www.jped.com.br
ORIGINAL
ARTICLE
Impact
of
maternal
diabetes
mellitus
on
mortality
and
morbidity
of
very
low
birth
weight
infants:
a
multicenter
Latin
America
study
夽
,
夽夽
Carlos
Grandi
a,∗,
Jose
L.
Tapia
b,
Viviane
C.
Cardoso
caDepartmentofPediatrics,FacultyofMedicine,UniversidaddeBuenosAires,BuenosAires,Argentina bDepartmentofPediatrics,FacultyofMedicine,PontificiaUniversidadCatolicadeChile,Santiago,Chile cRibeirãoPretoMedicalSchool,UniversidadedeSãoPaulo,SãoPaulo,Brazil
Received1April2014;accepted5August2014 Availableonline26November2014
KEYWORDS
Verylowbirthweight; Diabetesmellitus; Morbidity; Mortality; Neonatal; Network
Abstract
Objectives: Tocomparemortalityandmorbidityinverylowbirthweightinfants(VLBWI)born towomenwithandwithoutdiabetesmellitus(DM).
Methods: Thiswasacohortstudywithretrospectivedata collection(2001---2010,n=11.991) fromtheNEOCOSURnetwork.Adjustedoddsratiosand95%confidenceintervalswerecalculated fortheoutcomeofneonatalmortalityandmorbidityasafunctionofmaternalDM.Womenwith noDMservedasthereferencegroup.
Results: The rate of maternal DM was 2.8% (95% CI: 2.5-3.1), but a significant (p=0.019) increasewasobservedbetween2001-2005(2.4%,2.1-2.8)and2006-2010(3.2%,2.8-3.6). Moth-erswithDMweremorelikelytohavereceivedacompletecourseofprenatalsteroidsthanthose withoutDM.Infantsofdiabeticmothershadaslightlyhighergestationalageandbirthweight thaninfantsofborntonon-DMmothers.DistributionofmeanbirthweightZ-scores,smallfor gestationalagestatus,andApgarscores weresimilar.There werenosignificantdifferences betweenthetwo groupsregardingrespiratory distresssyndrome,bronchopulmonary dyspla-sia,intraventricularhemorrhage,periventricularleukomalacia,andpatentductusarteriosus. Deliveryroommortality,totalmortality,needformechanicalventilation,andearly-onset sep-sisratesweresignificantlylowerinthediabeticgroup,whereasnecrotizingenterocolitis(NEC) wassignificantlyhigherininfantsborntoDMmothers.Inthelogisticregressionanalysis,NEC grades2-3wastheonlyconditionindependentlyassociatedwithDM(adjustedOR:1.65[95% CI:1.2-2.27]).
Conclusions: VLBWIborntoDMmothersdonotappeartobeatanexcessriskofmortalityor earlymorbidity,exceptforNEC.
©2014SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Allrightsreserved.
夽
Pleasecitethisarticleas:GrandiC,TapiaJL,CardosoVC.Impactofmaternaldiabetesmellitusonmortalityandmorbidityofverylow birthweightinfants:amulticenterLatinAmericastudy.JPediatr(RioJ).2015;91:234---41.
夽夽StudyconductedatDepartmentofPediatrics,FacultyofMedicine,CatholicUniversity,Santiago,Chile.
∗Correspondingauthor.
E-mail:[email protected](C.Grandi).
http://dx.doi.org/10.1016/j.jped.2014.08.007
PALAVRAS-CHAVE
Muitobaixopeso;
Diabetesmellitus; Morbilidade; Mortalidade; Neonatal; Redes
Impactodadiabetesmellitusmaternalsobreamortalidadeemorbidadedecrianc¸as commuitobaixopesoaonascer:umestudoemdiversoscentrosdaAméricaLatina
Resumo
Objetivos: Compararmortalidadeemorbidadeemcrianc¸asdemuitobaixopeso(MBP)filhas demãescomesemdiabetesmellitus(DM).
Métodos: Estudodecoortecomcoletaretrospectivadedados(2001-2010,n=11.991)darede NEOCOSUR.Oddsratiosajustadosforamcalculadosparamortalidadeemorbilidadeneonatal emfunc¸ãodaDMmaterna.MulheressemDMserviramcomogrupodereferência.
Resultados: Ataxa deDMmaternafoi 2,8%(IC95%2,5-3,1), masum aumento significativo (p=0,019)entre2001-2005(2,4%)e2006-2010(3,2%)foi observado.Asmães comDMeram maispropensasateremrecebidoumcursocompletodeesteróidespré-nataisqueassemDM. Osbebêsdemãesdiabéticastinhamumaidadegestacionalepesoaonascerumpoucomaiordo quecrianc¸asfilhasdenãoDM.Distribuic¸ãodoszescoresdepesoaonascer,pequenoparaidade gestacionaleescoresdeApgarforamsemelhantes.Nãohouvediferenc¸assignificativasentre osdoisgruposemtermosdesíndromedodesconfortorespiratório,displasiabroncopulmonar, hemorragiaintraventricular,leucomaláciaperiventricularepersistênciadoductusarteriosus. Mortalidadenasaladeparto,mortalidadetotal,necessidadedeventilac¸ãomecânicaeastaxas de sepse neonatalprecoce foramsignificativamentemenores nogrupo diabético,enquanto enterocolitenecrosante(NEC)foisignificativamentemaioremrecém-nascidosdemães diabéti-cas.EmanálisesderegressãologísticaNECfoiaúnicacondic¸ãoindependentementeassociada comDM(ORajustado1,65[IC95%1,21-2,27]).
Conclusões: Crianc¸asdeMBPdemãescomDMnãotêmaumentodoriscodemortalidadeou morbidadeprecoce,excetoNEC.
©2014SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Todososdireitos reservados.
Introduction
Diabetesmellitus(DM)isthemostcommonmedical condi-tioncausingcomplicationsduringpregnancy.Itisestimated that 0.2% to 0.3% of all pregnancies are complicated by pregestationalDM,andanother1%to5%bygestationalDM.1
Numerous studies indicate that the rates of perinatal complicationsamongdiabeticwomenarestillsubstantially higherthanthoseofthegeneralpopulation.2
Althoughtherehasbeenconsiderableprogressinthecare of diabeticpregnant women,the risk ofpremature deliv-ery remains high.3 The exact incidenceof prematurityin
thepregnantdiabeticwomeniscontroversial.Alargeseries reportedthat 36% of infants born tomothers with gesta-tionalDMor thosewithpre-existinginsulin-dependentDM were born beforeterm, comparedto 9.7% in the general population.4
Adequatepre-conceptionalandgestationalcarereduces the frequency of congenital malformations and improves pregnancyoutcomes.5
Despitesubstantialreductionsin morbidityand mortal-ityrates achievedwithrecentadvances inneonatalcare, prematurityremainsthesinglemostimportantdeterminant ofneonatalmorbidityindiabeticpregnancies.6 Althougha
largenumberofinvestigatorshaveexaminedtheinfluence ofvariousperinatalriskfactorsontheoutcomeofverylow birth weight infants (VLBWI), studies that specifically has focusedontheoutcomeofVLBWIborntodiabeticmothers arescarce.7---9Furthermore,mostofthesedatawerefrom
centerswitha special interestin diabetes and pregnancy
and no difference was observed between pre-gestational andgestationalDM.
Thepresentstudyaimedtocomparemortalityratesand earlyandlatemorbidityratesinVLBWIborntowomenwith andwithoutDMin aregionalbirth cohortover aten-year period.
Methods
Datacollection
The NEOCOSUR South American Network (http://www. neocosur.org/neocosur/) is a voluntary nonprofits asso-ciation of neonatal intensive care units (NICUs) from six South American countries (Argentina, Brazil, Chile, Paraguay,Peru, andUruguay), whoseprimary objectiveis toimprove neonatalhealth.Briefly, thisnetwork provides acontinuouslyupdateddatabasethatprospectivelygathers informationfromalllive-bornVLBWI(birthweightranging from500gto1,500g)fromtheparticipatingcenters.
Thiswasacohortstudy withretrospective data collec-tiongatheredattheNEOCOSURNetworkbetween2001and 2010.ToscreenforanddiagnoseDM,theWorldHealth Orga-nization(WHO)protocolwasemployed,becauseitismore inclusive and simple, withan 75-g oral glucose tolerance testrecommendedat24---28weeksforallwomenwithrisk factorsforgestationalDM.12 As thiswasa studyacross22
maternityunits,thiscriteriawasnotuniversallyfollowed, andsomeindividualcentersusedlocalcriteriatoscreenfor anddiagnoseDM.
Outcomemeasures
Thegestationalage (GA)incompleted weekswasdefined asthebestestimateof GA onthebasis of lastmenstrual periodandearlyprenatalultrasoundexamination. Prematu-ritywasdefinedaccordingtoWHO13andwasclassifiedinto
thefollowingsubgroups:extremelypreterm(<28weeks), verypreterm(28-31weeks),andlateormoderatelypreterm (32-36.6weeks).
Becausetheentrycutoffinthedatabaseisdetermined by a birth weight of ≤ 1,500g, and since small for GA (SGA) infantsmight theoretically be overrepresented,the authorschosetoincludeonlythoseinfantswhowere deliv-ered before 36 completed weeks in this analysis, which resultedintheexclusionof20infants.Twenty-twoinfants below22weeksof gestationwerealsoexcluded, because mostofthemdidnotsurvive.Threeadditionalinfantswere excludedduetounknownGA,and110forunknownDM sta-tusofthemother.Thus,10,867deliveriesand11,991infants wereincludedintheanalysis.
Thegender-specificbirthweightZ-scorewascalculated in accordance with a local intrauterine growth chart.14
AccordingtoGruenwald,15SGAandlargeforGA(LGA)were
definedwhentheweightforGAandsexwerelessormore thantwoZscoresapartfromitsexpectedmedian, respec-tively.ResultsforSGA(n=308)andLGA(n=1,055)areonly presentedforGA22-32weeks,inordertoprevent overrep-resentationofbothconditions.
Respiratory distress syndrome (RDS) was diagnosed according to clinical and radiologic criteria. Necrotizing enterocolitis(NEC)wasdiagnosedbythepresenceof clini-calandradiologic characteristicsaccording tothecriteria of Bell et al.16 Only definite NEC (Bell grades 2 and 3)
caseswereincluded.Intraventricularhemorrhage(IVH)and periventricular leukomalacia (PVL) were diagnosed using cranialultrasonography,andIVHwasgradedusingthe clas-sification of Papile et al.17 Bronchopulmonary dysplasia
(BPD)wasdefinedaccording tothecriteriaofBancalari& Claure,includingclinical and radiologic featurestogether withtherequirementofoxygensupplementationat28days ofageorat 36weeksofpostmenstrualage.18 Patent
duc-tus arteriosus (PDA) was diagnosed according to clinical andultrasonographiccriteria.Early-onsetsepsiswasdefined in the presence of positive blood culture before72hours oflife. Delivery roomresuscitation wasdefinedasone or moreof the following: oxygentreatment, Ambu bag ven-tilation, intubation for ventilation, cardiac massage, and epinephrineadministration. Combinedrateofmortalityor majorcomplications included death or BPD, IVH 3-4,and NEC2-3.
TheNEOCOSUR scoreis aneonatalmortalityrisk score developed for VLBWI basedonvariables present at birth, beforeNICUadmission,anditisanimportanttoolfor com-parisonbetweenNICUsindevelopingcountries.10Surfactant
treatment forpreterminfantswasthestandardofcare in alltheNEOCOSURNICUsduringthestudyperiod.
Statisticalanalysis
Asamplesizecalculationassuming25%inhospitalmortality rate for thechildren of nondiabetic mothersshowed that at 80% power and 5% significance level, this study could detectarisk of1.5in144infantsofdiabeticmothersand 577infantsborntonon-DM(NDM)mothers.
Maternalcharacteristicsandneonataloutcomesbetween DMandNDM groups werecomparedusingthe chi-squared testforcategoricalvariablesandStudent’st-testor Mann-Whitney’s test for continuous variables.Bivariate analysis was applied to examine the effect of maternal diabetic status (DM or NDM) on mortality and several morbidities of VLBW infants. Multivariable logistic regression analysis wasusedtoassesstheindependenteffectofDMstatuson mortality andother complications of prematurity. Afixed set of clinically important variables was introduced into the models: maternal age, multiple pregnancy, maternal hypertensive disorders, prenatal steroidtreatment, mode of delivery, need for delivery room resuscitation, gender, GA,andbirthweightZ-score.
The results of the logistic models are presented as adjustedoddsratioswiththe95%confidenceintervals.Stata 9.2software(CollegeStation,Texas,USA)wasusedforall statisticalcalculations.Asignificancelevelof5%wasused but, because of the large numbers, many of the differ-encesexaminedwereextremelystatisticallysignificantso, forconvenience,anyp-value<0.001hasbeentruncatedto thisvalue.
Furthermore, because it is likely that, in the present population, publicand privatematernity units had differ-ingoutcomesforVLBWIduringthestudyperiod,theauthors alsoinvestigatedrates ofDMandcomparedperinatal out-comesbetweenbothgroupsinDMmothers.Inaddition,the periodsbetween2001-2005and2006-2010 werecompared toexplorewhethertherewereanyimpactin diagnosesor treatmentpracticesonperinataloutcomesofdiabetic preg-nanciesacrosstime.
The research was conducted in accord withprevailing ethical principles and was approved by the Institutional ReviewBoardoftheCatholicUniversity.
Results
FromJanuaryof2001toDecemberof2010,12,146VLBWI wereregisteredinthedatabase,accountingfor>93%ofall live-bornVLBWIofNEOCOSURcenters.
Table1 Comparisonofmaternaldemographic,pregnancyanddeliverycharacteristics,diabeticversusnondiabeticmothers.
Characteristic Diabetic(n=304) Non-diabetic(n=10,563) pb
n(%)a n(%)a
Maternalage(y)c 32.6(6.5) 27.4(7.3) 0.008
<16 2(0.5) 243(2.3) <0.001
16-19 10(3.1) 1,510(14.2)
20-35 184(60.4) 7,108(67.3)
>35 108(35.8) 1,702(16.1)
Education(HighSchool) 179/219(82) 6,109/7,162(85.3) 0.143
Prenatalcare 294/301(97.9) 9,039/10,426(86.7) <0.001
Multiplepregnancy 43(14.1) 1,081(10.2) 0.027
Hypertensiond 140(46.1) 2820(26.7) <0.001
Nonvaginaldelivery 253(83.5) 7,267(68.8) <0.001
Prenatalsteroids 300(98.8) 10,402(98.4)
Complete 221(73.7) 5,715(54.9) <0.001
Partial 45(14.8) 2,010(19.3)
None 34(11.4) 2,677(25.7)
a Thedenominator,whenspecified,indicatesthatthereweresomemissingvalues. b Student’st-testorchi-squaredtestbetweendiabeticandnondiabeticmothers. c Mean(SD).
d Chronichypertensionpluspregnancy-inducedhypertension.
The rateof ‘DM pregnancy’was2.8% (95% CI 2.5---3.1) oroneinevery35deliveries.Thecorrespondingfiguresfor publicandprivatecenterswere2.8%(238/8,238;1:33)and 2.5%(66/2,629; 1:39;p=0.305), respectively. The secular trendshowedastatisticallysignificantincreaseinDM preg-nanciesbetween2001-2005(2.4%,95%CI:2.1-2.8)and2006 -2010(3.2%,95%CI:2.8-3.6)periods(p=0.019).
Table 1 lists the demographic, pregnancy, and deliv-erycharacteristicsamongDMcomparedwithNDMwomen. Briefly, mothers in the DM group were older and were
more likely to have attended more prenatal care; have hadmultiplepregnancies,hypertensivedisorders,cesarean deliveries;andtohavereceivedacompletecourseof prena-talsteroids.Nointeractionwasfoundbetweenhypertensive disordersandSGA(pforinteraction=0.701).
Table2presentinfantscharacteristics,anddueto mul-tiple births, the numbers are higher than those of the mothers.TheDMgrouphadaslightlyhigherGA,lower pro-portionof extremely preterm infants, and lower need of deliveryroomresuscitation, buthighermeanbirth weight
Table2 Comparisonofinfantscharacteristics,diabeticversusnondiabeticmothers.
Characteristic Diabetic(n=347)a Nondiabetic(n=11,644)a pb
Malegenderc 171/346(49.4) 5,930/11,618(51.4) 0.552
Gestationalage(weeks)c 29.6(2.6) 28.9(2.9) <0.001
Extremelypretermd 73(21.2) 3644(31.3) <0.001
Verypretermd 187(53.8) 5595(48.1) 0.031
Latepretermd 87(25.0) 2405(20.6) 0.045
Birthweight(g)c 1138(262) 1085(279) <0.001
BirthweightZ-scorec −1.29(2.3) −1.14(2.1) 0.207
BirthweightZ-scorec,e −0.64(1.4) −0.55(1.2) 0.241
SGAd,e 11/300(3.6) 297/10,265(2.9) 0.432
LGAd,e 38/300(12.6) 1017/10,265(9.9) 0.116
Apgarscoreat5min≤3d 16/345(4.6) 736/11,514(6.4) 0.187
Deliveryroomresuscitationd,f 154/342(45.0) 6410/11,550(55.5) <0.001
SGA,smallforgestationalage(lessthantwoZscoresapartfromitsexpectedmedian);LGA,largeforgestationalage(morethantwoZ scoresapartfromitsexpectedmedian).
a Thedenominator,whenspecified,indicatesthatthereweresomemissingvalues. b Student’st-testorchi-squaredtestbetweendiabeticandnondiabeticmothers. c Mean(SD).
d n(%).
e Gestationalage22-32weeks.
f Definedasoneormoreofthefollowing:oxygentreatment,Ambubagventilation,intubationforventilation,cardiacmassage,and
Table3 Infantmortalityandmorbidities,diabeticversusnondiabeticmothers.
Characteristic Diabetic(n=347)a Nondiabetic(n=11,644)a pb
NEOCOSURScorec 0.189(0.246) 0.242(0.265) 0.002
Deliveryroomdeathd 6/291(2.0) 433/9,468(4.5) 0.041
Alldeathsinhospitald 65/344(18.9) 2,919/11,541(25.3) 0.007
RDSd 242/341(70.9) 8,244/11,270(73.1) 0.370
Mechanicalventilationd 197/341(57.7) 7,205/11,252(64.0) 0.017
Mechanicalventilation(days)e 1(5) 2(7) 0.008
CPAP(days)e 1(3) 1(4) 0.572
Surfactantdosese 1(2) 1(2) 0.454
BPD28daysd 80/336(23.8) 2,688/10,996(24.4) 0.789
BPD36weeksd 56/309(18.1) 1,805/10,357(17.4) 0.751
NECgrades2-3d 52/340(15.3) 1,238/11,256(11.0) 0.013
IVHgrades3-4d 9/309(2.9) 456/11,991(3.8) 0.417
PVLd 13/329(3.9) 552/10,781(5.1) 0.341
PDAd 86/338(25.4) 2875/11,179(25.7) 0.909
Early-onsetsepsisd 5/335(1.5) 409/11,172(3.6) 0.035
Combinedmajorcomplicationsd(deathor
BPD/IVH3-4/NEC2-3)
190/347(54.7) 7208/11,644(61.9) 0.006
RDS,respiratory distress syndrome;CPAP, continuouspositiveairway pressure;BPD, bronchopulmonarydysplasia;NEC,necrotizing enterocolitis;IVH,intraventricularhemorrhage;PVL,periventricularleukomalacia;PDA,patentductusarteriosus.
aThedenominator,whenspecified,indicatesthatthereweresomemissingvalues.
b Student’st-test,Mann-Whitney,orchi-squaredtestsbetweendiabeticandnondiabeticmothers. c Mean(SD).
d n(%).
e Median(interquartilerange).
thanthe NDMgroup. The meanstandardized birth weight score(Z-score)wasnearlyidenticalforbothgroups.
Table3comparesthemortalityratesandmajor neona-talcomplicationsbetweenthetwogroups.TheNEOCOSUR Score,deliveryroomdeath,in-hospitalmortality, mechan-ical ventilation, early-onset sepsis, and combined major complicationsratesweresignificantlylowerinthediabetic group.Noteworthy,therateofNECwastheonlymorbidity significantlyhigherintheDMgroup.
Afteradjustmentinthelogisticregressionanalyses,NEC grades2-3wastheonlyconditionindependentlyassociated withDMgroup(Table4).
Public centers (n=9,090) showed an increased risk of NECgrades2-3comparedwithprivatecenters(n=2,901)for VLBWIborntoDMmothers(adjustedOR:1.67;95%CI: 1.22-2.28;p<0.001);theremainingperinataloutcomeswerenot significantlydifferentbetweencenters.Also,NECgrades 2-3wastheonlydiseasethatshowedanincreasedriskinthe 2006-2010period(n=6,684)comparedwiththe2001-2005 period(n=5,307)forVLBWIborntoDMmothers(p=0.001), whereastheotheroutcomesdidnotdifferamongperiods.
Discussion
Tothebestoftheauthors’knowledge,thisisthefirststudy in Latin America to investigate the association between maternalDMandperinataloutcomesin VLBWIin thepast decade. The sample size waslarge, and the study period allowedfortheanalysisoftemporaltrends.
The currentstudy unexpectedlydemonstratedthatthe riskofmortalityorearly morbiditywasnotincreasedina largenumberofsmallpreterminfantsborntoDMmothers,
Table4 Crude andadjustedodds Ratios and95% CIfor
mortalityandmorbidities amongpreterm VLBWinfantsof diabeticmothers.
Variable CrudeOR
(95%CI)
AdjustedOR (95%CI)
Deliveryroom death
0.43(0.19-0.99) 1.14(0.44-2.92)
Alldeathsin hospital
0.68(0.52-0.90) 1.19(0.86-1.65)
RDS 0.89(0.70-1.13) 1.18(0.90-1.56) Mechanical
ventilation
0.76(0.61-0.95) 1.08(0.82-1.41)
BPD28days 0.96(0.74-1.24) 1.20(0.91-1.58) BPD36weeks 1.04(0.78-1.40) 1.22(0.89-1.67) IVHgrades3-4 0.63(0.48-0.83) 0.87(0.65-1.17) PVL 0.76(0.43-1.33) 0.97(0.55-1.72) NECgrades2-3 1.46(1.08-1.97) 1.65(1.21-2.27) PDA 0.99(0.77-1.28) 1.17(0.89-1.54) Early-onset
sepsis
0.39(0.16-0.96) 0.45(0.16-1.24)
Combinedmajor complications
0.74(0.59-0.91) 1.01(0.71-1.43)
VLBW, very low birth weight; OR, oddsratio; CI, confidence interval.
aAdjusted for maternal age, multiple pregnancy, maternal
allbornwithabirthweightof<1,500g,whencomparedwith infantsborntoNDMmothersinaregionalbirthcohortover aten-yearperiod.Moreover,multivariableanalysisdidnot identifymaternalDMasariskfactorformortalityorearly morbidity,exceptNEC,inthispopulationofpretermVLBWI. In recent years,the care of obstetric DM patients has changed,anditislikelythatthiscouldhaveresultedinthe trendforimprovementsindetection,glycemiccontrol,and pregnancyoutcomesamongobstetricDMpatients.
InarecentreviewoftheprevalenceofgestationalDMin Europeancountries,thereportedfigureswerebetween2.0% and6.0%inoverhalfofthestudies.2Inapreviousstudyof
DMinVLBWpregnancies,theprevalencewashigher(5.4%) thanthepresentstudy’sfigureof2.8%.6However,estimating
theprevalenceofgestationalDMismadedifficultbyalack ofauniversallyaccepteddiagnosticcriteria.19
Poorglycemiccontrolisassociatedwithanincreasedrisk ofpre-eclampsia,20 andmayexplainthefactthattherate
ofmaternalhypertensivedisordersweremoreprevalentin theDMgroup.Also,itwasreportedthatobesity,inaddition toDM,wasassociatedwithagreater riskof preeclampsia thaneitherfactor alone,therebyimplicating other poten-tialmechanisms suchasinflammation in thedevelopment ofpreeclampsiainthishigh-riskgroup.21
Women with DM were more likely to have cesarean-sectionandvaginaloperativedeliverythannormoglycemic women.Inaddition,thetrendforincreasedpre-pregnancy BMIobservedinLatinAmerica,22 coupledwithhigher
mul-tiplebirthsandhypertension,mighthavepartlyexplained theavoidanceofvaginaldeliveryasthebestchoiceforDM patientsinthepresentstudy.2
Ininternationalliterature,patientssufferingfrom gesta-tionalorpre-existingDMaregenerallyexposedtoahigher riskofpretermdelivery.23ApossibleexplanationisthatDM
patientswhodidnotachievethedesiredlevelofglycemic controlreflectasubgroup ofpatients withpoorer compli-anceandhigherriskofpretermVLBWdelivery.
Length of gestation was somewhat greater, whereas a lower proportion of extremely preterm infants were observedintheDMgroup.Thismaybeduetomodern man-agementandadequateglycemiccontrolinpregnancythat ledtoprolongedgestationandlowerriskofVLBWneonatal mortalityandmorbidityinpregnanciescomplicatedbyDM. There were nosignificant differences in anthropomet-riccharacteristicsbetweenthetwogroupsatbirth(except birthweight),inagreementwithapopulation-basestudyin Israel.7
Apgar scoresweresimilarinbothgroups inaccordance with previous studies,7---9 although resuscitation provided
wassignificantlylowerintheDMgroup.
ThesignificantlylowerNEOCOSURScoreobservedinthe DMgroupisinaccordancewithtotalmortalityduring hospi-talstaythatwassignificantlyincreasedintheNDMgroup.
The prevalence of respiratory morbidity wassimilarin thetwostudypopulations,whileseverity,illustratedbythe needforventilatorysupportandmediannumberofdayson mechanical ventilation,were statisticallylowerinthe DM group.Clinicalstudiesontheeffectsofmaternaldiabetes on fetal pulmonary maturation have produced conflicting data,9,24possiblyduetothedifferencesindiabeticcontrol,
prenatal steroids, sex distribution,GA, mode of delivery, birthasphyxia,definitionofRDS,andtheseverityofdisease
indifferentstudypopulations.Thepresentfindingsfurther supportthisobservation;i.e.,aftercontrollingforGA,sex, andmodeofdelivery,therewasnoincreaseinthelikelihood ofRDS.
Thiswasalsotrueforothermajorcomplicationsof pre-maturity, such as rates of BPD at 28 days’ or 36 weeks’ postmenstrual age, PDA, IVH, or PVL. Conversely, early-onsetsepsisandcombinedmajorcomplicationsweremore frequentintheNDMgroup.
In bivariate analyses, the odds ratio of delivery room death, all deaths in hospital, mechanical ventilation, IVH grades 3-4, early-onset sepsis and combined major complicationsweresignificantlylowerintheVLBWIofDM groupthaninthecontrolgroup.Theauthorsspeculatethat thesedifferencesmayhavebeeninpartaresultofa com-binationoffactorssuchas(1)aslightlyhigherGAandbirth weightinthe DMgroupand (2)a significantlyhigherrate ofcompletedcoursesofprenatalsteroidsintheDMgroup, whichmaybelinkedtobetterprenatalcare.Inthepresent study, approximately 80% of infants in both groups were exposedtoprenatalsteroids.Moreover,aCochraneanalysis revealedthatprenatalsteroidtherapy decreasestherisks ofBPDandIVH.25Athirdfactorwasdifferencesinmodeof
delivery:therewasahigherrateofcesarean deliveriesin thegroupwithDM.Althoughthetopicishighly controver-sial,some retrospective studies indicatethat theremight beareducedrateofcomplicationsrelatedtoprematurity whenthe infantis deliveredby cesarean section.26 Other
influentialfactorsincludedifferencesintherateof mater-nalhypertensivedisorders,whichwere,asexpected,more prevalentinthegroupwithDM;itappearsthatpreeclampsia mightreducetheriskfordevelopingRDS.27
In themultivariable analyses, onlyNEC persisted inde-pendently associated witha higher risk in VLBWIborn to DMmothers.Itspathogenesisismultifactorialandinvolves an overreactive response of the immune system to an insult(i.e.infectiousorresponsetotranslocationofnormal entericbacteria).28 Becausecesareansection-born
individ-ualsdonotmakecontactatbirthwithmaternalvaginaland intestinalbacteria,thiscouldleadtolong-termchangesin thegutmicrobiota thatcouldcontributetoNEC. Further-more,NECwastheonlymorbiditymorefrequentlyobserved inpubliccentersandshowedasignificanttrendinthestudy period.Inapopulationstudy NECwasnotassociatedwith DM, although rates halved that observed in the present study.7
This wasa retrospective cohortstudy including22 dif-ferentmaternity units in the Latin-American region, and consequentlysomeinconsistencyinthescreeningmethods anddiagnosisofDMaretobeexpected.Thismayhaveled totheunderreportingofDMcasesinsomeunits,and conse-quentlytheinclusionof somewomenwithoccultdiabetes intheNDMgroup.
thesmallerrateofpregestationalDM(0.2to0.3%)inother studies,1itislikelythatthepresentobservationsrepresent
thegeneraltrendsinoutcomeoftheseinfants.
Thepresentdatasuggestthatwithmodernmanagement andadequateprenatalcarethereisnosignificantincrease inmortalityratesorearlymorbidityratesinVLBWIbornto motherswithDM,exceptNEC.Itappearsthat,with reason-ablediabeticcontrol,prematurityratherthanthediabetic statedeterminestheneonataloutcome.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
WethankalltheNeocosurcentersthatparticipatedinthis study.The presentstudy includedthefollowing collabora-torsfromtheNeocosurNetwork:
Argentina: Guillermo Colantonio, Gabriel Musante,Luis Prudent,LilianaRochinotti,InesGalindez,MarianaSorgetti, LorenaSoler(ClinicayMaternidadSuizoArgentina,Buenos Aires); Isabel Kurlat, Oscar Di Siervi, Adriana Escarate (HospitaldeClínicasJosédeSanMartin,BuenosAires); Gon-zaloMariani, Jose MaríaCeriani, Silvia Fernandez,Carlos Fusti˜nana (Hospital Italiano, Buenos Aires); Jorge Tavos-naska, Liliana Roldan, Hector Sexer, Elizabeth Lombardo (HospitalJuan Fernandez, Buenos Aires);Gabriela Torres, Daniel Agost, Augusto Fischetti, Monica Rinaldi (Hospital Lagomaggiore, Mendoza); Carlos Grandi, Claudio Solana, JavierMeritano,MiguelLarguia(MaternidadSarda,Buenos Aires),MarceloDecaro,LionelCracco,GustavoBassi,Noemi Jacobi,AndreaBrum,NestorVain(SanatoriodelaTrinidad, Buenos Aires); Adriana Aguilar, Miriam Guerrero, Edgardo Szyld,AlciraEscandar(HospitalDr.DiegoParoissien,Buenos Aires);HoracioRoge,MarioMarsano,ElisaFehlmann,Jorge Rios(HospitalEspa˜noldeMendoza,Mendoza).
Brasil:VandaSimões,MaryneadoValeNunes,Marilia Mar-tins (Hospital Universitário Materno Infantil, Universidade FederaldoMaranhão).
Chile: Jorge Fabres, Alberto Estay, Alvaro Gonzalez, Sandra Vignes, Mariela Quezada, Jose L. Tapia, Soledad Urzua(HospitalClinicoUniversidadCatolicadeChile, Santi-ago);RodrigoRamírez,MariaEugeniaHübner,JaimeBurgos, JorgeCatalan(HospitalClinicoUniversidaddeChile, Santi-ago);LiliaCampos, AldoBancalari,LilianCifuentes,Jorge Leon,EduardoBroitman,RoxanaAguilar(HospitalGuillermo Grant, Concepción); Jane Standen, Marisol Escobar, Ale-jandra Nu˜nez (Hospital Gustavo Fricke, Vi˜na del Mar); Agustina González, Ana Luisa Candia, Lorena Tapia, Gio-vannaLoguercio,ClaudiaAvila(HospitalSanJose,Santiago); ClaudiaToro,PatriciaMena,AngelicaAlegria,AdolfoLlanos (Hospital Dr. Sotero del Rio, Santiago); Veronica Pe˜na, MarianneBachler, PatriciaDuarte(HospitalSanBorja Arri-aran, Santiago); Ivonne D‘Apremont,Guillermo Marshall, Sandra Vignes, Mariela Quezada, Luis Villarroel, Angelica Dominguez (Unidad Base de Datos, Pontifícia Universidad Catolica,Santiago).
Paraguay: Jose Lacarruba, Elizabeth Cespedes, Ramon Mir,ElviraMendieta,LarissaGenes,CarlosCaballero
(Depar-tamento de Pediatria, Hospital de Clinicas de Asuncion, Asuncion).
Peru: Jaime Zegarra, Veronica Webb, Fabiola Rivera,Marilu Rospigliosi, Silvia Febres, Enrique Bam-baren (Hospital Cayetano Heredia, Lima); Rosa Unjan, Walter Cabrera, Raul Llanos, Anne Casta˜neda, Oscar Chumbes, Roberto Rivera (Hospital Guillermo Almenara, Lima).
Uruguay: Ruben Panizza, Sandra Gugliucci, Silvia Fer-nandez,EduardoMayans,AliciaPrieto,CristinaHernandez (Facultad de Medicina, Servicio de Recien Nacidos, Montevideo).
References
1.National Collaborating Centre for Women’s and Children’s Health.Diabetes in pregnancy.Management ofdiabetesand itscomplicationsfrompre-conceptiontothepostnatalperiod. London(UK):NationalInstituteforHealthand Clinical Excel-lence(NICE);2008.(Clinicalguideline;no.63).
2.KlemettiM,NuutilaM,TikkanenM,KariMA,HiilesmaaV, Ter-amoK.TrendsinmaternalBMI,glycaemiccontrolandperinatal outcomeamongtype1diabeticpregnantwomenin1989-2008. Diabetologia.2012;55:2327---34.
3.Cousins L. Pregnancy complications among diabetic women: review1965-1985.ObstetGynecolSurv.1987;42:140---9. 4.Cordero L, Treuer SH, Landon MB, Gabbe SG. Management
of infants of diabetic mothers. Arch Pediatr Adolesc Med. 1998;152:249---54.
5.Beyerlein A, von Kries R, Hummel M, Lack N, Schiessl B, GianiG,etal.Improvementinpregnancy-relatedoutcomesin theoffspringofdiabeticmothersinBavaria,Germany,during 1987---2007.DiabetMed.2010;27:1379---84.
6.KöckK,KöckF,KleinK,Bancher-TodescaD,HelmerH.Diabetes mellitusand theriskofpretermbirthwithregardtotherisk ofspontaneouspretermbirth. JMaternFetal NeonatalMed. 2010;23:1004---8.
7.BentalY,ReichmanB,ShiffY,WeisbrodM,BoykoV,Lerner-Geva L,etal.Impactofmaternaldiabetesmellitusonmortalityand morbidityofpreterminfants(24-33 weeks’gestation). Pedi-atrics.2011;128:e848---55.
8.EversIM,deValkHW,VisserGH.Riskofcomplicationsof preg-nancyinwomenwithtype1diabetes:nationwideprospective studyintheNetherlands.BMJ.2004;328:915.
9.Rehan VK, Moddemann D, Casiro OG.Outcome of very-low-birth-weight (< 1,500 grams) infants born to mothers with diabetes.ClinPediatr(Phila).2002;41:481---91.
10.MarshallG,Tapia JL,D’ApremontI,GrandiC,BarrosC, Ale-gria A, et al. A new score for predicting neonatalvery low birthweightmortalityriskintheNEOCOSURSouth American Network.JPerinatol.2005;25:577---82.
11.GrandiC,GonzálezA. Meritano J.; Grupo colaborativo Neo-cosur. Patient volume, medical and nursing staffing and its relationship with risk-adjustedoutcomes ofVLBW infants in 15 Neocosur neonatal network NICUs. Arch Argent Pediatr. 2010;108:499---510.
12.World Health Organization (WHO). Definition, diagnosis and classificationofdiabetesmellitusanditscomplications.Report ofaWHOconsultation.Part1:Diagnosisandclassificationof diabetesmellitus. Geneva: Departmentof noncommunicable diseasesurveillance,WorldHealthOrganization;1999. 13.WHO: recommended definitions, terminology and format for
14.Urquia ML, Alazraqui M, Spinelli HG, Frank JW. Reference birthweights for the Argentine population by multiplicity of birth, sex, and gestational age. Rev Panam Salud Publica. 2011;29:108---19.
15.GruenwaldP.Growthofthehumanfetus.I.Normalgrowthand itsvariation.AmJObstetGynecol.1966;94:1112---9.
16.BellMJ,TernbergJL,FeiginRD,KeatingJP,MarshallR,BartonL, etal.Neonatalnecrotizingenterocolitis.Therapeuticdecisions baseduponclinicalstaging.AnnSurg.1978;187:1---7.
17.PapileLA,BursteinJ,BursteinR,KofflerH.Incidenceand evolu-tionofsubependymalandintraventricularhemorrhage:astudy ofinfants withbirth weights lessthan 1,500 gm. JPediatr. 1978;92:529---34.
18.BancalariE,ClaureN. Definitionsand diagnostic criteriafor bronchopulmonarydysplasia.SeminPerinatol.2006;30:164---70. 19.ReeceEA,LeguizamónG,WiznitzerA.Gestationaldiabetes:the
needforacommonground.Lancet.2009;373:1789---97. 20.HiilesmaaV,SuhonenL,TeramoK.Glycaemiccontrolis
asso-ciated with pre-eclampsia but not with pregnancy-induced hypertensioninwomenwithtypeIdiabetesmellitus. Diabetolo-gia.2000;43:1534---9.
21.CatalanoPM,McIntyreHD,CruickshankJK,McCanceDR,Dyer AR,MetzgerBE,etal.Thehyperglycemiaand adverse preg-nancyoutcome study: associationsof GDM and obesity with pregnancyoutcomes.DiabetesCare.2012;35:780---6.
22.Grandi CA. Relationship between maternal anthropometry and weight gain with birth weight, and risks of low birth
weight,smallforgestationalageandprematurityatanurban population of Buenos Aires, Argentina. Arch Latinoam Nutr. 2003;53:369---75.
23.MachadoJúniorLC,PassiniJúniorR,RodriguesMachadoRosa I. Late prematurity: a systematic review. J Pediatr (Rio J). 2014;90:221---31.
24.RobertMF,NeffRK,HubbellJP,TaeuschHW,AveryME. Associ-ationbetweenmaternaldiabetesandtherespiratory-distress syndromeinthenewborn.NEnglJMed.1976;294:357---60. 25.Roberts D,DalzielS.Antenatal corticosteroidsfor
accelerat-ingfetallungmaturationforwomenatriskofpretermbirth. CochraneDatabaseSystRev.2006;(3).CD004454.
26.Skupski DW, Greenough A, Donn SM, Arabin B, Bancalari E, VladareanuR,etal.Deliverymodefortheextremely prema-ture fetus:a statementoftheprematurityworkinggroupof the World Association ofPerinatal Medicine. J Perinat Med. 2009;37:583---6.
27.ChiswickML.Prolongedruptureofmembranes,pre-eclamptic toxaemia,and respiratorydistress syndrome.Arch DisChild. 1976;51:674---9.
28.BermanL,MossRL.Necrotizingenterocolitis:anupdate.Semin FetalNeonatalMed.2011;16:145---50.
