Advertisement

Umbilical cord milking in nonvigorous infants: a cluster-randomized crossover trial

Published:August 12, 2022DOI:https://doi.org/10.1016/j.ajog.2022.08.015

      Background

      Delayed cord clamping and umbilical cord milking provide placental transfusion to vigorous newborns. Delayed cord clamping in nonvigorous newborns may not be provided owing to a perceived need for immediate resuscitation. Umbilical cord milking is an alternative, as it can be performed more quickly than delayed cord clamping and may confer similar benefits.

      Objective

      We hypothesized that umbilical cord milking would reduce admission to the neonatal intensive care unit compared with early cord clamping in nonvigorous newborns born between 35 and 42 weeks’ gestation.

      Study Design

      This was a pragmatic cluster-randomized crossover trial of infants born at 35 to 42 weeks’ gestation in 10 medical centers in 3 countries between January 2019 and May 2021. The centers were randomized to umbilical cord milking or early cord clamping for approximately 1 year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if nonvigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to umbilical cord milking or early cord clamping according to their birth hospital randomization assignment. The baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the neonatal intensive care unit for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy. Data were analyzed by the intention-to-treat concept.

      Results

      Among 16,234 screened newborns, 1780 were eligible (905 umbilical cord milking, 875 early cord clamping), and 1730 had primary outcome data for analysis (97% of eligible; 872 umbilical cord milking, 858 early cord clamping) either via informed consent (606 umbilical cord milking, 601 early cord clamping) or waiver of informed consent (266 umbilical cord milking, 257 early cord clamping). The difference in the frequency of neonatal intensive care unit admission using predefined criteria between the umbilical cord milking (23%) and early cord clamping (28%) groups did not reach statistical significance (modeled odds ratio, 0.69; 95% confidence interval, 0.41–1.14). Umbilical cord milking was associated with predefined secondary outcomes, including higher hemoglobin (modeled mean difference between umbilical cord milking and early cord clamping groups 0.68 g/dL, 95% confidence interval, 0.31–1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude odds ratio, 0.72; 95% confidence interval, 0.56–0.92); cardiorespiratory support at delivery (61% vs 71%, modeled odds ratio, 0.57; 95% confidence interval, 0.33–0.99), and therapeutic hypothermia (3% vs 4%, crude odds ratio, 0.57; 95% confidence interval, 0.33–0.99). Moderate-to-severe hypoxic-ischemic encephalopathy was significantly less common with umbilical cord milking (1% vs 3%, crude odds ratio, 0.48; 95% confidence interval, 0.24–0.96). No significant differences were observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude odds ratio, 0.81; 95% confidence interval, 0.62–1.06), or a serious adverse event composite of death before discharge.

      Conclusion

      Among nonvigorous infants born at 35 to 42 weeks’ gestation, umbilical cord milking did not reduce neonatal intensive care unit admission for predefined criteria. However, infants in the umbilical cord milking arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate-to-severe hypoxic-ischemic encephalopathy, and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that umbilical cord milking in nonvigorous infants is feasible, safe and, superior to early cord clamping.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Wall S.N.
        • Lee A.C.C.
        • Niermeyer S.
        • et al.
        Neonatal resuscitation in low-resource settings: what, who, and how to overcome challenges to scale up?.
        Int J Gynaecol Obstet. 2009; 107: S47-S64
        • Mercer J.
        • Erickson-Owens D.
        • Skovgaard R.
        Cardiac asystole at birth: is hypovolemic shock the cause?.
        Med Hypotheses. 2009; 72: 458-463
        • Menticoglou S.
        • Schneider C.
        Resuscitating the baby after shoulder dystocia.
        Case Rep Obstet Gynecol. 2016; 20168674167
        • Perez A.
        • Ritter S.
        • Brotschi B.
        • et al.
        Long-term neurodevelopmental outcome with hypoxic-ischemic encephalopathy.
        J Pediatr. 2013; 163: 454-459
        • Martinez-Biarge M.
        • Cheong J.L.
        • Diez-Sebastian J.
        • Mercuri E.
        • Dubowitz L.M.
        • Cowan F.M.
        Risk factors for neonatal arterial ischemic stroke: the importance of the intrapartum period.
        J Pediatr. 2016; 173: 62-68.e1
        • Nielsen L.F.
        • Schendel D.
        • Grove J.
        • et al.
        Asphyxia-related risk factors and their timing in spastic cerebral palsy.
        BJOG. 2008; 115: 1518-1528
        • Getahun D.
        • Rhoads G.G.
        • Demissie K.
        • et al.
        In utero exposure to ischemic-hypoxic conditions and attention-deficit/hyperactivity disorder.
        Pediatrics. 2013; 131: e53-e61
        • Zhu T.
        • Gan J.
        • Huang J.
        • Li Y.
        • Qu Y.
        • Mu D.
        Association Between perinatal hypoxic-ischemic conditions and attention-deficit/hyperactivity disorder: a meta-analysis.
        J Child Neurol. 2016; 31: 1235-1244
        • Weiner G.M.
        • Zaichkin J.
        • Kattwinkel J.
        Textbook of Neonatal Resuscitation.
        7th edition. American Academy of Pediatrics, Elk Grove Village, IL2016
        • Committee Opinion No
        684: delayed umbilical cord clamping after birth.
        Obstet Gynecol. 2017; 129: 1
        • WHO guidelines approved by the guidelines review committee
        Guidelines on basic newborn resuscitation.
        World Health Organization, Geneva2012 (Available at:)
        • Katheria A.C.
        • Leone T.A.
        • Woelkers D.
        • Garey D.M.
        • Rich W.
        • Finer N.N.
        The effects of umbilical cord milking on hemodynamics and neonatal outcomes in premature neonates.
        Am J Perinatol. 2014; 164: 1045-10450.e1
        • Takami T.
        • Suganami Y.
        • Sunohara D.
        • et al.
        Umbilical cord milking stabilizes cerebral oxygenation and perfusion in infants born before 29 weeks of gestation.
        J Pediatr. 2012; 161: 742-747
        • Colozzi A.E.
        Clamping of the umbilical cord; its effect on the placental transfusion.
        N Engl J Med. 1954; 250: 629-632
        • Upadhyay A.
        • Gothwal S.
        • Parihar R.
        • et al.
        Effect of umbilical cord milking in term and near term infants: randomized control trial.
        Am J Obstet Gynecol. 2013; 208 (e1–6): 120
        • Erickson-Owens D.A.
        • Mercer J.S.
        • Oh W.
        Umbilical cord milking in term infants delivered by cesarean section: a randomized controlled trial.
        J Perinatol. 2012; 32: 580-584
        • Walsh S.Z.
        Early clamping versus stripping of card: comparative study of electrocardiogram in neonatal period.
        Br Heart J. 1969; 31: 122-126
        • Jaiswal P.
        • Upadhyay A.
        • Gothwal S.
        • Chaudhary H.
        • Tandon A.
        Comparison of umbilical cord milking and delayed cord clamping on cerebral blood flow in term neonates.
        Indian J Pediatr. 2015; 82: 890-895
        • Al-Wassia H.
        • Shah P.S.
        Efficacy and safety of umbilical cord milking at birth: a systematic review and meta-analysis.
        JAMA Pediatr. 2015; 169: 18-25
        • Katheria A.C.
        • Truong G.
        • Cousins L.
        • Oshiro B.
        • Finer N.N.
        Umbilical cord milking versus delayed cord clamping in preterm infants.
        Pediatrics. 2015; 136: 61-69
        • Katheria A.
        • Rich W.
        • Finer N.
        Development of a strategic process using checklists to facilitate team preparation and improve communication during neonatal resuscitation.
        Resuscitation. 2013; 84: 1552-1557
        • Katheria A.
        • Blank D.
        • Rich W.
        • Finer N.
        Umbilical cord milking improves transition in premature infants at birth.
        PLoS One. 2014; 9e94085
        • Hosono S.
        • Mugishima H.
        • Fujita H.
        • 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. 2008; 93: F14-F19
        • Mercer J.S.
        • Erickson-Owens D.A.
        Rethinking placental transfusion and cord clamping issues.
        J Perinat Neonatal Nurs. 2012; 26: 202-217
        • Kurinczuk J.J.
        • White-Koning M.
        • Badawi N.
        Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy.
        Early Hum Dev. 2010; 86: 329-338
        • Lee A.C.
        • Kozuki N.
        • Blencowe H.
        • et al.
        Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990.
        Pediatr Res. 2013; 74: 50-72
        • Wyckoff M.H.
        • Aziz K.
        • Escobedo M.B.
        • et al.
        Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
        Circulation. 2015; 132: S543-S560
        • Sarnat H.B.
        • Sarnat M.S.
        Neonatal encephalopathy following fetal distress. a clinical and electroencephalographic study.
        Arch Neurol. 1976; 33: 696-705
      1. Delayed umbilical cord clamping after birth: ACOG committee opinion summary, Number 814.
        Obstet Gynecol. 2020; 136: 1238-1239
        • Perlman J.M.
        • Wyllie J.
        • Kattwinkel J.
        • et al.
        Part 7: neonatal resuscitation: 2015 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations (reprint).
        Pediatrics. 2015; 136: S120-S166
        • Finer N.N.
        • Katheria A.
        Slow to change: new cord clamping policies for premature infants.
        J Neonatal Perinatal Med. 2014; 7: 85-87
        • Yao A.C.
        • Moinian M.
        • Lind J.
        Distribution of blood between infant and placenta after birth.
        Lancet. 1969; 2: 871-873
        • Lawton C.
        • Acosta S.
        • Watson N.
        • et al.
        Enhancing endogenous stem cells in the newborn via delayed umbilical cord clamping.
        Neural Regen Res. 2015; 10: 1359-1362
        • González-Orozco J.C.
        • Camacho-Arroyo I.
        Progesterone actions during central nervous system development.
        Front Neurosci. 2019; 13: 503
        • Chaudhury S.
        • Saqibuddin J.
        • Birkett R.
        • et al.
        Variations in umbilical cord hematopoietic and mesenchymal stem cells with bronchopulmonary dysplasia.
        Front Pediatr. 2019; 7: 475
        • Rajnik M.
        • Salkowski C.A.
        • Thomas K.E.
        • Li Y.Y.
        • Rollwagen F.M.
        • Vogel S.N.
        Induction of early inflammatory gene expression in a murine model of nonresuscitated, fixed-volume hemorrhage.
        Shock. 2002; 17: 322-328
        • Nelle M.
        • Zilow E.P.
        • Kraus M.
        • Bastert G.
        • Linderkamp O.
        The effect of Leboyer delivery on blood viscosity and other hemorheologic parameters in term neonates.
        Am J Obstet Gynecol. 1993; 169: 189-193
        • Oh W.
        • Lind J.
        Venous and capillary hematocrit in newborn infants and placental transfusion.
        Acta Paediatr Scand. 1966; 55: 38-48
        • Oh W.
        • Oh M.A.
        • Lind J.
        Renal function and blood volume in newborn infant related to placental transfusion.
        Acta Paediatr. 1966; 55: 197-210
        • Oh W.
        • Fanaroff A.A.
        • Carlo W.A.
        • Donovan E.F.
        • McDonald S.A.
        • Poole W.K.
        Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effects of delayed cord clamping in very-low-birth-weight infants.
        J Perinatol. 2011; 31 Suppl 1(Suppl 1): S68-S71
        • Linderkamp O.
        • Nelle M.
        • Kraus M.
        • Zilow E.P.
        The effect of early and late cord-clamping on blood viscosity and other hemorheological parameters in full-term neonates.
        Acta Paediatr. 1992; 81: 745-750
        • Nelle M.
        • Zilow E.P.
        • Bastert G.
        • Linderkamp O.
        Effect of Leboyer childbirth on cardiac output, cerebral and gastrointestinal blood flow velocities in full-term neonates.
        Am J Perinatol. 1995; 12: 212-216
        • Bhatt S.
        • Alison B.J.
        • Wallace E.M.
        • et al.
        Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs.
        J Physiol. 2013; 591: 2113-2126
        • McAdams R.M.
        • Fay E.
        • Delaney S.
        Whole blood volumes associated with milking intact and cut umbilical cords in term newborns.
        J Perinatol. 2018; 38: 245-250
        • Mercer J.S.
        • Erickson-Owens D.A.
        • Collins J.
        • Barcelos M.O.
        • Parker A.B.
        • Padbury J.F.
        Effects of delayed cord clamping on residual placental blood volume, hemoglobin and bilirubin levels in term infants: a randomized controlled trial.
        J Perinatol. 2017; 37: 260-264
        • Bin-Nun A.
        • Mimouni F.B.
        • Kasirer Y.
        • et al.
        Might bilirubin serve as a natural antioxidant in response to neonatal encephalopathy?.
        Am J Perinatol. 2018; 35: 1107-1112
        • Girish M.
        • Jain V.
        • Dhokane R.
        • Gondhali S.B.
        • Vaidya A.
        • Aghai Z.H.
        Umbilical cord milking for neonates who are depressed at birth: a randomized trial of feasibility.
        J Perinatol. 2018; 38: 1190-1196