Kaempf, Joseph W. MD; Tomlinson, Mark W. MD; Kaempf, Andrew J. BS; Wu, YingXing MD; Wang, Lian MS; Tipping, Nicole RN; Grunkemeier, Gary PhD
OBJECTIVE: Delayed umbilical cord clamping is reported to increase neonatal blood volume. We estimated the clinical outcomes in premature neonates who had delayed umbilical cord clamping compared with a similar group who had early umbilical cord clamping.
METHODS: This was a before–after investigation comparing early umbilical cord clamping with delayed umbilical cord clamping (45 seconds) in two groups of singleton neonates, very low birth weight (VLBW) (401–1,500 g) and low birth weight (LBW) (greater than 1,500 g but less than 35 weeks gestation). Neonates were excluded from delayed umbilical cord clamping if they needed immediate major resuscitation. Primary outcomes were provision of delivery room resuscitation, hematocrit, red cell transfusions, and the principle Vermont Oxford Network outcomes.
RESULTS: In VLBW neonates (77 delayed umbilical cord clamping, birth weight [mean±standard deviation] 1,099±266 g; 77 early umbilical cord clamping 1,058±289 g), delayed umbilical cord clamping was associated with less delivery room resuscitation, higher Apgar scores at 1 minute, and higher hematocrit. Delayed umbilical cord clamping was not associated with significant differences in the overall transfusion rate, peak bilirubin, any of the principle Vermont Oxford Network outcomes, or mortality. In LBW neonates (172 delayed umbilical cord clamping, birth weight [mean±standard deviation] 2,159±384 g; 172 early umbilical cord clamping 2,203±447 g), delayed umbilical cord clamping was associated with higher hematocrit and was not associated with a change in delivery room resuscitation or Apgar scores or with changes in the transfusion rate or peak bilirubin. Regression analysis showed increasing gestational age and birth weight and delayed umbilical cord clamping were the best predictors of higher hematocrit and less delivery room resuscitation.
CONCLUSION: Delayed umbilical cord clamping can safely be performed in singleton premature neonates and is associated with a higher hematocrit, less delivery room resuscitation, and no significant changes in neonatal morbidities.
LEVEL OF EVIDENCE: II
In virtually all mammalian births, the umbilical cord remains a blood conduit from placenta to newborn for minutes to hours after birth. Potential advantages include increased neonatal blood volume and red cell mass, improved iron stores, more hematopoietic stem cells, and cardiovascular stability.1–4 Early umbilical cord clamping (less than 5–10 seconds after birth) has been a widespread obstetric practice for decades, presumably adopted to facilitate management of the third stage of labor and to allow immediate cardiopulmonary resuscitation of the neonate. The shift to early umbilical cord clamping was not driven by randomized controlled trial data and is now increasingly questioned because recent meta-analyses conclude delayed umbilical cord clamping (30 seconds or more) to be associated with greater neonatal blood volume and iron stores, less anemia, fewer red blood cell transfusions, and decreased intraventricular hemorrhage.5–7 Untoward effects such as lower Apgar scores, polycythemia, jaundice, and respiratory distress do not appear to be significant risks of delayed umbilical cord clamping.
Our obstetric and neonatology service adopted delayed umbilical cord clamping as a potentially better practice in 2010 after thorough evidence review and provider consensus. We agreed to delay cord clamping for 45 seconds in all singleton premature births less than 35 weeks postmenstrual age. We estimated neonatal outcomes associated with this quality-improvement project as well as discuss some of the unresolved questions of refining safe and effective delayed umbilical cord clamping.
PATIENTS AND METHODS
Permission was obtained at the outset from the Providence Health System institutional review board to conduct this investigation as a before–after application of one specific intervention (delayed umbilical cord clamping). Individual consent was not required because this was conducted as a quality-improvement application of an evidence-based potentially better practice. Providence St. Vincent Medical Center has a high-risk obstetric service with approximately 5,000 deliveries per year partnered with a level III neonatal intensive care unit (NICU) with approximately 900 admissions per year, approximately 400 of which occur at less than 35 weeks postmenstrual age (approximately 67% singleton).
The control period in which early umbilical cord clamping was standard practice was January 1 through December 31, 2009. All obstetric health care providers performed immediate early umbilical cord clamping, virtually always at approximately 5 seconds. Delayed umbilical cord clamping began January 1, 2010, and was continued until an equal number of premature neonates were treated with delayed umbilical cord clamping. We felt this time period was long enough to measure potential changes in delayed umbilical cord clamping–related outcomes but not so long as to put an undue number of premature neonates at risk for untoward events. We focused our study on neonates born at less than 35 weeks postmenstrual age (neonates who are all admitted into the NICU) so that we could closely monitor Vermont Oxford Network outcomes and both physiologic and laboratory measurements during their hospital course. Our participation in the Vermont Oxford Network requires a robust, standardized, and error-checked database, which includes a wide range of diagnostic and therapeutic variables for every newborn admitted to the NICU (data collected and verified with the Vermont Oxford Network by coauthors N.T. and J.W.K.). Two subgroups were evaluated, the neonates with high morbidity and very low birth weight (VLBW) (401–1,500 g), a cohort for whom we track detailed outcomes as defined by the Vermont Oxford Network.8 These outcomes include mortality, chronic lung disease, retinopathy of prematurity, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, spontaneous intestinal perforation, hospital-acquired infection, growth rates, and length of stay. The second group included neonates with LBW (greater than 1,500 g but before 35 weeks of gestation), a much lower risk group in terms of neonatal morbidities but nevertheless of interest in terms of hematocrit and delivery room resuscitation interventions that might be affected by delayed umbilical cord clamping. There were no other intended major changes in obstetric or neonatal care during this investigation.
Exclusions from delayed umbilical cord clamping included multiple gestations (insufficient published data to support delayed umbilical cord clamping), neonates with congenital anomalies, and neonates who were born with no respiratory effort and significant bradycardia in which the health care providers felt immediate major resuscitation interventions were needed.
The delayed umbilical cord clamping protocol for neonates delivered vaginally instructed the obstetrician to hold the neonate approximately 10–20 cm below the introitus in a warm towel, gently dry, stimulate as necessary, bulb suction if needed, and then clamp the umbilical cord after 45 seconds (the NICU nurse called out the time in 10-second intervals and assigned the Apgar scores). Forty-five seconds was chosen because this was felt to be the midpoint of the majority of delayed umbilical cord clamping studies in premature neonates.5 The neonate was then handed to the awaiting NICU team. For cesarean deliveries, the neonate was placed on the sterile drapes between the mother's legs, dried with a warm towel, stimulated as necessary, bulb suction if needed, and then the umbilical cord was clamped at 45 seconds. Umbilical cord milking was not done (insufficient published evidence to support its safety). Although we recommended the delivery room temperature be 72°F for all deliveries during both eras, this was not strictly controlled.
Other than delayed umbilical cord clamping, subsequent NICU care was unchanged between eras, and there were no changes in resuscitation practices or red blood cell transfusion recommendations. We compared delivery room resuscitation interventions, Apgar scores, initial temperature, hematocrit, red blood cell transfusion rates, and all the principle Vermont Oxford Network NICU morbidities. Our potentially better practice did not specify any mandatory laboratory or radiographic studies to be performed on the neonates with delayed umbilical cord clamping.
For comparison of categorical variables, χ2 or Fisher's exact test was used and for continuous variables, t test or Mann-Whitney U test was used where applicable. Stepwise logistic regression was used to determine the possible predictors for red blood cell transfusion and delivery room resuscitation interventions. Stepwise linear regression was used to determine the possible predictors for hematocrit. Delayed umbilical cord clamping was forced into the models to evaluate its effect when adjusted by the predictors. Statistical analysis was performed using PASW 17 and R 2.12.
Table 1 provides demographic descriptors of the study patients in both eras. It took 264 singleton births less than 35 weeks of postmenstrual age in the delayed umbilical cord clamping era to match the 249 neonates in the early umbilical cord clamping era. Six (2%) of the eligible neonates born in the second era did not have delayed umbilical cord clamping because the health care providers felt the neonate needed immediate major resuscitation. These six neonates had a mean postmenstrual age of 31 0/7 weeks, mean birth weight 1,618 g, Apgar score at 1 minute ranged from 0 to 5, Apgar score at 5 minutes ranged from 2 to 7, and all survived. Their Vermont Oxford Network NICU outcomes data are included in the delayed umbilical cord clamping group results (Table 2). Nine (3%) of the eligible neonates in the second era did not have delayed umbilical cord clamping because the obstetrician was not fully aware of the new delayed umbilical cord clamping guideline.
Table 1 shows that the overall provision of any delivery room resuscitation intervention was significantly less in the VLBW delayed umbilical cord clamping group (61% compared with 79%, P=.01) but not different between the LBW groups (30% compared with 27%, P=.55). Delayed umbilical cord clamping was associated with higher Apgar scores at 1 minute in VLBW neonates but no significant differences in neonates with LBW. Delayed umbilical cord clamping did not affect initial temperature in the VLBW group and had a minimal upward effect in the LBW group.
All neonates had a hematocrit determination (largely peripheral venous) 30–60 minutes after birth. Table 3 shows that VLBW and LBW neonates who underwent delayed umbilical cord clamping had a significantly higher hematocrit, but delayed umbilical cord clamping did not significantly lower the overall NICU red blood cell transfusion rate. Delayed cord clamping was associated with higher mean systolic and diastolic blood pressures in neonates with LBW. Highest measured total bilirubin concentration and use of phototherapy were not significantly different between the early umbilical cord clamping and delayed umbilical cord clamping groups. Table 2 shows that we observed no significant differences in any of the principle Vermont Oxford Network VLBW morbidities, mortality, growth rates, or length of stay (the LBW low-risk group had minimal to zero rates of all the Vermont Oxford Network outcomes in both eras).
Linear regression analysis demonstrated that increasing gestational age coefficient 0.89 (95% confidence interval [CI] 0.68, 1.10, P<.001) and the delayed umbilical cord clamping era coefficient 2.53 (95% CI 1.40, 3.66, P<.001) were the best predictors of increased hematocrit. Logistic regression analysis demonstrated that increasing gestational age, birth weight, and the delayed umbilical cord clamping era best predicted less provision of delivery room resuscitation interventions (Table 4). Red blood cell transfusion rates were best predicted by gestational age and birth weight (Table 4).
Our before–after observational investigation in two distinct time periods suggests that delayed umbilical cord clamping for 45 seconds can safely be performed in 98% of singleton premature neonates, is associated with less delivery room resuscitation interventions in neonates with VLBW, and increases the hematocrit modestly. Mortality, peak total bilirubin concentrations, and the full spectrum of Vermont Oxford Network NICU morbidities did not change significantly. We concur with others that early umbilical cord clamping, a practice presumably adopted to facilitate management of the third stage of labor and immediate resuscitation of premature neonates, is a less advantageous (and unproven) obstetric intervention.1,4
Recent meta-analysis concludes that at least 30 seconds of delayed umbilical cord clamping in premature neonates is safe and associated with higher circulating blood volume, less need for transfusions, and a lower grade 1–2 intraventricular hemorrhage rate.5 Additionally, investigations have suggested that delayed umbilical cord clamping might reduce nosocomial infection,9 enhance hematopoietic stem cell transfer,10 reduce motor disability,11 and improve cerebral blood oxygenation.12 Although the increase in hematocrit seen in our delayed umbilical cord clamping group was relatively modest, this is not unexpected given that the hematocrit does not consistently reflect red blood cell mass,13 and delayed umbilical cord clamping has been shown to increase iron stores, which might improve long-term neurodevelopmental outcome.6,7,14–17 Untoward effects such as lower Apgar scores, hypothermia, or higher rates of jaundice, polycythemia, and respiratory distress have been notably few or absent from published reports including our study.
Our quality-improvement project highlights two major issues: 1) delayed umbilical cord clamping can safely be done in a variety of obstetric conditions in almost all premature singleton neonates; and 2) we had little evidence during delayed umbilical cord clamping which way and how much blood was being transferred. This emphasizes the need to develop more sophisticated means of optimal patient selection, delayed umbilical cord clamping technique, and accurate measurement of blood transfer.
Substantial unresolved issues regarding delayed umbilical cord clamping include: 1) what is the desired blood volume related to a placental transfusion for a premature neonate; 2) what is the optimal duration of delayed umbilical cord clamping; 3) how important is neonate position in relation to the placenta; 4) can delayed umbilical cord clamping be safely done on twins and triplets; 5) umbilical cord milking is a quicker technique, but is it a safe and effective means to improve placental blood transfusion18; 6) how can we improve patient selection to avoid those neonates who might be harmed by delayed umbilical cord clamping, eg, placental abruption or surgical incision, asphyxia, multiple births; 7) what are the long-term hematopoietic and neurodevelopmental consequences of delayed umbilical cord clamping; and 8) should there be any gestational age restrictions?
Our investigation is the first published delayed umbilical cord clamping experience since the recently updated 2010 Neonatal Resuscitation Program summary recommendation: “Delay in umbilical cord clamping for at least one minute is recommended for newborns not requiring resuscitation. There is insufficient evidence to support or refute a recommendation to delay cord clamping in babies requiring resuscitation.”19 Unfortunately, “resuscitation” is not specifically defined, no gestational age or twin guidelines are mentioned, and no particular delayed umbilical cord clamping technique is specified. It is our opinion that delayed umbilical cord clamping, although previously shown to be reasonably safe and effective (enough so to conduct our investigation), does need further exploration and refinement. Carefully planned and documented quality-improvement projects can add important experience to the clinical knowledge base.20 Limitations of our investigation include the single-center, nonrandomized design, inclusion of singletons only, and the exclusion of a very small number of potentially eligible neonates. Randomized controlled trials minimize the effect of confounding variables and unmeasured practices changes and are preferable to observational trials to answer major therapeutic controversies. However, our inclusion of 95% of eligible neonates likely exceeds that of typical randomized controlled trials, and well-designed observational trials can provide practical guidance in clinical controversies where there are issues of equipoise and external validity.21,22
In conclusion, delayed umbilical cord clamping appears to be a safe procedure for the vast majority of premature singleton neonates, is associated with less delivery room resuscitation interventions, increases the hematocrit, and has no significant effect on hyperbilirubinemia management or the broad array of principle Vermont Oxford Network NICU morbidities. Our experience may be valuable for others planning to implement delayed umbilical cord clamping and based on our investigation and the recent Neonatal Resuscitation Program guidelines, we now perform delayed umbilical cord clamping on all singleton neonates for 60 seconds regardless of gestational age while we await further investigations to refine the practice.
1. Levy T, Blickstein I. Timing of cord clamping revisited. J Perinat Med 2006;34:293–7.
2. Reynolds GJ. Beyond sweetness and warmth: transition of the preterm infant. Arch Dis Child Fetal Neonatal Ed 2008;93:F2–3.
3. Aladangady N, McHugh S, Aitchison TC, Wardrop CAJ, Holland BM. Infants' blood volume in a controlled trial of placental transfusion at preterm delivery. Pediatrics 2006;117:93–8.
4. Eichenbaum-Pikser G, Zasloff JS. Delayed clamping of the umbilical cord: a review with implications for practice. J Midwifery Womens Health 2009;54:321–6.
5. Rabe H, Reynolds G, Diaz-Rosello J. A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants. Neonatology 2008;93:138–4.
6. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full term infants: systematic review and meta-analysis of controlled trials. JAMA 2007;297:1241–52.
7. Cochrane Update: Effect of timing of umbilical cord clamping at birth of term infants on mother and baby outcomes. Obstet Gynecol 2008;112:177–8.
8. Vermont Oxford Network. Vermont Oxford Network manual of operations. Release 14.0. Burlington (VT): Vermont Oxford Network; 2010.
9. Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M, Oh W. Delayed cord clamping in very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized, controlled trial. Pediatrics 2006;117:1235–42.
10. Tolosa JN, Park DH, Eve DJ, Klasko SK, Borlongan CV, Sanberg PR. Mankind's first natural stem cell transplant. J Cell Mol Med 2010;14:488–95.
11. Mercer JS, Vohr BR, Erickson-Owens DA, Padbury JF, Oh W. Seven-month developmental outcomes of very low birth weight infants enrolled in a randomized controlled trial of delayed versus immediate cord clamping. J Perinatol 2010;30:11–6.
12. Baenziger O, Stolkin F, Keel M, von Siebenthal K, Fauchere JC, Das Kundu S, et al.. The influence of the timing of cord clamping on postnatal cerebral oxygenation in preterm infants: a randomized, controlled trial. Pediatrics 2007;119:455–9.
13. Strauss RG, Mock DM, Johnson KJ, Cress GA, Burmeister LF, Zimmerman MB, et al.. A randomized clinical trial comparing immediate versus delayed clamping of the umbilical cord in preterm infants: short-term clinical and laboratory endpoints. Transfusion 2008;48:658–65.
14. Chaparro CM. Timing of umbilical cord clamping: effect on iron endowment of the newborn and later iron status. Nutr Rev 2011;69:S30–6.
15. Lukowski AF, Koss M, Burden MJ, Jonides J, Nelson CA, Kaciroti N, et al.. Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory. Nutr Neurosci 2010;13:54–70.
16. Andersson O, Hellström-Westas L, Andersson D, Domellöf M. Effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months: a randomized controlled trial. BMJ 2011;343:d7157.
17. Oh W, Fanaroff AA, Carlo WA, Donovan EF, McDonald SA, Poole WK. Effects of delayed cord clamping in very-low-birth-weight infants. J Perinatol 2011;31:S68–71.
18. Hosono S, Mugishima H, Fujita H, Hosono A, Minato M, Okada T, et al.. Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks gestation: a randomized controlled trial. Arch Dis Child Fetal Neonat Ed 2008;93:F14–9.
19. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al.. Special report—neonatal resuscitation: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Pediatrics 2010;126:e1319–44.
20. Van Cleave J, Dougherty D, Perrin JM. Strategies for addressing barriers to publishing pediatric quality improvement research. Pediatrics 2011;128:e678–86.
21. Black N. Why we need observational trials to evaluate the effectiveness of health care. BMJ 1996;312:1215–8.
22. Berwick DM. The science of improvement. JAMA 2008;299: 1182–4.