spontaneous preterm birth;
icalpresentationofapriorspontaneouspre- however, it is unclear whether this increased
term birth, patients with a history of riskisduetothesurgeryitselfortothecervical
advanced cervical dilatation are at an intraepithelialneoplasiaunderlyingthesurgery
increased risk of having recurrent preterm (Bruinsma and Quinn 2011). Women who
birth and cervical shortening in a subse- attend colposcopy for precancerous changes
quent pregnancy compared with women in cervix are at a higher risk of a subsequent
with prior preterm birth associated pretermbirth(regardlessofwhetherornotthey
PPROM or preterm labor (Drassinower are treated) (Castanon et al. 2012, 2015). The
et al. 2015). Spontaneous preterm births riskisgreaterstillamongthosewhoreceivean
are also more common among women excisional treatment (biopsy sample or loop
with a history of giving birth between electrocautery excision), and it is particularly
16 and 20 weeks of gestation or with a high when the depth of the tissue excised is
historyofstillbirthbefore24weeksofges- (cid:1)15mm(Castanonetal.2014).
tation (McManemy et al. 2007; Edlow
etal.2007). ExternalFactors
MaternalDisorders – Stress: Mothers experiencing psychological
stress are at increased risk of PTB (Dole
etal.2003).Althoughthemechanismunderly-
– Systemic diseases: Thyroid diseases, asthma, ing the link between psychological or social
diabetes,andhypertensionareassociatedwith stressandincreasedriskofPTBisunknown,a
increased rates of PTB (Czeizel and Bánhidy role has been proposed for corticotrophin-
2011;Bramhametal.2014;AmericanCollege releasing hormone (Voltolini and Petraglia
of Obstetricians and Gynecologists 2015; 2014; Ruiz et al. 2015). Moreover, exposure
Gageetal.2015). totwoormoreadversechildhoodexperiences
– Local or systemic infections: Infections, such was associated with a twofold risk of preterm
as pyelonephritis and asymptomatic bacteri- birthinadulthood,demonstratingthatstressors
uria, pneumonia, and appendicitis, are associ- throughoutlifecanhaveasignificanteffecton
atedwithPTB(Wingetal.2014).Periodontal pregnancyoutcomes(Christiaensetal.2015).
diseaseappearstocauseaninflammatorycon- – Smoking: Tobacco use increases the risk of
dition, predisposing to increased risk of PTB PTB. Both nicotine and carbon monoxide are
(HortonandBoggess2012). powerful vasoconstrictors and are associated
– Reproductive disorders: Women with uterine with placental damage and decreased
fibroids, endometriosis, adenomyosis, and uteroplacental blood flow, leading to fetal
polycystic ovary syndrome (PCOS) have an growthrestrictionandPTB(ShahandBracken
increased risk of poor obstetric outcome, 2000;Koetal.2014;Ionetal.2015).
RiskFactorsforGestationalDiseases 5
– Drugsandsubstancesofabuse:Severalmater- in the fetal membranes leads to PPROM
nal drugs affect the developing fetus, and the (Kemp 2014). Recent studies have examined
babyafterbirthmaymanifestsignsattributable the role of the vaginal, gastrointestinal, and
to withdrawal. Maternal cocaine, opiate, and oral microbiome and possible associations
diazepam use are particularly relevant, as a withPTB.AdvancesinDNAsequencingtech-
history of excessive alcohol ingestion, espe- nologyhavedramaticallyimprovedourunder-
ciallybingedrinking(Bonelloetal.2014). standing of the maternal microbiome and its
impact on pregnancy and PTB, far beyond
Pregnancy-AssociatedRiskFactors what traditional culture-based technology has
done to date (Fox and Eichelberger 2015).
Metagenomicstudieshavebeguntocharacter-
– Assisted reproductive technologies (ART): izethehealthyvaginalandgutmicrobiomesin
Pregnancies from assisted conception are at the nongravid and gravid state, as well as the
increased risk of both spontaneous and indi- richdiverseplacentalmicrobiome.Ithasbeen
cated preterm births than those with natural proposed that the increased stability of the
conception. In vitro techniques, ovarian stim- vaginal microbiome during pregnancy may
ulation,culturemedia,andpossiblyadditional play a protective role in the prevention of
freezing or vitrification procedures, together ascending vaginal infection by means of the
with infertility itself, seem to play a role in dominance of lactobacilli (Romero
thepathogenesisofadverseobstetricoutcome et al. 2014b). Disturbances in lactobacilli in
in ART pregnancies (Pinborg et al. 2013; thevaginalmicrobiomeoftenleadtodysbiosis
Messerlianetal.2013;Dunietzetal.2015). and bacterial vaginosis (BV), a known risk
– Multiple pregnancy: Multiple gestations carry factorforpretermdelivery.Commonbacterial
ariskofPTBandresultin15–20 %ofallPTB. speciesidentifiedinPTB-associatedinfections
Uterine overdistension, resulting in contrac- includeUreaplasmaurealyticum,Mycoplasma
tions and PPROM, isbelievedto be thecaus- hominis, Bacteroides spp., Gardnerella
ative mechanism for the rate of increased vaginalis, and Fusobacterium nucleatum.
spontaneousPTB(Voltolinietal.2013). These organisms typically display low viru-
– Bacterial vaginosis (BV) and intrauterine lence unless they reach the intrauterine envi-
infection:Inflammation,whetherornotrelated ronment(MysorekarandCao2014;Petricevic
to infection, is one of the best-studied path- etal.2014).
ways in humans and animal models of PTB. – Vaginal bleeding: Uterine contractions and
Infection commonly ascends from the vagina PTB can be instigated by bleeding between
and cervix into the choriodecidual space, the chorion and decidua at the placental bed,
affecting the myometrium, fetal membranes, causing overt or subclinical separation of the
and amniotic fluid.Ascending bacterial infec- placentafromtheimplantationsiteattheuter-
tionisimplicatedinabout40–50 %ofpreterm ine wall, clinically known as abruption (Nor-
births. Infection may infrequently enter the man et al. 2010). The plasma protease
uterus by the hematogenous route, through thrombin plays a central role in the signaling
retrograde seeding via the fallopian tube cascade that is initiated by blood in the
(Witkin 2015). Intrauterine infection is an subchorionic space. Vaginal bleeding caused
importantmechanismleadingtoPTBthrough by placental abruption is associated with a
the activation of the innate immune system. very high risk of PTB. Similarly, placental
Microbial endotoxins and proinflammatory implantation abnormalities such as placenta
cytokines stimulate the production of prosta- previa, placenta accreta, and vasa previa are
glandinsandmatrix-degradingenzymes.Pros- associatedwithincreasedriskofpretermbirth
taglandins stimulate uterine contractility, (Vahanian et al. 2015). However, bleeding in
whereasdegradationoftheextracellularmatrix the first and second trimesters, that is not
6 S.Vannuccinietal.
associated with either placental abruption or simultaneous screening of thousands of genes
placental abnormalities, is also associated and gene products from small samples of tissue
withsubsequentPTB(Krupaetal.2006). orbodyfluidhasbecomepossible.Hormonesand
– Shortcervixandcervicalinsufficiency:Atthe inflammatoryandangiogenicmediatorsareimpli-
beginningofpregnancy,theetiologyofashort cated in PTB pathogenesis. However, it has
cervix differs from what occurs in the middle becoming evident that single biomarker
andattheendofpregnancy.Acervixthatstarts approaches for the early detection of preterm
todiminishatthebeginningofpregnancymay birth may never achieve the desired diagnostic
be a sign of previous damage to the cervix, efficiency (Klein et al. 2014; De Bonis
suchasthroughsurgery(conizationorexcision etal.2012).
using a LEEP loop) or due to uterine There are two commonly used clinical bio-
malformations (Vaisbuch et al. 2010; Poon marker tests for the prediction of preterm labor,
et al. 2012; Miller et al. 2015). In the second namely, fetal fibronectin (fFN) and phosphory-
trimesterofpregnancy,isthmocervicalincom- latedinsulin-likegrowthfactorbindingprotein-1
petenceisthemostimportantcauseofcervical (phIGFBP1). The most useful biochemical PTB
shortening,therebycausinglateabortionsand predictor is fetal fibronectin, a glycoprotein that
spontaneous preterm delivery. This may be whenpresentincervicovaginalfluidisamarkerof
congenital (primary) or be acquired (second- choriodecidual disruption (Goldenberg
ary) through trauma to the isthmocervical etal.1996).Althoughfetalfibronectinisnormally
region, such as untimely cervical dilatation, absent from cervicovaginal secretions from
application of a high forceps, or amputation. 24weeksuntilterm,3–4 %ofwomenundergoing
However,distinguishingcervicalinsufficiency routinescreeningat24–26weeksarepositiveand
from cervical shortening attributable to other atincreasedriskofPTB.Owingtoitshighnega-
causeshasprovendifficult,andtheexactcon- tive predictive value, a negative fFN result has
tribution to preterm birth is unknown. Short beenshowntoreduceunnecessaryinterventions,
cervical length (i.e., values below the tenth change patient management, and reduce
percentile for gestational age), as measured healthcare costs, by allowing early reassurance
with the use of transvaginal ultrasonography and return to normal care pathways, while care
at 18–24 weeks of gestation, is a consistent can be concentrated on those at risk. Indeed, the
predictorofanincreasedriskofpretermdeliv- fFN test appears to be more informative in
ery, regardless of other factors. The risk predicting spontaneous preterm birth within the
increases as cervical length decreases in the 7–14 days in women presenting with threatened
second trimester; the risk associated with a preterm labor, due to its generally poor positive
cervical length below the tenth percentile predictivevalue(FosterandShennan2014).
(25 mm) is 25–30 %, and the risk associated phIGFBP1 is secreted by decidual cells and
with a cervical length at or below the third leaks into cervical secretions when fetal mem-
percentile(15mm)is50 %(Hughesetal.2015). branes detach from decidua. It has been used to
clinically assess cervical maturation. Clinical
BiochemicalMarkers diagnostic trials indicate that, like fFN,
Biological fluids (amniotic fluid, urine, cervical phIGFBP1isagoodnegativepredictorofpreterm
mucus, vaginal secretions, serum or plasma, and birth (92 % specificity) but lacks suitable sensi-
saliva)havebeenusedtoassessthevalueofbio- tivityandpositivepredictivevalueinasymptom-
markers for the prediction of PTB. These body aticwomen(Conde-AgudeloandRomero2015).
fluidsproviderichsourcesofproteinsandmetab-
olites that vary in concentration in response to BiophysicalMarkers
pregnancy and adverse pregnancy states. With Ultrasound measurement of uterine cervical
thedevelopmentofgenomicandproteomictech- length can be useful in evaluating the likelihood
nologies over the past two decades, the of early labor in those women known to be at
RiskFactorsforGestationalDiseases 7
increased risk for prematurity (Hughes diseases.AnalternativeviewisthatPEisaspec-
etal.2015).Astatisticallysignificantinverserela- trumdisorder,thedegreeofwhichisreflectedin
tionship between cervical length seen on gestational ageat thetime of delivery (Poon and
transvaginal ultrasonography in the second tri- Nicolaides2014).
mester and the risk of preterm delivery has been The exact cause of preeclampsia is currently
demonstratedinbothlow-riskasymptomaticsin- unknown, but there is a consensus that the pla-
gle pregnancies and high-risk patients, including centaplays acardinalroleinthepathogenesisof
thosewithpreviouspretermdelivery.Theriskof preeclampsia because delivery of the placenta
pretermdeliveryvariesasafunctionofthegesta- resolves the clinical symptoms. Changes in the
tional age at the time of diagnosing the cervical oxygenation levels of the placenta due to failure
shortening.Almosttwo-thirdsofthewomendiag- of spiral artery transformation are thought to be
nosedwithashortcervixbeforethe20thweekof responsible for the underlying pathology of pre-
pregnancywilldeliveratthethresholdofviability eclampsia. This syndrome is thought to occur in
(<24weeksofgestation),andlessthanonequar- twostageswithabnormalplacentationleadingto
ter of them will still be pregnant when the 28th amaternalinflammatoryresponse.Inpreeclamp-
week of gestation is completed. Between 22 and sia, cytotrophoblast invasion of the interstitial
30weeks,thetenthpercentileforcervicallength uterine compartment is frequently shallow, and
is25mm,andalengthlessthanthismeasurement inmanylocationsspiralarteryinvasionisincom-
is significantly associated with preterm birth. plete. There are many fewer endovascular
Women with a history of preterm birth and a cytotrophoblasts,andsomevesselsretainportions
cervical length less than 25 mm are 3.3–4.5 of their endothelial lining with relatively intact
times more likely to experience preterm birth muscularcoats,showingdeficitsinthedifferenti-
than the general population (Iams et al. 1996; ation program that enables cytotrophoblast inva-
Hibbardetal.2000). sionoftheuterinewall(Fisher2015).
Recent discoveries of an imbalance in
antiangiogenic factors and loss of cytoprotective
Preeclampsia mechanisms in preeclamptic placentas have pro-
vided new insights into the pathophysiology of
PE is defined as persistent blood pressure eleva- PE. Systemic maternal vascular dysfunction
tion, edema, and proteinuria first diagnosed after seems to be a major phenotype of pregnancies
20weeksofgestation.Theminimalcriteriaforthe with preeclampsia, contributing to increased
diagnosisofPEareproteinuria,definedas300mg peripheralvascularresistance,maternalhyperten-
ormoreofurinaryproteinexcretionper24h,and sion, and proteinuria. The mechanisms of sys-
hypertension, defined as blood pressure of temic vascular dysfunction in preeclamptic
140/90 mmHg or higher (Sibai et al. 2005). PE pregnancies involve an imbalance in the produc-
affects5–7 %ofall pregnancies and isresponsi- tion of constrictors and dilators in vascular cells,
ble for 7–15 % of maternal mortality. Severe hyperresponsiveness to constrictor stimuli,
and/or early-onset PE is an important cause of reduced endothelium-dependent dilation, and
fetal and maternal morbidity and mortality. Neo- oxidative stress (Goulopoulou and Davidge
natal outcomes are directly related to iatrogenic 2015).
prematurity,althoughuteroplacentalinsufficiency
mayalsobeassociatedwiththedisease.Theonly
known cure is cessation of pregnancy, although RiskFactorsforPreeclampsia
temporizingmeasuresareoftenundertaken(Sibai
2005;Steegersetal.2010).Ingeneral,themater- Early identification of women at risk for pre-
nal risk factor profiles vary between early-onset eclampsia (before 13 weeks) is a core tenet of
PE(<32weeks)andlate-onsetPE.Thishasledto management. Several studies identified risk fac-
the view that early and late PE may be different tors for early detection of high risk women
8 S.Vannuccinietal.
Table2 Riskfactorsforpreeclampsia low birth weight (Duckitt and Harrington
Preconceptional 2005).
Age – Time between pregnancies: The association
Nulliparity between risk of preeclampsia and interval is
Previouspreeclampsia more significant than the association between
Familyhistory riskandchangeofpartner.Theriskinasecond
Maternaldisorders or third pregnancy was directly related to the
Chronichypertensionandrenaldiseases timeelapsedsincethepreviousdelivery.When
Obesity the interval was 10 years or more, the risk of
Insulinresistanceanddiabetes preeclampsia was about the same as that in
PCOS
nulliparouswomen(Skjaervenetal.2002).
Thrombophilicdisorders
Externalfactors
MaternalDisorders
Stress
Pregnancy-associatedriskfactors
Oocytedonation
– Chronic hypertension and renal disease: The
Multiplepregnancy
risk of developing superimposed PEispartic-
Congenitalandchromosomalanomalies
ularly increased in women with severe hyper-
Biophysicalmarkers
tension and in those with cardiovascular or
UterinearteryDopplerstudy
Biochemicalmarkers renal disease. The incidence of superimposed
hCG,activinA,inhibinA,PIGF,VEGF,sFlt-1,PAPP-A PE increases in patients with chronic renal
disease,especiallyifthereiscoexistinghyper-
tension(Bramhametal.2014).
(Table 2) (Dekker and Sibai 2001; Duckitt – Obesity,insulinresistance, PCOS, anddiabe-
andHarrington2005). tes: Obesity, insulin resistance, and glucose
intolerance are strongly associated with
PreconceptionalFactors nonpregnant hypertension and PCOS. Essen-
tial hypertension is an insulin-resistant state
itself. Obesity is probably the most common
– Age: The risk of preeclampsia increases by causeofinsulinresistanceandrepresentsarisk
30 %foreveryadditionalyearofagepast34. factor for developing pregnancy-induced
Womenaged(cid:1)40hadapproximatelytwicethe hypertension as well as PE (Bhattacharya
risk of developing preeclampsia (Lamminpää et al. 2007; Spradley et al. 2015). In women
etal.2012). with PCOS, the prevalence of gestational
– Nulliparity: Nulliparous women have almost hypertensionandpreeclampsiaisestimatedat
three times the risk for preeclampsia, asconse- 10–30 %and8–15 %,respectively.Thispreva-
quenceofanabnormalresponsetopaternalanti- lencemaybeevenhigherwhenPCOSwomen
gensinfetoplacentalunit(Bdolahetal.2014). are obese and hyperinsulinemic (Petraglia
– A family history of preeclampsia: Severe PE etal.2015).Thereisacertaindegreeofinsulin
and eclampsia have a familial occurrence. A resistanceandhyperinsulinemiainpreeclamptic
familyhistoryofPEisassociatedwithathree- womenduringpregnancy.Theinsulinresistance
fold increased risk of PE and a fourfold appearstobebasedonahighermeanbodymass
increasedriskofseverePE(Northetal.2011). indexinwomenwithPE.Overttype1diabetes
– Previous preeclampsia: Mothers who had PE mellitus is associated with an increased inci-
intheirfirstpregnancyareathigherriskforthe denceofPE(Colatrellaetal.2010).
developmentofPEinasubsequentpregnancy, – Thrombophilicdisorders:Patientswithsevere
especially when PE is severe, occurs early early-onsetPEoftenhavehemostaticormeta-
during the pregnancy, or is associated with a bolicabnormalities,whichareassociatedwith
RiskFactorsforGestationalDiseases 9
atendencytovascularthrombosis.Thereisan associatedwithnoncriticalheartdefectsinoff-
increased incidence of activated protein C spring, while PE before 34 weeks was associ-
(aPC) resistance or factor V Leiden mutation ated with critical heart defects (Auger
inwomenwithahistoryofPEand/oradverse etal.2015).
perinataloutcome.Thus,womenwithfamilial
thrombophiliaareatincreasedrisknotonlyof BiophysicalMarkers
PE but also of fetal loss. Protein S deficiency Reduceduteroplacental blood flow andplacental
and aPC resistance both result in an impaired ischemia leads to the release of placental factors
aPC pathway. This impairment appears to be with detrimental effectsonthe maternal vascular
associatedwithamoreaggressivecourseofthe endothelium, leading to a rise in blood pressure
pathologic changes (thrombosis, acute and changes in the uterine artery flow velocities.
atherosis) in the spiral arteries. Classic Intheearlydays,themostimportantpredictorsof
homocystinuria is the homozygous form of PE were those related to the early recognition of
the autosomal recessively inherited raised blood pressure in the mother (Wright
cystathionine β-synthase deficiency. The inci- etal.2015);more recently,there hasbeendetec-
denceofhyperhomocysteinemia increases the tion of impaired uterine artery blood velocities
riskforpreeclampsia,mainlyforsevereearly- andparticularlytheirwaveformsbyuterineartery
onsetPE(Berksetal.2015). Doppler sonography (notch). Assessed during
midtrimester, such abnormal Doppler findings
ExternalFactors indicate a substantially increased risk for the
development of PE. Uterine artery Doppler
sonography more accurately predicted PE than
– Stress:Workingwomenhave2.3timestherisk intrauterinegrowthretardation,andthemostpow-
of developing PE compared with nonworking erful Doppler index for predicting PE was an
women (Klonoff-Cohen et al. 1996), even if increased pulsatility with notching in the second
more recent studies reported controversial trimester(Akolekaretal.2013).
results(Vollebregtetal.2008).
BiochemicalMarkers
Pregnancy-AssociatedRiskFactors Trophoblasticabnormalitiesplayacentralrolein
the development of PE and precede the appear-
ance of clinical signs and symptoms; some pla-
– Oocyte donation: The risk of preeclampsia is cental hormones change in the maternal
higher in oocyte donation pregnancies com- circulation, indicating altered placental function.
paredtoothermethodsofassistedreproductive Thelevelsofseveralplacentalhormonesareele-
technology or natural conception (Masoudian vated in maternal serum before the diagnosis of
etal.2016). PE,andthesemaybeconsideredpreclinicalman-
– Multiplepregnancy:Theincidenceandsever- ifestationsoftheearlierstagesofthedisease.Such
ity of PE, the incidence of eclampsia, and the hormones have therefore been proposed as early
incidence of early-onset PE are significantly predictivemarkersofPE(Andersonetal.2012).
increased in patients with twin pregnancies, Women with PE in the third trimester have
who have a fourfold increased risk of PE increased maternal serum human chorionic
(Foxetal.2014). gonadotropin(hCG)levels. MaternalhCG levels
– Congenital and chromosomal anomalies: are already increased in the second trimester in
Malformations of the male genital apparatus pregnancies that subsequently develop PE
should be considered as risk factors for PE (Kalinderis et al. 2011; Bahado-Singh
(Vesce et al. 1997). There is also an increased etal.1998).MaternalserumactivinAandinhibin
incidence of preeclampsia in cases of fetal A levels are increased in the presence of hyper-
hydrops. Preeclampsia was significantly tensivedisorders.BecauseactivinAisinvolvedin
10 S.Vannuccinietal.
thecontroloftrophoblastcelldifferentiationinthe maternal factors, uterine artery pulsatility index,
first trimester, altered expression of this protein mean arterial pressure, and placental growthfac-
mayaffectplacentalinvasiveness,resemblingthe torpredicted75 %ofPE(O’Gormanetal.2016).
pathogenesisofPE.InhibinAiselevatedseveral
weeks before the onset of clinical signs of
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