Pregnancy, parturition and preeclampsia in women of African ancestry

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Pregnancy, parturition and preeclampsia in women
of African ancestry
AnnetteeNakimuli,MBChB,MMed(Obs&Gyn);OlympeChazara,PhD;
JosaphatByamugisha,MBChB,MMed(Obs&Gyn),PhD;AlisonM.Elliott,MA,MBBS,MD,DTM&H,FRCP;
PontianoKaleebu,MD,PhD;FlorenceMirembe,MBChB,MMed(Obs&Gyn),PhD;
AshleyMoffett,MA,MB,BChir,MD,MRCP,MRCPath
States are 4, 12, and 21, respectively,
Maternal and associated neonatal mortality rates in sub-Saharan Africa remain unac- whereas those of Chad, Nigeria, and
ceptablyhigh.InMulagoHospital(Kampala,Uganda),2majorcausesofmaternaldeath Congoare1100,630,and540per100,000
arepreeclampsiaandobstructedlaborandtheircomplications,conditionsoccurringat livebirths,respectively.InSSA,themajor
the extremes of the birthweight spectrum, a situation encapsulated as the obstetric direct causes of maternal mortality are
dilemma.Wehavequestionedwhethertheprevalenceofthesedisordersoccursmore hemorrhage, preeclampsia/eclampsia,
frequentlyinindigenousAfricanwomenandthosewithAfricanancestryelsewhereinthe obstructed labor, and sepsis.4 Infections,
worldbyreviewingavailableliterature.Weconcludethatthesewomenareatgreaterrisk pretermbirth,birthasphyxia,stillbirths,
of preeclampsia than other racial groups. At least part of this susceptibility seems in- and small-for-gestational-age infants
dependent of socioeconomic status and likely is due to biological or genetic factors. are the leading causes of perinatal
Evidenceforageneticcontributiontopreeclampsiaisdiscussed.Wegoontopropose mortality.2,5
thattheobstetricdilemmainhumansisresponsibleforthissituationanddiscusshow Theseobservations are representative
parturitionandbirthweightaresubjecttostabilizingselection.Otherdatawepresentalso ofourowninstitution,MulagoHospital
suggest that there are particularly strong evolutionary selective pressures operating inKampala(Uganda)inwhichtheMMR
duringpregnancyanddeliveryinAfricans.Thereismuchgreatergeneticdiversityand has remained high at 438 per 100,000
lesslinkagedisequilibriuminAfrica,andthegenesresponsibleforregulatingbirthweight live births, even though there has been
andplacentationmaythereforebeeasiertodefinethaninnon-Africancohorts.Inclusion
an increase in skilled birth attendance
ofAfricanwomenintoresearchonpreeclampsiaisanessentialcomponentintackling
(58%) and very good attendance rate
thismajordisparityofmaternalhealth. (95%)atantenatalclinics.6
Key words: evolutionary selective pressure, great obstetric syndromes, length of Mulago Hospital is the busiest ma-
gestation,obstetricdilemma ternityhospitalinSSA, servingasater-
tiary referral center for Uganda. Details
of deliveries and maternal deaths are
shown in Table 1. Even with the lack
Morethan90%ofmaternaldeaths partners, and others.1-3 The majority of of good medical records that is charac-
worldwide occur in sub-Saharan these deaths are related to pregnancy teristic of much of SSA, our experience
Africa(SSA)andsouthAsia.Thesehigh complications that are inadequately in Mulago Hospital is that causes of
maternal and associated neonatal mor- managed because of a lack of access to maternal deaths are similar to the rest
tality rates persist despite considerable emergency health care. The maternal ofSSA,withhemorrhage,preeclampsia/
efforts from the World Health Organi- mortality ratios (MMRs) of Sweden, eclampsia, and sepsis occurring very
zation, governments, development the United Kingdom, and the United commonly.4,7,8 The large number of
FromtheDepartmentofObstetricsandGynaecology,MakerereUniversityandMulagoHospital,Kampala,Uganda(DrNakimuliandDrsByamugishaand
Mirembe);DepartmentofPathologyandCentreforTrophoblastResearch,UniversityofCambridge,Cambridge,UnitedKingdom(DrsChazaraand
Moffett);MedicalResearchCouncil/UgandaVirusResearchInstituteUgandaResearchUnitonAIDS,Entebbe,Uganda(DrsElliottandKaleebu);and
LondonSchoolofHygieneandTropicalMedicine,London,UnitedKingdom(DrElliott).
ReceivedSept.11,2013;revisedOct.22,2013;acceptedOct.28,2013.
ThisstudywassupportedbytheWellcomeTrust(grants090108/Z/09/Zand085992/Z/08/Zandavacationscholarshipin2011);theBritishHeart
Foundation(grantPG/09/077/27964);theCentreforTrophoblastResearchattheUniversityofCambridge;andaWellcomeTrustUgandaPhD
FellowshipinInfectionandImmunityheldbyA.N.,supportedbyaWellcomeTrustStrategicAward(grant084344).
Theauthorsreportnoconflictofinterest.
Reprints:AshleyMoffett,MA,MB,BChir,MD,MRCP,MRCPath,DepartmentofPathologyandCentreforTrophoblastResearch,Universityof
Cambridge,TennisCourtRd.,CambridgeCB21QP,[email protected].
0002-9378/$36.00
ª2014Mosby,Inc.Allrightsreserved.
http://dx.doi.org/10.1016/j.ajog.2013.10.879
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women seen with preeclampsia, partic-
ularly recurrent, severe, and early-onset TABLE1
DataforthematernityunitinMulagoHospital,Uganda
preeclampsia and eclampsia, is of par-
ticular concern to us because these Variable 2009 2010 2011
conditions have a high mortality and
Livebirths 30,247 31,585 32,633
morbidity, are impossible to predict,
Stillbirths 1260 1303 1230
andtheirpathogenesisisstillsomewhat
mysterious. Cesareansections 6849 6702 6800
Here we review data relating to pre- Ruptureduterus 125 119 206
eclampsiainindigenousAfricansandin
Maternaldeaths 187 152 188
women of African ancestry elsewhere
Attendanceatantenatalclinic 78,157 76,673 69,129
intheworld.Wediscusstheideathatin
these women, apart from the obvious, Nakimuli.Pregnancy,parturitionandpreeclampsiainAfrica.AmJObstetGynecol2014.
cultural and socioeconomic factors and
different priorities in health care, there
areadditionalbiologicalreasonswhythe
preeclampsia syndromes are such a prevalence of preeclampsia in SSA is PreeclampsiaamongAfrican
prominentfeatureofAfricanobstetrics. unknown because detailed clinical re- Americans
Our findings also lead us to question cords of all births are lacking. Dis- Although African Americans are obvi-
whetherthereareothercharacteristicsof tinguishing between true preeclampsia ously not directly comparable with
pregnancyandparturitionthatdiffer in and pregnancy-induced hypertension is indigenous Africans because of consid-
Africanwomen. also difficult because proteinuria may erable genetic admixture (7-23%),18,19
not be adequately measured. A further the large number of reports and the
Preeclampsiaandthegreatobstetric problem is a lack of information on consistencyofthefindingsareinforma-
syndromes preexisting hypertension because pre- tive (Table 2). For decades it has been
Animportantdeterminantofpreeclamp- sentationtotheclinicisoftenlate. clearthattherearedisparitiesinobstet-
siaisfailureofplacentation,particularly Given this dearth of accurate records ric outcomes including preeclampsia
thephysiologicaltransformationofspi- of pregnancy outcomes in Uganda and between AA and other groups; indeed,
ral arteries, which leads to a stressed, SSA generally, to review the incidence black ethnicity is cited as a risk factor
underperfused placenta.9,10 Preeclamp- of preeclampsia in women of African for preeclampsia in reviews.20,21 Of 4
sia is one of a spectrum of pregnancy ancestry, we have reviewed reports re- million births recorded in the National
disorders that may result from this un- latingtopreeclampsiainAfricanAmer- Vital Statistics Report, pregnancy-
derlying pathogenesis, including fetal icans(AA)and immigrantsfromAfrica associatedhypertensionwasmorecom-
growth restriction (FGR), stillbirth, to other high-income countries as moninAA(5.0%)andleastfrequentin
abruptio placentae, and some cases of compared with other ethnic groups. Hispanics(2.9%).22
preterm labor with intact membranes Studieswereidentifiedthroughasearch Astudyofmorethan2millionpreg-
andprelaborruptureofmembranes.11,12 of the PubMed database for relevant nancies in New York using data from
Because of the overlap in these condi- peer-reviewed articles published in En- hospital discharge records found that
tions, it is useful to think of them to- glish using the search terms, pre- the rates of preeclampsia were substan-
gether as the great obstetric syndromes eclampsia or eclampsia or hypertensive tially higher among AA compared with
(GOS)(Appendix).13-15 disease in pregnancy or gestational hy- European Americans. This was even
All these conditions are seen very pertensionorseverematernalmorbidity moreobviouswhenconfounderssuchas
frequentlyinMulagoHospital.However, andethnicityorrace(Tables2and3). diabetes and maternal age were taken
FGR cannot be reliably diagnosed In this review, we designate women into account. Furthermore, the differ-
without accurate knowledge of gesta- of African ancestry as those women ence persisted after stratification for
tional age, and low birthweight may descended from inhabitants of SSA. socioeconomic status based on area of
resultfromavarietyofcauses.Similarly, Thereareobviouscaveatswhenreviewing residence.23
stillbirth is a heterogeneous condition datafromwomenofAfricandescentwho TwootherlargestudiesintheUnited
thatcanresultfromcongenitalinfection, have migrated to new environments. States, each with more than 1 million
birthasphyxia,orbirthtraumaaswellas Those who have the energy to migrate womenalsofoundthatpreeclampsiawas
pooruteroplacentalperfusion. may be healthier than those left behind. more common in AA compared with
Becausepreeclampsiaisarecognized Furthermore, factors such as diet, life- European Americans.24,25 One of these
clinical entity characterized by new style,education,healthcare,climate,and studies took data from the National
onset of hypertension and proteinuria indigenous pathogens are different and Inpatient Sample in which information
after 20 weeks’ gestation, we have necessarily become an integral part of was also available on health insurance
focusedonthisdisorder.16,17Theexact theimmigrant’snewenvironment. and income level; when this was taken
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TABLE2
PreeclampsiaoreclampsiastudiesamongAfricanAmericans
Preeclampsiaor
Cohortsize(total/AA) eclampsia,OR(95%CI) Comments Reference
2,571,069/450,098 1.67(1.64e1.71)a PEinwomeninNewYorkstate 23
1,030,350/161,780 1.59(1.49e1.69) Adjustedformaternalcharacteristicsandobstetrichistory 24
1,472,912/420,576 1.30(1.28e1.33) Adjustedformaternalcharacteristicsandobstetrichistory 25
299,499/n.a. 1.39(1.26e1.54)a SeverePEinwomenwithoutchronichypertension 26
206,428/19,512 2.12(1.85e2.42) Adjustedformaternalcharacteristicsandobstetrichistory 27
330/124 2.25(0.88e5.78) Eclampsia,adjustedformaternalcharacteristicsandobstetrichistory 29
4702/740 1.40(1.20e1.80) Adjustedformaternalcharacteristicsandobstetrichistory 30
271/38 2.50(0.97e6.40) Adjustedformaternalcharacteristicsandobstetrichistory 31
4314/1998 1.23(0.88e1.72) Adjustedformaternalcharacteristicsandobstetrichistory 32
153/35 2.27(1.26e5.92) LatepostpartumPE,notadjusted 33
2394/592 1.53(1.00e2.35) Adjustedformaternalcharacteristics,obstetrichistory,andbiochemicalfactors 34
103,860/13,748 1.36(1.27e1.45)a PEinwomenwithsingletonbirthatfirstdelivery 35
2,770,871/121,017 1.81(1.51e2.17) Eclampsia,adjustedformaternalcharacteristicsandobstetrichistory 36
127,544/12,639 1.41(1.25e1.62) Adjustedformaternalcharacteristics,chronichypertensionexcluded 28
16,300/6000 1.63(1.58e1.69)a Eclampsiainracialminorities,notadjusted,notsignificant 38
1355/374 3.20(1.04e9.93) PEinwomenwithoutchronichypertension 40
500/68 2.29(1.16e4.53) RecurrentPE,adjustedformaternalcharacteristicsandobstetrichistory 67
10,755/5555 1.30(1.07e1.58) Adjustedformaternalcharacteristics 44
2947/156 1.62(0.00e3.20) Noeffectwhenanalyzedbyrecruitmentcenter 69
Maternalcharacteristicsgenerallyincludematernalage,bodymassindex,andsmoking.Obstetrichistorygenerallyincludesparity,chronichypertension,anddiabetes.
CI,confidenceinterval;n.a.,notavailable;OR,oddsratio;PE,preeclampsia.
aORwascalculatedfromthedata.
Nakimuli.Pregnancy,parturitionandpreeclampsiainAfrica.AmJObstetGynecol2014.
into account, the findings remained the for both eclampsia and preeclampsia revealed a higher incidence of pre-
same.24Theotherstudyuseddatafrom in nulliparous and parous women have eclampsia and eclampsia among AA
womenwhowereallMedicaidenrollees also shown AA are at higher risk women compared with their European
in14southernstates.25AAwomenwere (Table2).28-36 counterparts, irrespective of whether
also most likely to have other poor Confounding factors such as obesity, therewaspreexistinghypertension.41
maternal outcomes like preterm labor, preexisting chronic hypertension, and Investigation of the GOS other than
abruptioplacenta,andstillbirth. diabetes are difficult to control for and preeclampsia is more difficult because
AnotherlargestudyfromtheNational are likely to contribute to the increased of the problems in accurate diagnosis
Hospital Discharge Survey found AA risk of preeclampsia among AA, partic- described above. Nonetheless, a consis-
women had a higher incidence of all ularly in the case of chronic hyperten- tent message is that ethnic disparities
hypertensivedisordersinpregnancyand sion.37-39Thatpreeclampsiamaynotbe exist for all the GOS (spontaneous pre-
a greater risk of severe complications of wholly explained by higher rates of term labor, FGR, stillbirth, and other
preeclampsia such as abruptio placenta chronic hypertension among AAwomen poorobstetricoutcomes),andallhavean
and stillbirth compared with European is suggested by a comparison between increased frequency among AA.26,42-45
Americans.26Similarfindingsweremade AfricanandEuropeanAmericanswithout In a study of more than 5 million
inalargeWisconsinstudyrecruitedfrom chronic hypertension; the prevalence of births comparing birth outcomes be-
hospitaldischargedata.AAwomenhad hypertension in pregnancy was similar, tween US-born and foreign-born
thehighestriskforallthedifferenttypes but AA women still had an increased women, women of African ancestry
of preeclampsia when compared with diagnosis of preeclampsia.40 Similar had the highest rates of infant mor-
European American women.27 Several findingsweremademuchearlierbythe tality, low birthweight, and preterm
other studies looking at risk factors Collaborative Perinatal project, which births, whether US born or foreign
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TABLE3
PreeclampsiastudiesamongrecentAfricanimmigrantstoothercountries
Cohortsize Preeclampsia,
(total/Africans) ORorRR(95%CI) Africanorigin Comments Location Reference
118,849/15,218 3.34(2.25e4.96) Caribbean Adjustedformaternalcharacteristics Canada 49
118,849/9130 3.14(2.04e4.83) SSA Adjustedformaternalcharacteristics Canada 49
2413/317 2.40(1.10e5.60) SSA,Surinam, Univariateanalysis TheNetherlands 50
Antilles
2506/29 2.70(1.20e6.20) Antilles EclampsiaincasesofSAMM,adjustedfor TheNetherlands 51
maternalcharacteristicsandobstetrichistory
2506/90 6.20(3.60e10.6) SSA EclampsiaincasesofSAMM,adjustedfor TheNetherlands 51
maternalcharacteristicsandobstetrichistory
6215/331 2.06(1.04e4.09) CapeVerde Adjustedformaternalcharacteristicsand TheNetherlands 52
obstetrichistory
6215/264 1.87(0.86e4.06) Antilles Adjustedformaternalcharacteristics TheNetherlands 52
andobstetrichistory
1728/576 2.47(1.02e6.00) Ethiopia Standardizedcarebetweenthegroups Israel 53
compared
76,158/11,395 2.60(2.32e2.92) Caribbean Adjustedformaternalcharacteristics UnitedKingdom 54
andobstetrichistory
8366/1581 3.64(1.84e7.21) n.a. Adjustedformaternalcharacteristics UnitedKingdom 55
andobstetrichistory
15,639/356 0.90(0.53e1.51)a SSA Noincreasedrisk Sweden 56
165,001/986 n.a. African,Somalia Noincreasedrisk Finland 58
526/158 3.90(1.70e8.94)a SSA Early-onsetPEcomparedtolateonset France 68
(<28or<34weeks)
Maternalcharacteristicsgenerallyincludematernalage,bodymassindex,andsocioeconomicstatus.Obstetrichistorygenerallyincludesparity,chronichypertension,anddiabetes.
CI,confidenceinterval;n.a.,notavailable;OR,oddsratio;PE,preeclampsia;RR,relativerisk;SAMM,severeacutematernalmorbidity.
aORwascalculatedfromthedata.
Nakimuli.Pregnancy,parturitionandpreeclampsiainAfrica.AmJObstetGynecol2014.
born.46 In addition, the risk of pre- outcomes also apply to the Hispanic because these births often take place
term birth, stillbirth, and low birth- population in the United States, yet incountrieswithgoodrecordsanduni-
weight is increased not only in AA several studies have noted that pre- versalhealthcaresystems(Table3).For
women but also with AA fathers.47,48 eclampsia, low birthweight, and still- example, a large study of more than
Explanationsforthedisparitiesfound birth aresimilaroreven better than for 100,000 women who immigrated to
between women with African or Euro- whitewomen,theHispanicparadox.28,44 Ontariobetween1985and2000showed
peanancestryhavebeenpoorsocioeco- Using information from the Duke Uni- that the racial groups with the highest
nomic status with lower incomes and versity Birth Database, AA women had risk of severe preeclampsia were from
level of education, lack of medical in- higher rates of preeclampsia (10.2%) theCaribbeanorSSA.49
surance, poor utilization of precon- than the European (8%) or Hispanic Similar findings were made in The
ception and antenatal services, stress, women (6.2%), even though the socio- Netherlands where the highest risk for
discrimination, and residential segre- economic status of Hispanic and AA eclampsia and preeclampsia was from
gation. Several reports have tried to womenwassimilar.44 womenfromSSA.50,51CapeVerdeanand
determine the impact of these factors; Antilleanwomenwerealsoathigherrisk
forexample,womenofAfricanancestry Preeclampsiaamongmorerecent ofpreeclampsiainareportfromRotter-
were at an increased risk of pre- Africanimmigrantstoothercountries dam,TheNetherlands.52Alargenumber
eclampsia in a second pregnancy, but LargenumbersofAfricanshavemigrated of Ethiopians have settled in Israel since
this was not associated with Medicaid toEuropeandotherhigh-incomecoun- the 1980s where prenatal and obstetric
enrollment.30 tries, mainly in the past 50 years. Ob- care is standardized with equal medical
Many of the socioeconomic factors stetricoutcomesfortheserecentAfrican insurance, and in this group severe pre-
that may contribute to poor obstetric immigrantsareinformative,particularly eclampsiawasmorelikelytooccur.53
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Large groups of women of African Increased risk of other GOS, even if pregnancy,arealsoatincreasedrisk.73-77
ancestry live in London where access preeclampsia does not occur, is also Thesefindingsoffamilialaggregationin
to National Health Service hospitals is clear from another large study in Swe- preeclampsia are also true for the other
freely available and home deliveries are den, and other reports support this GOS.78-81 Although environmental fac-
rare. In a survey of 80,000 pregnancies conclusion.35,63-66 tors, particularly influences acting in
that included women of European and Largestudiesofthiskindarestillnot utero,areimportant,someoftheriskis
Asian ancestry, 15% had African an- available for Africanwomen resident in likely to be genetic. Indeed, a study of
cestry,andthiswasthesecondstrongest SSA,butourownexperienceinKampala female twin pairs with known zygosity
riskfactorforpreeclampsiaafterchronic isthatrecurrentpreeclampsiadoesoccur estimated that the heritability of pre-
hypertension and also carried a higher frequently. In London, 23% of 500 eclampsia was approximately 54%.82
risk of other poor obstetric outcomes womenwithpreviouspreeclampsiahad Could there be particular susceptibility
such as FGR and stillbirth.54 Similarly, recurrent disease that required delivery genes associated with the higher fre-
African ancestry was a risk factor for before37weeks, and African compared quency of preeclampsia in women of
early-onsetpreeclampsiacomparedwith withEuropeanancestrywasasignificant Africanancestry?Acase-controlstudyof
allotherracialgroups,andthisremained predictor.67 It also seems that when preeclampsia in Latinas, a group with
so, even after adjusting for age, body preeclampsia does occur in the second admixturefromEuropean,African,and
massindex,andothermaternalcharac- pregnancy in AA women, it is severe, native Americans, did show, using
teristics.55 These and other studies of early-onset disease with associated FGR ancestryinformativemarkers,thatAfri-
African immigrants also highlight the andpretermbirth.45Arecentstudyfrom can ancestry was associated with
increasedriskofGOSsuchasstillbirths France suggests that women of African preeclampsia.83
andFGRsimilartoAA.56-58 ancestryaremoreatriskforearly-onset Theroleofthefetal(father’s)genesis
preeclampsia and more likely to have lessobvious,butmanyreportsindicatea
Severityandrecurrence had a previous history of preeclampsia paternal contribution to the risk.84-87
ofpreeclampsia compared with other groups, including Intergenerational and familial aggrega-
The early onset and severity of pre- women from North Africa, despite the tionalsopointtogeneticfactorsderived
eclampsiainwomenfromUgandaisalso evenhigherincidenceofchronichyper- frombothmaternalandfetalgenes,with
a cause of concern, although the latter tensioninthelattergroup.68 most risk coming from maternal genes
mayreflectthelateadmittancetoMulago thatmayactineitherthemotherorher
Hospital. In a US national hospital Summary fetus.71,74,77,88 A drive to look for the
discharge survey, higher mortality from Our comprehensive review of the liter- susceptibilitygenesforpreeclampsiahas
preeclampsiaandeclampsiawasreported atureidentifiedveryfewpapersthatrun so far been disappointing. The studies
among women of African ancestry countertoourconclusionthatwomenof generallyhavesmallnumbersofsubjects
comparedwithEuropeanAmericans,but African ancestry are at increased risk of andhavenotbeenreplicated.89
only one-third or less of the difference developingpreeclampsia.First,3studies Genome-wideassociationscreening is
couldactuallybeattributedtothehigher showed that these women were not at an unbiased approach to look for sus-
prevalence.59 Pregnancy-related deaths increased riskof preeclampsia, but they ceptibilitygenesincomplexdisordersand
from preeclampsia/eclampsia were 3 hadlowpowertodetectanyeffect.56,58,69 has been used in preeclamptic cohorts,
times higher in AA women compared Second, the apparent increased suscep- but, although various single-nucleotide
withEuropeans.60 tibility to preeclampsia among AA has polymorphism candidates have been
In the UK Maternal Death Review beendismissedasaproblemofincorrect identified, the lackof statistical power is
for the period 2006-2008, 22 deaths diagnosis.37 Third, race was discounted again a problem.90-93 Systematic meta-
occurredasaresultofpreeclampsiaand as a significant risk factor for pre- analyses of these studies found 7 single-
eclampsia. Despite being a minority eclampsia in another study, but data nucleotide polymorphisms significantly
group, 6 of these deaths were Africans regarding AA women were combined associated near genes involved in pro-
and the authors noted: “Black African withthatforotherminorityracessothat cesses such as coagulation, the renin-
women seem particularly susceptible to the analysis could not provide a mean- angiotensinsystem,andinflammation.
aggressive forms of preeclampsia. To ingfulcomparison.38 This highlights an important issue:
establish if this is true, and what might searching for variants associated with
be the underlying genetic or other Geneticsofpreeclampsia preeclampsia only in the maternal ge-
pathophysiologicalmechanisms,further That there is a genetic component nomewillrevealgenesmainlyassociated
researchisrequired.”61 to preeclampsia has long been sus- withthetertiarysystemicsyndromeand
After a woman has had preeclampsia pected.70-72 Daughters of women with not those maternal and/or fetal genes
inherfirstpregnancy,theriskofrecur- preeclampsia have more than twice the involvedinphysiologicaltransformation
renceisincreased,witharelativeriskof risk of developing the disease them- ofthearteriesortothesubsequentstress
15.0citedinanauthoritativeNorwegian selves, and sisters of affected women, response of the placenta to the reduced
study of more than 2 millionwomen.62 even if not born from a preeclamptic blood flow. The clear increased risk of
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cardiovascular disease in women who
FIGURE1
havehadpreeclampsiaagainpointstoa
MaternalKIR/fetalHLA-Cinteractionsatthesiteofplacentation
separate set of susceptibility genes that
are acting systemically and not during
earlyplacentation.94,95
Wehavetakenadifferentapproachand
focused on the primary defect of poor
placentation. This is based on the idea
that regulation of trophoblast behavior
during placentation is mediated by allo-
geneic recognition of trophoblast major
histocompatibilitycomplexmoleculesby
maternal lymphocytes.96 The findings
that specialized immune cells, uterine
natural killer (NK) cells, accumulate at
thesiteofplacentation,togetherwiththe
discovery of NKreceptors, the killer-cell
immunoglobulin-like receptor family
(KIR)andtheircognateHLA-Ctropho-
blastligandshavedemonstratedhowthe
mother can discern the presence of a
geneticallydifferentindividual.97-99
KIR and HLA are the most poly-
morphic gene families in humans, and
we have shown that particular maternal
KIR in combination with fetal HLA-C
variantsareassociatedwithpreeclampsia
and the other GOS.100-102 Women who
have2KIRAhaplotypes(KIRAAgeno-
type) are at risk when there is a HLA-C
allele belonging to the C2 group in
the fetus. Furthermore, the origin of the
fetalHLA-C2isimportant;themostriskis
fromaC2alleleinheritedfromthefather.
We are now undertaking a similar
study at Mulago Hospital, and pre- Inthese2 scenarios,the motherisHLA-C1 homozygousandthefetus hasinheritedan HLA-C2
liminary findings illustrate the same groupallelefromthefather.IfthemotherhasaKIRAAgenotypethatlacksactivatingKIRandhasa
maternalKIR/fetalHLA-Ccombinations stronginhibitoryKIRforHLA-C2(KIR2DL1),poorplacentationresults.Incontrast,ifthemotherhasa
associated with preeclampsia in African KIRABorBBgenotypecontainingtheactivatingKIRforHLA-C2(KIR2DS1),uterinenaturalkillercells
women. Interestingly, the frequency of are triggered to produce increased amount of cytokines and chemokines (eg, granulocyte-
the fetal HLA-C2 variant that confers macrophagecolonyestimulatingfactor)thatenhanceplacentation.
riskisincreasedinUgandanscompared
Nakimuli.Pregnancy,parturitionandpreeclampsiainAfrica.AmJObstetGynecol2014.
with Europeans and Asians.103 Further-
more, there is enormous variability of
KIRgenesinAfricanswithfarmorege- women who have a protective KIR B receives sufficient nourishment for nor-
notypes and more allelic variation at haplotype (in which the activating KIR maldevelopmentthroughremodelingof
individualKIRloci.104 forHLA-C2,KIR2DS1,islocated)results thespiralarteries.
How these genetic findings translate insecretionofcytokinesandchemokines
intothefunctionofuterineNKcellsisa that may facilitate trophoblast invasion Theobstetricdilemma
challenge,giventheethicalandlogistical andvasculartransformation.105Thus,we Overall, the data we have brought
difficulties in experimenting with these proposethattheuterineimmunesystem together inthisreviewsuggestthatpre-
cells.Functionally,wewouldpredictthat using highly variable maternal KIR/fetal eclampsia and other GOS occur more
the risky combination results in very HLA-C interactions subtly defines the commonlyinwomenofAfricanancestry
strong inhibition of uterine NK cells boundary between mother and baby, comparedwithotherethnicgroups,and
(Figure1).TriggeringofuterineNKcells limitingthehighlyinvasiveplacentawhile thisisnotwhollyaccountedforbycon-
by HLA-C2 target cells in vitro from at the same time ensuring the fetus founding social, cultural, and medical
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pelvic trauma, sepsis, and long-term
FIGURE2 problems such as vesicovaginal fis-
Birthweightandneonatalmortalityrates(n[13,730).
tula.109 In Uganda, 2% of all women
havehadanobstetricfistula.6Therefore,
thehighercesareansectionratesseenin
high-income countries in women of
African ancestry may reflect not just
delivery of women with preeclampsia
but also an increased frequency of
obstructedlabor.24,54,58,110
A detailed audit from the Royal Col-
legeofObstetriciansandGynaecologists
in the United Kingdom highlighted the
higher cesarean section rates in women
of African ancestry, even when con-
founderssuchasage,parity,birthweight,
and presentation were considered.110
Furthermore, shoulder dystocia has also
been reported to occur more commonly
inAAwomen.111
These findings may in part be
accounted for by measurements of the
bony pelvis revealing that there is even
lessroomforthefetalheadinwomenof
African ancestry. Although pelvimetry
may not be a useful indicator in pre-
dicting cephalopelvic disproportion in
Adapted,withpermission,fromCavalli-SforzaandBodmer.108 individualpatients,112themeasurements
Nakimuli.Pregnancy,parturitionandpreeclampsiainAfrica.AmJObstetGynecol2014.
made of the pelvis, notably the pelvic
inlet,outlet,lengthofsacrum,andpelvic
influences.50,54,57,68Italsoseemsthatthe Compared with other primates, the floor area, are all smaller in women of
risk of preeclampsia in African immi- passage of the large human fetal head Africanancestrycomparedwiththoseof
grantstoEuropeisincreasedirrespective through a bony pelvis is a tight fit, Europeanancestry.113-115
of their area of origin in Africa, apart requiring rotationoftheheadasitgoes A possible consequence is that the
from North Africans.68 All these obser- throughthebirthcanalasaconsequence fetal head engages into the pelvis late,
vations point to a need to investigate of adaptation to bipedalism.106,107 The only when labor commences, whereas
possible biological/genetic reasons con- high maternal and neonatal mortality thisoccursinthelastmonthofgestation
tributing to the higher risk of pre- associatedwithextremesofbirthweight, in European and Asian women.116
eclampsiainSSA. sometimescalledtheobstetricdilemma, Several reports also document the fact
Wewouldanticipatethattherewould has been described as “perhaps the thatnormalterminAfricanpregnancy
be strong selective pressure against a most clear-cut example of a human occursatonlyapproximately38weeks’
disorderthat,withoutmedicalinterven- charactersubjecttostabilizingselection” gestation,whichis2weeksearlierthan
tion, is frequently fatal to mother and (Figure2).108 in non-Africans, possibly facilitating
child and occurs in 5-10% of firstpreg- Theoptimalsurvivalofbabiesweigh- birth before the baby becomes too
nancies. A failure of the physiological ingbetween6and8lb(2.5-3.5kg)seems big.117-120Ifbirthsareoccurringearlier,
transformation of uterine arteries is a tobeauniversalfeatureofhumanpop- itwouldcertainlythenbeadvantageous
commonfeatureofalltheGOS,andthis ulations.Ifbabiesbecometoolarge,the for the fetus to mature more quickly,
results in a reduced placental supply risk of obstructed labor is increased. As and indeed, African babies frequently
of oxygen and nutrients, lower birth- intherestofSSA,atMulagoHospitalwe pass meconium with no sign of fetal
weights, and the risk of preterm labor not only have many disordered preg- distress.119,121 There is also accelerated
and superimposed preeclampsia. How- nancies arising from failure of placenta- lung maturity.122,123 Thus, the diffi-
ever,atthesametime,wehavetoconsider tion, but we also experience frequent cultiesimposedbythebirthprocessand
that maternal and neonatal mortality is births with prolonged obstructed labor the passage of the head and shoulders
not only high under circumstances of because of cephalopelvic disproportion. through the bony pelvis seem to have
reduced fetal nutrition but also when Without cesarean section, this leads to driven biological changes in many as-
babiesaretoolargeforthepelvis. birthasphyxia,postpartumhemorrhage, pectsofpregnancy.
516 AmericanJournalofObstetrics&Gynecology JUNE2014
Expert Reviews
www.AJOG.org Obstetrics
Thiscleartrade-offbetweenthesizeof out-of-Africa migrations have reduced maternal death: a systematic review. Lancet
the pelvis and head room will benefit theextentofgeneticvariationintheEu- 2006;367:1066-74.
5.LawnJE,CousensS,ZupanJ.Fourmillion
babies who have intermediate birth- ropean populationsthat are thefocusof
neonatal deaths: when? where? why? Lancet
weights, and the 2 extremes with re- thegreatmajorityofstudiesofpregnancy
2005;365:891-900.
duced survival will be selected against. disorders. 6.UgandaBureauofStatistics(UBOS)andICF
Of interest will be a study of maternal Studyingbiologicaldiversitywillshed International Inc.Uganda Demographic and
KIR/fetalHLA-Cvariantsinpregnancies light on pathological pregnancies in all Health Survey 2011, Kampala, Uganda. Kam-
pala (Uganda): Ganda Bureau of Statistics
withobstructedlaborastheKIRAandB populations, and inclusion of African
(UBOS)andICFInternationalInc;2012.
haplotypes and HLA-C1 and C2 groups women into research on preeclampsia 7.KayeD,MirembeF,AzigaF,NamulemaB.
are under stabilizing selection and are is an essential component in tackling Maternalmortalityandassociatednear-misses
foundatdifferentfrequenciesacrossthe thismajordisparityofmaternalhealth.It among emergency intrapartum obstetric re-
world’spopulations.124 has been highlighted that “Africa is a ferrals in Mulago Hospital, Kampala, Uganda.
Therefore,whenconsideringwhypre- geneticallyspecialplace”withgreaterge- EastAfrMedJ2003;80:144-9.
8.WandabwaJN,DoyleP,Longo-MbenzaB,
eclampsia persists in populations, it is neticdiversityandlowerlevelsoflinkage et al. Human immunodeficiency virus and
importantnotonlytoconsidertheGOS disequilibrium.126Thegenescontributing AIDS and other important predictors of
but also the morbidity and mortality at to defective placentation are therefore maternal mortality in Mulago Hospital Com-
the other end of the birth weight distri- likely to become obvious more quickly. plex Kampala Uganda. BMC Public Health
2011;11:565.
bution. It may be that the consequences Indeed,ourinitialstudyofKIRgeneshas
9.Redman CWG, Sargent IL. Immunological
of these contrasting selective pressures foundamuchgreaternumberofdifferent
factors and placentation: implications for pre-
notonlyaffecthigherbirthweightbabies KIR haplotypes in women delivering at eclampsia. In: Lyall F, Belfort M, eds. Pre-
but also the tendency for enhanced MulagoHospitalbutalsohighlightedthe eclampsia. Cambridge (United Kingdom):
numbersof undernourished babies with extentofvariabilityofthesegeneswithin CambridgeUniversityPress;2007.
the concomitant maternal syndrome of the African continent.103 Denying the 10.RedmanCW,SargentIL.Latestadvances
inunderstandingpreeclampsia.Science2005;
preeclampsia.Thatistosaythatselection existenceofgeneticdifferencesinAfricans
308:1592-4.
inapopulationforreducedfetalsizemay and their interactions with nongenetic 11.AnanthCV,VintzileosAM.Ischemicplacental
lead to the persistence of factors predis- factorsonlydelaystheidentificationofthe disease: epidemiology and risk factors. Eur J
posingtopreeclampsia. causalgenesorallelesthatwouldallowus ObstetGynecolReprodBiol2011;159:77-82.
12.Khong TY, De Wolf F, Robertson WB,
to move away from racial/ethnic catego-
Brosens I. Inadequate maternal vascular
Futuredirections rization of individuals. Knowing the ge-
response to placentation in pregnancies
There is an urgent need to document netic variants will allow a better complicatedbypre-eclampsiaandbysmall-for-
obstetric events better in SSA, and the understandingofthemolecularpathways gestational age infants. Br J Obstet Gynaecol
lack of detailed electronic hospital re- and better health care for the women 1986;93:1049-59.
13.Brosens I, Pijnenborg R, Vercruysse L,
cordsinthehospitalsaswellasthefail- carrying the risky genotypes, indepen-
Romero R. The “Great Obstetrical Syndromes”
uretorecordallbirthsinthepopulation dentlyfromtheirethnicity. -
areassociatedwithdisordersofdeepplacenta-
is a major difficulty for any maternal tion.AmJObstetGynecol2011;204:193-201.
health research program. For example, ACKNOWLEDGMENTS 14.RomeroR,KusanovicJP,KimCJ.Placental
proper assessment of gestational age at bed disorders in the genesis of the great
Wethankalltheclinicalandresearchstaffofthe
obstetricalsyndromes.In:BrosensI,Pijnenborg
delivery will be crucial in the accurate Mulago Hospital and the patients and their
R, Romero R, eds. Placental bed disorders:
diagnosisoftheGOS.Therecordsystems familieswhomadethisworkpossible.Weare
basic science and its translation to obstetrics.
documenting obstetric and neonatal alsogratefultoGrahamBurton,HilaryCritchley, Cambridge, NY: Cambridge University Press;
DavidDunne,andChristopherRedmanfortheir
problemsarestillinadequatethroughout 2010:271-89.
SSA,andthis is clearly a major priority. helpfulcommentsonthedraftmanuscript. 15.Smith GC. First-trimester determination of
complications of late pregnancy. JAMA
Introduction of record systems in
2010;303:561-2.
Zambia had an immediate impact on 16.NorthR.Classificationanddiagnosisofpre-
health care such as penicillin adminis- REFERENCES eclampsia. In: Lyall F, Belfort M, eds.
trationforsyphilisaswellashighlighting 1.World Health Organization. Trends in Pre-eclampsia. Cambridge (United Kingdom):
theshortergestationalageanddescribing maternal mortality: 1990 to 2008. Geneva CambridgeUniversityPress;2007.
thenormalbirthweightdistribution.125 (Switzerland):WorldHealthOrganization;2010. 17.Cunningham FG, Leveno KJ, Bloom SL,
2.WorldHealthOrganization.TheWorldHealth HauthJC,GilstrapL,WenstromKD.Hyperten-
The majority of studies on pre-
Report 2005. Make every mother and child sivedisordersinpregnancy.Williamsobstetrics.
eclampsia and the other GOS are from count.Geneva(Switzerland):WorldHealthOr- NewYork:McGrawHill;2005.
Europe and the Americas, but if these ganization;2005. 18.Reed TE. Caucasian genes in American
conditionsareindeedoccurringatgreater 3.World Health Organization. Reduction of Negroes.Science1969;165:762-8.
frequencyinwomenofAfricanancestry, maternal mortality: a joint WHO/UNFPA/ 19.Chakraborty R, Kamboh MI, Ferrell RE.
itmakesscientificandeconomicsenseto U(SNwICitzEeFrl/aWndo)r:ldWorBldanHkealthstOatregmaneinzta.tionG;e1n9e9v9a. “eUgnyiqfoured”eatlelerlmesiniinngad“hmeixreedditparoyp”uplaotpiounla:taiosntrdaitf--
study them in the setting in which they 4.KhanKS,WojdylaD,SayL,GulmezogluAM, ferences of disease frequencies. Ethn Dis
have a major impact. Furthermore, the Van Look PF. WHO analysis of causes of 1991;1:245-56.
JUNE2014 AmericanJournalofObstetrics&Gynecology 517
Expert Reviews
Obstetrics www.AJOG.org
20.DekkerGA.Riskfactorsforpreeclampsia. 37.Chesley LC. History and epidemiology of 52.Bouthoorn SH, Gaillard R, Steegers EA,
ClinObstetGynecol1999;42:422-35. preeclampsia-eclampsia. Clin Obstet Gynecol etal.Ethnicdifferencesinbloodpressureand
21.RobertsJM,CooperDW.Pathogenesisand 1984;27:801-20. hypertensive complications during pregnancy:
genetics of pre-eclampsia. Lancet 2001;357: 38.SaftlasAF,OlsonDR,FranksAL,AtrashHK, theGenerationRstudy.Hypertension2012;60:
53-6. Pokras R. Epidemiology of preeclampsia and 198-205.
22.MartinJA,HamiltonBE,VenturaSJ,etal. eclampsiaintheUnitedStates,1979-1986.Am 53.SalimR,MfraA,GarmiG,ShalevE.Com-
Births: final data for 2009. Natl Vital Stat Rep JObstetGynecol1990;163:460-5. parison of intrapartum outcome among immi-
2011;60:1-70. 39.Samadi AR, Mayberry RM, Zaidi AA, grant women from Ethiopia and the general
23.TanakaM,JaamaaG,KaiserM,etal.Racial PleasantJC,McGheeNJr,RiceRJ.Maternal obstetric population in Israel. Int J Gynaecol
disparityinhypertensivedisordersofpregnancy hypertension and associated pregnancy com- Obstet2012;118:161-5.
in New York State: a 10-year longitudinal plications among African-American and other 54.Khalil A, Rezende J, Akolekar R,
population-based study. Am J Public Health women in the United States. Obstet Gynecol Syngelaki A, Nicolaides KH. Maternal racial
2007;97:163-70. 1996;87:557-63. origin and adverse pregnancy outcome: a
24.Shen JJ, Tymkow C, MacMullen N. Dis- 40.Bryant AS, Seely EW, Cohen A, cohort study. Ultrasound Obstet Gynecol
paritiesinmaternaloutcomesamongfourethnic Lieberman E. Patterns of pregnancy-related 2013;41:278-85.
populations.EthnDis2005;15:492-7. hypertension in black and white women. 55. Poon LC, Kametas NA, Chelemen T,
25.Zhang S, Cardarelli K, Shim R, Ye J, HypertensPregnancy2005;24:281-90. LealA,NicolaidesKH.Maternalriskfactorsfor
Booker KL, Rust G. Racial disparities in eco- 41.NiswanderKR,GordonM.Thewomenand hypertensive disorders in pregnancy: a multi-
nomic and clinical outcomes of pregnancy their pregnancies: the collaborative perinatal variateapproach.JHumHypertens2010;24:
amongMedicaidrecipients.MaternChildHealth study of the National Institute of Neurological 104-10.
J2013;17:1518-25. Diseases and Stroke. Philadelphia, PA: W. B. 56.Essen B, Hanson BS, Ostergren PO,
26.Zhang J, Meikle S, Trumble A. Severe SaundersCo;1972. Lindquist PG, Gudmundsson S. Increased
maternalmorbidityassociatedwithhypertensive 42.MacDorman MF. Race and ethnic dispar- perinatal mortality among sub-Saharan immi-
disorders in pregnancy in the United States. ities in fetal mortality, preterm birth, and infant grants in a city-population in Sweden. Acta
HypertensPregnancy2003;22:203-12. mortality in the United States: an overview. ObstetGynecolScand2000;79:737-43.
27.Cabacungan ET, Ngui EM, McGinley EL. SeminPerinatol2011;35:200-8. 57.JenumAK,SommerC,SletnerL,MorkridK,
Racial/ethnicdisparitiesinmaternalmorbidities: 43.Bryant AS, Worjoloh A, Caughey AB, Baerug A, Mosdol A. Adiposity and hyper-
a statewide study of labor and delivery hospi- WashingtonAE.Racial/ethnicdisparitiesinob- glycaemiainpregnancyandrelatedhealthout-
talizationsinWisconsin.MaternChildHealthJ stetric outcomes and care: prevalence and comes in European ethnic minorities of Asian
2012;16:1455-67. determinants.AmJObstetGynecol2010;202: and African origin: a review. Food Nutr Res
28.CaugheyAB,StotlandNE,WashingtonAE, 335-43. 2013:57.
Escobar GJ. Maternal ethnicity, paternal 44.BrownHL,ChireauMV,JallahY,HowardD. 58.MalinM,GisslerM.Maternalcareandbirth
ethnicity,andparentalethnicdiscordance:pre- The “Hispanic paradox”: an investigation of outcomes among ethnic minority women in
dictors of preeclampsia. Obstet Gynecol racialdisparityinpregnancyoutcomesatater- Finland.BMCPublicHealth2009;9:84.
2005;106:156-61. tiarycaremedicalcenter.AmJObstetGynecol 59.TuckerMJ,BergCJ,CallaghanWM,HsiaJ.
29.Abi-Said D, Annegers JF, Combs- 2007;197:197.e1-7;discussion97.e7-9. The black-white disparity in pregnancy-related
CantrellD,FrankowskiRF,WillmoreLJ.Case- 45.Mbah AK, Alio AP, Marty PJ, Bruder K, mortalityfrom5conditions:differencesinprev-
controlstudyoftheriskfactorsforeclampsia. WilsonR,SalihuHM.Recurrentversusisolated alence and case-fatality rates. Am J Public
AmJEpidemiol1995;142:437-41. pre-eclampsia and risk of feto-infantmorbidity Health2007;97:247-51.
30.Mostello D, Catlin TK, Roman L, outcomes:racial/ethnicdisparity.EurJObstet 60.MacKay AP, Berg CJ, Atrash HK. Preg-
Holcomb WL Jr, Leet T. Preeclampsia in the GynecolReprodBiol2011;156:23-8. nancy-relatedmortalityfrompreeclampsiaand
parous woman: who is at risk? Am J Obstet 46.SinghGK,YuSM.Adversepregnancyout- eclampsia.ObstetGynecol2001;97:533-8.
Gynecol2002;187:425-9. comes: differences between US- and foreign- 61.Cantwell R, Clutton-Brock T, Cooper G,
31.Eskenazi B, Fenster L, Sidney S. born women in major US racial and ethnic etal.Savingmothers’lives:reviewingmaternal
A multivariate analysis of risk factors for pre- groups.AmJPublicHealth1996;86:837-43. deathstomakemotherhoodsafer:2006-2008.
eclampsia.JAMA1991;266:237-41. 47.Palomar L, DeFranco EA, Lee KA, TheEighthReportoftheConfidentialEnquiries
32.Sibai BM, Ewell M, Levine RJ, et al. Risk AllsworthJE,MugliaLJ.Paternalraceisarisk Into Maternal Deaths in the United Kingdom.
factorsassociatedwithpreeclampsiainhealthy factor for preterm birth. Am J Obstet Gynecol BJOG2011;118(Suppl1):1-203.
nulliparous women. The Calcium for Pre- 2007;197:152.e1-7. 62.Klungsoyr K, Morken NH, Irgens L,
eclampsiaPrevention(CPEP)StudyGroup.Am 48.SrinivasjoisRM,ShahS,ShahPS.Biracial Vollset SE, Skjaerven R. Secular trends in the
JObstetGynecol1997;177:1003-10. couples and adverse birth outcomes: a sys- epidemiology of pre-eclampsia throughout 40
33.LarsenWI,StrongJE,FarleyJH.Riskfac- tematicreviewandmeta-analyses.ActaObstet years in Norway: prevalence, risk factors and
torsforlatepostpartumpreeclampsia.JReprod GynecolScand2012;91:1134-46. perinatal survival. Paediatr Perinat Epidemiol
Med2012;57:35-8. 49.UrquiaML,YingI,GlazierRH,BergerH,De 2012;26:190-8.
34.MyattL,CliftonRG,RobertsJM,etal.First- Souza LR, Ray JG. Serious preeclampsia 63.Hjartardottir S, LeifssonBG, GeirssonRT,
trimester prediction of preeclampsiain nullipa- among different immigrant groups. J Obstet Steinthorsdottir V. Recurrence of hypertensive
rous women at low risk. Obstet Gynecol GynaecolCan2012;34:348-52. disorder in second pregnancy. Am J Obstet
2012;119:1234-42. 50.Knuist M, Bonsel GJ, Zondervan HA, Gynecol2006;194:916-20.
35.Mostello D, Kallogjeri D, Tungsiripat R, Treffers PE. Risk factors for preeclampsia in 64.van RijnBB, Hoeks LB, BotsML, Franx A,
Leet T. Recurrence of preeclampsia: effects of nulliparouswomenindistinctethnicgroups:a BruinseHW.Outcomesofsubsequentpregnancy
gestationalageatdeliveryofthefirstpregnancy, prospective cohort study. Obstet Gynecol afterfirstpregnancywithearly-onsetpreeclamp-
bodymassindex,paternity,andintervalbetween 1998;92:174-8. sia.AmJObstetGynecol2006;195:723-8.
births.AmJObstetGynecol2008;199:55.e1-7. 51.Zwart JJ, Jonkers MD, Richters A, et al. 65.WikstromAK,StephanssonO,CnattingiusS.
36.Fong A, Chau CT, Pan D, Ogunyemi DA. Ethnic disparity in severe acute maternal Previous preeclampsia and risks of adverse
Clinicalmorbidities,trends,anddemographics morbidity: a nationwide cohort study in The outcomes in subsequent nonpreeclamptic
ofeclampsia:apopulation-basedstudy.AmJ Netherlands. Eur J Public Health 2011;21: pregnancies.AmJObstetGynecol2011;204:
ObstetGynecol2013;209:229.e1-7. 229-34. 148.e1-6.
518 AmericanJournalofObstetrics&Gynecology JUNE2014
Expert Reviews
www.AJOG.org Obstetrics
66.Ananth CV, Peltier MR, Chavez MR, 81.Winkvist A, Mogren I, Hogberg U. Familial 96.MoffettA,LokeC.Immunologyofplacen-
KirbyRS,GetahunD,VintzileosAM.Recurrence patternsinbirthcharacteristics:impactonindi- tationineutherianmammals.NatRevImmunol
ofischemicplacental disease.ObstetGynecol vidual and population risks. Int J Epidemiol 2006;6:584-94.
2007;110:128-33. 1998;27:248-54. 97.Moffett-King A. Natural killer cells and
67.BramhamK,BrileyAL,SeedP,PostonL, 82. Salonen Ros H, Lichtenstein P, pregnancy.NatRevImmunol2002;2:656-63.
Shennan AH, Chappell LC. Adverse maternal Lipworth L, Cnattingius S. Genetic effects on 98.ChazaraO,XiongS,MoffettA.MaternalKIR
andperinataloutcomesinwomenwithprevious the liability of developing pre-eclampsia and andfetalHLA-C:afinebalance.JLeukocBiol
preeclampsia:aprospectivestudy.AmJObstet gestational hypertension. Am J Med Genet 2011;90:703-16.
Gynecol2011;204:512.e1-9. 2000;91:256-60. 99.BulmerJN,LashGE.Humanuterinenatural
68.AnselemO,GirardG,StepanianA,AzriaE, 83.Shahabi A, Wilson ML, Lewinger JP, killercells:areappraisal.MolImmunol2005;42:
MandelbrotL.Influenceofethnicityontheclin- Goodwin TM, Stern MC, Ingles SA. Genetic 511-21.
icalandbiologicexpressionofpre-eclampsiain admixtureandriskofhypertensivedisordersof 100.HibySE,WalkerJJ,O’ShaughnessyKM,
the ECLAXIR study. Int J Gynaecol Obstet pregnancy among Latinas in Los Angeles et al. Combinations of maternal KIR and fetal
2011;115:153-6. County.Epidemiology2013;24:285-94. HLA-Cgenesinfluencetheriskofpreeclampsia
69.Sibai BM, Gordon T, Thom E, et al. Risk 84.Esplin MS, Fausett MB, Fraser A, et al. and reproductive success. J Exp Med
factors for preeclampsia in healthy nulliparous Paternalandmaternalcomponentsofthepre- 2004;200:957-65.
women: a prospective multicenter study. The disposition to preeclampsia. N Engl J Med 101. Hiby SE, Regan L, Lo W, Farrell L,
National Institute of Child Health and Human 2001;344:867-72. Carrington M, Moffett A. Association of
DevelopmentNetworkofMaternal-FetalMedicine 85.Lie RT, Rasmussen S, Brunborg H, maternal killer-cell immunoglobulin-like re-
Units.AmJObstetGynecol1995;172:642-8. GjessingHK,Lie-NielsenE,IrgensLM.Fetaland ceptors and parental HLA-C genotypes with
70.Chesley LC, Cooper DW. Genetics of hy- maternalcontributionstoriskofpre-eclampsia: recurrent miscarriage. Hum Reprod 2008;23:
pertension in pregnancy: possible single gene population based study. BMJ 1998;316: 972-6.
control of pre-eclampsia and eclampsia in the 1343-7. 102.Hiby SE, Apps R, Sharkey AM, et al.
descendantsofeclampticwomen.BrJObstet 86. Robillard PY, Dekker GA, Hulsey TC. MaternalactivatingKIRsprotectagainsthuman
Gynaecol1986;93:898-908. Revisiting the epidemiological standard of reproductivefailuremediatedbyfetalHLA-C2.
71.ArngrimssonR,BjornssonS,GeirssonRT, preeclampsia:primigravidityorprimipaternity? JClinInvest2010;120:4102-10.
BjornssonH,WalkerJJ,SnaedalG.Geneticand Eur J Obstet Gynecol Reprod Biol 1999;84: 103.NakimuliA,ChazaraO,FarrellL,etal.Killer
familial predisposition to eclampsia and pre- 37-41. cell immunoglobulin-like receptor (KIR) genes
eclampsiainadefinedpopulation.BrJObstet 87.LiDK,WiS.Changingpaternityandtherisk andtheirHLA-CligandsinaUgandanpopula-
Gynaecol1990;97:762-9. of preeclampsia/eclampsia in the subsequent tion.Immunogenetics2013;65:765-75.
72.van Dijk M, Oudejans C. (Epi)genetics of pregnancy.AmJEpidemiol2000;151:57-62. 104. Norman PJ, Hollenbach JA, Nemat-
pregnancy-associated diseases. Front Genet 88.CincottaRB,BrenneckeSP.Familyhistory Gorgani N, et al. Co-evolution of human
2013;4:180. of pre-eclampsia as a predictor for pre- leukocyte antigen (HLA) class I ligands with
73.Mogren I, Hogberg U, Winkvist A, eclampsia in primigravidas. Int J Gynaecol killer-cell immunoglobulin-like receptors (KIR)
StenlundH.Familialoccurrenceofpreeclamp- Obstet1998;60:23-7. in a genetically diverse population of
sia.Epidemiology1999;10:518-22. 89.ChappellS,MorganL.Searchingforgenetic sub-Saharan Africans. PLoS Genet 2013;9:
74.Skjaerven R, Vatten LJ, Wilcox AJ, cluesto thecausesof pre-eclampsia.ClinSci e1003938.
Ronning T, Irgens LM, Lie RT. Recurrence of (Lond)2006;110:443-58. 105.XiongS,SharkeyAM,KennedyPR,etal.
pre-eclampsia across generations: exploring 90.ZhaoL,BrackenMB,DeWanAT.Genome- Maternal uterine NK cell-activating receptor
fetal and maternal genetic components in a wideassociationstudyofpre-eclampsiadetects KIR2DS1 enhances placentation. J Clin Invest
populationbasedcohort.BMJ2005;331:877. novelmaternalsinglenucleotidepolymorphisms 2013;123:4264-72.
75.Carr DB, Epplein M, Johnson CO, and copy-number variants in subsets of the 106.RosenbergK,TrevathanW.Birth,obstet-
Easterling TR, Critchlow CW. A sister’s risk: Hyperglycemia and Adverse Pregnancy rics and human evolution. BJOG 2002;109:
familyhistoryasapredictorofpreeclampsia.Am Outcome(HAPO)studycohort.AnnHumGenet 1199-206.
JObstetGynecol2005;193:965-72. 2013;77:277-87. 107.AbitbolMM,ChervenahF,LedgerW.Birth
76.DawsonLM,ParfreyPS,HeffertonD,etal. 91. BuurmaAJ,TurnerRJ,DriessenJH,etal. andhumanevolution:anatomicalandobstetrical
FamilialriskofpreeclampsiainNewfoundland:a Genetic variants in pre-eclampsia: a meta- mechanics in primates. Westport Bergin and
population-based study. J Am Soc Nephrol analysis. Hum Reprod Update 2013;19: Garvey;1996.
2002;13:1901-6. 289-303. 108.Cavalli-Sforza LL, Bodmer WF. The ge-
77.Nilsson E, Salonen Ros H, Cnattingius S, 92.Staines-Urias E, Paez MC, Doyle P, et al. netics of human populations. San Francisco:
LichtensteinP.Theimportanceofgeneticand Genetic association studies in pre-eclampsia: W.H.FreemanandCompany;1971:612-3.
environmental effects for pre-eclampsia and systematic meta-analyses and field synopsis. 109.WittmanAB,WallLL.Theevolutionaryor-
gestationalhypertension:afamilystudy.BJOG IntJEpidemiol2012;41:1764-75. igins of obstructed labor: bipedalism, enceph-
2004;111:200-6. 93.Goddard KA, Tromp G, Romero R, et al. alization, and the human obstetric dilemma.
78.Plunkett J, Borecki I, Morgan T, Candidate-gene association study of mothers ObstetGynecolSurv2007;62:739-48.
Stamilio D, Muglia LJ. Population-based esti- withpre-eclampsia,andtheirinfants,analyzing 110.ThomasJ,ParanjothyS.RoyalCollegeof
mate of sibling risk for preterm birth, preterm 775SNPsin190genes.HumHered2007;63: ObstetriciansandGynaecologistsClinicalEffec-
premature rupture of membranes, placental 1-16. tiveness Support Unit. National Sentinel Cae-
abruption and pre-eclampsia. BMC Genet 94.GopecConsortium.Disentanglingfetaland sareanSectionAuditReport.London,UK:RCOG
2008;9:44. maternal susceptibility for pre-eclampsia: a Press;2001.
79.Toivonen S, Keski-Nisula L, Saarikoski S, BritishMulticentercandidate-genestudy.AmJ 111.ChengYW,NorwitzER,CaugheyAB.The
HeinonenS.Riskofplacentalabruptioninfirst- HumGenet2005;77:127-31. relationship of fetal position and ethnicity with
degree relatives of index patients. Clin Genet 95.Rich-Edwards JW, Fraser A, Lawlor DA, shoulderdystociaandbirthinjury.AmJObstet
2004;66:244-6. CatovJM,etal. Pregnancycharacteristicsand Gynecol2006;195:856-62.
80.PorterTF,FraserAM,HunterCY,WardRH, women’sfuturecardiovascularhealth:anunder- 112.PattinsonRC.Pelvimetryforfetalcephalic
Varner MW. The risk of preterm birth across used opportunity to improve women’s health? presentationsatterm.CochraneDatabaseSyst
generations.ObstetGynecol1997;90:63-7. EpidemiolRev2014;36:57-70. Rev2000:CD000161.
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