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Heterogeneity of respiratory distress syndrome: risk factors and morbidity associated with early and… Mehrabadi, Azar; Lisonkova, Sarka; Joseph, K.S. Sep 27, 2016

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RESEARCH ARTICLE Open AccessHeterogeneity of respiratory distresssyndrome: risk factors and morbidityassociated with early and late gestationdiseaseAzar Mehrabadi1,2*, Sarka Lisonkova1 and K.S. Joseph1,3AbstractBackground: Although respiratory distress syndrome (RDS) is considered a disease of prematurity, there is evidenceto suggest heterogeneity between early and late gestation RDS. We examined the epidemiologic features of RDSoccurring at early and late gestation.Methods: We conducted a retrospective cohort study including live births in the United States in 2005–06, withinformation obtained from the National Center for Health Statistics. Early (<32 weeks) and late gestation RDS(≥39 weeks) were contrasted in terms of risk factors and associations with pregnancy complications, obstetricintervention and co-morbidity. Logistic regression was used to quantify the effects of risk factors, while otherassociations were quantified descriptively.Results: There were 27,971 RDS cases, yielding an incidence of 6.4 per 1000 live births. Early and late gestation RDSdiffered in terms of risk factors, with factors such as multi-fetal gestation more strongly associated with early(adjusted odds ratio [aOR] 11.6, 95 % confidence interval 11.0–12.2) compared with late gestation RDS (aOR 3.66,95 % confidence interval 2.68–4.98). The morbidity correlates of early and late gestation RDS also differedsubstantially; neonatal seizures were less strongly associated with early (OR 5.90, 95 % confidence interval 3.67–9.47)compared with late gestation RDS (OR 33.1, 95 % confidence interval 27.2–40.2), while meconium aspirationsyndrome was not significantly associated with early gestation RDS (OR 1.87, 95 % confidence interval 0.94–3.72)and very strongly associated with late gestation RDS (OR 39.8, 95 % confidence interval 34.7–45.6).Conclusions: Differences in risk factors and morbidity correlates of early and late gestation RDS suggest that theseentities represent two distinct diseases.Keywords: Respiratory distress syndrome, Respiratory morbidity, Hyaline membrane disease, Preterm, Termnewborns, Gestational age, Risk factors* Correspondence: azar.mehrabadi@mail.mcgill.caElectronic supplementary materialThe online version of this article(doi:10.1186/s12884-016-1085-7) contains supplementary material, which isavailable to authorized users.1Department of Obstetrics and Gynaecology, University of British Columbiaand the Children’s and Women’s Hospital and Health Centre of BritishColumbia, Vancouver, BC, Canada2Department of Epidemiology, Biostatistics, and Occupational Health, McGillUniversity, Purvis Hall, 1020 Pine Ave. West, Montreal, QC H3A 1A2, CanadaFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Mehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 DOI 10.1186/s12884-016-1085-7BackgroundRespiratory distress syndrome in the newborn (RDS) is adisease caused by the absence or inadequate production ofpulmonary surfactant and the related underdevelopment ofthe lungs [1, 2]. The gestational age-specific incidence ofRDS has a bimodal distribution, with a first peak inincidence rates at early gestation and a second peak at lateterm gestation [3]. Such a bimodal pattern of diseaseincidence has been traditionally interpreted as suggestingdisease heterogeneity. For instance, the bimodal ageincidence curve of Hodgkin disease was first described byMacMahon in the 1950s and ascribed to etiologic hetero-geneity [4, 5]. Subsequent discoveries, including the detec-tion of Epstein-Barr virus (EBV) DNA in tumour cells,have led to the understanding that the early incidence ofHodgkin disease among young adults is caused by primaryinfection (non-EBV), while the second peak among olderadults is due to loss of immunity to latent infection (mostlyEBV) [6, 7]. Similarly, the bimodal gestational age incidenceof RDS suggests that RDS occurring at early and late gesta-tion represents two distinct disease entities [3]. Proposedmechanisms for RDS at term include meconium aspirationsyndrome [8], diabetes [9], cesarean delivery, in particularcesarean delivery without labour [10–13], delay in onset ofrespiration [14], birth asphyxia (neonatal encephalopathy)[14], congenital anomalies [8], and rare genetic mutationsof surfactant protein [2].Newborns with RDS at late term gestation comprise asignificant and under-recognized subpopulation of RDSinfants [15]. In addition, studies have not adequatelycharacterized RDS at late term, even though the conditionwas documented in 1959 and has been routinely identifiedin subsequent years [8, 14, 15]. We hypothesized that thepeak in the incidence of RDS at late gestation signifiesetiologic and other heterogeneity as compared with earlygestation RDS. We therefore carried out a study to describethe risk factors, morbidity correlates and other epidemio-logic features of RDS occurring at early and late gestation.MethodsThe study was a retrospective cohort study of live birthsin the United States in 2005 and 2006. These years werechosen for the study as they represented the most recentperiod that information on RDS status was collected onthe birth certificate. Information on these infants wasobtained from the National Center for Health Statisticsbirth-infant death (period linked) data files, a set of publi-cally available databases maintained by the US Center forDisease Control [16]. These files included routinelycollected demographic information, maternal and infantcharacteristics, and birth outcomes. Data were uniformlycoded according to standard specifications and wereedited and reviewed to satisfy quality control standards[16]. We restricted our study to live births for whominformation was based on the 1989 revision of the USstandard certificate of live birth, as this version includedinformation on whether the infant was diagnosed withRDS. RDS was defined as a diagnosis of hyalinemembrane disease recorded in the birth certificate.Further, we excluded live births with a gestational ageoutside the 24 to 43 weeks range. Gestational age at birthwas based on the clinical estimate of gestation, whichstudies demonstrate to be more accurate than gestationalage based on the reported last menstrual period [17, 18].We first determined the incidence pattern of RDS bygestational age using the fetuses-at-risk approach [3].For these calculations, gestational age-specific incidencerates were estimated by using number of RDS cases atany gestational week in the numerator and the numberof fetuses (at risk of birth and RDS) at that gestation inthe denominator. Cases of RDS were also categorizedinto those that occurred at <32 weeks, 32–36 weeks,37–38 weeks and ≥39 weeks, with the gestational agecategories chosen a priori based on the previouslydescribed incidence pattern of RDS [3]. The rate of RDSat <32 weeks (cumulative incidence between 24 and31 weeks) was calculated by dividing the number of RDScases <32 weeks by the number of fetuses at 24 weeks,while the rate of RDS at ≥39 weeks (cumulative inci-dence between 39 and 43 weeks) was calculated bydividing the number of RDS cases ≥39 weeks by thenumber of fetuses at 39 weeks. The primary analysiscontrasting early vs late gestation RDS in terms of riskfactors and morbidity focused on early gestation RDS (at<32 weeks) and late gestation RDS (at ≥39 weeks).The fetuses-at-risk approach was used for quantifyingthe effects of risk factors that were considered to be stable(invariant) through the course of pregnancy from 24 weeksgestation onwards. The fetuses-at-risk approach was pre-ferred for this analysis as risk factors such as older maternalage and chronic hypertension affect fetal growth and birthrates and consequently RDS risk. Gestational age wastreated as survival time and took into account the fetal-infant time continuum [19]. Maternal and infant charac-teristics of interest included maternal age (<20, 20–34,and ≥35 years), pre-existing or gestational diabetes melli-tus, chronic hypertension, multi-fetal gestation, smokingstatus, congenital anomalies and infant sex. Logisticregression was used to obtain unadjusted and adjustedodds ratios (OR) and 95 % confidence intervals (CI)for each risk factor associated with RDS at early andlate gestation for this fetuses-at-risk analysis ofinvariant risk factors.Other potential factors with a variable time of onset inearly or late pregnancy (e.g., preeclampsia, placentalabruption) were not included in the fetuses-at-riskanalysis as our data source did not contain informationon their gestational age of onset (thus precluding a timeMehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 2 of 10varying assessment of effects). The relationship betweenpregnancy complications and obstetric interventions andearly versus late gestation RDS was studied among livebirths. Pregnancy complications included placental abrup-tion, placenta previa, and hypertension in pregnancy,eclampsia, and premature rupture of membranes. Obstet-ric interventions included labour induction and cesareandelivery. We also examined the morbidity correlates ofearly vs late gestation RDS among live births by examiningthe association between RDS and other neonatal morbidityincluding 5-min Apgar scores (<4, 4–7 and ≥7), small-for-gestational age live birth, neonatal seizures, assisted ventila-tion <30 min, assisted ventilation ≥30 min, birth asphyxiaand meconium aspiration syndrome. Infants born small-for-gestational age were identified based on birth weight-for-gestational age being less than the 10th percentile of thesex-specific United States national reference for fetalgrowth [20]. Birth asphyxia [21] was defined as a 5-minApgar score <4, neonatal seizures and receipt of anyassisted ventilation. Associations between early (and late)gestation RDS and pregnancy complications, obstetricinterventions and other neonatal morbidity, were quanti-fied using ORs and 95 % CIs calculated among live birthsin each gestational age category. No adjustment wasattempted for this descriptive analysis.Sensitivity analyses examined associations between riskfactors, pregnancy complications, obstetric interventionsand co-morbidity and RDS occurring at 32–36 weeksand 37–38 weeks. Sensitivity analyses also assessedwhether results changed upon adding fetal deaths to thefetuses-at-risk analyses. All analyses were carried outusing SAS version 9.3. This study used publicly availabledata and did not include patient identifiers; ethicalreview was therefore not sought.ResultsBetween 2005 and 2006, a total of 4,368,265 live birthscontained information on RDS status and the riskfactors of interest, and were included in the study. Ofthese, 27,971 received a diagnosis of RDS, yielding aRDS rate of 6.4 per 1000 live births. Most of the RDScases occurred at 32–36 weeks gestation (42.7 %); 26.6 %occurred at <32 weeks, 15.3 % occurred at 37–38 weeksand 15.3 % occurred at ≥39 weeks. The cumulative inci-dence of RDS by gestational week (which approximatesthe incidence density of RDS) displayed a bimodal inci-dence pattern by gestational age, peaking at late pretermgestational, then declining slightly at 37 weeks only torise again at 39 weeks and beyond (Fig. 1).Maternal and infant risk factors for early versus lategestation RDSThe cumulative incidence rate of early gestation RDS (be-tween 24 and 31 weeks, denominator of live births andongoing pregnancies at 24 weeks) was 1.7 per 1000 fetusesat risk, while the cumulative incidence rate of late gestationRDS (between 39 and 43 weeks, denominator of live birthsand ongoing pregnancies at 39 weeks) was 1.6 per 1000fetuses at risk. In unadjusted analyses, maternal age<20 years and ≥35 years, multi-fetal gestation, smoking,diabetes, chronic hypertension, small-for-gestational age,congenital anomalies and infant sex were all significantlyassociated with both early and late gestation RDS (Table 1).Older maternal age (≥35 years) was significantly associatedwith early gestation RDS but protective for late gestationRDS.Adjusted analyses showed that several factors differedin their strength of association with early versus lategestation RDS (Table 2). Diabetes mellitus was weaklyFig. 1 Gestational age-specific incidence pattern of respiratory distress syndrome (RDS) expressed per 1000 fetuses at risk, United States 2005–06Mehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 3 of 10associated with RDS < 32 weeks (OR 1.31, 95 % CI 1.18–1.44) and more strongly associated with RDS ≥39 weeks(OR 1.74, 95 % CI 1.51–2.00; P value for heterogeneityof odds ratios <0.05). Similarly, male sex was lessstrongly associated with RDS <32 weeks (OR 1.09, 95 %CI 1.04–1.14) as compared with RDS ≥39 weeks (OR1.45, 95 % CI 1.36–1.54; P value for difference in oddsratios <0.05). On the other hand, associations betweenmaternal age <20 years, multi-fetal pregnancy, chronichypertension, and congenital anomalies were strongerwith early gestation RDS than with late gestation RDS(Table 2). For instance, chronic hypertension wasstrongly associated with early gestation RDS (OR 3.89,95 % CI 3.49–4.35) and moderately associated with lategestation RDS (OR 1.65, 95 % CI 1.25–2.20).Pregnancy complications and early versus late gestationRDSThe rate of RDS among live births <32 weeks gestationwas 113.2 per 1000 live births, whereas the rate amongthose born at ≥39 weeks was 1.6 per 1000 live births.Rates of early gestation RDS were significantly higheramong live births with pregnancy complications such asplacental abruption, placenta previa, hypertension inpregnancy, eclampsia and premature rupture of mem-branes (Table 3). Rates of late gestation RDS were alsosignificantly higher among women with pregnancycomplications compared with women without pregnancycomplications. However, the associations betweenpregnancy complications and early versus late gestationRDS were markedly different and substantially strongerbetween pregnancy complications and late gestationRDS. For instance, placental abruption was moderatelyassociated with early gestation RDS (OR 1.76, 95 % CI1.63–1.90) and strongly associated with late gestationRDS (OR 6.33, 95 % CI 4.90–8.18; P value for differencein odds ratios <0.05). Similarly, placenta previa, hyper-tension in pregnancy, eclampsia and premature ruptureof membranes were weakly associated with earlygestation RDS and strongly associated with late gestationRDS (Table 3).Table 1 Rates of respiratory distress syndrome (RDS) per 1000 fetuses at risk at early (<32 weeks) and late (≥39 weeks) gestationand unadjusted odds ratios and 95 % confidence intervals (CI) expressing the association between maternal and infantcharacteristics and RDS, United States, 2005–2006Risk factors RDS <32 weeks RDS ≥39 weeksCases Fetuses at risk Rate/1000a Odds ratiosb [95 % CI] Casess Fetuses at risk Rate/1000a Odds ratiosb [95 % CI]Age <20 years 959 434,604 2.2 1.38 [1.29, 1.48] 545 272,042 2.0 1.25 [1.14, 1.37]20–34 5314 3,312,305 1.6 Reference 3249 2,024,271 1.6 Reference≥35 1177 621,356 1.9 1.06 [1.04, 1.08] 493 354,606 1.4 0.95 [0.92, 0.98]Multi-fetal gestation 2169 150,761 14.4 11.6 [11.1, 12.2] 41 7103 5.8 3.61 [2.65, 4.91]Smoking 1081 450,149 2.4 1.48 [1.39, 1.58] 582 253,288 2.3 1.49 [1.36, 1.62]Diabetes 445 163,802 2.7 1.63 [1.48, 1.80] 207 74,377 2.8 1.76 [1.53, 2.02]Chronic hypertension 355 47,353 7.5 4.60 [4.13, 5.12] 49 17,144 2.9 1.78 [1.34, 2.36]Congenital anomaly 1000 64,417 15.5 10.5 [9.83, 11.2] 358 31,777 11.3 7.59 [6.81, 8.46]Male sex 4004 2,235,753 1.8 1.11 [1.06, 1.16] 2581 1,340,148 1.9 1.48 [1.39, 1.57]All 7450 4,368,265 1.7 - 4287 2,650,919 1.6 -aRates of RDS <32 weeks represent cumulative incidence from 24 to 31 weeks (8 week period) and cannot be directly compared with rates of RDS ≥39 weekswhich represent cumulative incidence from 39 to 43 weeks (5 week period)bOdds ratios were estimated by contrasting the RDS rate among those with and those without the risk factor e.g., RDS < 32 weeks among infants of smokers vsnonsmokers. Since odds ratios express the relative effect of risk factors on RDS, the odds ratios for early gestation RDS can be directly compared with the oddsratios for late gestation RDSTable 2 Adjusted odds ratios and 95 % confidence intervals (CI)expressing the association between maternal and infantcharacteristics and early (<32 weeks) and late (≥39 weeks)gestation respiratory distress syndrome (RDS), United States,2005–2006Adjusted odds ratios [95 % CI]RDS <32 weeks RDS ≥39 weeksMaternal age <20 years 1.59 [1.48, 1.71] 1.25 [1.14, 1.37]20–34 Reference Reference≥35 0.99 [0.97, 1.01] 0.95 [0.92, 0.98]Multifetal gestation 11.6 [11.0, 12.2] 3.66 [2.68, 4.98]Smoking 1.53 [1.43, 1.63] 1.44 [1.32, 1.57]Diabetes 1.31 [1.18, 1.44] 1.74 [1.51, 2.00]Chronic hypertension 3.89 [3.49, 4.35] 1.65 [1.25, 2.20]Any congenital anomaly 9.41 [8.79, 10.1] 7.25 [6.50, 8.09]Male sex 1.09 [1.04, 1.14] 1.45 [1.36, 1.54]Odds ratios were estimated by contrasting the outcome among those withand those without the risk factor e.g., RDS < 32 weeks among infants ofsmokers vs non-smokersMehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 4 of 10Obstetric interventions and early and late gestation RDSTable 3 also shows the association between labourinduction and cesarean delivery and early versus lategestation RDS. Labour induction had a significant pro-tective effect on early gestation RDS and was a signifi-cant but weak risk factor for late gestation RDS.Cesarean delivery was significantly associated with bothearly and late gestation RDS but the effect was substan-tially larger at late gestation (OR 1.28 vs OR 2.27;P value for difference in odds ratios <0.05). Restrictingthe analysis to women without pregnancy complications(i.e., without maternal hypertension, eclampsia, diabetesmellitus, placental abruption/previa and congenitalanomaly) did not drastically alter the results, althoughthe association between labour induction with earlygestation RDS became non-significant.Morbidity correlates of early and late gestation RDSThe association between neonatal co-morbidity and earlygestation RDS was very different from the associationbetween neonatal co-morbidity and late gestation RDS(Table 4). Apgar score < 4 at 5 min, small-for-gestationalage live birth, and meconium aspiration syndrome were notassociated with early gestation RDS, while neonatalseizures, ventilation, and birth asphyxia were stronglyassociated with early gestational RDS. On the other hand,small-for-gestational age live birth was significantly andmoderately associated with late gestation RDS, while theTable 3 Rates respiratory distress syndrome (RDS) at early (<32 weeks) and late (≥39 weeks) gestation per 1000 live births andunadjusted odds ratios and 95 % confidence intervals (CI) expressing the association between pregnancy complications andobstetric interventions, and RDS, United States, 2005–2006RDS <32 weeks RDS ≥39 weeksNo. Rate per 1000 Odds ratio [95 % CI] No. Rate per 1000 Odds ratio [95 % CI]Pregnancy complicationsPlacental abruption 836 176 1.76 [1.63, 1.90] 60 10 6.33 [4.90, 8.18]Placenta previa 199 153.2 1.43 [1.23, 1.67] 25 7.2 4.51 [3.04, 6.69]Hypertension in pregnancy 1007 154.3 1.50 [1.39, 1.61] 230 3.6 2.31 [2.02, 2.63]Eclampsia 287 174 1.68 [1.47, 1.91] 27 6.9 4.33 [2.96, 6.33]Premature rupture of membranes 1510 141.9 1.37 [1.29, 1.46] 107 4.2 2.65 [2.19, 3.21]InterventionsLabour induction 280 90.9 0.78 [0.68, 0.88] 1225 1.8 1.17 [1.09, 1.25]Cesarean delivery 5146 121.9 1.28 [1.22, 1.35] 1881 2.8 2.27 [2.13, 2.41]Labour inductiona 115 65.8 0.70 [0.58, 0.85] 947 1.6 1.18 [1.09, 1.27]Cesarean deliverya 2503 94.0 1.12 [1.05, 1.19] 1429 2.3 2.16 [2.02, 2.31]All live births 7450 113.2 - 4287 1.6 -aExcluding live births with maternal hypertension, eclampsia, diabetes mellitus, placental abruption, placenta previa and any congenital anomalyTable 4 Rates respiratory distress syndrome (RDS) at early (<32 weeks) and late (≥39 weeks) gestation per 1000 live births andunadjusted odds ratios and 95 % confidence intervals (CI) expressing the association between neonatal co-morbidity and RDS,United States, 2005–2006RDS <32 weeks RDS ≥39 weeksNo. Rate per 1000 Odds ratio [95 % CI] No. Rate per 1000 Odds ratio [95 % CI]Apgar at 5 min <4 404 111.5 1.03 [0.92, 1.14] 108 45 33.1 [27.2, 40.2]4–6 1272 142.1 1.36 [1.27, 1.45] 421 34.1 24.8 [22.4, 27.5]≥7 5688 108.8 Reference 3741 1.4 ReferenceSmall for gestational age 786 113 1.00 [0.92, 1.08] 562 2.6 1.73 [1.58, 1.89]Neonatal seizures 30 428.6 5.90 [3.67, 9.47] 30 22.6 14.4 [10.0, 20.7]Ventilation≥ 30 min 4416 320.9 7.64 [7.26, 8.04] 695 93.6 75.9 [69.7, 82.6]Ventilation <30 min 503 145.4 1.36 [1.23, 1.50] 351 9.5 6.36 [5.70, 7.10]Birth asphyxia 4983 255.5 6.20 [5.88, 6.53] 1106 23.5 19.7 [18.4, 21.2]Meconium aspiration syndrome 10 192.3 1.87 [0.94, 3.72] 228 57.6 39.8 [34.7, 45.6]All live births 7450 113.2 - 4287 1.6 -Birth asphyxia was defined as Apgar at 5 min <4, presence of neonatal seizures, or any assisted ventilation. Births with missing Apgar values excluded fromthe analysisMehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 5 of 10other types of neonatal morbidity were all very stronglyassociated with late gestation RDS. These differences inmorbidity correlates between early and late gestation RDswere particularly evident with regard to 5-min Apgar <4, 5-min Apgar 4–6, neonatal seizures, ventilation ≥30 min,birth asphyxia and meconium aspiration syndrome. Forexample, meconium aspiration syndrome was non-significantly associated with early gestation RDS (OR 1.87,95 % CI 0.94–3.72) but very strongly associated with lategestation RDS (OR 39.8, 95 % CI 34.7–45.6).Sensitivity analysesThe strength of the association between the factors studiedand RDS at 32–36 and 37–38 weeks was generally inbetween that observed with early gestation RDS (<32 weeks)and late gestation RDS (≥39 weeks) with some exceptions.Diabetes mellitus was more strongly associated with RDS at37–38 weeks (OR 2.74, 95 % CI 2.74–3.03) compared withRDS at other gestational ages. Similarly, the associationbetween congenital anomalies and RDS at 32–36 weeksgestation (OR 4.47, 95 % CI 4.41–5.09) was stronger thanthat observed with RDS in other gestational age categories.Associations between placenta previa, eclampsia, prematurerupture of membranes and RDS at 37–38 weeks were simi-lar in magnitude to associations between the same compli-cations and RDS at 32–36 weeks, while associationsbetween neonatal co-morbidity and RDS at 37–38 weekswere more similar to associations between neonatal co-morbidity and RDS at ≥39 weeks (Appendix Tables 5–8).Sensitivity analyses including stillbirths in the denominatormade no marked change in the results or interpretation(Appendix Tables 9–10).DiscussionOur study showed that RDS occurring at late termgestation (≥39 weeks) constituted an important frac-tion (15.3 %) of RDS. Early and late gestation RDSdiffered in terms of potential etiologic factors; mater-nal and infant characteristics such as maternal age<20 years, multi-fetal gestation, chronic hypertension,and congenital anomalies were more strongly associ-ated with early gestation RDS, while factors such aspre-existing diabetes, gestational diabetes and maleinfant sex were more strongly associated with lategestation RDS. Associations between pregnancycomplications, obstetric intervention and neonatalmorbidity and early RDS also differed from associa-tions with late gestation RDS. Of particular interestwere the differential and very strong associationsbetween late gestation RDS and pregnancy complica-tions (such as placental abruption, placenta previa andeclampsia) and neonatal co-morbidity (especiallyApgar <4 at 5 min, neonatal seizures, ventilation≥30 min, birth asphyxia and meconium aspirationsyndrome). These differences suggest substantialheterogeneity in the etiology, pathologic features andclinical presentation of early and late gestation RDS.Our findings confirm previous reports that RDS at termis associated with [8–12, 14] meconium aspirationsyndrome, diabetes, cesarean delivery, birth asphyxia andcongenital anomalies [8–12, 14]. In addition, we identifiedseveral other risk factors for RDS ≥39 weeks includingmulti-fetal gestation, chronic hypertension and male infantsex. The strong associations between late gestation RDSand Apgar <4 at 5 min, neonatal seizures, ventilation≥30 min and birth asphyxia appears to be more consistentwith a clinical picture of encephalopathy as opposed tosurfactant deficiency or other pulmonary causes. Thedifferential and much stronger associations between preg-nancy complications such as placental abruption, placentaprevia, and eclampsia and late RDS, suggest that the fetalcentral nervous system is increasingly susceptible to seriouscompromise at later gestation. The stronger associationsbetween male sex and small-for-gestational age and lategestation RDS may also indicate a greater susceptibility toencephalopathy [22, 23]. There is a substantial body ofanimal and human literature showing that the fetal gasexchange and oxygenation is significantly reduced at termgestation and beyond [24–27]. Although uterine arteryblood flow increases with gestation, blood flow per unit offetal weight does not, and arterial partial pressure ofoxygen, base excess, oxygen saturation, oxygen content,and arterial partial pressure of carbon dioxide are allreduced at late gestation. The increase in rates of placentalcomplications at late gestation is also congruent with epide-miologic models of stillbirth and perinatal death (whichalso increase at late gestation) [3].It is unclear why we observed a negative associationbetween induction and RDS at <32 weeks gestation. Onepossible explanation is that infants induced at <32 weeks(as opposed to those that delivered spontaneously at thisage) were more likely to have received antenatal corticoster-oid therapy, which is protective for RDS [28]. The associ-ation between cesarean delivery and RDS at ≥39 weeksgestation is consistent with findings from previous studies[10–13] which have proposed mechanisms such as lungimmaturity [13], the lack of hormonal processes thatinitiate and propagate labour and which may be involved inlung function, and the effects of labour and vaginal deliveryin clearing lung fluid [29].The limitations of our study include the absence of infor-mation on maternal infection and severity of respiratorydistress syndrome. In addition, the information in our datasource was obtained through routine abstraction and hencemay have been subject to some coding variation and tran-scription errors. However, these problems are likely to havebeen non-differential by gestational age and RDS status andhence would have had a limited impact on our findings.Mehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 6 of 10ConclusionsOur study shows that a significant fraction of RDSoccurs at late term gestation. Risk factors such asmaternal age, pre-existing and gestational diabetesmellitus, multi-fetal gestation, chronic hypertensionand infant sex are differently associated with early andlate gestation RDS. Also, the associations between preg-nancy complications, and neonatal co-morbidity (thatare components of neonatal encephalopathy) are muchstronger with late gestation RDS as compared withearly gestation RDS. The clinico-epidemiologic pictureassociated with early and late gestation RDS suggeststhat these two conditions are distinct disease entities.Further research elucidating the pathogenesis of lategestation RDS will help to clarify the managementoptions for better treating this condition.Table 5 Rates of respiratory distress syndrome (RDS) at 32–36 weeks and 37–38 weeks per 1000 fetuses at risk and unadjusted oddsratios and 95 % confidence intervals (CI) expressing the association between maternal and infant characteristics and RDS, UnitedStates, 2005–2006Risk factors RDS 32–36 weeks RDS 37–38 weeksCases Fetuses at risk Rate/1000a Odds ratiosb [95 % CI] Cases Fetuses at risk Rate/1000a Odds ratiosb [95 % CI]Age <20 years 1165 426,327 2.7 1.00 [0.94, 1.06] 360 386,323 0.93 0.83 [0.74, 0.92]20–34 8969 3,265,775 2.7 Reference 3364 2,978,793 1.13 Reference≥35 1808 610,342 3.0 1.03 [1.01, 1.04] 568 545,748 1.04 0.97 [0.95, 1.00]Multi-fetal gestation 2770 133,526 20.7 9.61 [9.21, 10.0] 214 55,869 3.83 3.63 [3.16, 4.17]Smoking 1613 441,604 3.7 1.37 [1.30, 1.44] 632 392,595 1.61 1.55 [1.42, 1.69]Diabetes mellitus 996 160,801 6.2 2.35 [2.20, 2.51] 414 136,882 3.02 2.95 [2.67, 3.27]Chronic hypertension 423 44,759 9.5 3.52 [3.19, 3.88] 126 35,036 3.60 3.35 [2.81, 4.01]Congenital anomaly 832 61,034 13.6 5.26 [4.90, 5.65] 346 50,707 6.82 6.71 [6.01, 7.50]Male sex 7130 2,200,877 3.2 1.42 [1.37, 1.47] 2739 1,994,128 1.37 1.70 [1.59, 1.81]All 11,942 4,302,444 2.8 - 4292 3,910,864 1.10 -aRates of RDS <32 weeks represent cumulative incidence from 24 to 31 weeks (8 week period) and cannot be directly compared with rates of RDS ≥39 weekswhich represent cumulative incidence from 39 to 43 weeks (5 week period)bOdds ratios were estimated by contrasting the RDS rate among those with and those without the risk factor e.g., RDS < 32 weeks among infants of smokers vsnonsmokers. Since odds ratios express the relative effect of risk factors on RDS, the odds ratios for early gestation RDS can be directly compared with the oddsratios for late gestation RDSTable 6 Adjusted odds ratios and 95 % confidence intervals (CI) expressing the association between maternal and infantcharacteristics and respiratory distress syndrome (RDS) at 32–36 weeks and 37–38 weeks, United States, 2005–2006Adjusted odds ratios [95 % CI]RDS 32–36 weeks RDS 37–38 weeksMaternal age <20 years 1.14 [1.07, 1.21] 0.86 [0.78, 0.96]20–34 Reference Reference≥35 0.97 [0.95, 0.98] 0.95 [0.92, 0.97]Multi-fetal gestation 9.6 [9.2, 10.0] 3.65 [3.18, 4.20]Smoking 1.42 [1.35, 1.50] 1.55 [1.42, 1.68]Diabetes mellitus 2.04 [1.90, 2.18] 2.71 [2.45, 3.01]Chronic hypertension 2.86 [2.59, 3.16] 2.74 [2.29, 3.28]Any congenital anomaly 4.81 [4.48, 5.17] 6.22 [5.57, 6.94]Male sex 1.41 [1.36, 1.46] 1.67 [1.57, 1.77]Odds ratios were estimated by contrasting the outcome among those with and those without the risk factor e.g., RDS 37–38 weeks among infants/fetuses at riskof smokers vs. non-smokersAppendixMehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 7 of 10Table 9 Sensitivity analysis including stillbirths: Crude odds ratios and 95 % confidence intervals (CI) expressing the associationbetween early antepartum characteristics and respiratory distress syndrome (RDS), United States, 2005–2006Unadjusted odds ratios [95 % CI]RDS < 32 weeks RDS 32–36 weeks RDS 37–38 weeks RDS ≥39 weeksMaternal age <20 years 1.38 [1.29, 1.48] 1.00 [0.94, 1.06] 0.83 [0.74, 0.92] 1.25 [1.14, 1.37]20–34 Reference Reference Reference Reference≥35 1.06 [1.04, 1.08] 1.03 [1.01, 1.04] 0.97 [0.95, 1.00] 0.95 [0.92, 0.98]Multifetal gestation 11.6 [11.1, 12.2] 9.60 [9.20, 10.0] 3.63 [3.16, 4.17] 3.60 [2.65, 4.91]Smoking 1.48 [1.38, 1.58] 1.37 [1.30, 1.44] 1.55 [1.42, 1.68] 1.49 [1.36, 1.62]Diabetes 1.63 [1.48, 1.79] 2.35 [2.20, 2.51] 2.95 [2.66, 3.26] 1.76 [1.53, 2.02]Chronic hypertension 4.57 [4.10, 5.08] 3.51 [3.18, 3.87] 3.35 [2.81, 4.00] 1.78 [1.34, 2.36]Any congenital anomaly 10.3 [9.61, 11.0] 5.20 [4.84, 5.58] 6.67 [5.97, 7.45] 7.55 [6.78, 8.42]Male sex 1.11 [1.06, 1.16] 1.42 [1.37, 1.47] 1.70 [1.59, 1.81] 1.48 [1.39, 1.57]Table 7 Rates respiratory distress syndrome (RDS) at 32–36 weeks and 37–38 weeks per 1000 live births and unadjusted odds ratios and95 % confidence intervals (CI) expressing the association between pregnancy complications and obstetric interventions, and RDS at 32–36weeks and 37–38 weeks, United States, 2005–2006RDS 32–36 weeks RDS 37–38 weeksNo. Rate per 1000 Odds ratio [95 % CI] No. Rate per 1000 Odds ratio [95 % CI]Pregnancy complicationsPlacental abruption 645 78.0 2.79 [2.57, 3.03] 102 17.9 5.43 [4.45, 6.62]Placenta previa 348 63.8 2.20 [1.97, 2.46] 44 9.0 2.67 [1.98, 3.59]Hypertension in pregnancy 1748 44.1 1.55 [1.47, 1.63] 449 6.8 2.12 [1.92, 2.34]Eclampsia 321 58.0 1.98 [1.77, 2.22] 43 8.9 2.66 [1.97, 3.59]Premature rupture of membranes 1430 46.3 1.62 [1.53, 1.71] 104 6.3 1.88 [1.55, 2.29]InterventionsLabour induction 1455 26.6 0.85 [0.81, 0.90] 953 3.6 1.08 [1.00, 1.16]Labour inductiona 697 20.7 0.80 [0.74, 0.87] 586 2.9 1.07 [0.98, 1.17]Cesarean delivery 6971 40.7 1.84 [1.77, 1.91] 2340 5.7 2.48 [2.34, 2.64]Cesarean deliverya 3826 32.8 1.64 [1.57, 1.72] 1512 4.5 2.32 [2.16, 2.49]All live births 11,942 30.5 - 4292 3.4 -Odds ratios were estimated by contrasting outcomes among those with and those without the risk factor e.g., RDS at 37–38 weeks among infants of womendelivering with placental abruption vs. infants of women without placental abruptionaExcluding live births with maternal hypertension, eclampsia, diabetes mellitus, placental abruption, placenta previa and any congenital anomalyTable 8 Rates respiratory distress syndrome (RDS) at 32–36 weeks and 37–38 weeks per 1000 live births among infants with otherneonatal morbidity, and unadjusted odds ratios and 95 % confidence intervals (CI) expressing the association between neonatalcomorbidity and RDS at 32–36 weeks and 37–38 weeks, United States, 2005–2006RDS 32–36 weeks RDS 37–38 weeksNo. Rate per 1000 Odds ratio [95 % CI] No. Rate per 1000 Odds ratio [95 % CI]Apgar at 5 minutes <4 165 85.2 3.13 [2.67, 3.68] 50 34.5 11.4 [8.6, 15.1]4–6 733 99.9 3.73 [3.45, 4.04] 309 45.1 15.0 [13.3, 16.9]≥7 11,009 28.9 Reference 3917 3.1 ReferenceSmall for gestational age 2202 32.7 1.09 [1.04, 1.14] 645 4.8 1.48 [1.36, 1.61]Neonatal seizures 27 102.3 3.63 [2.44, 5.40] 12 20.1 6.04 [3.41, 10.70]Ventilation ≥ 30 min 3428 236.1 13.4 [12.8, 14.0] 858 144.4 61.5 [56.8, 66.6]Ventilation <30 min 766 64.9 2.29 [2.12, 2.47] 294 16.3 5.14 [4.56, 5.79]Birth asphyxia 4244 153.1 8.37 [8.05, 8.71] 1175 46.3 19.2 [18.0, 20.6]Meconium aspiration syndrome 38 140.7 5.22 [3.70, 7.36] 66 72.8 23.3 [18.1, 30.0]All live births 11,942 30.5 - 4292 3.4 -Birth asphyxia was defined as Apgar at 5 minute <4, presence of neonatal seizures, or any assisted ventilation. Births with missing Apgar values excluded from theanalysis. Odds ratios were estimated by contrasting outcomes among those with and those without the risk factor e.g., RDS at 37–38 weeks among infants withand without meconium aspiration syndromeMehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 8 of 10AbbreviationsCI: Confidence interval; OR: Odds ratio; RDS: Respiratory distress syndromeAcknowledgementsK.S. Joseph is supported by an Investigator award from the Child and FamilyResearch Institute and a Canadian Institutes of Health Research (CIHR) Chairin maternal, fetal and infant health services research (APR-126338). AzarMehrabadi is supported by a CIHR postdoctoral fellowship.FundingThis work is supported by a Canadian Institutes of Health Research (CIHR)Team grant in Severe Maternal Morbidity (MAH-115445). The funders had norole in the design of the study, the interpretation of data or writing of themanuscript.Availability of data and materialsInformation on these infants was obtained from the National Center forHealth Statistics birth-infant death (period linked) data files, a set of publicallyavailable databases maintained by the US Center for Disease Control (http://www.cdc.gov/nchs).Authors’ contributionsAM conceptualized and designed the study, carried out the analyses, draftedthe initial manuscript, and approved the final manuscript as submitted. SLconceptualized and designed the study, reviewed and revised themanuscript and approved the final manuscript as submitted. KSJconceptualized and designed the study, reviewed and revised themanuscript and approved the final manuscript as submitted.Competing interestsAll authors declare that they have no competing interests.Consent for publicationNot applicable as this study does not contain individual level data.Ethics approval and consent to participateThis study used publicly available data and did not include patientidentifiers; ethical review was therefore not sought.Author details1Department of Obstetrics and Gynaecology, University of British Columbiaand the Children’s and Women’s Hospital and Health Centre of BritishColumbia, Vancouver, BC, Canada. 2Department of Epidemiology,Biostatistics, and Occupational Health, McGill University, Purvis Hall, 1020 PineAve. West, Montreal, QC H3A 1A2, Canada. 3School of Population and PublicHealth, University of British Columbia, Vancouver, BC, Canada.Received: 9 October 2015 Accepted: 16 September 2016References1. Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatalrespiratory distress syndrome. Cochrane Database Syst Rev. 2012;11:CD001456.2. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, SaugstadOD, Simeoni U, Speer CP, Halliday HL. European consensus guidelineson the management of neonatal respiratory distress syndrome inpreterm infants–2010 update. Neonatology. 2010;97(4):402–17.3. Joseph KS. The natural history of pregnancy: diseases of early and lategestation. Br J Obstet Gynaecol. 2011;118(13):1617–29.4. Macmahon B. Epidemiological evidence of the nature of Hodgkin’sdisease. Cancer. 1957;10(5):1045–54.5. MacMahon B. Epidemiology of Hodgkin’s disease. Cancer Res.1966;26(6):1189–201.6. Hjalgrim H, Engels EA. Infectious aetiology of Hodgkin and non-Hodgkinlymphomas: a review of the epidemiological evidence. J Intern Med.2008;264(6):537–48.7. Jarrett RF. Viruses and lymphoma/leukaemia. J Pathol. 2006;208(2):176–86.8. Clark RH. The epidemiology of respiratory failure in neonates born at anestimated gestational age of 34 weeks or more. J Perinatol. 2005;25(4):251–7.9. Robert MF, Neff RK, Hubbell JP, Taeusch HW, Avery ME. Associationbetween maternal diabetes and the respiratory-distress syndrome in thenewborn. N Engl J Med. 1976;294(7):357–60.10. Hales KA, Morgan MA, Thurnau GR. Influence of labor and route of deliveryon the frequency of respiratory morbidity in term neonates. Int J GynaecolObstet. 1993;43(1):35–40.11. Madar J, Richmond S, Hey E. Surfactant-deficient respiratory distress afterelective delivery at ‘term’. Acta Paediatr. 1999;88(11):1244–8.12. Krantz ME, Wennergren M, Bengtson LG, Hjalmarson O, Karlsson K, Sellgren U.Epidemiological analysis of the increased risk of disturbed neonatal respiratoryadaptation after caesarean section. Acta Paediatr Scand. 1986;75(5):832–9.13. Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB. Risk of respiratorymorbidity in term infants delivered by elective caesarean section: cohortstudy. Br Med J. 2008;336(7635):85–7.14. James LS. Physiology of respiration in newborn infants and in therespiratory distress syndrome. Pediatrics. 1959;24:1069–101.15. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-terminfants. Pediatrics. 2004;114(2):372–6.16. Public Use Data File Documentation: 2005 Period Linked Birth/Infant DeathData Set. http://www.cdc.gov/nchs/data_access/VitalStatsOnline.htm.Accessed 1 Dec 2015.17. Callaghan WM, Dietz PM. Differences in birth weight for gestational agedistributions according to the measures used to assign gestational age.Am J Epidemiol. 2010;171(7):826–36.18. Joseph KS, Huang L, Liu S, Ananth CV, Allen AC, Sauve R, Kramer MS.Reconciling the high rates of preterm and postterm birth in the UnitedStates. Obstet Gynecol. 2007;109(4):813–22.19. Joseph KS. Theory of obstetrics: the fetuses-at-risk approach as a causalparadigm. J Obstet Gynaecol Can. 2004;26(11):953–60.20. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United Statesnational reference for fetal growth. Obstet Gynecol. 1996;87(2):163–8.Table 10 Sensitivity analysis including stillbirths: Adjusted odds ratios and 95 % confidence intervals (CI) expressing the associationbetween early antepartum characteristics and respiratory distress syndrome (RDS), United States, 2005–2006Adjusted odds ratios [95 % CI]RDS <32 weeks RDS 32–36 weeks RDS 37–38 weeks RDS ≥39 weeksMaternal age <20 years 1.59 [1.48, 1.71] 1.14 [1.07, 1.21] 0.86 [0.78, 0.96] 1.25 [1.14, 1.37]20–34 Reference Reference Reference Reference≥35 0.99 [0.97, 1.01] 0.97 [0.95, 0.98] 0.95 [0.92, 0.97] 0.95 [0.92, 0.98]Multifetal gestation 11.6 [11.0, 12.2] 9.61 [9.20, 10.0] 3.65 [3.18, 4.20] 3.66 [2.68, 4.98]Smoking 1.53 [1.43, 1.63] 1.42 [1.35, 1.50] 1.55 [1.42, 1.68] 1.44 [1.32, 1.57]Diabetes 1.31 [1.18, 1.44] 2.04 [1.90, 2.18] 2.71 [2.45, 3.01] 1.74 [1.51, 2.00]Chronic hypertension 3.89 [3.49, 4.35] 2.86 [2.59, 3.16] 2.74 [2.29, 3.28] 1.65 [1.25, 2.20]Any congenital anomaly 9.4 [8.79, 10.1] 4.81 [4.48, 5.17] 6.22 [5.57, 6.94] 7.25 [6.50, 8.09]Male sex 1.09 [1.04, 1.14] 1.41 [1.36, 1.46] 1.67 [1.57, 1.77] 1.45 [1.36, 1.54]Mehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 9 of 1021. Dzakpasu S, Joseph KS, Huang L, Allen A, Sauve R, Young D.Decreasing diagnoses of birth asphyxia in Canada: fact or artifact.Pediatrics. 2009;123(4):e668–72.22. Hayes BC, McGarvey C, Mulvany S, Kennedy J, Geary MP, Matthews TG, King MD.A case-control study of hypoxic-ischemic encephalopathy in newborn infants at>36 weeks gestation. Am J Obstet Gynecol. 2013;209(1):29 e1–e19.23. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR,Pemberton PJ, Stanley FJ. Antepartum risk factors for newbornencephalopathy: the Western Australian case-control study. Br Med J.1998;317(7172):1549–53.24. Ferrazzi E, Rigano S, Padoan A, Boito S, Pennati G, Galan HL. Uterine arteryblood flow volume in pregnant women with an abnormal pulsatility indexof the uterine arteries delivering normal or intrauterine growth restrictednewborns. Placenta. 2011;32(7):487–92.25. Goldkrand JW, Moore DH, Lentz SU, Clements SP, Turner AD, Bryant JL.Volumetric flow in the umbilical artery: normative data. J Matern Fetal Med.2000;9(4):224–8.26. Konje JC, Kaufmann P, Bell SC, Taylor DJ. A longitudinal study of quantitativeuterine blood flow with the use of color power angiography in appropriate forgestational age pregnancies. Am J Obstet Gynecol. 2001;185(3):608–13.27. Thaler I, Manor D, Itskovitz J, Rottem S, Levit N, Timor-Tritsch I, Brandes JM.Changes in uterine blood flow during human pregnancy. Am J ObstetGynecol. 1990;162(1):121–5.28. Altman M, Vanpee M, Cnattingius S, Norman M. Risk factors for acuterespiratory morbidity in moderately preterm infants. Paediatr PerinatEpidemiol. 2013;27(2):172–81.29. Bland RD. Loss of liquid from the lung lumen in labor: more than a simple“squeeze”. Am J Physiol Lung Cell Mol Physiol. 2001;280(4):L602–5.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Mehrabadi et al. BMC Pregnancy and Childbirth  (2016) 16:281 Page 10 of 10

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