Outcomes following indomethacin prophylaxis in extremely preterm infants in an all-referral NICU
TD Nelin Journal of Perinatology 2017
Extreme prematurity (EP), defined herein as birth before 27 completed weeks of gestational age, is associated with a myriad of adverse short- and long-term outcomes involving the cardiovascular, pulmonary, gastrointestinal and neurologic systems.1–3 A delicate transition exists from fetal to newborn life as the immature organs continue to develop in the extrauterine environment. As such, decisions regarding the threshold gestational age for providing active care are very delicate. Most centers routinely administer active care for infants born at ⩾25 weeks of gestational age, but in many centers parental agreement is required for active care provided at 23 and/or 24 weeks of age.4,5 This threshold is a moving target within neonatology as more care is routinely provided to younger infants as data continue to show improved outcomes at younger gestational ages.3,6
Intraventricular hemorrhage (IVH) and patent ductus arteriosus (PDA) are among the many causes of morbidity requiring intervention in the neonatal intensive care unit (NICU). Severe IVH is a form of central nervous system injury that is associated with both short- and long-term adverse outcomes. The significance and clinical outcomes after development of PDA vary based on the size of the PDA, the amount and direction of shunting and the condition of the pulmonary vasculature. Patients with PDA are at risk of developing congestive heart failure and pulmonary vascular disease.7–9 Recent evidence suggests that survival of EP infants is increasing, but the major causes of neonatal morbidity and mortality remain unchanged.10,11 In a report from the NICHD (National Institute of Child Health and Human Development) Neonatal Research Network, Patel et al.10 recently reported that between the years 2004 and 2011 the overall in-hospital mortality rate decreased by 9.6% for in-born infants born at o29 weeks of gestational age, and that deaths specifically attributed to central nervous system or pulmonary causes also decreased.
Prior studies demonstrated a beneficial effect of providing prophylactic indomethacin (PI) as a means of decreasing severe IVH and need for PDA ligation.12–14 These studies were done in the 1990s when rates of mortality, severe IVH and PDA ligation were much higher than they are today. Although the TIPP (Trial of Indomethacin Prophylaxis in Preterm Infants) trial suggested that PI did not improve long-term outcomes, it did demonstrate a reduction in the incidence of PDA and of severe IVH.14 The findings from the TIPP trial, specifically those related to the incidence of PDA and severe IVH, along with similar studies from Ment et al.12,13 and Narayanan et al.,15 have led to variations in PI use among different providers and among different centers. Furthermore, no one has studied the effect of PI in EP infants subsequently transferred to a level IV Children’s Hospital NICU for subspecialty care. This is particularly interesting as the age at admission for these patients is usually after the time that PI is administered.
The objective of this study was to determine whether PI use in a contemporary cohort of EP infants admitted to an all-referral NICU continues to be associated with beneficial outcomes. We defined PI as it was used in the TIPP trial—receiving indomethacin 0.1 mg kg− 1 daily for the first 3 days of life. Current practice for delivery hospitals with level III NICUs in Franklin County, Ohio, is to encourage, but not require, the use of PI in EP infants. Therefore, variation exists in the care of EP infants related to PI administration and we sought to explore whether the outcomes at our referral hospital were related to the use of PI at the referring hospital.
The study was approved by the institutional review board at Nationwide Children’s Hospital. The Small Baby Pod of the NICU at Nationwide Children’s Hospital comprised an all-referral, tertiary NICU specializing in the care of infants born at o27 weeks of gestational age. The small baby ICU utilizes specific protocols for the care of these EP infants.16–18 The small baby database was queried for PI use in all infants admitted between 2005 and 2014. Specific data and outcome measures that were gathered included gestational age at birth, mortality, development of any IVH, severe IVH, PDA ligation, need for mechanical ventilation, duration of mechanical ventilation, need for nasal continuous positive airway pressure, need for dopamine and dopamine days, need for insulin, need for supplemental oxygen at 36 weeks of postmenstrual age and diagnosis of necrotizing enterocolitis.
Because of the all-referral nature of the NICU at Nationwide Children’s Hospital, there were only limited maternal data available, although the care provided to the infant in the referring level III NICU before transfer to the Small Baby Pod was readily available, including the use of PI. Only patients with known disposition data and recorded PI use were included in the study (671 patients). The demographic data used to compare the characteristics of the two groups, that is, those who received PI (PI) and those who did not receive PI (control), included: gestational age (weeks), birth weight (g), Apgar scores at 1 and 5 min, admission day of life and county of birth (Franklin County vs non-Franklin County). Data were collected for birth in Franklin County because in our referral population it is a surrogate marker for birth at an institution with a level III NICU.16 Mortality was assessed and compared over the entire study period and was also divided into 3-year epochs (2005 to 2007; 2008 to 2010; and 2011 to 2013).
Continuous data are shown as mean ± s.d. if normally distributed or median and intraquartile range when not normally distributed. Categorical data are shown as numbers and percent (%). Comparisons between infants who received PI and those who did not receive PI (control) were analyzed using Fisher’s exact test for categorical data (SigmaPlot, Jandel Scientific, Carlsbad, CA, USA). For continuous data, groups were compared using a t-test for normally distributed data and the Mann–Whitney rank sum test for nonnormally distributed data (SigmaPlot). Relative risks (RRs) were calculated using SigmaPlot. Significance was defined as a P-value of o0.05.
During the study period, a total of 837 EP infants were admitted to the small baby ICU at Nationwide Children’s Hospital. Of the 837 admissions, 671 (80%) infants had documentation of whether they received PI or not. Of these 671 infants who had documentation of whether PI was used or not, 141 (21%) infants did not receive PI and were included in the control group, whereas 530 (79%) infants received PI and were included in the PI group. The gestational age at birth and the birth weight of the control group were not significantly different from the PI group (Table 1). Furthermore, neither the gestational age at birth (Figure 1a) nor the birth weight (Figure 1b) changed over the study period within this cohort; and the two groups did not differ in gestational age at birth or birth weight at any given time during the study period. The Apgar scores were similar between the two groups at 1 and 5 min, although statistically there was a small difference between the two groups (Table 1). There was no difference in the day of life of admission to the small baby ICU between the two groups (Table 1). Of the control EP infants, 81% were born at another level III NICU (born in Franklin County), whereas 82% of the PI group were born at another level III NICU (Table 1).
The in-hospital mortality rate for the entire cohort was 17.1%. The control infants had a significantly (P = 0.0004) greater mortality rate (40/141 or 28.4%) than infants who received PI (78/528 or 14.8%). The RR for mortality in the PI group was 0.52 (95% confidence interval (CI) 0.37 to 0.73, P = 0.0001) as compared with the group that did not receive PI, and the number needed to treat with PI was 7.4. There was no difference in the age at which death occurred between the two groups (median 13.5 (intraquartile range 7.25 to 53.5) days control and 20.0 intraquartile range 8.0 to 41.0) days PI, P = 0.58). As mortality may have changed over time in our cohort of patients we examined the mortality data in 3-year epochs, 2005 to 2007, 2008 to 2010 and 2011 to 2013. Although there was a tendency for the mortality rate to be lower in the PI group than in the control group during the first epoch, the mortality rates were significantly lower in the PI groups than in the control groups for the last two epochs (Figure 1c). The RR of mortality in the PI group was substantially lower than in the control group in the two most recent epochs (Table 2).
PI was significantly associated with decreased use of insulin, fewer days on dopamine and fewer days on continuous positive airway pressure (Table 3). There was a tendency (P = 0.08) for the incidence of supplemental oxygen at 36 weeks in survivors to be lower in the PI group, with a RR of requiring supplemental oxygen at 36 weeks of 0.92 in the PI group (95% CI 0.84 to 1.01, P = 0.087) as compared with the control group. When considering the combined outcome of death or bronchopulmonary dysplasia (BPD), then PI conferred a small but significant advantage with a RR of 0.91 (95% CI 0.85 to 0.98, P = 0.012) of the combined outcome as compared with the control group. Interestingly, PI administration was significantly associated with receiving indomethacin as treatment for a PDA and undergoing PDA ligation (Table 3). Use of dopamine, total parenteral nutrition, days on total parenteral nutrition, intermittent positive pressure ventilation, intermittent positive pressure ventilation days, necrotizing enterocolitis, development of IVH, development of severe IVH and length of stay in survivors were not significantly different between the PI group and the control group (Table 3).
We administered the Bayley Scales of Infant Development at 18 to 22 months of age to assess neurodevelopmental outcomes. Bayley Scales were available for 358 of the infants who received PI (79% of the 452 survivors to discharge) and 56 of the infants in the control group (55% of the 101 survivors to discharge). There were no significant differences between the groups on any of the three scales of the Bayley scores: cognitive, language (referred to as communication) or motor (Figure 2a). To determine whether there were any differences among the groups in the number of infants ith a potentially clinically significant low score on any of the three scales, we examined the percentage of scores o80. We found no difference between the groups in percentage of infants with a Bayley score o80 for each of the 3 scales (Figure 2b). We also analyzed the follow-up data looking for infants with no score of o80 on any of the 3 scales, that is, if a patient had a score o80 on one scale but 480 on the other two, then they were counted as having at least one score o80. We found no differences between the groups in the number of infants with no score o80, and 66% of the controls and 63% of the PI group (P = 0.66) had no score o80 on the Bayley Scales of Infant Development at 18 to 22 months.
The care of extremely preterm infants is multifaceted and has evolved tremendously over the past few decades with the implementation of resources such as golden hour checklists that define a standard of care.4 Furthermore, Horbar et al.29 found that the rates of mortality before discharge, severe retinopathy of prematurity, severe IVH, severe necrotizing enterocolitis and late-onset infection decreased for extremely preterm infants admitted to NICUs across the United States between 2005 and 2014. Although numerous variations in practices still exist among neonatologists, the outcomes of extremely premature infants have improved over the past decade. Prophylactic indomethacin administration is one intervention utilized in many centers today. The evidence from the studies conducted in the 1990s suggested that the benefits associated with PI administration were to decrease the rate of severe IVH and to close the PDA.12–15 Ment et al.12 and Schmidt et al.14 published two of the most influential randomized controlled trials (RCTs) exploring the effects of prophylactic indomethacin in extremely premature infants.
Ment et al.12,13 demonstrated that prophylactic indomethacin administration decreased the incidence of severe IVH, closed the PDA and was not associated with adverse outcomes. The TIPP trial also found advantageous effects of PI on the incidence of severe IVH and PDA closure; however, the trial did not demonstrate any mortality or neurodevelopmental benefit at 18 months corrected age.14 Fowlie et al.19 conducted a metaanalysis of the available literature regarding PI use, and their findings were consistent with the aforementioned studies in that PI use was associated with reduction in symptomatic PDA, PDA ligation and severe IVH; however, no mortality or neurodevelopmental benefit was found. Although there can be no question that these trials were well designed and thus represent valid findings, it is important to note that the study population was EP infants born in the 1990s. Since that time, the field of neonatology and the standard of care for extremely preterm infants have both evolved, resulting in higher NICU survival rates and improved outcomes.10,11
Our cohort comprised infants born at o27 weeks of gestational age and transferred to a level IV, all-referral NICU between the years 2005 and 2014. This cohort of EP infants was born at outside hospitals and transferred to our level IV NICU with a mean age on admission of 13 days, well after the PI would have been administered. Thus, our cohort is different from those studied in the 1990s not only in terms of being contemporary, but also in terms of being outborn. There were no significant differences between our groups in the severity of illness or the demographics of the patients who received PI compared with the controls. Most strikingly and unexpectedly, we found that in this cohort PI administration was associated with a substantial improvement in survival. In terms of mortality, the RR of mortality at out institution was 48% less in those babies who received PI than in those who did not, and the number needed to treat was only 7.4. We also found that the improvement in survival was not associated with lower rates of IVH, severe IVH or PDA ligation. Thus, although a clear survival benefit seems to be linked with PI administration in this cohort, the mechanism of that survival benefit is not clear. Previous studies have demonstrated that PI use has either a slightly beneficial effect or no effect on neurodevelopment.12,13,20,21
Despite a greater proportion of PI patients surviving in our cohort, PI use was not associated with any difference in Bayley Scores or the rate of poor neurodevelopmental outcomes (as defined by a Bayley Score o80). These findings suggest that PI administration is not associated with adverse neurodevelopmental outcomes in this cohort even in the face of significantly improved survival. We found a tendency for a lower incidence of BPD in the PI group but it did not reach statistical significance. When we examined the combined outcome of death or BPD there was a small but significant advantage associated with the PI group. There have been reports of other therapies that can prevent BPD and/or the combined outcome of death or BPD in EP infants.22–24 In a large Canadian database analysis it was found that early caffeine decreased the risk of death or BPD with an odds ratio of 0.81 (95% CI 0.67 to 0.98), but had no effect on mortality.25 A similar analysis of a large neonatal database found that early caffeine decreased the combined outcome of death or BPD with an odds ratio of 0.77 (95% CI 0.63 to 0.94).26
Interestingly, a Cochrane review of 8 studies investigating vitamin A use demonstrated a RR of 0.91 (95% CI 0.0.82 to 1.00) for the combined outcome of death or supplemental oxygen at 36 weeks.23 Considered together these studies suggest that PI may be associated with a similar effect of reducing the risk of death or BPD in EP infants. In the face of the current literature, these findings likely deserve further study in a well-powered RCT in a contemporary cohort. Unfortunately, we did not have access to caffeine use in this cohort, however we wonder if a RCT trial combining PI with early caffeine use might demonstrate a synergistic effect on survival and/or need for supplemental oxygen at 36 weeks.
Interestingly and unexpectedly, we found that a greater proportion of patients in the PI group had treatment courses of indomethacin or ibuprofen for a PDA and a greater proportion had PDA ligation. This finding was unexpected given that previous RCTs have found that symptomatic PDA is decreased with PI use.12,14,15,19 The populations studied in these RCTs were different from ours in that they were inborn and they were done in the 1990s; our objective therefore was to examine whether PI use in the first 3 days of life in a contemporary cohort of outborn EP infants continues to be associated with beneficial outcomes after referral.
Furthermore, it is important to keep in mind that a great deal of variability exists among neonatologists regarding the use of PI and the use of PI has also changed over time.27 In the current study, the decision to administer PI in these extremely preterm infants was left to the discretion of the attending neonatologist. We speculate that neonatologists who utilize PI in extremely preterm infants may be more likely to obtain an early echocardiogram to evaluate the PDA and therefore be more likely to treat the PDA that is found on the early echocardiogram.30 However, despite greater treatment of the PDA in the PI group, a clear survival benefit was observed in our cohort suggesting that PI had some effect on improving survival that was likely independent of PDA closure. It is important to note that the care of extremely preterm infant did not change dramatically during the time frame of this study.
We unfortunately do not have uniformly reliable data in our outborn population on antenatal steroid use in the two groups. However, antenatal steroids have been the standard of care in central Ohio and during the time frame of the study ~ 90% of all preterm births at o29 weeks received antenatal steroids. Over the course of the study, a tendency arose in Central Ohio to use more continuous positive airway pressure in the delivery room that then resulted in less use of delivery room surfactant. In addition, the initiation of postnatal therapies such as caffeine and hydrocortisone were also at the discretion of the attending physician, and are started after the time that the decision to give or not to give PI is made by the attending neonatologist. However, the key point is to note that the two groups were recruited concurrently over the entire study period, and therefore it is reasonable to assume that exposure to these therapies would have been similar between the groups.
Our findings suggest that receiving PI is correlated with improved survival without increasing adverse outcomes. However, numerous limitations exist within our study that must be discussed to characterize the conclusions of our findings. First, our study is a retrospective analysis of data. This observational study design cannot specifically demonstrate cause and effect but certainly contributes to generating hypotheses for larger RCTs. Second, data collection was carried out over a longer period of time in which the care that EP infants received could conceivably have changed. Third, our patients may not be representative of all extremely preterm infants as our center is an all-referral, level IV NICU. However, our population comprises an important subset of extremely preterm infants as many of these infants require transport to a Children’s Hospital during their NICU care for subspecialty care (that is, pediatric surgery, neurology, neurosurgery, gastroenterology, infectious diseases and so on). Fourth, treatment with PI was not mandated in the delivery level III NICUs, and the care of the EP infant often varies from provider to provider within any given center.
Clyman et al.27 found marked variability in PI practices in EP patients within the NICHD Neonatal Research Network. Centers demonstrating the current lack of consensus regarding standard of care for PI use in EP patients. On the other hand, we took advantage of these practice differences in PI use within our cohort to develop two clear groups: those receiving PI and those not receiving PI. The factors underlying the decision to use PI or not to use PI are not clear for this cohort. However, the differentiation of the two groups based on PI administration offers a unique platform to explore these data, as no significant differences existed between the two groups in terms of the degree of illness. Finally, consistent neurodevelopmental follow-up was not recorded for all patients in this cohort. This is not a unique phenomenon as Guillén et al.28 found that higher rates of neurodevelopmental impairment were associated with greater loss to follow-up in a recent systematic review.
We found that PI was associated with improved survival in a cohort of EP infants admitted to a level IV all-referral Children’s Hospital NICU. Although past RCTs demonstrated certain beneficial effects of PI, they came to very different conclusions regarding recommendations for the use of PI. Thus, our findings strongly support the need for a large RCT exploring the effect of PI on outcomes of EP infants to provide the definitive evidence for or against the use of PI in EP infants.
Table 1. Demographics
Table 2. Mortality by epoch
Table 3. Prophylactic indomethacin and outcomes
Figure 1. Prophylactic indomethacin (PI) was significantly associated with reduced mortality in the two most recent epochs. (a) Gestational age (GA) and (b) birth weight did not change over time or differ between the two groups. (c) PI use did not differ significantly between epochs. PI-associated mortality rate in 3 epochs: 2005 to 2007, 2008 to 2010 and 2011 to 2013. Mortality difference in same epoch: *Po0.05, **Po0.005.
Figure 2. No difference in Bayley Scores of Infant Development III between the two groups. (a) The mean± s.d. score for each of the three scales of the Bayley test includes cognitive (Cog), language (Com) and motor (Motor) for the two groups. (b) The percent of the infants tested who had scores on each scale o80 for each of the 3 scales.
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