Article Text

Transport of premature infants is associated with increased risk for intraventricular haemorrhage
1. Mohamed A Mohamed,
2. Hany Aly
1. Newborn Services Department, The George Washington University Medical Center, Washington, DC, USA
1. Correspondence to Dr Mohamed A Mohamed, Newborn Services Department, The George Washington University Medical Center, 900 23rd St NW, Suite G-2092, Washington, DC 20037, USA; mmohamed{at}mfa.gwu.edu

## Abstract

Background Intraventricular haemorrhages (IVH) greatly impact the outcome of very low birth weight (VLBW) infants. This study examines the correlation between inter-hospital transport and the incidence and severity of IVH in VLBW infants in a large cohort of data.

Methods The US National Inpatient Sample Database (NIS) and its KID subportion were analysed for the years 1997–2004. Infants <1500 g were included in the study and were classified into transport and inborn groups. Groups were further classified according to birth weight into <1000 g and 1000–1499 g. IVH and severe IVH (grades 3–4) were compared between groups and subgroups. Adjusted OR for IVH or severe IVH in correlation with inter-hospital transport were calculated using logistic regression models while controlling for clinical and demographic confounders. We examined changing trends of the incidence of IVH, incidence of neonatal transport and OR for IVH in correlation with neonatal transport in VLBW infants over the years.

Results A total of 67 596 VLBW infants were included in the study. Overall incidence of IVH in the sample was 14.7%; the transport group had more IVH compared to inborn group (27.4% vs 13.42%): adjusted OR 1.75 (95% CI 1.64 to 1.86; p<0.001). Severe IVH was higher in the transport group compared to the inborn group (44.1% vs 32.9%); adjusted OR 1.44 (95% CI 1.22 to 1.70, p=0.001). Similar results were demonstrated in weight-based subgroups. There was increasing trends for neonatal transport and for IVH over the years (p<0.001 for both) with no significant change in the OR for IVH in transported infants.

Conclusion Inter-hospital transport of VLBW Infants is correlated with increased incidence and severity of IVH. This correlation has remained constant over the recent years.

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## Introduction

Intraventricular haemorrhages (IVH) greatly impact the outcome of very low birthweight (VLBW) infants. Severe haemorrhages (grades 3–4) are associated with high mortality and morbidity.1 Out of the 4 million infants born every year in the USA, approximately 1.4% will have birth weight (BW) <1500 g.2 Of those, approximately 10% might develop severe IVH. The expected survival rate of those with severe IVH is about 75%.3 4 Almost 70% of those survivors may develop cerebral palsy (CP) or mental retardation (MR), resulting in about 3000 handicapped infants accumulating each year.5 The estimated lifetime cost of care for each handicapped infant is about US$1 000 000, resulting in an accumulating cost of 3 billion US dollars every year.6 In addition, even milder grades of IVH (grades 1–2) are associated with less favourable neurodevelopmental outcomes compared to those who never had IVH.7 ### What is already known on this topic Inter-hospital transport was associated with intraventricular haemorrhages in very low birth weight infants in small samples from individual hospitals or small networks. ### What this study adds • This study confirms the correlation of inter-hospital transport with intraventricular haemorrhages in very low birth weight infants from one of the largest databases in USA collecting data from more than 1000 hospitals with different care levels and management strategies. • It will have implications on clinical management and policy making regarding care options of these preterm infants as well as healthcare planning. In general, IVH occurs in association with hemodynamic instability associated with extreme prematurity,8 severe perinatal infections,9 10 use of mechanical ventilation, hypercarpia or acidosis associated with respiratory distress syndrome (RDS),8 11 hypoperfusion-reperfusion insults,12,,14 or patent ductus arteriosus (PDA).15 There have been few retrospective reports linking inter-hospital transport with IVH in VLBW infants. Seeking higher level of care, the need for surgical intervention and parental requests were among the indications for transporting these infants. Increased morbidities and mortality were among the complications associated with the transport process, none were proved to have a casual relationship with transport.16,,21 Given the impact of such finding on current practice and health policies, this relationship needs further exploration using a large size and widely diverse dataset. We aimed in this epidemiologic study to examine the correlation between neonatal transport and the incidence and severity of IVH in VLBW infants. We utilised a large national database that has clinical data of more than one million newborns. ## Methods ### Database We used the de-identified datasets produced by the Healthcare Cost and Utilization Project (HCUP) from the US federal Agency for Healthcare Research and Quality. These datasets came from an all-payer database collected annually from the hospitalisation records of inpatient admissions from more than 1000 hospitals across the USA. Datasets included more than 100 data elements for each hospital stay such as: primary and secondary diagnoses (using International Classification of Disease 9 ‘ICD-9’), primary and secondary procedures (using Current Procedural Terminology), admission and discharge status, patient demographics, expected payment source and total charges. HCUP produced the National Inpatient Sample Database (NIS) and its paediatric version (KID). NIS data represent a 10% sample of all hospital admissions during any given year for patients of all ages. KID dataset has similar data elements to those included in the NIS but it includes only paediatric patients. KID dataset is available for the years 1997, 2000 and 2003; we used the data for these 3 years. We used the NIS dataset for the years: 1998, 1999, 2001, 2002 and 2004 when KID dataset was not available.22 23 In this study we obtained data on BW categories, gestational age, sex, race, multiple gestations, mode of delivery, source of admission, maternal diagnoses related to the admission, neonatal diagnoses accumulated during the hospitalisation, disposition at discharge and time of death. ### Patient selection All babies <1500 g were included in the study. The ICD-9 diagnostic codes: 765.15, 765.14, 765.03, 765.02 and 765.01 were used to identify BW categories 1250–1499, 1000–1249, 750–999, 500–749 and <500 g, respectively. The diagnostic codes: 772.1, 772.10, 772.11, 772.12, 772.13 and 772.14 were used to identify IVH cases and IVH grades 1–4. Infants with missing data for transport status or BW were excluded from the study. Infants transported after the first 48 h of life were excluded as IVH, beyond this age, occurs independent of the transport process. Transported infants were counted only once at the recipient hospital to avoid duplicate inclusion at both transferring and receiving hospital. Infants with central nervous system anomalies, congenital heart disease (except PDA), congenital lung anomalies, congenital abdominal wall defects, multiple congenital anomalies and chromosomal disorders were excluded as they can directly attribute to the occurrence of IVH or affect the outcome of the preterm infants. The protocol for this study was approved by the Institutional Review Board of the George Washington University Medical Center. ### Data management and analysis Infants were classified according to their transport status into: transport or inborn groups. The two groups were subdivided into: <1000 g and 1000–1499 g subgroups. SAS V.8.2 was used to conduct all statistical analyses. χ2 And Fisher exact tests were used to calculate OR for IVH and severe IVH in the transport group compared to the inborn. Logistic regression models were used to calculate adjusted OR for IVH or severe IVH in transport group compared to the inborn, controlling for several demographic and clinical confounders. The following confounding variables were included in the regression analysis: sex, race, extremely low birth weight (ELBW <1000 g), birth asphyxia, fetal acidemia, apnoea of prematurity, RDS, persistent pulmonary hypertension of the newborn, pneumothorax, pulmonary haemorrhage, PDA, sepsis, necrotising enterocolitis, maternal hypertension, maternal infection or chorioamnionitis, antepartum haemorrhage, cord prolapse or nuchal cord, breech presentation and instrumental delivery. These confounders were identified in the datasets using ICD-9 diagnostic codes for each one. IVH grades 3 and 4 were considered to be severe IVH. Codes for the grade of IVH were not available for all patients. Severe IVH is presented as a proportion of overall IVH in those infants where ICD-9 code for the grade of IVH was available. Forty-eight infants had some missing data elements in the logistic regression model. They represented less than 0.001 of the total number included in the study and were ignored. χ2 Test was used to detect significant trends in the frequency of inter-hospital transport or the incidence of IVH over the years of the study. ## Results A total of 67 596 infants <1500 g met the inclusion and exclusion criteria. A 9.2% were transported in-between hospitals during the first 48 h of their life. The overall incidence of IVH was 14.7%, the overall mortality was 24.5% and 46% of the babies were <1000 g at birth. There was no difference between the transport and inborn groups with regards to sex or Caucasian race. The transport group had fewer African Americans, more Hispanics, more ELBW infants and more RDS. Table 1 shows demographic and clinical descriptions of both groups. Table 1 Differences between transport and inborn groups The transport group had more IVH compared to the inborn group (27.4% vs 13.42%); adjusted OR 1.75 (95% CI 1.64 to 1.86, p<0.001). Of the VLBW infants who had IVH, 41.9% had the diagnostic codes for the grade of IVH. The diagnosis of severe IVH (grades 3–4) was found in 35.3% of these cases. Severe IVH was higher in the transport when compared to the inborn group (44.1% vs 32.9% respectively); adjusted OR 1.44 (95% CI 1.22 to 1.70, p<0.001). For infants <1000 g, the overall IVH and severe IVH were increased in the transport compared to inborn group; adjusted OR 1.91 (95% CI 1.76 to 2.08, p<0.001) and 1.36 (95% CI 1.12 to 1.66, p=0.002), respectively. For infants 1000–1499 g, IVH and severe IVH were higher in transport group as well; adjusted OR 1.47 (95% CI 1.33 to 1.63, p<0.001) and 1.60 (95% CI 1.18 to 2.18, p=0.003), respectively, figure 1. Figure 1 IVH and severe IVH in transported versus inborn groups by birthweight subgroups. (A) Intraventricular haemorrhage. (B) Severe intraventricular haemorrhage. Filled bars, transported; empty bars, inborn. AOR, adjusted OR. Figure 2 shows a chronological follow-up for the frequency of inter-hospital transport, the incidence of IVH, and the adjusted OR for IVH in correlation with transport in VLBW infants across the years of the study. There were increasing trends for inter-hospital transport (p<0.001) and incidence of IVH (p<0.001). The OR for VLBW infants diagnosed with IVH in association with transport did not show significant change. Figure 2 Neonatal transport, intraventricular haemorrhage and adjusted OR for IVH in transported VLBW infants from 1997 to 2004. Circles, neonatal transport; squares, IVH; triangles, OR for IVH in relation to transport; dashed and dotted line, trend for neonatal transport; dashed line, trend for IVH; continuous line trend for OR. ## Discussion Our study demonstrated an increase in the IVH and severe IVH in VLBW infants in correlation with inter-hospital transport. This correlation was more significant in infants <1000 g when compared to infants weighing 1000–1499 g, possibly due to an increased vulnerability of the more premature infants to the risk factors of IVH. Paradoxically, the correlation of severe IVH with transport was less significant in infants <1000 g compared to those weighing 1000–1499 g. The assumption that severe IVH is more influenced by factors intrinsic to the extremely premature infants than to external factors such as neonatal transport may explain this phenomenon. The correlation between IVH and transport remained high after controlling for confounding factors that are known to increase the risk for IVH. These factors may indirectly reflect the effect of other confounders that were not included in the analysis but may have direct association with the occurrence of IVH. Factors included in the logistic regression such as extreme prematurity, PDA, pulmonary haemorrhage, pneumothorax, asphyxia or antepartum haemorrhage may reflect association with hemodynamic instability or episodes of hypercarpia or acidosis. Chorioamnionitis, perinatal infections or NEC may reflect association with severe systemic inflammatory response, and so on. Almost all IVH (98%) occur in the first week of life; the majority of them within the first 48 h after birth. Low grade IVH may progress into high grade IVH in the first 1 or 2 days after the first event.24 In this study, only infants transferred within the first 48 h of life were included to capture only those who might developed IVH in correlation with the transport process and exclude all of those who might had IVH after the transport. So, transported infants with established diagnoses of IVH were excluded from the study. We also included all infants with IVH regardless of the exact time of IVH occurrence. One may argue that it would have been better if we had the head ultrasound results before the transport, in order to better demonstrate a cause–effect relationship between transport and IVH. Regardless of the transport status, IVH may evolve in the first 48 h of life even after the initial scan was normal. It is important to note that doing a randomised trial to concretely prove the association is not ethical or feasible. Therefore, we thought that this huge national dataset could add in exploring the relationship and to quantify the impact of transport on IVH at a national level. Also in this study, we could not differentiate between early IVH that may be associated with early incidents in life such as vaginal delivery or low APGAR scores and late IVH that may be associated with mechanical ventilation, PDA, pneumothorax or low systemic blood flow. How inter-hospital transport of VLBW infants correlates with their risk for IVH is not yet understood, however, multiple factors could be considered. Vigorous manipulations, kinking or obstruction of the endotracheal tube, self extubation, or iatrogenic trauma while moving the infant, should all be considered.25 Hypothermia and temperature instability may occur while the transported infants are riding outside the hospital, and are known not only to compromise organ perfusion but also may induce lactic acidosis. Both factors may be associated with IVH, but this relationship has not been established to date.26 27 Despite the biological plausibility of the above mechanisms, neonatal transport can only be considered an indirect marker for the non-optimal settings that did not provide adequate care to these premature infants upon their arrivals. The clinical implication of this study is to urge clinicians for more regionalisation of care and to encourage the transport of high-risk mothers to tertiary care centres. Thereby, providing these infants with a prepared environment for their preterm arrival and avoid the hazards of inter-hospital transport. Of note, regionalisation of care has been shown to significantly improve neonatal outcomes.28,,30 Despite the rising calls for regionalisation of care, we report in this study an increased frequency of the neonatal transport over time in the USA, a non-decline in the incidence of transport-related IVH with an overall increase in the incidence in IVH in VLBW infants. This happens despite the increased familiarity of transportation technology and equipment. The de-regionalisation of perinatal care and the need for neonatal transport may have multiple clinical impacts. In this report we specifically targeted severe IVH because of its significant mortality, and devastating consequences for those who survive. Almost 60% of survivors may develop cerebral palsy, and about 70% will be mentally retarded.1,,5 These neurological deficits are even worse when IVH is complicated by post-haemorrhagic ventricular dilation (50%) or when a shunt insertion is required (75%).31 It was reported that approximately 90% of survivors may need assistance with special services before the age of 12 years.1 5 Although infants with non severe IVH are not at high risk for severe handicaps, they have lower test scores on the Mental Developmental Index or when their visual-motor integration was assessed.32 33 This indicates less favourable neurodevelopmental outcomes compared to those who never had IVH.7 Thus, the financial impact of IVH is beyond imagination. Out of the approximately 58 000 VLBW infants born in the USA every year, about 5800 may experience severe IVH. Knowing that 75% of them may survive and 70% of survivors may develop CP or MR means that approximately 3000 infants will survive with such major handicaps. Using the Centers for Disease Control and Prevention estimate of about US$1 million lifetime care cost for a child with MR, this adds up the cost to US\$3 billion every year for those handicapped children.2,,6 Adding to such a financial burden on the nation's economy, is the cost of special education needed by infants with grades 1–2 IVH.7 31

The incidence of IVH in VLBW infants significantly decreased over the few past decades from 40–50% in 198034 35 to approximately 20% in 1990,36 37 but has not improved thereafter.38 This study confirms the alarming trend for increased IVH nationwide that have started since 2003–2004. Such an increase in IVH is associated with a noticeable increase in the use of neonatal transport. This study further emphasises the need for regionalisation of perinatal care.

The novelty of this study stems from the mega sample size that best reflects the overall average outcome of VLBW infants born in the USA during the study period. The US NIS (and KID) database has the following unique capabilities: (1) it is one of the largest databases in the USA and in the world—more than 44 million hospital admission records over the years of the study with more than 5.4 million paediatric records and the VLBW infants' portion is more than 100 000 cases first time admission; (2) the quality of the data collection is superior since it is supervised by the US Department of Health; (3) data have every single clinical or demographic variable that has an ICD-9 diagnostic code and was reported by the caring physician during admission or upon discharge for every admission; (4) data contain other information that we could not find in other sources such as hospital size, hospital categories, zip code, and so on.

We analysed this very large data set that was collected from different states, geographical regions, levels of care, urban and suburban populations, transport indications and techniques.22 23 So, it is truly safe to claim that these data are representative of the entire country of USA without any selection bias. Previous studies showed increased overall mortality in transported versus inborn preterm infants,27,,29 while only few studies commented on the transport associated IVH and severe IVH. These studies either examined a small group of infants or a cohort from one place.17,,21

Similar to other large databases, we acknowledge the limitations of the datasets used in this study. There is no direct linkage between infants' data and some maternal data that may have affected the occurrence of IVH and thus these factors were not included in the logistic regression models. Although many maternal diagnostic codes were documented under the infants' hospital records and were used as possible confounders, we could not control for prenatal administration of corticosteroids, magnesium sulphate or antibiotics. We could not control for some postnatal catastrophic events such as prolonged resuscitation, incidents of difficult endotracheal intubation or acute hypotensive episodes. These variables either did not have ICD-9 diagnostic codes (eg, multiple intubation trials) or were underreported (eg, hypotensive episodes). To overcome this limitation, we included in the logistic regression model all the confounding variables that may indirectly reflect the clinical effect of these non-included factors.

## Conclusions

Neonatal transport in the first 48 h of life may be correlated with increased IVH and severe IVH in VLBW infants. There was an increasing trend for inter-hospital transport of VLBW infants in the USA over the years of the study accompanied with increase in the incidence of IVH. There was no change in the transport associated IVH.

View Abstract

## Footnotes

• Competing interests None.

• Ethics approval This study was conducted with the approval of the Internal Review Board, The George Washington University Medical Center.

• Provenance and peer review Not commissioned; externally peer reviewed.