Labor Management: Current Commentary

Time to Implement Delayed Cord Clamping Ryan M. McAdams,

MD

Immediate umbilical cord clamping after delivery is routine in the United States despite little evidence to support this practice. Numerous trials in both term and preterm neonates have demonstrated the safety and benefit of delayed cord clamping. In premature neonates, delayed cord clamping has been shown to stabilize transitional circulation, lessening needs for inotropic medications and reducing blood transfusions, necrotizing enterocolitis, and intraventricular hemorrhage. In term neonates, delayed cord clamping has been associated with decreased iron-deficient anemia and increased iron stores with potential valuable effects that extend beyond the newborn period, including improvements in long-term neurodevelopment. The failure to more broadly implement delayed cord clamping in neonates ignores published benefits of increased placental blood transfusion at birth and may represent an unnecessary harm for vulnerable neonates. (Obstet Gynecol 2014;123:549–52) DOI: 10.1097/AOG.0000000000000122

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n December 2012, an American College of Obstetricians and Gynecologists Committee Opinion was published that advocated delayed umbilical cord clamping in preterm neonates, when feasible.1 This practice statement, endorsed by the American Academy of Pediatrics, is based on mounting evidence that waiting to clamp the umbilical cord for 30–60 seconds after birth with the premature neonate at a level below the placenta is associated with neonatal benefits, including improved transitional circulation with

From the Department of Pediatrics, University of Washington, Seattle, Washington. The author thanks Paul Mann for helpful and critical comments on the manuscript. Corresponding author: Ryan M. McAdams, MD, Department of Pediatrics, Division of Neonatology, University of Washington, Box 356320, Seattle, WA 98195-6320; e-mail: [email protected]. Financial Disclosure The author did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14

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a reduced need for inotropic medications, more robust establishment of red blood cell volume, decreased need for blood transfusion, and reductions in necrotizing enterocolitis and intraventricular hemorrhage at all grades.1,2 Despite the Committee on Obstetric Practice recommendation, implementation of this practice has not happened at many institutions in the United States. What is delaying adoption of delayed cord clamping for these neonates? Immediate cord clamping remains standard in the United States despite little evidence to support the method. Although the origin of this practice is unclear, medical literature in the 1960s endorsed immediate cord clamping resulting from concerns that delayed cord clamping would lead to hyperbilirubinemia.3 Additionally, early cord clamping was used as one of the steps for active management of the third stage of labor, believing that it reduced risks of postpartum hemorrhage.4 Multiple trials have studied the risks and benefits of delayed cord clamping in preterm neonates. These trials have consistently demonstrated the safety of delayed cord clamping. A review by Rabe et al5 (15 total trials involving 738 premature neonates between 24 and 36 weeks of gestation at birth) revealed a higher peak bilirubin concentration with delayed cord clamping (umbilical cord clamping more than 30 seconds after birth) compared with early cord clamping (seven trials, 320 neonates, with a mean difference of 15.01 mmol/L, 95% confidence interval [CI] 5.62– 24.40 mmol/L). However, a resultant increase in phototherapy for jaundice associated with delayed cord clamping seen in three studies (totaling 180 preterm neonates) was statistically nonsignificant (risk ratio [RR] 1.21, 95% CI 0.94–1.55). Overall, there were no significant differences between early and delayed cord clamping for the primary outcome of neonatal mortality (RR 0.63, 95% CI 0.31–1.28).5 A compelling reason to implement delayed cord clamping in premature neonates is that efforts to improve neurodevelopmental outcomes for these highrisk neonates are needed. In 2011, there were 56,931 very low birth weight (less than 1,500 g) neonates born

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in the United States.6 The prevalence of intraventricular hemorrhage diagnosed by cranial ultrasonography in these neonates can be as high as 30%.7 Cognitive, behavioral, attentional, or socialization deficits are subsequently found in 25–50% of very low birth weight neonates, including major motor deficits (eg, cerebral palsy) in 5–10%8 and are associated with grade 3 and 4 intraventricular hemorrhage. Implementing delayed cord clamping could contribute to improved neurodevelopmental outcomes in preterm neonates through decreases in intraventricular hemorrhage incidence and reductions in blood transfusion. Although the meta-analysis review by Rabe et al looking at the effect of umbilical cord clamping timing on outcomes in preterm neonates did not demonstrate a clear difference between delayed compared with early cord clamping with regard to severe intraventricular hemorrhage (grades 3–4), there was an association for a lower risk ratio when all grades of intraventricular hemorrhage were considered (10 trials, 539 neonates, RR 0.59, 95% CI 0.41–0.85).5 Given that delayed cord clamping may decrease intraventricular hemorrhage by nearly 50%,1 thereby preventing one case of intraventricular hemorrhage for every 15 neonates treated, implementation of delayed cord clamping for all very low birth weight neonates could conceivably prevent 3,795 yearly cases of intraventricular hemorrhage in the United States alone. Additionally, for every eight premature neonates treated with delayed cord clamping, a red blood transfusion for anemia would be avoided.2,5 Neonatal red blood cell transfusions are not without risk or cost, because transfusions in preterm neonates are associated with an increased risk of developmental delay, intraventricular hemorrhage, and necrotizing enterocolitis.9 Failure to adopt beneficial practices, especially evidence-based ones, may constitute unnecessary harm. Reluctance to implement delayed cord clamping nationally may place thousands of children born this year at unnecessary risk for neurodevelopmental delays, cerebral palsy, and behavioral problems. The ripple effect of brain injury in premature neonates is extensive and has the potential to affect quality of life adversely for these children and their families, elevate medical care expenditures, and consume precious resources needlessly (eg, packed red blood cells). Procrastination in delayed cord clamping implementation on a global scale carries the potential for unfavorable consequences. Roughly 25% of the world is affected by anemia and iron deficiency factors in half of those cases.10 Iron-deficient anemia during infancy is associated with abnormal long-term neurodevelopmental outcomes.10 Even mild iron deficiency

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without anemia is associated with developmental abnormalities.11 Despite awareness of the prevalence of iron deficiency, this entity is not typically considered a primary etiology to pediatric neurologic diseases such as stroke.11 Delayed cord clamping is an easily performed and seemingly effective intervention, which would reduce the global burden of irondeficient neonates in settings with a high prevalence of iron deficiency anemia. Delayed cord clamping does not pose any additional financial burden to newborn care and actually can be viewed as cost-saving if the benefits of decreased red blood cell transfusions and prevention of adverse outcomes are considered. The first minute after the umbilical cord is clamped has been called “the golden minute” (Helping Babies Breathe, http://www.helpingbabiesbreathe.org), emphasizing the importance of skilled attendance at every delivery with temperature support, stimulation to breathe, and assisted ventilation (as needed) to prevent hypoxic injury after birth. The time period before umbilical cord clamping may be viewed as “the iron minute,” an equally critical and influential time window during which iron-laden blood can be placentally transfused back to the neonate to potentially promote hemodynamic stability and improved neurodevelopmental outcomes. Anemia affects an estimated 24.8%10 of the 385,046 global births per day (Population Reference Bureau, 2012 World Population Data Sheet, http://www.prb.org), equaling 95,491 cases of anemia; half of these cases are affected by iron deficiency anemia, equaling 47,745 cases (33 every minute). Therefore, failure to globally implement delayed cord clamping could contribute to an enormous population of people affected by poor neurodevelopmental outcomes. Trials investigating the risks and benefits of delayed cord clamping in term neonates have consistently demonstrated safety for both mothers and neonates. McDonald et al4 recently reviewed 15 trials, comprising a total of 3,911 women and neonate pairs, that compared delayed cord clamping (defined as umbilical cord clamping at more than 60 seconds after birth or until cessation of cord pulsation) with early cord clamping (within 60 seconds of birth). No differences were shown for the primary outcome of severe postpartum hemorrhage (RR 1.04, 95% CI 0.65–1.65) or for a postpartum hemorrhage of 500 mL or more (RR 1.17, 95% CI 0.94–1.44). Although fewer neonates in the early cord clamping group required phototherapy for jaundice (seven trials, 2,324 neonates, RR 0.62, 95% CI 0.41–0.96), there was not a significant difference for the primary outcome of neonatal mortality (term neonates, RR 0.37, 95% CI 0.04–3.41).4

Time to Implement Delayed Cord Clamping

OBSTETRICS & GYNECOLOGY

A meta-analysis by Hutton and Hassan (15 controlled trials, including eight randomized controlled trials reviewed by McDonald et al) comparing delayed cord clamping (clamping at least 2 minutes after birth, n51,001 newborns) with early clamping (clamping immediately after birth, n5911 newborns) in term neonates demonstrated benefits for delayed cord clamping that extend beyond the neonatal period.12 Delayed cord clamping was associated with an estimated 47% reduction in anemia risk, a 33% reduction in risk for deficient iron stores at ages 2–3 months, and higher ferritin values during the first 6 months after birth. Delayed cord clamping increased asymptomatic polycythemia but was not associated with any significant harm as measured by the need for phototherapy to treat jaundice or neonatal intensive care unit admission. The American College of Obstetricians and Gynecologists Committee Opinion did not advocate delayed cord clamping for term neonates; however, a benefit in available trials has been consistently demonstrated. Delayed cord clamping in term neonates promotes improved iron stores, prevents anemia beyond the neonatal period, and is more physiological than early cord clamping. Although the effect of delayed cord clamping may be more apparent in settings with a high prevalence of anemia in neonates and children,13 it is likely to have an important effect on all newborns, independent of birth setting. Standardizing the process for delayed cord clamping for all neonates, both term and preterm, will likely result in a more optimal widespread implementation and provide a safeguard against medical errors from the practice. A standardized approach should eliminate practice variation and prevent questions in the delivery room of whether a particular delivery should have delayed clamping, thus improving compliance. For both term and preterm neonates, the neonate should be held at the level of the introitus for vaginal deliveries and on the mother’s thighs above the level of the uterus during cesarean deliveries while waiting to clamp the umbilical cord. Cord clamping should be delayed for 2–3 minutes in term neonates and 30–60 seconds in preterm neonates to enhance placental-toneonate transfusion. Delayed cord clamping is not recommended in cases of severe maternal hypotension, maternal abruption, ruptured vasa previa, placenta previa, a true umbilical cord knot, and suspected perinatal asphyxia. Other potential contraindications to delayed cord clamping include suspected meconium aspiration syndrome, fetal anomalies that require immediate resuscitation (eg, congenital diaphragmatic hernia), and maternal infections (eg, human immunodeficiency

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virus, hepatitis A, B, or C). Cord milking, an alternative placental transfusion method to delayed cord clamping, could achieve placental transfusion without hindering neonatal resuscitation efforts in many of these situations. Cord milking minimizes the potential for resuscitative interference by manually “stripping” an approximate 20-cm cord segment toward the umbilicus over a period of 2 seconds. This technique is repeated three to four times before clamping the cord. For this procedure, the neonate is held at or below the level of the placenta if delivered vaginally or at the level of the placenta if delivered by cesarean. Cord milking has not been studied to the same extent as delayed cord clamping in premature neonates but appears to be safe with similar associated benefits.14–16 Available cord milking trials are promising; however, additional sufficiently powered studies are needed to confirm the efficacy of the intervention, especially regarding potential reductions in red blood cell transfusions and intraventricular hemorrhage for premature neonates. Optimal umbilical cord timing could be the difference between normal and abnormal neurodevelopment for some preterm neonates. Ongoing and future trial results might further clarify the benefit of delayed compared with early cord clamping for neonates; however, sufficient evidence-based advantages for delayed cord clamping have already been established with good safety.2,4,5,12 Institutions that implement delayed cord clamping should observe decreases in intraventricular hemorrhage incidence, allowing for potential improvement in long-term neurologic outcomes in premature neonates. Monitoring short-term and long-term outcomes of neonates treated with delayed cord clamping will enable further understanding of this promising intervention and its resultant effects on outcomes for all neonates. Like the golden minute, the iron minute offers an intervention window that could improve neurodevelopmental outcomes for neonates. For those privileged enough to participate in the birth of neonates, there is a need for increased appreciation and awareness of which precious minutes may count most. REFERENCES 1. Timing of umbilical cord clamping after birth. Committee Opinion No. 543. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:1522–6. 2. Raju TN. Timing of umbilical cord clamping after birth for optimizing placental transfusion. Curr Opin Pediatr 2013;25: 180–7. 3. Saigal S, O’Neill A, Surainder Y, Chua LB, Usher R. Placental transfusion and hyperbilirubinemia in the premature. Pediatrics 1972;49:406–19.

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4. 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. 5. Rabe H, Diaz-Rossello JL, Duley L, Dowswell T. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. The Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD003248. doi: 10.1002/14651858.CD003248.pub3. 6. Martin JA, H B, Ventura SJ, Osterman MJK, Mathews TJ. Births: final data for 2011. Natl Vital Stat Rep. 2013. 7. Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, et al. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 2001;107:E1. 8. Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol 2009;8:110–24. 9. Christensen RD, Del Vecchio A, Ilstrup SJ. More clearly defining the risks of erythrocyte transfusion in the NICU. J Matern Fetal Neonatal Med 2012;25(suppl 5):90–2. 10. de Benoist B, McLean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993–2005: WHO Global Database on

Anaemia. Geneva (Switzerland): World Health Organization; 2008. 11. Yager JY, Hartfield DS. Neurologic manifestations of iron deficiency in childhood. Pediatr Neurol 2002;27:85–92. 12. 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. 13. Chaparro CM, Neufeld LM, Tena Alavez G, Eguia-Líz Cedillo R, Dewey KG. Effect of timing of umbilical cord clamping on iron status in Mexican infants: a randomised controlled trial. Lancet 2006;367:1997–2004. 14. March MI, Hacker MR, Parson AW, Modest AM, de Veciana M. The effects of umbilical cord milking in extremely preterm infants: a randomized controlled trial. J Perinatol 2013;33:763–7. 15. 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 randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2008;93:F14–9. 16. Rabe H, Jewison A, Alvarez RF, Crook D, Stilton D, Bradley R, et al. Milking compared with delayed cord clamping to increase placental transfusion in preterm neonates: a randomized controlled trial. Obstet Gynecol 2011;117:205–11.

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Time to Implement Delayed Cord Clamping

OBSTETRICS & GYNECOLOGY

Time to implement delayed cord clamping.

Immediate umbilical cord clamping after delivery is routine in the United States despite little evidence to support this practice. Numerous trials in ...
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