Is Preterm Birth a Human-Specific Syndrome? Julie Baker Phillips, Patrick Abbot, Antonis Rokas ...

33 Pages·2015·0.67 MB·English

136
review Evolution,Medicine,andPublicHealth[2015]pp.136–148
doi:10.1093/emph/eov010
Is preterm birth a
human-specific syndrome?
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Julie BakerPhillips, Patrick Abbot andAntonis Rokas* w
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DepartmentofBiologicalSciences,VanderbiltUniversity,VUStationB35-1364,Nashville,TN37235,USA d
*Correspondingauthor.DepartmentofBiologicalSciences,VanderbiltUniversity,VUStationB35-1364,Nashville,TN fro
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37235,USA.Tel:[phone];E-mail:[email protected] h
Received7February2015;revisedversionaccepted2June2015 ttp
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ABSTRACT em
Human preterm birth(PTB), a multifactorial syndrome affecting offspring born before 37 completed ic
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weeksofgestation,istheleadingcauseofnewborndeathworldwide.Remarkably,thedegreetowhich up
earlyparturitioncontributestomortalityinotherplacentalmammalsremainsunclear.Togaininsights .co
m
onwhetherPTBisahuman-specificsyndrome,weexaminedwithin-andbetween-speciesvariationin /e
m
gestation length across placental mammals and the impact of early parturition on offspring fitness. p
h
Withinspecies,gestationlengthisnormallydistributed,andallspeciesappeartooccasionallygivebirth /a
beforethe‘optimal’time.Furthermore,humangestationlength,likethatofmanymammalianspecies, rtic
le
scalesproportionallytobodymass,suggestingthatthistrait,likemanyothers,isconstrainedbybody -a
b
size.Prematurehumanssufferfromnumerouscognitiveimpairments,butlittleisknownofcognitive stra
impairmentsinotherplacentalmammals.Humangestationdiffersinthetimingofthe‘braingrowth c
t/2
spurt’,whereunlikemanymammals,includingcloselyrelatedprimates,thetrajectoryofhumanbrain 0
1
growthdirectlyoverlapswiththeparturitiontimewindow.Thus,althoughallmammalsexperienceearly 5/1
parturition, the fitness costs imposed by the cognitive impairments may be unique to our species. /1
3
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DescribingPTBbroadlyinmammalsopensavenuesforcomparativestudiesonthephysiologicaland /1
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geneticregulatorsofbirthtimingaswellasthedevelopmentofnewmammalianmodelsofthedisease. 9
6
5
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KEYWORDS: prematurity; fitness; gestation length; allometry b
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I. INTRODUCTION t o
increasinginalmostallcountries[3].PTBcanstem n 2
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Pretermbirth(PTB),definedinhumansasbirthbe- from environmental factors such as infection, in- M
a
fore37completedweeksofgestation,isacomplex flammationandstress[1],aswellasgeneticones; rc
h
multifactorial syndrome that originates when the forexample,familialstudieshavedemonstratedan 2
0
1
complexinterplayof‘anatomical,physiological,bio- increased risk for PTB in women with sisters who 9
chemical, endocrinological and immunological have given birth prematurely [4] and in women
events’ necessary for parturition is disrupted [1]. whose grandparents were born preterm [5]. More
ComplicationsofPTBaretheleadingcauseofdeath recently, genome-wide association studies have
innewbornsandinchildrenundertheageof5[2]. begun to identify candidate genes associated with
Globallymorethan1in10babiesisbornbefore37 increasedriskofPTBinvarioushumanpopulations
weeks of gestation, and PTB rates appear to be [1,6].
(cid:2)TheAuthor(s)2015.PublishedbyOxfordUniversityPressonbehalfoftheFoundationforEvolution,Medicine,andPublicHealth.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/4.0/),
whichpermitsunrestrictedreuse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Ispretermbirthhuman-specific? Phillipsetal. | 137
A complete understanding of PTB will require gestationlengthhasbeenuniquelyinfluencedbyse-
identifyingthemolecular andgeneticmechanisms lection.Forexample,ithasbeenrecentlyarguedthat
that control gestation length, pregnancy mainten- PTBismorecommoninhumansduetoselectionfor
anceandinitiationofparturition.Althoughthestudy shortened gestation length driven by fitness costs
ofanimalmodelshasyieldedmanyinsightsintothe associated with cephalopelvic disproportion [6].
physiology of pregnancy, the functional mechan- Finally,ifmammalsbroadlyexperiencePTB,whatis
isms that result in early parturition remain poorly the impact of variation in gestation length on off-
understood [7–9]. This is so in part to our lack of springfitnessacrossthespeciesthatexhibitit?Inthis
understanding of whether the syndrome of PTB is criticalreview,weaddressthefirstquestionbysur-
human-specific,orwhetherotherorganismsexperi- veyingthedistributionsofgestationallengthsandthe
ence PTB as well. Although to our knowledge this secondquestionthroughexaminingtheevolutionary
D
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question has not been heretofore explicitly ad- constraintsongestationlengthsrelativetobodysize w
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dressed,expertshavesofararguedfortheunique- andbrainsizeacrossawiderangeofplacentalmam- lo
a
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nessofhumanparturition[10,11].If,asSmithhas mals.Toaddressthethirdquestion,weexaminethe e
d
stated, ‘human parturition is a distinctly human fitness costs associated with early parturition in fro
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event’[10]thenitfollowsthatpathologiesofpartur- humans and other mammals. Finally, we discuss h
ition, such as PTB, might also be confined to our howtheanswerstothesequestionsprovideanovel ttp
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species.Severalstatementsinthepublishedlitera- evolutionary perspective to studying the molecular ://a
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tureseemtosupportthisnotionwithrespecttoPTB basisofPTBbroadlyinmammals. ad
e
[12–15].Forexample,the2007NationalAcademies m
ic
reportonPTBstatedthat‘mostanimalspeciesdo .o
II. GESTATION LENGTH SHOWS u
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not have significant rates of spontaneous preterm .c
SIMILAR INTRA-SPECIES VARIATION o
birth’[15],Rubensetal.recentlyopinedthat‘spon- m
ACROSS MAMMALS /e
taneous idiopathic PTB is very uncommon in m
p
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species other than humans’ [12], and Bryant- Allquantitativetraits,suchashumanheight[18–20], /a
Greenwood et al. stated that ‘the serious clinical haveacontinuousrangeofvariation.Inthiscontext, rtic
le
problemofspontaneousPTBappearstobealmost we expect the presence of measurable variance in -a
b
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unknowninspeciesotherthanhumans’[14]. reproductivetraits.Forexample,long-termpopula- tra
IfindeedPTBisuniquetohumans,thenconsid- tion studies in British islands, such as with Soay ct/2
erable nuance is required in translating studies of sheep in St Kilda island and red-tailed deer on the 01
5
animalmodelstoanunderstandingoftheetiology IsleofRum,haveuncoveredabundantvariationin /1
/1
ofPTB,aspresumablymostofthegeneticcontribu- longevity,ageatprimiparity,lifetimefecundityand 36
/1
tors to the disease evolved after the divergence of lifetime reproductive success [21–23], and have 7
9
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humansfromthechimps,e.g.[6,16,17].However,if providedstrongevidencefortheheritabilityofsuch 5
6
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PTBisnotrestrictedtohumans,knowledgeonthe variation[21,22].Forexample,theaveragelifetime b
y
prevalenceandsymptomsofPTBinplacentalmam- fecundityintheRamMountainpopulationofSoay g
u
mals has the potential to invigorate research sheep is 5.3 lambs, ranging from 0 to 15, and its es
t o
strategies through comparative studies on the estimated heritability is significantly larger than n
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physiologicalandgeneticregulatorsofbirthtiming zero, suggesting that this reproductive trait is not 8
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as well as the development of new mammalian only variable, but that its variance has a heritable a
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modelsofthedisease. component[23].Theinsightswehavegainedfrom h 2
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AddressingthedegreetowhichPTBisahuman- theselong-termstudiesonvariationinreproductive 1
9
specificsyndromerequirescarefullyexaminingthree traits suggest that heritable variation in gestation
questions.First,istheamountofvariationingesta- length, like other reproductive traits, should also
tion length of humans distinct from that of other be a general feature of mammalian life history.
mammals? Additionally, is there large enough vari- Indeed,gestationlengthdatafromdiverseplacental
ationinbirthtiming,asthereisinhumans,suchthat mammalsshowthatallexperiencevariationinbirth
somebirthsnormallyoccurbeforefull-termgestation timing (Fig. 1). For example, guinea pigs, Cavia
inothermammals?Second,istheaveragegestation porcellus, have gestation lengths ranging from 8.5
length of human pregnancy in any way unusual to 10 weeks [24], whereas humans have gestation
comparedtoothermammals?Answeringthisques- lengths ranging from 28 to 50 weeks [25]. From
tionisdirectlyrelevanttoaddressingwhetherhuman Fig.1,weseethereisnoexpectationfromlife-history
138 | Phillipsetal. Evolution,Medicine,andPublicHealth
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Figure 1. Intra-speciesvariationingestationlengthissimilaramongmanymammals.(A)Wecollectedthearithmeticmeansandstandarddeviations,when ttp
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available,indaysforallplacentalmammalswithcompletegenomes.Samplesizesrangedfrom2to17000,withamedianof104.Inallcases,onlylivebirthswere ://a
considered.Examinationofthepotentialforskewinmodelchoice(normalvslog-normal)showedthatthemeansquarederrorbetweenthetwodistributionswas ca
d
likelywellbelowtheerrorinmeasurementofgestationlengthsreportedintheoriginalresearch.Boxescontainthemeanplus/minus1SD;whiskersextendtoplus/ e
m
minus3SD.Verticallinesindicate92.5%completedgestationtimesuggestingeachspeciesexperiences‘preterm’birthaccordingtothehumandefinitionwiththe ic
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exclusionofhorses,goatsandrodents.(B)Comparisonofthecoefficientofvariationacrossspecies.Plotsandanalysiswereperformedusingtheggplot2package u
p
inR3.1.2[122,123].Referencesforeachspeciescanbefoundasfollows:human[25],chimpanzee[29],gorilla[124],orangutan[125],long-tailedmacaqueand .co
m
rhesusmacaque[126],baboon[127],marmoset[128],ratandrabbit[129],guineapig[24],goatandmouse[130],cow[131]andhorse[132] /e
m
p
h
/a
theory that gestation length variation is absent in howthegestationallength-baseddefinitionofhuman rtic
mammalsgenerally,noristhereevidencethatvari- PTBappliestootherspecies.Forexample,generalizing le
-a
ation in human gestation length is remarkable or thehuman-baseddefinitionofPTBas‘parturitionprior bs
unusual compared to other mammal species, par- to92.5%(259daysor37weeks/280daysor40weeks) trac
ticularlyotherprimates. completed gestation’ and assuming that gestational t/20
1
length is a normally distributed variable [25] allows 5/1
ustoexaminetheoccurrenceofPTBinanyplacental /13
III. PTB IS OBSERVED IN MANY mammal species for which population gestational 6/1
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MAMMALS 9
lengthdataareavailable. 6
5
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Althoughallmammalsexperiencevariationinges- Applying this generalized, percentage-based cut- 1 b
tationlength,isthesyndromeofPTBitselfuniqueto off definition of PTB to gestation length data from y g
u
humans? The World Health Organization defines diversespeciesshowsthatparturitionbefore92.5% es
human PTB as ‘babies born alive before 37 weeks completed gestation occurs in many organisms, t on
ofpregnancyarecompleted’[26].Contributedbythe includinginallexaminedprimates,suchaschimpan- 28
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World Health Organization and supported by the zeesandgorillas(Fig.1).Interestingly,onedefinition a
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International Federation of Gynecology and of PTB in chimpanzees, defined as 2 SD below the h
2
Obstetrics, the basis of this definition stems from mean[29],resultsinanestimated16%ofchimpan- 01
9
astatisticalanalysisofthedistributionofgestational zeesbornpreterm,suggestingthattheprevalenceof
ageatbirth,basedonthefirstdayofthelastmen- ‘PTB’inchimpanzees,ourclosestrelatives,appears
strualperiod[27].Thepurposeofsuchadefinition tobesimilartotheprevalenceofPTBinhumans[2].
wastoprovideastandardizedlanguageforPTB,but AlthoughitisgenerallyunclearwhetherPTBisspon-
thedefinitionlacksmedicalorbiological meaning; taneousorinducedintheseanimals,evidencefrom
asa result ‘preterm’ shouldbe distinguished from horses suggests that PTB in non-human mammals
‘premature’, which describes a lack of completed can result from placental infections [30], a well-
fetaldevelopment[28]. documentedcauseofPTBinhumans[31].
Although no definition of PTB exists for species Interestingly,‘PTB’appearstobeabsentinmost
other than our own, it is interesting to contemplate of the animal models of the human syndrome.
Ispretermbirthhuman-specific? Phillipsetal. | 139
Thegestationlengthsofnewbornsinmice,rats,and bodymass,orthatthetwotraitsareunderashared
guineapigsdonotappeartocrossbelowathreshold constraint.Forexample,recentworkhassuggested
of92.5%ofcompletedgestation(Fig.1).Theappar- thathumangestationlengthmaybeprimarilycon-
entabsenceofPTBinRodentiaisparticularlyinter- strainedbymetabolism[51],raisingthealternative
esting as this order shows remarkable diversity in hypothesisthatgestationlengthandmaternalbody
bothgestationlength,whichcanrangefrom20days mass,whichalsoallometricallyscaleswithmetabol-
(e.g.Musmusculus)to150days(e.g.Hydrochoerus ism,maybeunderasharedmetabolicconstraint.
hydrochaeris), and developmental strategy; young Thediversityoftraitsassociatedwithmammalian
may be precocial (e.g. Mus musculus) or altricial reproduction and pregnancy may also play an im-
(e.g. Cavia porcellus). This diversity suggests that portantroleincontrollinggestationlength.Forex-
the mechanisms underlying the apparent absence ample, mammals employ different precocial and
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ofPTBinthislineagemaynotbeinfluencedbyges- altricialstrategiesinneonatedevelopmentstateat w
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tationlengthorbydevelopmentalstrategy. birth.Precocialspecieshaveoffspringthataretyp- lo
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ically well-developed, born with eyes open and are e
d
IV. OPTIMAL GESTATIONAL LENGTH immediately mobile (e.g. most ungulates). In con- from
SCALES WITH BODY SIZE trast,offspringfromaltricialspeciesarebornwhile h
relativelyimmobile,deaf,blindandunabletoobtain ttp
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Allometry,namelyhowtraitsscalewithoneanother food without parental assistance. Precocial mam- ://a
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[32], has long provided a framework for not only mals typically have longer gestation periods ad
e
understanding how traits function and vary across compared to altricial ones. When a distinction is m
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ecologicalandevolutionarytime,butalsoforiden- made between altricial and precocial mammals, .o
u
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tifyingoutliersandtheunderlyingecologicalorevo- the scaling relationships of precocial and altricial .c
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lutionary reasons that gave rise to them [33]. mammals become distinct, but retain similar m
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Allometricstudieshavebeenusedextensivelytopre- scalingexponents[48,50](Fig.2).Additionally,off- m
p
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dict the values of morphological, ecological, and springinaltricialmammalsaretypicallyborninlit- /a
physiological traits as a function of an organism’s ters; increased litter sizes have been shown to rtic
le
bodysize,asmeasuredbybodymass[34–41].Well- reducegestationlengthsincats[52]anddogs[53]. -a
b
s
knownexamplesofallometrictraitsthatscalewith Similarly,multiplebirthsinhumansshowreduced tra
bodymassincludevertebratebrainsize[35,39],lon- gestationlengths,with50%oftwinand90%oftrip- ct/2
gevity[38,40]andbasalmetabolicrate[34,36,37, letspregnanciesbornpreterm[54]. 01
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41].Forexample,boththebasalmetabolicrateand Another pregnancy-associated phenotype that /1
/1
brainsizescalewithmammalianbodymasstothe varies extensively across mammals is placental 36
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three-fourthofthepower[37,42]. morphology. Mammalian placentas can be classi- 7
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Allometricrelationshipshavealsobeendescribed fiedintothreeprincipletypesofinterfaces,namely 5
6
1
formanymammalianreproductivetraits,suchaslit- epitheliochorial, endotheliochorial and hemo- b
y
ter weight [38,43, 44],neonate weight [38, 43–45], chorial. Frequently more than one placental inter- g
u
neonatebrainweight[42,43,46]andthepercapita faceoccurswithinanorder,e.g.epitheliochorialin es
t o
growth rate (Malthusian parameter) [38, 45], strepsirrhine primates and hemochorial in haplor- n
2
providingawindowforunderstandingtheevolution rhineprimates.Placentalshapeandinterdigitation 8
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of pregnancy-associated traits in mammalian spe- also vary frequently within mammalian orders. a
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ciesandtheidentificationoftrendsandconstraints. Interestingly,placentalstructurecorrelatedwithdif- h 2
0
Forexample,studyoftherelationshipbetweenneo- ferences in gestation length and fetal growth [55]. 1
9
natal brain mass and body size has identified an Analysis of gestation length against body mass in
evolutionary trend toward larger brain size relative haplorrhine primates, which all have hemochorial
tofetalbodymasscomparedtonon-primates[42]. placentas,showsthathumansaretypicalfororgan-
Gestation length has also been found to scale to ismswithhemochorialplacentas(Fig.2).
maternalbodymassby1/4[38,43,47,48],butsub- Human encephalization has resulted in a
sequentstudiesutilizingphylogeny-informedstatis- cephalopelvic disproportion that has been argued
ticssupportascalingexponentcloserto0.10[49,50] toplayaroleinthecomplicationoflabor[56],and
(Fig. 2). The relationship between body mass and that the dramatic cephalopelvic changes have re-
gestationlengthsuggeststhatthetimingofgesta- sulted in shortened gestation lengths in humans
tioninmammalsiseitherconstrainedbymaternal [6].Encephalizationisnotaprimatetraitbutrather
140 | Phillipsetal. Evolution,Medicine,andPublicHealth
A
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Figure 2. Gestationlengthisconstrainedbymaternalbodymassinplacentalmammals.Logarithmicplotofgestationlength es
(days)againstmaternalbodymass(grams)for1100placentalmammals(A)and120primates(B).Thescalingcoefficientforall t on
mammalsis0.09(SE=0.007).Altricialandprecocialmammalshavesimilarslopes,0.10(SE=0.008)and0.10(SE=0.01), 28
M
respectively.Withinprimates,thescalingcoefficientis0.08(SE=0.02).Epitheliochorialandhemochorialhavesimilarslopes,
a
0.10(SE=0.04)and0.09(SE=0.02),respectively.MassandgestationlengthdatatakenfromthePanTheriadatabase[133]. rch
2
Offspringnumberperlitterwasusedasaproxyforneonatedevelopmentstate.PlacentalstructurewasasdescribedbyMossman 0
1
[134].Datawerelinkedtoasupertreeofextantmammals[135].Wepresenttherelationshipbetweenlog-transformedbodymass, 9
andlog-transformedgestationlengthusingphylogeneticgeneralizedleastsquares.StatisticaltestswereperformedinR3.1.2
[123]usingthepackagesape[136],caper[137]andnlme[138]
acomplexcombinationofchangesinbraingrowth in humans. To make allometric analyses from an
specific to the human lineage [57]. Humans and obviouslyenlargedfeaturewouldbeakintosuggest-
closely related primates do not share a common ingthathumanskeletalmassisdecreasedrelativeto
brain ontology [57], thus calculating human gesta- brainsize, whenstudies havedemonstrated areli-
tion by comparing brain size is not sufficient evi- ableallometricrelationshipbetweenbodyandskel-
dence to suggest a shortening of gestation length etalmass[58].
Ispretermbirthhuman-specific? Phillipsetal. | 141
Characterization of allometric relationships also ‘preterm’, which denotes an earlier than expected
providestheopportunitytoidentifyoutliers:organ- timing of parturition and the quantity that most
isms in which the relationship between two biolo- humanPTBstudiesrelyon,and‘premature’,which
gicalvariablesofinterestsignificantlydeviatesfrom denotesalackofcompletedfetaldevelopmentand
themajorityofothers.Suchoutlierscanbeinform- the source ofany fitness consequences associated
ativeaboutevolution,astheyreflectcasesinwhich withPTB[28].BecausePTBisdefinedbygestational
oneofthevariableshasbeensculptedbyadaptive age in humans, it is often divided into three
evolution.Forexample,primatestendtohavelarger subcategories: extremely preterm (birth before
brainsizesthanpredictedbyascalingrelationship 28weekscompletedgestation),verypreterm(birth
between brain size and body mass in mammals. before32weekscompletedgestation,butafter28)
Withinprimates,humanshaveabrainsize3.1times and moderate/late preterm (birth before 37 weeks
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larger than predicted for the average primate [59]. completed gestation, but after 32). As each sub- w
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Forgestation length,organismswithlongergesta- category has associated complications and levels lo
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tionlengthsthanexpectedgiventheirbodymassare ofprematurity[69],fitnessdifferentialsbetweenpre- e
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primarilyfromtheorderChiroptera,whereasorgan- termandfull-termoffspringcanbeinterpolatedby fro
m
isms with shorter than expected gestation lengths thedifferentialsurvivalratesofeachgroup. h
are largely from Cetacea [47]. Mammals in these Neonatemortalityislowestininfantsbornatfull- ttp
s
ordersmaybeidealforcomparativeandfunctional term, between 38 and 41 weeks of gestation, with ://a
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genomicanalysestobetterunderstandregulationof mortalityratesrisinginverselytogestationalagein ad
e
gestationtiming. preterm infants [70, 71]. The significant impact of m
ic
In summary, optimal gestation length in most PTBonoffspringfitnessisindicatedbythefactthat .o
u
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mammals appears to be strongly correlated with PTBistheleadingdirectcauseofneonatemortality .c
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bodysize;simplyput,formostmammals,including (defined as deaths within the first 4 weeks of life) m
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humans, gestation length can be easily be worldwide; for example, approximately 27% of the m
p
h
extrapolatedfromtheirbodymass.Thiscorrelation 4millionneonataldeathsin2000wereattributedto /a
israthersurprising,notonlygiventhatmanyofthe complications fromPTB[72].Preterminfantshave rtic
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reproduction- and pregnancy-associated traits dis- higherratesofcerebralpalsy[73–75],chroniclung -a
b
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cussedabovevarywidelyacrossmammalsbutalso disease [76–78], necrotizing enterocolitis [79–81], tra
c
given the genetic complexity stemming from the retinopathy [82–84], hearing impairments [75] and t/2
0
interplay of maternal, paternal and fetal genomes hospitalreadmissions[85,86]comparedtofull-term 1
5
inherentinmammalianpregnancy[60].Thus,even infants. Neonate deaths and increased rates of /1
/1
though control of parturition, whether maternal, chronic health conditions arise from immature 36
/1
fetal or both, has been shown to be an important organsystemsthatarenotyetdevelopedtosupport 7
9
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regulator of gestation length and birth timing lifeoutsidetheintrauterineenvironment[15]. 5
6
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[61–64], it appears that such molecular control InthefewrecordsoffitnessoutcomesforPTBin b
y
mechanisms of parturition are evolutionarily primates,bothchimpanzeesandpigtailmacaques g
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coupledwithorganismbodysize. experience decreased survival rates resulting from s
t o
preterm delivery [29, 87]. In chimpanzees, all but n
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one chimpanzee in 17 recorded preterm deliveries 8
V. PREMATURITY IMPOSES FITNESS M
((cid:2)208 days as defined by Wildman et al.) were a
CONSEQUENCES rc
aborted,stillbornordiedduringtheneonatalperiod h 2
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Fitnessisacomplexmeasurethataccountsfornu- [29].Inpigtailmacaques,greaterthan95%of‘high 1
9
merous life-history traits in age-structured popula- risknewborns’,whichincludepremature,lowbirth
tions. Fitness has been equated with reproductive weight,andmaternallyrejectedoffspring,dieifleft
success[65,66],andforthepurposeofevolutionary in maternal care. In contrast, if provided care in a
genetics, fitness measures the rate of increase in nurseryenvironment,themortalityrateofhighrisk
individualspossessingspecificgenotypesorpheno- newbornpigtailmacaquesisreducedtoonly20%.
types [67]. Individuals with increased rates of sur- Premature pigtail macaques have not only
vival and reproductive success are expected to decreased survival but complex patterns of behav-
haveincreasedfitness[66,68]. ioraltraitsthatdifferfromfull-termoffspring[87].
Discussing the fitness consequences of PTB ThefitnessconsequencesofPTBcontinuetobe
requires that we first disentangle the meanings of highlynoticeableinearlychildhood[73,88,89],with
142 | Phillipsetal. Evolution,Medicine,andPublicHealth
complicationsfromPTBbeingthelargestcauseof reddeerareassociated withseasonaltemperature
mortalityinchildrenunder5[2].Forexample,mor- fluctuations during the final months of gestation;
tality rates in early childhood, ages 1–5, in a large lowerbirthweightsincoolertemperaturesarelinked
Swedishcohortnotonlyshowedastrong,significant todecreasedneonatalsurvivalandincreasedageat
inverse relationship with gestational age [90], and first reproduction [101]. In Soay sheep, increased
thusreducedfitnesscomparedtofull-termchildren, populationdensity,whichprobablyleadstocompe-
but also a significant association between titionforlimitedfoodresourcesandincreasedcom-
decreasing gestational age and the severity of the petitionformates,isassociatedwithreducedbirth
fitnesscost. weightsandneonatalsurvival[102].
Fewer studies have examined the long-term ef- Insummary,thesynthesisofthecurrentlyavail-
fects of prematurity in young adults [90–96]. abledatasuggeststhatalthoughthefitnessconse-
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Mortalityratesinyoungadulthood,ages18–36,also quencesofPTBintheearlyyearsofhumanlifeare w
n
show an inverse relationship with gestational age verylargeininfancyandearlychildhood,theconse- lo
a
d
[90,96].Theoutcomesofextremelylowbirthweight quencesmaybesmallerinadulthood.Furthermore, e
d
(ELBW)infants,whoseaveragegestationalagewas NSI are the most consistently reported difference fro
m
27.1weeks,includeasubstantiallylargernumberof betweenpretermandfulltermneonates.Cognitive h
incidents of neurosensory impairments (NSI) deficits,intheabsenceofmajormotordefects,are ttp
s
including cerebral palsy, mental retardation, blind- thedominantneurodevelopmentalsequelaeinPTB ://a
c
nessanddeafness,andweremorelikelytoinclude infants[105].Thedegreetowhichhuman-specificor ad
e
multipleimpairments[96].Additionally,maleELBW human-elaborated adaptations contribute to these m
ic
infantshaveincreasedprevalenceofphysicalcondi- cognitive deficits is unknown. Although little data .o
u
p
tionsincludingseizures,asthmaandrecurrentbron- exist on either the rate of incidence of prematurity .c
o
chitis[92,95,96].EventhoughtheprevalenceofNSI inothermammalsortheresultingcognitiveimpair- m
/e
was higher inyoung adultswithlow birth weights, mentsofPTBinothermammals,theresultstodate m
p
h
studies support that young adults born with low indicatethatneonatefitnessislinkedtogestational /a
birth weights are only slightly disadvantaged in re- age, environmental fluctuations and reduced birth rtic
le
gards to participation in sports and other social weights[29,87,101,102]. -a
b
s
activities, as well as romantic and sexual relation- tra
c
ships [92, 95, 97, 98]. The argument that preterm VI. TIMING OF BRAIN DEVELOPMENT t/2
0
bornadultshavesimilarqualityoflifeissurrounded 1
MAY PLAY AN IMPORTANT ROLE IN 5
by dissention both in the medical community [97, /1
HUMAN PREMATURITY /1
98]andbyparents[99,100].Theprecisedegreeto 36
/1
whichfitnessisaffectedinpreterminfantsthatsur- One obvious difference between humans and our 7
9
6
vivetoadulthood,especiallythoseimpactedbyNSI, closelyrelatedprimatesisourhighlyincreasedim- 5
6
1
remainsunclear. maturityattermbirth,primarilyduetothesubstan- b
y
DefiningPTBbyapercentagebasedcut-offleads tial postnatal brain growth required for normal g
u
to the inference that many placental mammals ex- human development [56, 107]. The ‘brain growth es
periencepretermdelivery.However,understanding spurt’definesthewindowduringdevelopmentwhen t on
2
theimpact,ifany,ofvariationingestationlengthon thebrainispassingthroughitsmostrapidperiodof 8
M
offspring fitness in non-human mammals is chal- growth [108, 109], and can be visualized as a sig- a
rc
lengingduetothelackofstudies[12,29].Onearea moidalcurvewhenbraingrowthisplotted against h 2
0
wheretherelationshipbetweenfitnessandparam- age [110]. Rough categorization of growth spurts 1
9
eters associated with reproduction has been well suggeststhreecategories:(i)prenatal,(ii)perinatal
studiedinbothhumansandothermammals[101– and (iii) postnatal. Altricial young undergo growth
104]isinthecontextofchangesintheenvironment. spurts prenatally, precocial young postnatally,
Inhumans,offspringbornduringtheFinnishfamine whereas organisms that exhibit intermediates be-
experienced decreased survival rates, but the tween altriciality and precociality undergo growth
increasedmortalityratesdidnotpersistinlaterlife spurtsperinatally.Forexample,theperinatalgrowth
[104] suggestingthe fitness differential due toma- spurtinhumansplacesthespeciesintheintermedi-
ternalexposuretoenvironmentalhardshipslessens ate state of development, previously described as
oncetheoffspringreachesreproductiveage.Inwild ‘secondarily altricial’ [111], which is evidenced by
mammalpopulations,differencesinbirthweightsof thetypicallysingletonbirthsofneonateswithopen
Ispretermbirthhuman-specific? Phillipsetal. | 143
eyesandearsatbirth(precociality)combinedwith PrematurelybornhumanssuffernumerousNSI,but
relativehelplessnessofhumanbabiescomparedto knowledgeofcognitiveimpairmentsinotherplacen-
other primates (altriciality) [56, 107] and by the talmammalsislackingbecausestudiesarerareand
reducedneonatebrainsizerelativetotheadultsize difficult, given the drastic mortality rate of PTB in
inhumanscomparedtochimps[112]. mammals outside of humans. The timing of the
Importantly,thebraingrowthspurttimewindow human‘braingrowthspurt’hasthepotentialtoex-
notonlyreflectsaperiodwherebrainsizegrowsdra- plainincreasedcognitiveimpairmentsinpremature
matically,butalsoaperiodofenhancedvulnerability humansasthetrajectoryofgrowthisunlikeclosely
ofthegrowingbrainandorganismtoendogenous relatedprimatesanddirectlyoverlapswiththepar-
andexogenousinsults[105,108,109,113].Humans turitiontimewindow.
experience themostrapidbraingrowthduringthe Whatguidance,ifany,doesthisevolutionaryper-
D
o
perinatal and into the postnatal phase of develop- spectiveprovideforfurtheringourunderstandingof w
n
ment[113,114],butrecentcomparisontochimpan- themolecularbasisofPTB?Webelievethatthiscrit- lo
a
d
zeeshasshownourclosestextantrelativedoesnot icalreviewillustratesthreeways,whichhavegenerally e
d
sharethispatternofbraingrowth[114].Rapidbrain notbeenconsideredinthePTBliterature,toadvance fro
m
growthinchimpanzeescontinuestoapproximately ourunderstandingofthisserioussyndrome. h
22 weeks of the 34–35 week gestation period, First, the widespread occurrence of PTB in wild ttp
s
whereasrapidhumanbraingrowthcontinuestoat mammal populations strongly argues for decoupl- ://a
c
least32weeks[114].Therefore,inamannerdistinct ingpretermparturitionfromprematureparturition ad
e
from our closest primate relatives, the period of andsuggeststhatallmammalscouldinprinciplebe m
ic
enhanced vulnerability resulting from the brain useful,atleastthroughcomparativeandfunctional .o
u
p
growthspurtoverlapswithparturitioninhumans. genomicsexperiments,forunderstandinggestation .c
o
Braingrowthpatternsarehighlyvariableinclosely lengthandbirthtiming,eveniftheyarepoormodels m
/e
relatedprimates[115];amorecompleteunderstand- for understanding the pathogenesis of the syn- m
p
h
ingofthevariationinthesepatternsisnecessaryto drome.Infact,itcanbearguedthatamechanistic /a
betterunderstandcognitiveimpairmentsthatresult understandingoftheregulationofmammalianges- rtic
le
fromPTB.Thevulnerabilityofthebrainduetorapid tationlengthwouldinfactcontributetounderstand- -a
b
s
growth rates at parturition may play an important ingPTBpathogenesis,albeitnotbydirectinference. tra
c
role in the cognitive impairments resulting from Second,thesignificantdeviationsintheallomet- t/2
0
early parturition in humans, and as such this may ricrelationshipsbetweengestationlengthandbody 1
5
explainthelackofcognitiveimpairmentsinorgan- mass of organisms in the orders Chiroptera and /1
/1
ismswith‘growthspurts’primarilyoccurringduring Cetacea relative to the relationships observed in 36
/1
prenatalorpostnataldevelopment(Fig.3).Recent most other mammals, raises the hypothesis that 7
9
6
workinbaboonshasprovidedevidencethatthese- the evolution of these two traits (gestation length 5
6
1
quenceofcerebraldevelopmentandpatternofcere- and body mass) might be less correlated or b
y
bral injury between the prematurely delivered decoupled in these two orders. Much like species g
u
e
baboonsisremarkablysimilartothatofprematurely with exaggerated or novel characters, which have s
t o
born humans [116], but the long-term behavioral beenexploitedbyevolutionarydevelopmentalbiolo- n
2
phenotypes have yet to be described in this gists to generate insights into the genetic basis of 8
M
promisinganimalmodel. theunderlyingcharacters[117,118],speciesinthese a
rc
two orders can be viewed as outliers that harbor h 2
0
greatpromiseforbeginningtoelucidatethemolecu- 1
VII. THE SIGNIFICANCE OF AN 9
larmechanismsthatcontrolmammaliangestation
EVOLUTIONARY PERSPECTIVE FOR
lengthandtiming.
UNDERSTANDING HUMAN PTB
Third,a comparative perspective across develop-
Gestationlengthisnormallydistributedandscales ment at the tissue level provides a way to identify
proportionallytobodymassacrossawidediversity organismsthatbettermodeldiseaseaspectsofthe
of placental mammals, suggesting that not only is PTB syndrome. For example, the resemblance be-
this trait correlated with body size, but also that tween the lung histopathology of premature lambs
manymammalsgivebirthbeforethe‘optimal’time. to that of chronic lung diseases in preterm infants
Thus,humansarenotuniqueinthevariationorin hasledtothedevelopmentoflambsasamodelfor
thelengthofgestation relativetoothermammals. bronchopulmonary dysplasia [119]. Similarly, the
144 | Phillipsetal. Evolution,Medicine,andPublicHealth
A B
D
o
w
n
lo
a
d
Figure 3. Pretermbirthinhumansmayresultingreaterfitnessdifferentialcomparedtonon-humanprimates.Normalfetal ed
growth(purple)issimilarbetweenhumans(A)andnon-humanprimates(B).Unlikefetalgrowth,humansexperienceagrowth fro
m
spurtinbraindevelopment(teal)lateringestationaltimecomparedtonon-humanprimates.Asaresult,thefitness(orange) h
differentialbetweenapre-termhumanbornat80%completedgestationandahumanbornat92.5%completedgestationcould ttp
s
besubstantiallylargerthanthatofnon-humanprimates ://a
c
a
d
e
m
brain growth spurt in pigs, like humans, spans the Conflictofinterest:Nonedeclared. ic
.o
prenatal, perinatal and postnatal development, u
p
leadingtosuggestionsthatithaspotentialasanap- references .co
m
propriatemodelforhumaninfantbraindevelopment /e
m
[120,121].Finally,thepresenceofsimilarpatternsof 1.Romero R, Espinoza J, Kusanovic JP et al. The preterm p
h
c[1e1r6eb]sraulgignejsutrsythinatpnroemn-ahtuumreanbapbriomoantsesanmdayhbuemuasnes- 2.LpuaritLu,rOitizoanSs,yHndorgoamneD.BetJOalG.G2lo00b6a;l1,r1e3g:1io7n–a4l2,.andnational /article
fulmodelsofNSIthatresultfromhumanPTB. causesofchildmortalityin2000–13,withprojectionsto -ab
s
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