Background
Umbilical cord arterial and venous blood gas values reflect the acid-base balance status of a newborn at birth. Derangement in these values has been linked to poor neonatal outcomes in term and late preterm neonates; however, the utility of these values in preterm neonates of <29 weeks’ gestation is unclear.
Objective
This study aimed to determine the associations of umbilical cord arterial and venous blood gas values with neonatal mortality and severe neurologic injury in extremely preterm neonates and to identify the cutoff values associated with 2.5-fold increases or decreases in the posttest probabilities of outcomes.
Study Design
This was a retrospective cohort study of neonates who were born at 23+0 to 28+6 weeks’ gestation between January 1, 2018 and December 31, 2019, and who were admitted to neonatal units in Canada.
Exposure
Various cut-offs of umbilical cord blood gas values and lactate values were studied.
Main Outcomes and Measures
The main outcomes were mortality before discharge from the neonatal unit and severe neurologic injury defined as grade 3 or 4 periventricular or intraventricular hemorrhage or periventricular leukomalacia. The outcome rates were calculated for various cutoff values of umbilical cord blood gas parameters and were adjusted for birthweight, gestational age, sex, and multiple births. Likelihood ratios were calculated to derive posttest probabilities.
Results
A total of 1040 and 1217 neonates had analyzable umbilical cord arterial and venous blood gas values, respectively. In the cohort, the mean (standard deviation) gestational age was 26.5 (1.5) weeks, the mean birthweight was 936 (215) g, the prevalence of mortality was 10% (105/1040), and the prevalence of severe neurologic injury was 9% (92/1016). An umbilical cord arterial pH of ≤7.1 and base excess of ≤−12 mmol/L were associated with >2.5-fold higher posttest probability of mortality, and an umbilical cord arterial or venous lactate value of <3 was associated with a 2.5-fold lower posttest probability of mortality. An umbilical cord arterial lactate value of <3 was associated with a lower posttest probability of severe neurological injury.
Conclusion
In preterm neonates of <29 weeks’ gestation, low umbilical cord arterial pH and high umbilical cord arterial base excess values were associated with a clinically important increase in the posttest probability of mortality, whereas low umbilical cord arterial or venous lactate values were associated with a decrease in the posttest probability of mortality.
Introduction
Umbilical cord arterial (UA) and umbilical cord venous (UV) blood gas analyses are performed to assess the acid-base balance status of a newborn at birth. , The umbilical cord vein carries oxygenated blood from the mother to fetus, which reflects the combined effects of maternal acid-base status and placental function. The umbilical cord arteries carry deoxygenated blood rich in carbon dioxide and other metabolic waste products from the fetus, which reflects fetal acid-base status. Changes in blood gas parameters can indicate the status of the mother, placenta, and fetus immediately before birth.
Why was this study conducted?
Derangement in the values of umbilical cord blood gas parameters has been linked to poor neonatal outcomes in term and late preterm neonates; however, their utility in preterm neonates of <29 weeks’ gestation is unclear.
Key findings
An umbilical cord arterial pH of ≤7.1 and umbilical cord arterial base excess of ≤–12 mmol/L were associated with a 2.5-fold higher posttest probability of mortality. Umbilical cord arterial or venous lactate values <3 mmol/L were associated with a 2.5-fold lower posttest probability of mortality. Umbilical cord arterial lactate value of <3 was associated with a lower posttest probability of severe neurological injury.
What does this add to what is known?
Umbilical cord arterial gas values suggestive of metabolic acidosis are associated with the outcome of mortality and not brain injury in preterm neonates of <29 weeks’ gestation.
Impaired gas exchange in the mother or fetus leads to metabolic acidosis, which has been linked to poor neonatal outcomes including low Apgar scores, respiratory distress, sepsis, seizures, intracranial hemorrhage, hypoxic-ischemic encephalopathy, cerebral palsy, delayed development, necrotizing enterocolitis, and neonatal death. In a 2010 systematic review, Malin et al identified 4 studies that reported that a UA or UV pH value of <7.0 was associated with mortality (odds ratio [OR], 6.1; 95% confidence interval [CI], 0.90–41.6). However, none of the 4 studies specifically included preterm neonates of <29 weeks’ gestation. In preterm neonates, the association between deranged umbilical cord blood gas values and neurologic morbidities is inconsistent with some studies reporting higher odds of intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and seizures with varying pH thresholds and others reporting no associations. In term neonates, lower pH, higher partial pressure of arterial CO 2 (PaCO 2 ), and higher mean base excess (BE) in the umbilical cord arteries were associated with hypoxic-ischemic encephalopathy, cardiopulmonary resuscitation, seizure, intubation, and intrauterine growth restriction. In term neonates, cerebral palsy occurred more frequently at a UA pH value <7.0 and a UA BE ≥–12 mmol/L. In preterm neonates, a UA pH value <7.0 was associated with early onset of neonatal seizures. Most of the studies have included term or late preterm neonates and those that included preterm neonates of <29 weeks’ gestation are few. Because the impact of fetal acidosis on the developing fetal brain and organs in preterm neonates could be different to that of term neonates, and because the type of brain injury caused by acidosis could also be different, we undertook this study of preterm neonates <29 weeks’ gestation. Our objectives for this study were to explore the associations of UA and UV blood gas values with neonatal mortality and severe neurologic injury (SNI) in a national cohort of preterm neonates born at <29 weeks’ gestation and to identify the cutoff values associated with a 2.5-fold increase or decrease from baseline in the posttest probabilities of the outcomes.
Materials and Methods
Study design and setting
We conducted a retrospective cohort study of preterm neonates admitted to neonatal units participating in the Canadian Neonatal Network (CNN) and Canadian Preterm Birth Network (CPTBN). Data from neonates admitted between January 1, 2018 and December 31, 2019, were included. Individual-level data from all 31 level 3 neonatal intensive care units in Canada were used for this study. We obtained ethical approval for this study from the Research Ethics Board at Mount Sinai Hospital, Toronto, Ontario, Canada (approval # MSH REB 20-0191C; date, September 8, 2020). The requirement for informed consent was waived because we accessed only deidentified patient data.
Data sources and collection
Information on maternal and obstetrical variables, neonatal characteristics, UA and UV blood gas values, and the outcomes was extracted from the existing CNN and CPTBN database, which contains data from the individual hospital sites. The original data were collected at each site by trained data abstractors following a standardized manual of operations and definitions. The database has been shown to have very high reliability and internal consistency.
Study population
Neonates born at 23+0 to 28+6 weeks’ gestation who had UA or UV blood gas analysis results available were included. We excluded those with major congenital anomalies; those who were small for gestational age (SGA) (birthweight <third percentile for gestational age and sex) or large for gestational age (LGA) (birthweight >97th percentile for gestational age and sex); and those whose reason for preterm birth was uterine rupture, placental abruption, or antepartum hemorrhage. The exclusion criteria were developed to ensure assembly of a homogenous and uncomplicated cohort that was not predisposed to abnormal umbilical cord gas results from their underlying conditions.
Exposure: umbilical arteries and umbilical vein blood gas values
Sampling of umbilical cord blood was preformed immediately after birth following individual institutional guidelines. To reduce the possibility of incorrect results, the following steps were taken to correctly assign the data:
- 1.
It is well known that blood in the umbilical arteries has a lower pH and higher PaCO 2 than blood in the umbilical vein. Thus, a negative difference in venous-arterial pH and arterial-venous partial pressure of CO 2 (PCO 2 ) is not physiological and is usually caused by swapping of samples. We only used UV results in such cases.
- 2.
If the differences in the values for the umbilical cord arteries and umbilical cord vein were ≤0.02 for pH and ≤5 mm Hg for PCO 2 we only used the UV results for those patients because the values were likely from the umbilical cord vein only.
- 3.
Cases with UV PCO 2 values of <22 mm Hg were excluded because this is >2 standard deviations (SDs) below normal for women in labor.
We planned a priori to evaluate the cutoff values for UA and UV blood gases based on the literature for term neonates. The cutoff values for pH were pH ≤7.2, ≤7.1, and ≤7.0; cutoffs for PCO 2 were ≥55, ≥65, and ≥75 mm Hg; cutoffs for BE were ≤–8, ≤–12, and ≤–16 mmol/L; and cutoffs for lactate were ≥3, ≥4 and ≥5 mmol/L.
Outcomes
The outcomes were mortality before discharge from the neonatal unit and SNI. Mortality was defined as death owing to any cause before the first discharge home. SNI was defined as ≥grade 3 periventricular hemorrhage or IVH with ventricular dilatation or parenchymal injury (including PVL) , diagnosed using a cranial ultrasound scan or magnetic resonance imaging.
Variable definitions
Gestational age was determined as the best estimate according to the hierarchy of first trimester ultrasound, last menstrual period, obstetrical estimate, and pediatric estimate. SGA was defined as a birthweight <10th percentile for gestational age and sex. LGA was defined as a birthweight >90th percentile for gestational age and sex.
Statistical analysis
Descriptive data were presented as means (with SD) or medians (with interquartile ranges [IQRs]) for continuous variables and as percentages for categorical variables. Outcome comparisons were carried out using Student’s t tests or Wilcoxon rank-sum tests for continuous variables and chi-square or Fisher’s exact tests for categorical variables. Multivariable logistic regression was used to calculate ORs and 95% CIs. Birthweight, gestational age, sex, and multiple births were considered potential confounders and were adjusted for in logistic regressions. Diagnostic characteristics of sensitivity, specificity, positive likelihood ratio (+LR), and negative likelihood ratio (−LR) for these cutoff values were calculated. Based on the prevalence (pretest probability) in our study population, to be useful in the clinical context, we aimed to identify cutoffs that were associated with a ≥2.5-fold (for +LR) or ≤2.5-fold (for −LR) difference in posttest probability. These values were chosen arbitrarily, because increases or decreases in these values would add very little to the predictive utility of these cutoffs. All statistical analyses were completed using SAS software version 9.4 (SAS Institute Inc, Cary, NC).
Results
Between January 1, 2018 and December 31, 2019, a total of 3334 neonates born at 23+0 to 28+6 weeks’ gestation were admitted to tertiary neonatal units in Canada. Of these, 1106 patients were excluded based on the defined criteria and 662 were excluded because of data issues, leaving 1566 neonates with data on either UV or UA blood gases: 1040 had UA gas values and 1217 had UV gas values available for analysis ( Figure 1 ).
Baseline characteristics of the 1566 neonates included in the analyses and the 662 neonates excluded because of data issues are presented in Table 1 . For the included cohort, the mean (SD) gestational age was 26.2 (1.5) weeks and the mean (SD) birthweight was 937 (215) g. The proportion of neonates born via cesarean delivery, those whose mothers received any antenatal steroids, and those who had delayed cord clamping was higher among the included cohort than the excluded cohort. The included patients also had a marginally higher gestational age and birthweight. The proportion of outborn neonates was higher among the excluded cohort.
| Characteristics | Neonates with data included (n=1566) | Neonates with data excluded owing to missing or incorrect data (n=662) | P Value |
|---|---|---|---|
| Maternal characteristics | |||
| Age (y), mean (SD) | 31.3 (6.1) | 31.0 (5.9) | .56 |
| Cesarean delivery, n (%) | 984 (62.9) | 379 (57.3) | .01 |
| Multiple births, n (%) | 483 (30.8) | 213 (32.2) | .54 |
| Maternal hypertension, n (%) | 223 (14.4) | 79 (13.0) | .38 |
| Maternal diabetes, n (%) | 211 (13.9) | 66 (11.1) | .09 |
| Neonate characteristics | |||
| Birthweight (g), mean (SD) | 937 (215) | 907 (225) | <.01 |
| Gestational age (wk), mean (SD) | 26.2 (1.5) | 26.0 (1.6) | <.01 |
| Male, n (%) | 867 (55.4) | 360 (54.5) | .70 |
| Any antenatal steroid, n (%) | 1440 (92.1) | 517 (79.7) | <.01 |
| Outborn, n (%) | 117 (7.5) | 226 (34.2) | <.01 |
| Multiples, n (%) | 483 (30.8) | 213 (32.2) | .54 |
| Deferred cord clamping, n (%) | 876/1452 (60.3) | 274/532 (51.5) | <.01 |
In the study cohort, the overall prevalence of mortality and SNI were 10% and 9%, respectively. The adjusted ORs for the outcome of mortality at each cutoff value of the umbilical cord gas parameters (pH, pCO 2 , base deficit, and lactate) are presented in Figure 2 . For the UA gas parameters, significant increases in the odds of mortality were observed with lower pH, higher PCO 2, lower BE, and higher lactate values. However, for the UV gas parameters, an increase in the odds of mortality was identified only with higher lactate values. Adjusted ORs for the outcome of SNI for each set of umbilical cord gas cutoff values are presented in Figure 3 . Associations between SNI and UA or UV blood gas values were observed only for lactate levels in the UA.
Next, we calculated the sensitivity and specificity of UA and UV blood gas value cutoffs. Based on those, we calculated the +LR and −LR values for the outcomes of mortality and SNI ( Tables 2 and 3 , respectively). Using the prevalence data from our study population as the baseline pretest probability, we the calculated the posttest probability for each cutoff value. Threshold values for clinically significant changes were identified as a posttest probability of ≥25% for a positive test and ≤7.5% for a negative test for mortality and as a posttest probability of ≥22.5% for a positive test and ≤6.75% for a negative test for SNI. For the outcome of mortality, UA pH values of ≤7.0 and ≤7.1 and UA BE values of ≤–12 and ≤–16 were associated with ≥25% posttest probability for positive tests, whereas lactate values of <3 mmol/L for both UA and UV samples were associated with a ≤7.5% posttest probability for a negative test ( Table 2 ). For the outcome of SNI, UA lactate values of <3 were associated with a ≤6.75% posttest probability of SNI ( Table 3 ).
| Sample | Variable | Sensitivity | Specificity | AUC | LR positive | LR negative | Posttest probability for positive test considering 10% prevalence | Posttest probability for negative test considering 10% prevalence |
|---|---|---|---|---|---|---|---|---|
| UA | pH ≤7.0 | 11 (5–18) | 98 (97–99) | 0.57 (0.31–0.83) | 5.53 (2.64–11.21) | 0.91 (0.85–0.98) | 38.1 a | 9.2 |
| pH ≤7.1 | 20 (13–29) | 94 (92–95) | 0.61 (0.46–0.77) | 3.17 (2.01–5.00) | 0.85 (0.77–0.94) | 26.0 a | 8.6 | |
| pH ≤7.2 | 30 (21–39) | 80 (77–82) | 0.72 (0.62–0.82) | 1.45 (1.05–2.00) | 0.88 (0.78–1.01) | 13.9 | 8.9 | |
| PaCO 2 ≥75 mm Hg | 12 (6–20) | 96 (94–97) | 0.62 (0.44–0.80) | 2.74 (1.49–5.05) | 0.92 (0.86–0.99) | 23.3 | 9.3 | |
| PaCO 2 ≥65 mm Hg | 20 (13–29) | 88 (86–90) | 0.65 (0.51–0.79) | 1.63 (1.06–2.50) | 0.91 (0.83–1.01) | 15.4 | 9.2 | |
| PaCO 2 ≥55 mm Hg | 35 (25–45) | 65 (62–68) | 0.65 (0.55–0.76) | 0.99 (0.74–1.31) | 1.01 (0.87–1.17) | 9.9 | 10.1 | |
| BE ≤−16 | 5 (2–11) | 99 (98–99) | 0.67 (0.38–0.96) | 4.13 (1.46–11.64) | 0.96 (0.92–1.01) | 31.5 a | 9.6 | |
| BE ≤−12 | 11 (6–19) | 96 (95–97) | 0.63 (0.42–0.84) | 3.03 (1.58–5.80) | 0.92 (0.86–0.99) | 25.2 a | 9.3 | |
| BE ≤−8 | 25 (17–35) | 86 (84–89) | 0.59 (0.46–0.72) | 1.83 (1.26–2.67) | 0.87 (0.77–0.98) | 16.8 | 8.8 | |
| Lactate ≥5 mmol/L | 48 (37–59) | 82 (78–84) | 0.56 (0.46–0.67) | 2.61 (1.99–3.42) | 0.64 (0.51–0.78) | 22.5 | 6.6 a | |
| Lactate ≥4 mmol/L | 53 (42–64) | 74 (70–77) | 0.65 (0.57–0.74) | 2.00 (1.58–2.54) | 0.64 (0.51–0.81) | 18.2 | 6.6 a | |
| Lactate ≥3 mmol/L | 57 (45–67) | 63 (59–66) | 0.72 (0.65–0.79) | 1.51 (1.22–1.86) | 0.69 (0.54–0.89) | 14.4 | 7.1 a | |
| UV | pH ≤7.0 | 3 (1–8) | 98 (97–99) | 0.51 (0.26–0.76) | 1.69 (0.59–4.86) | 0.99 (0.96–1.02) | 15.8 | 9.9 |
| pH ≤7.1 | 7 (3–13) | 96 (94–97) | 0.47 (0.27–0.66) | 1.65 (0.83–3.29) | 0.97 (0.92–1.02) | 15.7 | 9.7 | |
| pH ≤7.2 | 14 (8–21) | 89 (87–91) | 0.53 (0.36–0.69) | 1.30 (0.82–2.06) | 0.96 (0.90–1.04) | 12.7 | 9.6 | |
| PCO 2 ≥75 mm Hg | 3 (1–8) | 97 (96–98) | 0.82 (0.59–1.00) | 1.02 (0.37–2.84) | 1.00 (0.97–1.03) | 10.3 | 10.0 | |
| PCO 2 ≥65 mm Hg | 6 (3–12) | 95 (93–96) | 0.65 (0.47–0.82) | 1.16 (0.57–2.38) | 0.99 (0.95–1.04) | 11.5 | 9.9 | |
| PCO 2 ≥55 mm Hg | 13 (8–20) | 86 (84–88) | 0.45 (0.32–0.58) | 0.95 (0.60–1.51) | 1.01 (0.94–1.08) | 9.5 | 10.1 | |
| BE ≤−16 | 2 (0–6) | 99 (98–99) | N/A | 1.59 (0.36–7.07) | 0.99 (0.97–1.02) | 15.0 | 9.9 | |
| BE ≤−12 | 7 (3–13) | 97 (96–98) | 0.58 (0.36–0.81) | 2.69 (1.25–5.79) | 0.96 (0.91–1.01) | 23.0 | 9.6 | |
| BE ≤−8 | 10 (6–18) | 89 (87–91) | 0.70 (0.53–0.87) | 0.98 (0.56–1.72) | 1.00 (0.94–1.07) | 9.8 | 10.0 | |
| Lactate ≥5 mmol/L | 42 (32–52) | 80 (77–83) | 0.61 (0.51–0.72) | 2.08 (1.59–2.71) | 0.73 (0.62–0.86) | 18.8 | 7.5 a | |
| Lactate ≥4 mmol/L | 50 (40–60) | 70 (67–74) | 0.66 (0.58–0.74) | 1.68 (1.34–2.09) | 0.72 (0.59–0.87) | 15.7 | 7.4 a | |
| Lactate ≥3 mmol/L | 66 (56–75) | 57 (54–61) | 0.62 (0.54–0.69) | 1.54 (1.32–1.81) | 0.59 (0.45–0.78) | 14.6 | 6.2 a |
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