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Association between early metabolic acidosis and bronchopulmonary dysplasia/death in preterm infants born at less than 28 weeks’ gestation: an observational cohort study

BMC Pediatrics volume 24, Article number: 605 (2024) Cite this article

Abstract

Background

Metabolic acidosis occurs frequently during the first postnatal days in extremely preterm infants and is mainly attributed to renal immaturity. Recent studies suggested a link between metabolic acidosis and the development of BPD. The aim of this study was to systematically investigate the association between severe metabolic acidosis during the first two weeks of life and bronchopulmonary dysplasia (BPD) / mortality among preterm infants born before 28 weeks’ gestation.

Methods

Monocentric observational cohort study including 1748 blood gas samples of 138 extremely preterm infants born 2020–2022. Metabolic acidosis was defined as pH < 7.2 with base excess (BE) < -10 mmol/L or standard bicarbonate (SBC) < 12 mmol/L. Primary outcome was BPD and/or death at 36 weeks postmenstrual age.

Results

Fifty-six (40.6%) infants had BPD/death. Metabolic acidosis occurred in 50.0% of infants with BPD/death, compared to 22.0% of BPD-free survivors (p = 0.001) during the first 14 postnatal days. Minimum pH (median 7.12 vs. 7.19, p < 0.001), BE (median -10.9 vs. -9.5 mmol/L, p = 0.005), SBC (median 14.7 vs. 16.1 mmol/L, p < 0.001) were different between the two groups. After adjusting for confounders, pH (postnatal days 2–6), BE (postnatal day 3) and SBC (postnatal days 2–4) were significantly lower in infants with BPD/death. Metabolic acidosis on postnatal days 1–7 was associated with higher odds of BPD (adjusted Odds Ratio (aOR) 3.461, 95% CI 1.325–9.042) and BPD/death (aOR 3.087, 95% CI 1.225–7.778).

Conclusions

Metabolic acidosis during the first week of life was associated with higher odds of BPD/death in extremely preterm infants.

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Background

Bronchopulmonary dysplasia (BPD) is the most common and serious chronic respiratory disease in preterm infants [1,2,3,4]. Extremely low gestational age newborns (ELGAN), those born before 28 completed weeks of gestational age, are in particular at high-risk of developing BPD [2, 5]. Despite improved survival in extremely preterm infants and advances in neonatal care, the number of infants with BPD has steadily increased [2]. The pathogenesis of BPD is multifactorial and attributed to impaired alveolar and vascular development [6, 7]. Intrauterine growth restriction and infections, gestational age, birth weight, male sex, and mechanical ventilation are among the important risk factors for developing BPD [8,9,10,11]. BPD is associated with poor neurodevelopmental outcomes throughout childhood and causes relevant health care utilization and costs [12,13,14,15,16,17].

Metabolic acidosis in the first days after birth is common in ELGAN [18]. Metabolic acidosis has a multifactorial etiology. Renal immaturity, parenteral nutrition, protein metabolism, medication, respiratory failure, hemodynamic disturbances, and hypovolemia influence acid-base homeostasis in extremely preterm infants [19,20,21,22,23,24]. In particular, renal tubular immaturity is characterized by a lower renal bicarbonate threshold, leading to increased urinary bicarbonate losses and a reduced urinary excretion of ammonium and titratable acids [18, 19, 25]. In addition, high chloride levels are associated with the development of metabolic acidosis [23, 26]. Metabolic acidosis in ELGAN is self-limiting and resolves within the second week of life, in parallel with a renal maturation process during this period [18, 19].

The management of metabolic acidosis in preterm infants can be challenging. Metabolic acidosis has been described as a risk factor for intraventricular hemorrhage in preterm infants and has been associated with longer hospitalization and a poorer neurological outcome in very low birth weight infants [20, 27,28,29]. Whether or at what threshold metabolic acidosis needs to be treated at all is still controversial [30]. Sodium bicarbonate is routinely used in preterm infants despite evidence of increased rates of intraventricular hemorrhage and mortality (30–31). Alternatively, sodium acetate can be used to correct metabolic acidosis [32].

Results from recent studies may indicate a link between metabolic acidosis and the development of BPD. Lower minimum pH values during the first 14 postnatal days have been associated with the development in BPD in premature infants < 32 weeks of gestational age [33]. In addition, the administration of sodium acetate instead of sodium chloride in parenteral nutrition has been shown to reduce the frequency of metabolic acidosis and BPD in preterm infants [34].

The objective of this study was to investigate the association between metabolic acidosis during the first two postnatal weeks and BPD and/or mortality in ELGAN. The underlying null hypothesis was that infants with metabolic acidosis during the first 14 days of life would not have a higher incidence of BPD/death.

Methods

Study population

This monocentric observational cohort study included infants born between January 1, 2020 and December 31, 2022 with a gestational age between 22 0/7 and 27 6/7 weeks (ELGAN) at a single tertiary-level neonatal intensive care unit. All infants who died within the first 14 postnatal days (including those who received comfort care) and those with severe congenital malformations or syndromic disorders were excluded. The local Ethics Committee (Cantonal Ethics Committee Zurich) approved this study, based on a positive General Consent for the use of routinely collected health-related data for research projects [35].

Data collection

Data were collected from the medical records or exported from the Swiss National Registry of very preterm infants of the Swiss Society of Neonatology (SwissNeoNet). Data acquired included blood gas parameters, demographic and perinatal/neonatal data. All blood gas results from the first 14 postnatal days were reviewed for this study. Blood gas tests were carried out according to clinical necessity. As arterial lines were usually removed within a few days after birth at this institution, data from arterial, capillary and venous blood gas samples were included. For each 24-hour period (midnight to midnight), one blood gas sample was selected for further analysis. Blood gas samples in which both the pH or the BE were validly available were analysed for further selection, as were all other values without technical measurement errors. The sample with the highest base deficit within the 24-hour period was selected for each day and each patient. Subsequent selection criteria were lower pH value, then higher lactate value, and lastly the earlier sample.

The pH, base excess (BE), standard bicarbonate (SBC, HCO3−), sodium (Na+), chloride (Cl−) and lactate values of the selected daily blood gas samples were extracted from the medical records for further analysis. The anion gap was calculated as [Na+]-[Cl−]-[HCO3−] [36]. The following clinical data were analysed for each infant: (1) demographic and obstetric data, including sex, gestational age, birth weight, small for gestational age (SGA) status (defined as < 10th percentile for gestational age and sex according to Voigt percentile curves [37]), number of infants, complete prenatal steroids and mode of delivery; (2) data on perinatal transition, including the Apgar score at 5 min and umbilical arterial cord blood pH; (3) data on postnatal surfactant treatment.

Definition of metabolic acidosis

Metabolic acidosis was defined as pH < 7.2 with BE < -10 mmol/L or SBC < 12 mmol/L [38]. The main exposure was metabolic acidosis during the first two postnatal weeks. As acidosis was expected to be more pronounced in the first week of life than in the second, the association between metabolic acidosis during the first postnatal week and the outcomes was analysed separately [18]. In addition, associations between the individual blood gas parameters listed above and the primary outcome were analysed.

Outcomes

The primary outcome of this study was the composite of BPD and/or death, as BPD and mortality are competing outcomes in extremely preterm infants [39]. BPD was defined as the requirement for supplemental oxygen at 36 weeks postmenstrual age and/or positive pressure, provided that the infant had received oxygen for at least 28 days before reaching 36 weeks, corresponding to moderate to severe BPD according to Jobe et al. [1]. Death was defined as mortality after the fourteenth postnatal day and before reaching 36 weeks of postmenstrual age to avoid survival bias. In addition, the individual components of the composite outcome were analysed separately.

Statistics

All statistical analyses were conducted using RStudio v2023.09.1 + 494 (RStudio, Boston, MA) in R, Version 4.3.1 (The R Foundation for Statistical Computing, Vienna, Austria). Categorical variables were presented as frequencies (with percentages) and continuous variables as medians with interquartile ranges (IQR). For unadjusted comparisons between infants with BPD/death and BPD-free survivors, Pearson’s Chi-squared and Fisher’s exact test were applied for dichotomous variables and Wilcoxon rank sum test for continuous variables. To explore the effect of each daily exposure variables (pH, BE, SBC, lactate, sodium and chloride) on BPD/death, unadjusted comparisons were made using Wilcoxon rank sum test and adjusted associations were explored using binary logistic regression. For each daily blood gas parameter with an independent association with BPD/death, receiver operating characteristics (ROC) analysis was conducted to evaluate model performance. Youden index was used to determine optimal cut-off values for each variable, and corresponding sensitivity and specificity for association with BPD/death were reported. Binary logistic regression analysis was used to explore associations between metabolic acidosis and each outcome, and adjusted odds ratios (aOR) with corresponding 95% confidence intervals (CI) were calculated accordingly. All logistic regression analyses were adjusted for sex, gestational age, SGA status, prenatal steroids, mode of delivery, 5-min Apgar < 7, and surfactant application. Goodness-of-fit was assessed using the Hosmer-Lemeshow test. A p value < 0.05 was considered statistically significant.

Results

Two hundred and one neonates were admitted during the study period. Sixty-three were excluded: Fifty-one infants who died between postnatal day 1 and 14, 11 neonates with a severe congenital malformation or syndromic disorder and one infant without data on the primary outcome, who was transferred before 36 weeks postmenstrual age (Additional Fig. 1).

Fifty-six (40.6%) of the included 138 neonates had the composite outcome of BPD and/or death at 36 weeks postmenstrual age. Fifty-one (37.0%) infants developed BPD, and 5 (3.6%) infants died before reaching 36 weeks of postmenstrual age. Among the infants who developed BPD, 44 (31.9%) infants had developed moderate BPD, and seven (5.1%) developed severe BPD, according to the BPD severity classification by Jobe et al. [1]. The causes of death were gastrointestinal complications (necrotizing enterocolitis, volvulus, intestinal perforation) in four cases and circulatory collapse of unknown cause in one case. Infants with BPD/death were born at a lower gestational age and birth weight, were more often SGA and had received surfactant more frequently, as compared to BPD-free survivors (Table 1).

Table 1 Characteristics of infants with and without BPD/death
Full size table

Metabolic acidosis occurred primarily in the first week of life and was more common in neonates with BPD/death compared to BPD-free survivors (Table 2). Minimum laboratory values for pH, BE and SBC were significantly lower in infants with BPD/death, and maximum lactate values were higher.

Table 2 Metabolic acidosis among infants with and without BPD/death
Full size table

The daily blood gas values showed different patterns during the first 14 days of life (Fig. 1). The pH values decreased in the first days after birth, reached a nadir on the fourth postnatal day and increased thereafter. Infants with BPD/death had significantly lower pH values from postnatal day 2 to day 6. Base deficit was highest on day 3 of life, with significant differences between both groups on day 3. SBC, which was lowest around postnatal day 3, showed lower values from day 2 to 4 in neonates with BPD/death compared to BPD-free survivors. Sodium and chloride values showed no differences between the two groups during the first two weeks after birth (Additional Fig. 2). Both parameters increased during the first days of life and started to decrease in the second half of the first week after birth. Completeness of blood gas data and missing values were reported in Additional Table 1.

Fig. 1
figure 1

Daily pH, base excess, standard bicarbonate and lactate values in extremely preterm neonates during the first 14 days of life. A pH. B Base excess. C Standard bicarbonate. D Lactate. Notched boxplots represent median, 25% quantile and 75% quantile of BPD-free survivors (light grey) and infants with BPD/death (dark grey), respectively. ° unadjusted p < 0.05; °° unadjusted p < 0.01; °°° unadjusted p < 0.001.* adjusted p < 0.05; ** adjusted p < 0.01

Full size image

In the adjusted analysis, the first occurrence of metabolic acidosis during postnatal days 1 to 7 was associated with a 209% increase in the odds of BPD/death, and a 246% increase in the odds of BPD alone. In addition, there was a trend to more BPD/death in infants with metabolic acidosis during the first two postnatal weeks (aOR 2.409, 95% CI 0.967–6.003) (Table 3). Metabolic acidosis with onset in the second week of life was not independently associated with BPD/death, BPD, or mortality (Additional Table 2).

Table 3 Association of metabolic acidosis with outcomes
Full size table

A cut-off value of 7.26 for pH on postnatal day 4 had the best combined sensitivity (86%) and specificity (52%) in ROC curve analysis to predict BPD/death among all blood gas variables during the first postnatal week, with an area under the curve of 0.725 (95% CI 0.639–0.810) (Additional Table 3).

Discussion

An important finding in this study was the potential role of the acid-base status in the development of BPD. Metabolic acidosis, as defined for this study, occurred frequently in extremely preterm infants, particularly in the first postnatal week, and was associated with higher odds of BPD/death and BPD alone.

Metabolic acidosis was common in extremely preterm infants [18, 22]. Bourchier et al. described in detail the time course of metabolic acidosis in a cohort of premature infants of less than 26 weeks’ gestation. Metabolic acidosis was most pronounced on the fourth postnatal day and normalised in almost all infants during the second week of life [18]. The results of this study were consistent with the described time course. In contrast, Bonsante et al. found the lowest pH and maximum base deficit in a cohort of preterm infants ≤ 29 weeks’ gestation to be slightly later, around postnatal day 5–7 22.

Most of the neonates in the study cohort experienced acidosis to some extent during the first week of life, when pH values decreased before increasing again. However, there is no consensus as to which severity of metabolic acidosis is clinically relevant in ELGAN [30]. Various definitions of metabolic acidosis have been used in previous studies. The thresholds for metabolic acidosis ranged from a pH below 7.20 to 7.35 or a base deficit > 4 to > 10 mmol/L, whereas a cut-off value for bicarbonate was less frequently used [18, 29, 40, 41]. Other studies examined pH or base deficit as a continuous variable without setting a threshold [20, 22, 33, 34, 42]. In this study, the definition of severe metabolic acidosis (pH < 7.2 with base deficit > 10 mmol/L or bicarbonates < 12 mmol/L) from the European pediatric parenteral nutrition guidelines was applied [38].

The development of BPD might already begin during the first days of life [7, 43]. Whether metabolic acidosis after birth influences the development of BPD is still unclear. He et al. reported that the minimum blood pH value obtained during the first 14 days of life was an independent risk factor for BPD severity in preterm infants born < 32 weeks of gestational age based on a machine learning prediction model [33]. In contrast, Brown et al. found no difference in the minimum arterial pH within the first 72 h of life in a cohort of preterm infants that developed BPD [44]. Both studies did not distinguish between metabolic and respiratory acidosis. Respiratory blood gas abnormalities in the first postnatal days have been associated with the development of BPD [45]. However, there is limited data on the potential link between the metabolic component of early postnatal acidosis and BPD. Ali et al. reported that the use of sodium acetate instead of sodium chloride in parenteral nutrition was associated with less metabolic acidosis and a lower BPD rate among preterm infants born before 33 weeks’ gestation. Infants who received sodium acetate had significantly higher mean pH and BE values on postnatal days 4–6 [34]. It remains unclear why the metabolic acidosis that first occurred in the first week of life was associated with BPD/death, in contrast to acidosis with onset in the second week of life. Differences in the severity or the number or duration of acidotic episodes as well as a higher sensitivity to acidosis in the first week of life might contribute to this finding. No further studies have systematically examined the impact of early metabolic acidosis on the development of BPD in extremely preterm infants. There is no evidence of a potential causal relationship between metabolic acidosis and BPD, or between alkalisation and protection against the development of BPD to date. However, since inflammation and oxygen toxicity contribute to the pathogenesis of BPD, anti-inflammatory and antioxidant effects of sodium acetate might be considered as possible underlying mechanisms for a potential protective effect [7, 46, 47].

The results of this study do not allow any definitive conclusions to be drawn about the cause of the metabolic acidosis in this contemporary study cohort. However, due to the low gestational age and the low bicarbonate levels, renal involvement with bicarbonate loss can be assumed as a contributory cause of acidosis [19]. Since parenteral nutrition with amino acids and lipids was routinely started on the day of birth, an influence of the nutritional components on the acid-base homeostasis is also conceivable [22]. The administration of chloride, whether by bolus administration of normal saline or as an electrolyte supplement to parenteral nutrition, may have also contributed to metabolic acidosis [23, 42]. Hyperchloremia can in turn lead to renal vasoconstriction and a reduced glomerular filtration rate, thus potentially affect the fluid balance [48]. In addition, higher lactate levels on postnatal day 3 in the BPD/death cohort may indicate that inadequate tissue oxygenation and lactic acidosis due to poor cardiac function could have contributed to metabolic acidosis in some patients through hypoxia-hypoperfusion mechanism [22]. Whether specifically metabolic (lactate-)acidosis due to hypoxia/hypovolemia was associated with BPD/death could not be adequately answered, as there is no defined threshold for the lactate value to clearly differentiate acidosis caused by hypoxia from acidosis due to other causes in preterm infants. Several studies have reported an association between the fluid intake including parenteral nutrition in early life, which may also affect the acid-base balance, and the development of BPD [49].

It would be conceivable that metabolic acidosis was not causally related to the development of BPD, but was merely a marker for a higher risk of BPD influenced by other factors. Adequately powered translational studies are therefore required to evaluate the impact of metabolic acidosis on BPD and to investigate potential treatment thresholds for metabolic acidosis in extremely preterm neonates.

Limitations

This study has several limitations, such as its retrospective and monocentric nature. Differences in the duration and number of acidotic episodes were not analysed, nor were further pH, BE or SBC cut-off values to define metabolic acidosis, which could lead to bias. Respiratory parameters such as arterial partial pressure of carbon dioxide or the type of respiratory treatment and data on nutrition including fluid status were not included in this study. Not every patient had a blood gas sample taken every single day, and sicker neonates may have had more tests performed, which may lead to bias. Metabolic acidosis due to hypoxia/hypoperfusion was not separately analysed. Based on it’s nature and results, this study cannot ascertain a causal relationship between metabolic acidosis and a higher risk of BPD/death, but rather generates hypothesis.

Conclusions

Early metabolic acidosis was associated with higher odds of BPD/death among preterm infants born before 28 weeks of gestation. In the first postnatal week, pH and SBC values were lower and base deficits higher in infants with BPD/death compared to BPD-free survivors. The acid-base status in early life might influence development of BPD in extremely preterm infants.

Data availability

The raw dataset analyzed in this study are available from the corresponding author on reasonable request.

Abbreviations

aOR:

adjusted Odds Ratios

AUC:

Area Under the Curve

BE:

Base Excess

BPD:

Bronchopulmonary Dysplasia

CI:

Confidence Intervals

ELGAN:

Extremely Low Gestational Age Newborns

IQR:

Interquartile Ranges

ROC:

Receiver Operating Characteristics

SGA:

Small for Gestational Age

SBC:

Standard Bicarbonate

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Authors and Affiliations

  1. Department of Neonatology, Newborn Research, University Hospital Zurich (USZ), University of Zurich (UZH), Frauenklinikstrasse 10, Zurich, 8091, Switzerland

    Laura Notz, Mark Adams, Dirk Bassler & Vinzenz Boos

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  1. Laura Notz
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  2. Mark Adams
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  3. Dirk Bassler
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  4. Vinzenz Boos
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Contributions

L.N. acquired the data, contributed to data analysis and wrote the initial draft of the manuscript. M.A. contributed to data collection and data interpretation. D.B. contributed to study design and data interpretation. V.B. designed the study, contributed to data collection, realized the data analysis and interpretation, contributed to the initial draft of the manuscript and edited the final version of the manuscript. All authors reviewed and revised the manuscript for important intellectual content, approved the final version and agree to be accountable for all aspects of the work.

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Correspondence to Vinzenz Boos.

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The local ethics committee (Cantonal Ethics Committee Zurich, BASEC No. 2023-00084) approved this study. The informed consent to the general consent was obtained from the parents or legal guardians and enabled the further use of routinely collected health-related data for this research project.

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Notz, L., Adams, M., Bassler, D. et al. Association between early metabolic acidosis and bronchopulmonary dysplasia/death in preterm infants born at less than 28 weeks’ gestation: an observational cohort study. BMC Pediatr 24, 605 (2024). https://doi.org/10.1186/s12887-024-05077-3

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  • DOI: https://doi.org/10.1186/s12887-024-05077-3

Keywords

BMC Pediatrics

ISSN: 1471-2431

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