Differential Determinants of Patent Ductus Arteriosus Outcomes for Prematurity of Varying Birth Body Weight

doi:10.21203/rs.2.10647/v1

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Differential Determinants of Patent Ductus Arteriosus Outcomes for Prematurity of Varying Birth Body Weight

https://doi.org/10.21203/rs.2.10647/v1

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Background

Patent ductus arteriosus (PDA) remains critically encountered every day for pediatricians and neonatologists along with the medical progress in prematurity neonatal care. In this study, we aimed to stratify premature neonates by their initial postnatal 24-hour clinical characteristics and maternal and gestational histories to early predict the risk of PDA at unfavorable treatment responses.

Methods

A retrospective analysis was conducted on preterm newborns who were consecutively admitted to a pediatric-neonatal-intensive-care-unit from 2008 to 2013 except some exclusion criteria. Data relating to birth histories, maternal histories, and clinical data from the first 24 hour of life were collected and analyzed according to three types of PDA outcomes—non-treated, medically-responded, and surgically-ligated PDA. Univariate analysis was performed using Mann-Whitney U test and Chi-square test or Fisher’s exact test. Multivariate analysis was performed using multinomial logistic regression to determine the independent risk factors for the PDA outcome.

Results

This study involved 682 preterm infants, composed of 352 male and 330 female neonates with median gestational age of 31 (interquartile, IQR: 28–34) week and BBW of 1360 (IQR: 1085–1861) g. Inclusively, 83% of PDAs in prematurity did not need any medical or surgical treatment, 8.8% of PDA medically responded and 7.9% needed surgical ligation. All subjects were further sub-grouped according to birth body weight (BBW) owing to significant differences in clinical characteristics and the rate of surgically-ligated PDA between neonates with BBW less than 1500 g (as the very low birth weight, VLBW group) and those with BBW greater or equal to 1500 g (as the non-VLBW group). The VLBW group had a significantly higher percentage of surgically-ligated PDA. For the VLBW group, the amount of first 24-hour intravenous fluid per kilogram, surfactant use and gynecological disorder were independent factors in predicting PDA outcomes. For the non-VLBW group, placenta previa, parity, BBW and intrauterine growth retardation were independent factors.

Conclusions

Neonatal care should be meticulously personalized according to their BBW. The first 24-hour perinatal factors, maternal and gestational history plays differential importance on PDA treatment outcome based on BBW.

Pediatrics

birth body weight

patent ductus arteriosus

preterm neonates

early postnatal

maternal factors

Patent ductus arteriosus (PDA) has been one of the most challenging issue occurring every day in the majority of pediatric neonatal intensive care units (PNICUs). It causes some of the highest morbidity and mortality rates among preterm neonates [1], associated with complications such as germinal matrix-intraventricular hemorrhage [2], congestive heart failure [3], chronic lung disease/bronchopulmonary dysplasia [4], and necrotizing enterocolitis [5].

PDA occurs when a normal fetal blood vessel that connects the descending aorta and the pulmonary artery fails to close soon after birth. The ductus arteriosus may not be able to close spontaneously when oxygenation is inadequate and/or fluid overload occurs soon after birth [1]. Clinical reports show that several risk factors are associated with symptomatic PDA, including an early gestational age (GA) [6, 7], low birth body weight (BBW) [7], respiratory distress syndrome [6, 8], PDA flow [9], sepsis [10], and maternal diabetes [11]. Every PNICU provides intensive care for these preterm population of varying BBW and maternal and gestational features. Since PDA can have a significant hemodynamic impact on premature infants, neonatologists have to make daily decisions about whether or not to close PDA. While prophylactic treatments for the medical closure of PDA are controversial [12], it remains clinically imperative to promptly determine whether PDA treatment is necessary and to predict which individuals are at high risk of medical failure.

The objective of this study was to investigate whether clinical factors in early life that are indicative of immediate postnatal oxygenation, hemodynamics, and/or intravascular volumes with the certain circumstances of maternal and gestational statuses can provide early predictions of the need for PDA treatment, predict the responsiveness to medical treatment, and predict the need for surgical ligation.

Subjects

This study was carried out retrospectively by reviewing the medical charts of preterm neonates with GAs of <37 weeks, regardless of BBW and sex, who were consecutively admitted to the PNICU of Kaohsiung Chang Gung Memorial Hospital, Taiwan, between October 2008 and September 2013. Neonates who had genetic/chromosomal anomalies, multiple congenital anomalies, PDA-dependent congenital heart disease, or congenital heart diseases that did not include patent foramen ovale/atrial septal defects or PDA, and those who died within 72 hours of birth were excluded from this study.

Patent Ductus Arteriosus Management

The diagnosis and size of the PDA were obtained from the echocardiography reports. According to therapeutic strategies for PDA, all subjects were categorized into groups of non-treated PDA (no pharmaceutical treatment required), medically-responded PDA, and surgically-ligated PDA. At our PNICU, the medical treatment and surgical ligation were stringently applied for hemodynamically significant PDA (hsPDA) [13, 14], which was defined as PDA that was concomitant with at least one of the heart failure signs, including respiratory distress, tachycardia, poor feeding and weight gain, and enlargement of the heart chamber size, and/or ventilator dependency, intraventricular hemorrhage, and necrotizing enterocolitis as well as pulmonary hypertension [14, 15]. The treatment was started with either at least one course of intravenous indomethacin (0.2 mg/kg, every 12 hours for 3 doses) or oral ibuprofen (10 mg/kg, followed by 5 mg/kg and 5 mg/kg for 3 consecutive days) [16] without prophylactic treatment. Surgical ligations were undertaken for either medically-poor-responded or medically-contraindicated hsPDA.

Data Collection

The clinical data were collected retrospectively from the medical records, and included the neonates’ birth histories, the maternal histories, and the immediate postnatal statuses of the infants.

Statistical Analyses

Data were expressed as the median (interquartile range, IQR) or the number with the proportion of the number. Owing to non-normal distribution of data, univariate analysis was performed using Mann-Whitney U test with/and without Kruskal-Wallis post-hoc modification or Chi-square test or Fisher’s exact test. Multinomial stepwise logistic regression was used for multivariate analysis by selecting all variables with p value no more than 0.2 in the univariate analysis to determine the independent risk factors for the PDA outcome. A P value of <0.05 that was determined using SPSS software was considered statistically significant.

Study Population

This study involved 682 preterm infants and the demographic characteristics were summarized in Table 1. Five premature neonates who suspiciously died of PDA-related cardiopulmonary failure either during or without the medical treatment (Supplementary table 1) and 54 neonates who died within 72-hours after birth were not recruited in this study. Owing the PDA outcome varies with BBW, these recruited subjects were further sub-categorized into the groups of BBW<1500 g (as very low birth weight, VLBW) and BBW ≥1500 g (as non-VLBW group). The VLBW group significantly had the lower GA, BBW, and Apgar scores at 1 minute and 5 minute and the higher percentage of small for GA (BBW<10^th percentile according to validated tables for Taiwan infants)[17] than the non-VLBW group. The gender, the percentage of twins and triplets, and the rate of Cesarean section did not significantly differ between groups.

PDA Outcomes

In overall, 83.3% of total PDAs did not require pharmaceutical treatment in the neonatal stage of prematurity. Though, the percentages of treatment-required PDAs did not significantly differ between the 2 groups, the VLBW group significantly had the higher percentages of medical irresponsiveness and surgically-ligated PDA than the non-VLBW group (Table 2). The percentage of direct surgical ligation did not differ between groups.

Maternal and Gestational History and Perinatal Status

Among 3 types of PDA outcomes, each factor of maternal and gestational history and perinatal status was evaluated by univariate analysis individually within the VLBW and non-VLBW groups (Table 3). In the VLBW group, neonates with surgically-ligated PDA significantly had the lower percentage of maternal preeclampsia, early GA, lower BBW and the Apgar scores at 1 and 5 minutes, and the higher percentages of maternal gynecologic ovarian and uterine disorders, delays in initial crying, the need to intubate and the use of surfactants when compared to those with non-treated PDA. The need to intubate and the surfactant use remained higher and the percentage of maternal preeclampsia and the Apgar score at 5 minute remained lower in neonates with medically-responded PDA. In the non-VLBW group, when compared to the neonates with non-treated PDA, those with surgically-ligated PDA significantly had the higher percentages of antenatal intrauterine growth retardation (IUGR), delays in initial crying and the need to intubate and those with medically-responded PDA significantly had less maternal gravidity and parity, and the higher percentages of placenta previa, IUGR, dexamethasone administration, delays in initial crying and the use of surfactants, and lower BBW.

Immediate Postnatal Clinical Parameters and Hemodynamic Profiles

The immediate postnatal clinical parameters and hemodynamic profiles were compared among PDA outcomes (Table 4). In the VLBW group, neonates with surgically-ligated PDA significantly had larger amount of the first 24-hour intravenous fluid administration per kilogram of BBW (IVF) and the higher percentages of diuretics use when compared to those with non-treated and medically-responded PDAs. Additionally, when compared to the neonates with non-treated PDA, the VLBW neonates with surgically-ligated PDA significantly had higher levels of enhanced fractional oxygen concentrations (FiO2) and peak inspiratory pressure (PIP), and the higher percentages of dopamine and fresh frozen plasma (FFP) transfusions; and similarly, the VLBW neonates with medically-responded PDA had higher level of FiO2 and the higher percentage of dopamine transfusion. In the non-VLBW group, neonates with medically-responded PDA had lower systolic BP, higher levels of FiO₂, PIP, and positive end-expiratory pressure (PEEP) and the higher percentage of dopamine transfusion when compared to neonates with non-treated PDA.

Furthermore, multinomial logistic regression controlling the confounding factors to determine the independent contributory factors to the PDA outcome revealed that the surfactant use and the first 24-hour IVF significantly increased the risks of medically-responded and surgically-ligated PDA in the VLBW group, and gynecological disorder additionally increased the risk for surgical ligation (Table 5). In the non-VLBW group, placenta previa increased but maternal parity and BBW decreased the risk of medically-responded PDA. IUGR increased the risk of surgically PDA.

PDA presents a daily challenge for neonatologists because of its high morbidity and mortality among premature infants. Indicative timings for therapeutic interventions and awareness about patients who are at a high risk of medical failure are imperative. In this study, approximately less than 20% of the preterm newborns developed hsPDA that required mandatory treatment at PNICU. For VLBW neonates, surfactant use and the larger amount of first 24-hour IVF predicted the requirement of PDA treatment. These two factors and maternal gynecological disorders predicted the possibility of surgical ligation. For neonates with BBW ≥1500 g, placenta previa, fewer maternal parity and lower BBW predicted the risk of PDA to treat and its medical responsiveness; and IUGR predicted the risk of surgical ligation. Taken together, these findings highlight the differential importance of maternal and gestational history and perinatal clinical parameters of varying BBW in the PDA of prematurity care.

Similarly to the report by Siassi et al. [7], we found that newborns with GA≥32 weeks had significantly higher spontaneous PDA closure rates (89%) than those with GA<32 weeks and ≥28 weeks and GA <28 weeks (84.3% and 69%, respectively). Furthermore, a GA of <28 weeks had a higher risk ratio for surgical ligation (20% in GA<28 weeks, 7.2% in GA <32 weeks and ≥28 weeks, 2.3% in GA ≥32 weeks). Since BBW and GA highly correlated (Spearman correlation r=0.76, p <0.001) and impacted post-natal status, multivariate analysis was performed, revealing that BBW remains a determinant factor for the need to treat and the medical response to non-VLBW PDA. Additionally, IUGR was significantly associated with non-VLBW neonates with surgically-ligated PDA. Thus, BBW seems to play more important role of PDA outcome for these non-VLBW neonates.

For all medically-treated 99 neonates regardless of GA and BBW, the neonates with medically-irresponsive PDA tended to have lower GA and BBW, lager postnatal age of starting medication, the greater first 24-hour IVF and the ratio of IVF over urine output and the higher percentage of diuretics use and FFP transfusions when compared to those in the medically-responded group (Supplementary table 2). After multivariate analysis, only BBW and the ratio of IVF over urine output could independently determine the medical response to PDA treatment (Supplementary table 3). The BBW increase per 100-gram lowered the risk and the greater ratio IVF over urine output increased the risk of medical irresponsiveness. None of aforementioned factors relating maternal and gestational histories and perinatal status was significantly associated with the medical responses.

When individually compared to the non-treated PDA groups, VLBW neonates with surgically-ligated PDA tended to receive larger amounts of the first 24-hour IVF, require FFP and dopamine transfusions and diuretics use, and higher levels of FiO2 and PIP for ventilator use; whereas, non-VLBW neonates with medically-responded PDA tended to have lower systolic BP, require higher levels of FiO2, PIP and PEEP for ventilator use, and require dopamine transfusion. These findings partially agree with those from previous studies that the administration of excessive fluid was a risk factor for PDA [18, 19]. When compared to the recent publication by Levinson et al. [18], our study showed that the amount of first 24-hour IVF independently determined the PDA outcome for VLBW neonates with BBW less than 1500 g. In their study, though not significantly, the larger the IVF, the greater the percentage of neonates requiring PDA medical or surgical treatment from 34% (no additional fluids), 44% (≥15-40% of excessive fluids) to 55% (≥40% of excessive fluids) [18]. Additionally, by using receiver operating characteristic curve analysis, we determined that the cutoff values of the amount of first 24-hour IVF were 87 and 89.5 ml/kg/day, respectively, to predict the treatment necessity (sensitivity = 73.8%, specificity = 58.4%) and medical treatment failure (sensitivity = 80%, specificity = 57.1%) for PDA outcomes in the VLBW group (Supplementary Figure 1). Several studies have addressed the relationship between hypotension and PDA [19, 20]. However, hypotension and low BP a few days after admission could be significant consequences of the hemodynamics associated with PDA. The mechanism underlying the effect of an initially low systolic BP or hypotension on hsPDA remains unknown. Clyman et al. proposed an evidence that increased circulating level of prostaglandin E associated with respiratory distress syndrome might contribute to the patency of ductus arteriosus [21]. This provides a direction for further investigations to determine whether the lower BP is a surrogated phenomenon, or whether the initially low BP, or hypotension, leads to the inadequate perfusion of the major end organs, which subsequently triggers vasodilation to increase blood flow, thereby exacerbating the PDA.

Respiratory distress syndrome [6, 8], the need for intubation with positive-pressure ventilation [19], and the surfactant use have been reported as risk factors for PDA [22]. Little had been addressed regarding to the independent roles of surfactant, placenta previa, the number of parity and gynecologic disorders on the outcome of neonatal PDA in prematurity. Increased ductal shunting after surfactant administration was ever reported [23]. To avoid the PDA-related morbidity and mortality, future exploration of the mechanistic effect of surfactant on PDA might be needed. Meanwhile, we observed that two thirds of VLBW neonates born to mothers with uterine myoma (n=3) tended to have surgically-ligated PDA (p=0.046) more than to have medically-responded PDA (n=0) and non-treated PDA (n=1, 33.3%). Owing to the limited number of the specific gynecologic disorder, carful explanation and further study design are necessary.

In contrast to previous reports, our data did not reveal significant associations between hsPDA and maternal diabetes [24], prolonged membrane rupture [6], twin births [25], and sex in the current study [19]. Although the limitations of this study may relate to its retrospective design and being performed at a single center in an Asian country, the sample size and multivariate analysis may have effectively adjusted its clinical significance.

In this study, we comprehensively studied the interactive effect of maternal and gestational issues and the clinical factors commonly encountered during the first day of postnatal life, which differentially and independently predicts PDA outcomes in the premature neonates of varying BBW. Based on these results, a cross-country multicenter-based clinical trial that targets a personalized therapeutic strategy for PDA might be developed in the future.

ABG, arterial blood gas; BBW, birth body weight; BE, base excess; CI, confidence intervals; DBP, diastolic blood pressure; FFP, fresh frozen plasma; FiO2, fractional oxygen concentrations; GA, gestational age; GDM, gestational diabetic mellitus; HCO3, bicarbonate; hsPDA, hemodynamically significant PDA; HTN, hypertension; IQR, interquartile range; IUGR, intrauterine growth retardation; IVF, intravenous fluid administration per kilogram of BBW; PDA, patent ductus arteriosus; PEEP, positive end expiratory pressure; PIP, peak inspiratory pressure; PNICU, pediatric neonatal intensive care unit; SBP, systolic blood pressure; VLBW, very low birth weight

Ethics approval and consent to participate

This study was approved by the institutional review board (Permit number: 102-1987B and 103-1077A3) of Chang Gung Memorial Hospital, Taiwan and conducted in accordance with the principles within the Declaration of Helsinki.

Consent for publication

Not applicable

Availability of data and material

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding

This study was in part supported by Kaohsiung Chang Gung Memorial Hospital (grants CMRPG8B1153, CMRPG8G0661, and CMPRG8D1552) to Lin IC. The funders had no role in study design, data collection, analysis and interpretation, decision to publish, or preparation of the manuscript.

Author Contributions: all authors will make final approval of the version to be published.

Lin, I.C.: Substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; drafting the article and revising it critically for important intellectual content.

Liu, H.Y.: Substantial contributions to acquisition and interpretation of data; drafting the article critically for important intellectual content;

Hsu, T.Y., Chen, C.C., Lai, Y.J, Tsai, C.C.: Substantial contributions to acquisition and interpretation of data.

Huang, E.Y.: Substantial contributions to analysis and interpretation of data.

Acknowledgements

Thanks the Biostatics Center, Kaohsiung Gung Memorial Hospital for statistics works.

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You are reading this latest preprint version

Differential Determinants of Patent Ductus Arteriosus Outcomes for Prematurity of Varying Birth Body Weight

Status:

Version 1

Abstract

Background

Methods

Subjects

Patent Ductus Arteriosus Management

Data Collection

Statistical Analyses

Results

Study Population

PDA Outcomes

Maternal and Gestational History and Perinatal Status

Immediate Postnatal Clinical Parameters and Hemodynamic Profiles

Discussion

Conclusion

Abbreviations

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and material

Competing interests

Funding

Acknowledgements

References

Supplementary Files

Status:

Version 1