Delaying cord clamping for at least 30–60 seconds after delivery is recommended by national and international organizations.1–6 In term newborns, delayed cord clamping has been shown to increase blood volume,7 hematocrit,8,9 hemoglobin,8–10 ferritin,8,9 and iron stores.8,9 It decreases anemia,8,9 and improves long-term neurodevelopmental outcomes.11,12 Delayed cord clamping likely does not increase maternal postpartum hemorrhage, nor interventions for neonatal hyperbilirubinemia or polycythemia.9,10,13
Cord blood gas analysis is used to assess acid–base status of newborns and to diagnose and treat those who are acidemic.14,15 It has significant medicolegal implications.16,17 Current cord blood gas reference ranges were defined when early cord clamping at less than 30 seconds was routinely practiced.18–22 As delayed cord clamping has become more prevalent, understanding its effect on newborn acid–base status and cord blood gas is important. Our objective is to compare the effect of early cord clamping and delayed cord clamping on arterial and venous cord blood gas values in term singleton newborns delivered vaginally.
This systematic review was prepared using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines.23 Details of the protocol for this systematic review were registered on PROSPERO (ID Number: CRD42019135779) and can be accessed at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42019135779.
Randomized controlled trials (RCTs) comparing delayed cord clamping at or after 30 seconds to early cord clamping in term newborns that measured cord blood gas parameters were eligible. Observational studies were included if cord blood gas parameters evaluated serial samples from the same umbilical cord collected at less than 30 seconds and again at or after 30 seconds after delivery. Outcome measures assessed were arterial and venous cord blood gas parameters including pH, PCO2, PO2, HCO3, lactate, and base deficit. A comprehensive literature review was performed on April 20, 2019. EBSCOhost-OneSearch was also used to simultaneously search, identify, and compile records from MEDLINE, CINAHL, and CENTRAL databases using the same search terms. EMBASE and ClinicalTrials.gov were searched separately. Forward and backward reference searches were also performed on each study ultimately included in this review. Broad search terms were used to search the titles, abstracts, and keywords: cord AND clamp* AND gas AND umbilicus*.
Two reviewers (M.J.R.N. and E.B.) independently performed a database search and reviewed each paper. Discrepancies between the two reviewers were discussed and further evaluated by an adjudicator (D.S.). During initial record screening, M.J.R.N. and E.B. classified each article as either “include, exclude, or unsure” and then evaluated full texts of screened records for eligibility. Two reviewers (M.J.R.N. and E.B.) independently extracted data using an Excel-based data-extraction form. If a study reported more than one study group, we included only the results and methodologic characteristics most pertinent to this research topic.
We performed a domain-based risk of bias assessment of individual studies using the following domains: randomization sequence generation, allocation concealment, blinding, incomplete data, confounding, successful blood draws, and sample validation. Each domain was rated as having either “high,” “low,” or “unknown” risk of bias.24 We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to evaluate the quality of evidence and rated it as high, moderate, low, or very low.
The preferable summary measure was the difference in means between early cord clamping and delayed cord clamping cord blood gas parameters. When a difference in means in cord blood gas parameters between delayed cord clamping and early cord clamping groups was unavailable, we extracted other available descriptive statistics such as mean, SD, median, and range for each group. The 95% CIs for the mean and the difference in means were calculated using the following equations: , Difference in means (95% CI)=, when sufficient information was available and gross assumptions about a study's original data were not required. Cohen's kappa coefficient (k) was used to measure inter-rater agreement between M.J.R.N. and E.B. All statistical analysis was performed using Stata 14.
The reviewers screened 148 unique records and identified 23 eligible studies. Subsequently, two RCTs and three observational studies records were included in the review (Fig. 1). The details relevant to the pertinent study arm from each study were summarized (Table 1 and Appendix 1 [Appendix 1 is available online at http://links.lww.com/AOG/B701]). Inter-reviewer agreement was 97% (k=0.89 [95% CI 0.81–0.91], P<.001) for the initial record screening and 100% during the eligibility assessment. Risk of bias within each study was low (Table 2). The domain-based risk of bias assessment is documented in Appendix 2, available online at http://links.lww.com/AOG/B701.
We gave “high” quality of evidence rating for RCTs and the observational studies because they used within-individual serial sampling. The overall quality of evidence was downgraded to “moderate” based on indirectness related to intervention heterogeneity in early cord clamping timing (0 seconds, less than 10 seconds, less than 30 seconds) and delayed cord clamping timing (45 seconds–180 seconds), which may have affected the summary estimate across the studies. The domain-based quality of evidence assessment is documented in Appendix 3, available online at http://links.lww.com/AOG/B701.
Each study used different descriptive statistics, and only Valero et al31 reported a difference in means. For both De Paco et al studies,32,33 we calculated 95% CI for each cord blood gas parameter using the reported M, SD, and n and an alpha of 0.05. We summarized the arterial and venous cord blood gas results of the included individual studies in Tables 3 and 4, respectively. Appendices 4 and 5, available online at http://links.lww.com/AOG/B701, provide additional findings for PO2, PCO2, and lactate.
The studies using within-individual serial umbilical arterial samples showed that delaying cord clamping 45–90 seconds was associated with mean decreases in pH (0.02–0.03), HCO3 (0.3–0.8 mmol/L), and mean increases in base deficit (0.3–1.3 mmol/L) and lactate (0.2–0.6 mmol/L) compared with early cord clamping at less than 30 seconds.31,34
Within-individual serial samples showed that delaying cord clamping 45–90 seconds was associated with mean increase in arterial PCO2 (0.8–3.2 mm Hg) compared with early cord clamping at less than 30 seconds.31,34
One RCT and one observational study showed that delaying cord clamping 45–120 seconds was associated with a mean increase in arterial PO2 (2.4–6.0 mm Hg) compared with less than 10-second early cord clamping.32,34
The study using within-individual serial umbilical venous samples showed that 90 seconds of delayed cord clamping was associated with mean decrease in pH of 0.01; delaying cord clamping 45–90 seconds was associated with mean decrease in HCO3 (0.1–0.2 mmol/L), increases in base deficit (0.1–0.3 mmol/L) and lactate (0.1–0.3 mmol/L) compared with 0-second early cord clamping.34
One study using within-individual serial umbilical venous samples showed that delaying cord clamping for 90 seconds was associated with mean increase in PCO2 by 0.9 mm Hg compared with immediate cord clamping.34
None of the studies showed any difference in the venous PO2 between delaying cord clamping 45–180 seconds and delaying it for less than 30 seconds.
We did not perform a meta-analysis owing to the methodologic heterogeneity between the studies. Additionally, consistent summary estimates (ie, difference in means and SDs) were unavailable and could not be estimated without making unsupportable assumptions about the study's original data.
This review identified two RCTs and three observational within-individual studies that evaluated the effect of delayed cord clamping compared with early cord clamping on cord blood gas values in 452 vaginally delivered, healthy, term singletons. Values obtained after delayed clamping were more acidemic, but only slightly, and were still within normal reference ranges.18–20,22,36
One within-individual study observed that delayed cord clamping was associated with a minimal decrease in pH, HCO3, and increase in PCO2, lactate, and BD in cord venous blood gas.31,34,35 However, the second within-individual study and the RCT studies showed that normal acid–base balance was maintained in cord venous blood, suggesting that effective placental gas exchange continues during delayed cord clamping.32,33
Cord blood sampling from a segment of double-clamped cord is widely used in clinical practice.37 Another cord blood sampling method is collecting blood from an unclamped, pulsating cord connecting the newborn and placenta. Andersson et al25 compared cord blood gas collected using the two sampling techniques and found that cord blood gas values were comparable. Collecting cord blood from an unclamped, pulsating cord in the setting of delayed cord clamping has been advocated by Xodo et al38 because this allows cord blood to be obtained immediately after birth, without being affected by delayed cord clamping. However, this method requires a designated person for sample collection at the time of delivery which may be not be feasible in some clinical situations.
Larger studies, similar to those originally used to describe cord blood gas reference ranges,18–20,22,36 are needed to more accurately describe the effect of delayed cord clamping on blood acid–base balance in term, singleton vaginal deliveries. Our review was limited to healthy, term newborns. Because delayed cord clamping is increasingly performed in preterm newborns, twins, and those born by cesarean delivery, its effect needs to be more widely studied given the direct implications of cord blood gas has on the diagnosis and treatment plan in medically complicated newborns.
There are discrepancies across the five studies. The observational studies showed delayed cord clamping up to 120 seconds had effects on both arterial and venous cord blood gas values, however, the magnitude of this effect is clinically insignificant in healthy, term, vaginally delivered newborns.
1. Royal College of Obstetricians and Gynaecologists (RCOG) Scientific Advisory Committee. Clamping of the umbilical cord and placental transfusion (Scientific Impact Paper No. 14). Available at: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/sip14/
. Retrieved December 17, 2019.
2. World Health Organization. Guideline: delayed umbilical cord clamping for improved maternal and infant health and nutrition outcomes. Geneva, Switzerland: World Health Organization; 2014.
3. Wyckoff MH, Aziz K, Escobedo MB, Kapadia VS, Kattwinkel J, Perlman JM, et al. Part 13: neonatal resuscitation: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care (reprint). Pediatrics 2015;136(suppl 2):S196–218.
4. Wyllie J, Bruinenberg J, Roehr CC, Rudiger M, Trevisanuto D, Urlesberger B. European resuscitation council guidelines for resuscitation 2015: section 7. Resuscitation and support of transition of babies at birth. Resuscitation 2015;95:249–63.
5. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European consensus guidelines on the management of respiratory distress syndrome—2016 update. Neonatology 2017;111:107–25.
6. Delayed umbilical cord clamping after birth. Committee Opinion No. 684. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;129:e5–10.
7. Yao AC, Lind J, Tiisala R, Michelsson K. Placental transfusion in the premature infant with observation on clinical course and outcome. Acta Paediatr Scand 1969;58:561–6.
8. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA 2007;297:1241–52.
9. Raju TN. Timing of umbilical cord clamping after birth for optimizing placental transfusion. Curr Opin Pediatr 2013;25:180–7.
10. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. The Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD004074. doi: 10.1002/14651858.CD004074.pub3.
11. Andersson O, Lindquist B, Lindgren M, Stjernqvist K, Domellof M, Hellstrom-Westas L. Effect of delayed cord clamping on neurodevelopment at 4 years of age: a randomized clinical trial. JAMA Pediatr 2015;169:631–8.
12. Mercer JS, Erickson-Owens DA, Vohr BR, Tucker RJ, Parker AB, Oh W, et al. Effects of placental transfusion on neonatal and 18 month outcomes in preterm infants: a randomized controlled trial. J Pediatr 2016;168:50–5.e1.
13. Chopra A, Thakur A, Garg P, Kler N, Gujral K. Early versus delayed cord clamping in small for gestational age infants and iron stores at 3 months of age—a randomized controlled trial. BMC Pediatr 2018;18:234.
14. MacLennan A. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999;319:1054–9.
15. Executive summary: neonatal encephalopathy and neurologic outcome. Am Coll Obstet Gynecol Obstet Gyencol 2014;123:896–901.
16. Perlman JM, Risser R. Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers? Pediatrics 1996;97:456–62.
17. Armstrong L, Stenson BJ. Use of umbilical cord blood gas analysis in the assessment of the newborn. Arch Dis Child Fetal Neonatal Ed 2007;92:F430–4.
18. Thorp JA, Sampson JE, Parisi VM, Creasy RK. Routine umbilical cord blood gas determinations? Am J Obstet Gynecol 1989;161:600–5.
19. Dickinson JE, Eriksen NL, Meyer BA, Parisi VM. The effect of preterm birth on umbilical cord blood gases. Obstet Gynecol 1992;79:575–8.
20. Riley RJ, Johnson JW. Collecting and analyzing cord blood gases. Clin Obstet Gynecol 1993;36:13–23.
21. Thorp JA, Dildy GA, Yeomans ER, Meyer BA, Parisi VM. Umbilical cord blood gas analysis at delivery. Am J Obstet Gynecol 1996;175:517–22.
22. Victory R, Penava D, Da Silva O, Natale R, Richardson B. Umbilical cord pH and base excess values in relation to adverse outcome events for infants delivering at term. Am J Obstet Gynecol 2004;191:2021–8.
23. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700.
24. Higgins JPT, Sterne JAC, Savović J, Page MJ, Hróbjartsson A, Boutron I, et al. A revised tool for assessing risk of bias in randomized trials. In: Chandler J, Clarke M, McKenzie J, Boutron I, Welch V, editors. Cochrane methods. The Cochrane Database of Systematic Reviews 2016;10(suppl 1). doi: 10.1002/14651858.CD201601.
25. Andersson O, Hellstrom-Westas L, Andersson D, Clausen J, Domellof M. Effects of delayed compared with early umbilical cord clamping on maternal postpartum hemorrhage and cord blood gas sampling: a randomized trial. Acta Obstet Gynecol Scand 2013;92:567–74.
26. Ackerman BD, Sosna MM, Ullrich JR. A technique for serial sampling of umbilical artery blood at birth. Biol Neonate 1972;20:458–65.
27. Marquis L, Ackerman BD. Placental respiration in the immediate neonatal period. Am J Obstet Gynecol 1973;117:358–63.
28. Ullrich JR, Ackerman BD. Changes in umbilical artery blood gas values with the onset of respiration. Biol Neonate 1972;20:466–74.
29. Chou PJ, Ullrich JR, Ackerman BD. Time of onset of effective ventilation at birth. Biol Neonate 1974;24:74–81.
30. Tang J, Fullarton R, Samson SL, Chen Y. Delayed cord clamping does not affect umbilical cord blood gas analysis. Arch Gynecol Obstet 2019;299:719–24.
31. Valero J, Desantes D, Perales-Puchalt A, Rubio J, Diago Almela VJ, Perales A. Effect of delayed umbilical cord clamping on blood gas analysis. Eur J Obstet Gynecol Reprod Biol 2012;162:21–3.
32. De Paco C, Florido J, Garrido MC, Prados S, Navarrete L. Umbilical cord blood acid-base and gas analysis after early versus delayed cord clamping in neonates at term. Arch Gynecol Obstet 2011;283:1011–14.
33. De Paco C, Herrera J, Garcia C, Corbalán S, Arteaga A, Pertegal M, et al. Effects of delayed cord clamping on the third stage of labour, maternal haematological parameters and acid-base status in fetuses at term. Eur J Obstet Gynecol Reprod Biol 2016;207:153–6.
34. Wiberg N, Kallen K, Olofsson P. Delayed umbilical cord clamping at birth has effects on arterial and venous blood gases and lactate concentrations. BJOG 2008;115:697–703.
35. Lievaart M, de Jong PA. Acid-base equilibrium in umbilical cord blood and time of cord clamping. Obstet Gynecol 1984;63:44–7.
36. Helwig JT, Parer JT, Kilpatrick SJ, Laros RK Jr. Umbilical cord blood acid-base state: what is normal? Am J obstetrics Gynecol 1996;174:1807–12.
37. Duerbeck NB, Chaffin DG, Seeds JW. A practical approach to umbilical artery pH and blood gas determinations. Obstet Gynecol 1992;79:959–62.
38. Xodo S, Xodo L, Berghella V. Delayed cord clamping and cord gas analysis at birth. Acta Obstet Gynecol Scand 2018;97:7–12.