Cord Management at Birth for Preterm Infants (NLS # 787) Systematic Review

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: None applicable

CoSTR Citation

Costa-Nobre DT, Davis PG, Soll R, Niermeyer S, El-Naggar W, de Almeida MF, Fabres JG, Fawke J, Foglia EE, Guinsburg R, Hosono S, Isayama T, Kawakami MD, Kapadia VS, Kim HS, Liley HG, McKinlay CJD, Perlman JM, Rabi Y, Roehr CC, Schmölzer GM, Sugiura T, Trevisanuto D, Weiner GM, Wyckoff MH, Wyllie JP, Aziz K. Preterm Umbilical Cord Management. International Liaison Committee on Resuscitation (ILCOR) Neonatal Life Support Task Force, Feb 2021. Available from: http://ilcor.org

Collaborators

None

Methodological Preamble (and Link to Published Systematic Review)

The continuous evidence evaluation process for the development of this Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of cord management during the delivery of preterm infants {Seidler 2021 e20200576} conducted by the Cochrane Knowledge Synthesis Unit with the involvement of clinical content experts. Additional evidence from the neonatal literature was sought and considered by the Neonatal Life Support Task Force. The resulting consensus on science was considered when formulating treatment recommendations.

PICOST

Cord Management at Birth for Preterm Infants PICOST

Population:

Moderate, very, and extremely preterm infants (or equivalent birth weight) less than 34 (+0) weeks’ (plus days) gestation.

Interventions:

Later (delayed) cord clamping

Intact-cord milking

Cut-cord milking

Definitions used in PROSPERO submission:

• Early cord clamping, defined as application of a clamp to the umbilical cord at <30 seconds after birth of the infant without cord milking.

• Later (or delayed) cord clamping, defined as application of a clamp to the umbilical cord ≥30 seconds after birth or based on physiologic parameters (such as when cord pulsation has ceased or breathing has been initiated), without cord milking.

• Intact-cord milking (also referred to as “stripping”) defined as repeated compression of the cord from the placental side toward the infant with the connection to the placenta intact at any time point immediately after birth.

• Cut-cord milking (also referred to as “stripping”) defined as drainage of the cord by compression from the cut end toward the infant after clamping and cutting of a long segment.

Comparisons:

Early clamping of the cord (clamping at < 30 seconds after birth) without cord milking or initiation of respiratory support compared to each of the above interventions.

Between-intervention comparisons

Later (delayed) cord clamping at ≥30 to <60 seconds compared to ≥60 seconds

Later (delayed) cord clamping based on time since birth compared to physiological approach to cord clamping (till cessation of pulsation or based on vital signs monitoring)

Outcomes:

Longer term

9 (Critical) – Survival

8 (Critical) – Neurodevelopmental outcomes (with age-appropriate, validated tools)

Medium term (inpatient)

7 (Critical) - Inpatient morbidities (e.g., intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, chronic lung disease)

6 (Important) - Hematological and cardiovascular status (in-hospital), hyperbilirubinemia treated with phototherapy

Short term (delivery setting)

7 (Critical) - Maternal complication (post-partum hemorrhage, infection)

6 (Important) – Resuscitation (Need for positive pressure ventilation ± intubation ± chest compressions ± medications)

Study Designs:

Randomized controlled trials and cluster randomized controlled trials of different strategies for umbilical cord management (including timing of clamping and cord milking) in preterm infants (<34 weeks' gestational age) or low birth weight infants <2500 g were included. For those studies that report on a broad population of infants (including both preterm infants <34 weeks’ gestation, late preterm infants, and term infants), studies recruiting a preponderance of preterm infants (defined as a mean gestational age of <34 weeks or report greater than 80% of infants as preterm <34 weeks’ gestational age) were included.

Timeframe:

All years and all languages were included if there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search was last conducted on 26^th July 2019.

A priori subgroups examined:

Mode of delivery: 1) cesarean section 2) vaginal delivery

Gestational age: 1) <30 weeks' gestational age 2) ≥30 to <34 weeks' gestational age 3) mixed gestation or not reported

Respiratory support with intact cord: respiratory support includes all aspects of resuscitation with intact cord including providing oxygen, non-invasive respiratory support and endotracheal intubation

Different timing of later (delayed) clamping based on different timed delays after birth (<1 minute; 1-2 minutes; >2 minutes) or based on physiologic parameters (e.g., cessation of cord pulsation, onset of spontaneous breathing)

Timing of administration of uterotonic agents

Placement of newborn relative to placenta (effect of gravity)

Timing of randomization (before or after delivery)

For studies of cord milking (or stripping): immediate versus delay prior to milking (or stripping)

Special populations:

Twins (monochorionic or dichorionic) or other multiples

Newborns with congenital anomalies or other conditions noted at or prior to birth including congenital diaphragmatic hernia, cardiac anomalies, anemia, alloimmune hemolytic disease)

Small for gestational age

Infant status at birth (vigorous or apneic)

Sex

Newborns born in different-resourced countries/settings

PROSPERO registration:

The review was registered with PROSPERO {2019 CRD42019155475}

Selecting outcomes

The choices of outcomes using the GRADE classifications of “critical, important, or less important” were debated by the Task Force. Highest priority was given to survival without neurodevelopmental impairment, severe intraventricular hemorrhage, morbidities (including necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity), and maternal mortality. {Strand 2020 328} Potential subgroups were also defined a priori. These lists (above) were converted into “Main outcomes” and “Additional outcomes” for submission to PROSPERO (as listed below). The subsequent review divided outcomes into “primary” or “secondary” and presented a limited number of “subgroup” analyses, considering them to have limited influence on conclusions.

Outcomes listed in PROSPERO submission:

Main outcome(s)

Infant

1. Survival to discharge from hospital

2. Survival without moderate to severe neurodevelopmental impairment in early childhood (see definitions in secondary outcomes)

3. Severe intraventricular hemorrhage (IVH): ultrasound diagnosis grades III and IV (as per Papile definitions)

Maternal

Postpartum hemorrhage (PPH): clinically estimated blood loss of at least 500 mL, or as defined by the trial authors

additional outcomes: Additional-outcome

Risk of Bias: Risk-of-Bias

GRADE evaluations:

With the possibility of at least 3 interventions (delayed cord clamping, intact-cord milking, and cut-cord milking) and one comparison (early cord clamping) and between-intervention comparisons, there were a large number of outcomes which were multiplied by several subgroup comparisons. No correction for multiple comparisons was undertaken, therefore measures of statistical significance should be interpreted cautiously. A methodological decision was made to omit the GRADE evaluations of some comparisons and all subgroups. However, the NLS Task Force decided that a GRADE evaluation of some additional comparisons might influence the strength of our final recommendation and therefore these were performed post hoc.

Consensus on Science

Comparison 1: Later (delayed) cord clamping (≥30 seconds) compared to early cord clamping (<30 seconds)

The systematic review identified 23 trials (3513 infants) in this category. Most studies included infants <34 weeks gestational age and most were done in high-income countries. {Aladangady 2006 93; Armanian 2017 4909; Backes 2016 35; Baenziger 2007 455; Das 2018 496; Dipak 2017 112; Dong 2016 635; Duley 2018 F6; Finn 2019 121; Gokmen 2011 323; Hofmeyr 1988 104; Hofmeyr 1993 110; Kazemi 2017 e6570; Kinmond 1993 172; Kugelman 2007 307; McDonnell 1997 308; Mercer 2003 466; Mercer 2006 1235; Oh 2011 S68; Rabe 2000 775; Rana 2018 655; Ruangkit 2019 156; Tarnow-Mordi 2017 2445}

For the critical outcome of survival to discharge, evidence of moderate certainty (downgraded for imprecision) from 16 trials involving 2988 infants showed improved survival or no difference from later cord clamping compared to early cord clamping (risk ratio (RR) 1.02, 95% confidence interval (CI) 1.00 to 1.04; risk difference (RD) 0.02, 95% CI -0.00 to 0.04; number needed to treat for benefit (NNTB) 50, 95% CI 25 to >1,000; I² = 0%; 18/1000 more infants survived when later cord clamping was intended than when early cord clamping was intended, [95%CI, 0 to 36 more per 1000]). {Armanian 2017 4909; Backes 2016 35; Baenziger 2007 455; Das 2018 496; Duley 2018 F6; Hofmeyr 1988 104; Hofmeyr 1993 110; Kinmond 1993 172; Kugelman 2007 307; McDonnell 1997 308; Mercer 2003 466; Mercer 2006 1235; Oh 2011 S68; Rabe 2000 775; Ruangkit 2019 156; Tarnow-Mordi 2017 2445}

For the critical outcome of mortality, evidence of moderate certainty (downgraded for imprecision) from 16 trials involving 2988 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 0.80, 95% CI 0.63 to 1.02; RD -0.02, 95% CI -0.04 to 0.00; NNTB 50, 95% CI 25 to >1,000 I² = 0%) (post hoc sensitivity analysis of mortality). {Armanian 2017 4909; Backes 2016 35; Baenziger 2007 455; Das 2018 496; Duley 2018 F6; Hofmeyr 1988 104; Hofmeyr 1993 110; Kinmond 1993 172; Kugelman 2007 307; McDonnell 1997 308; Mercer 2003 466; Mercer 2006 1235; Oh 2011 S68; Rabe 2000 775; Ruangkit 2019 156; Tarnow-Mordi 2017 2445}

For the critical outcome of severe intraventricular hemorrhage (IVH, ultrasound diagnosis grade III, IV), evidence of low certainty (downgraded for serious risk of bias and imprecision) from 14 trials involving 2972 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 0.98, 95% CI 0.67 to 1.42; I² = 0%). {Armanian 2017 4909; Backes 2016 35; Das 2018 496; Dong 2016 635; Duley 2018 F6; Finn 2019 121; Kazemi 2017 e6570; Kugelman 2007 307; Mercer 2003 466; Mercer 2006 1235; Rabe 2000 775; Rana 2018 655; Ruangkit 2019 156; Tarnow-Mordi 2017 2445}

For the critical outcome of chronic lung disease (supplemental oxygen at 36 weeks' postmenstrual age), evidence of high certainty from 10 trials involving 2427 infants showed that a large effect of benefit or harm was unlikely from later cord clamping compared to early cord clamping (RR 1.03, 95% CI 0.94 to 1.13; I² = 0%; RD 0.01, 95% CI -0.02 to 0.04). {Backes 2016 35; Das 2018 496; Duley 2018 F6; Kinmond 1993 172; Mercer 2003 466; Mercer 2006 1235; Oh 2011 S68; Rabe 2000 775; Ruangkit 2019 156; Tarnow-Mordi 2017 2445}

For the critical outcome of necrotizing enterocolitis (Bell staging greater than or equal to stage 2), evidence of moderate certainty (downgraded for imprecision) from 14 trials involving 2745 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 0.83, 95% CI 0.61 to 1.13; I² = 0%). {Armanian 2017 4909; Backes 2016 35; Das 2018 496; Dong 2016 635; Duley 2018 F6; Finn 2019 121; Gokmen 2011 323; Kugelman 2007 307; Mercer 2003 466; Mercer 2006 1235; Oh 2011 S68; Rabe 2000 775; Ruangkit 2019 156; Tarnow-Mordi 2017 2445}

For the important outcome of hyperbilirubinemia treated with phototherapy, evidence of high certainty from 6 trials involving 908 infants showed that a large effect of benefit or harm was unlikely from later cord clamping compared to early cord clamping (RR 0.99, 95% CI 0.95 to 1.03; I² = 0%; RD -0.01, 95% CI -0.04 to 0.03). {Backes 2016 35; Das 2018 496; Duley 2018 F6; Finn 2019 121; Rabe 2000 775; Rana 2018 655}

For the important outcome of hemoglobin concentrations within the first 24 hours after birth, evidence of moderate certainty (downgraded for inconsistency and imprecision) from 4 trials involving 196 infants showed higher hemoglobin values from later cord clamping compared to early cord clamping (mean difference (MD) 1.24g/dL, 95% CI 0.01 to 2.47g/dL; I² = 79%; random effects). {Baenziger 2007 455; Dong 2016 635; Finn 2019 121; Gokmen 2011 323}

For the important outcome of hematocrit within the first 24 hours after birth, evidence of high certainty from 14 trials involving 1022 infants showed higher hematocrit from later cord clamping compared to early cord clamping (MD 2.63%, 95% CI 1.85 to 3.42%; I² = 5%). {Armanian 2017 4909; Backes 2016 35; Baenziger 2007 455; Das 2018 496; Dipak 2017 112; Gokmen 2011 323; Kinmond 1993 172; Kugelman 2007 307; McDonnell 1997 308; Mercer 2003 466; Mercer 2006 1235; Oh 2011 S68; Rabe 2000 775; Ruangkit 2019 156}

For the important outcome of hematocrit within the first 7 days after birth, evidence of high certainty from 1 trial involving 1550 infants showed higher hematocrit from later cord clamping compared to early cord clamping (MD 2.70%, 95% CI 1.88 to 3.52%). {Tarnow-Mordi 2017 2445}

For the critical maternal outcome of postpartum hemorrhage (≥500ml), evidence of very low certainty (downgraded for risk of bias, inconsistency, and imprecision) from 3 trials involving 1477 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 0.93, 95% CI 0.54 to 1.62; I² = 52%; random effects). {Duley 2018 F6; Ruangkit 2019 156; Tarnow-Mordi 2017 2445}

For the critical maternal outcome of severe postpartum hemorrhage (≥1000ml), evidence of very low certainty (downgraded for risk of bias and imprecision) from 1 trial involving 254 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 0.81, 95% CI 0.38 to 1.73). {Duley 2018 F6}

For the critical maternal outcome of blood transfusion, evidence of low certainty from 2 trials involving 715 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 1.82, 95% CI 0.78 to 4.23; I² = 0%). {Das 2018 496; Duley 2018 F6}

For the critical maternal outcome of manual removal of the placenta, evidence of low certainty (downgraded for very serious imprecision) from 1 trial involving 105 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 0.99, 95% CI 0.32 to 3.04). {Duley 2018 F6}

For the critical maternal outcome of postpartum infection, evidence of low certainty (downgraded for very serious imprecision) from 1 trial involving 254 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 1.12, 95% CI 0.73 to 1.72). {Duley 2018 F6}

For the important maternal outcome of administration of uterotonic agents, evidence of high certainty from 1 trial involving 1566 infants showed that a large effect of benefit or harm was unlikely from later cord clamping compared to early cord clamping (RR 1.00, 95% CI 0.97 to 1.04; RD 0.00, 95% CI -0.02 to 0.03). {Tarnow-Mordi 2017 2445}

Post hoc GRADE evaluations:

For the important outcome of respiratory support after birth (mechanical ventilation or CPAP), evidence of low certainty (downgraded for risk of bias and imprecision) from 7 trials involving 515 infants could not exclude benefit or harm from later cord clamping compared to early cord clamping (RR 1.07, 95% CI 0.89 to 1.29; I² = 0%). {Armanian 2017 4909; Baenziger 2007 455; Duley 2018 F6; Finn 2019 121; Kinmond 1993 172; McDonnell 1997 308; Rabe 2000 775}

For the important outcome of infants receiving inotropic support for hypotension within the first 24 hours after birth, evidence of moderate certainty (downgraded for risk of bias) from 6 trials involving 351 infants showed benefit with fewer infants receiving inotropic support from later cord clamping compared to early cord clamping (RR 0.36, 95% CI 0.17 to 0.75; RD -0.09, 95% CI -0.15 to -0.03; NNTB 11, 95% CI 7 to 33; I² = 0%; 91/1000 fewer infants received inotropic support for hypotension within the first 24 hours after birth when later cord clamping was intended than when early cord clamping was intended, [95% CI, 30 fewer to 143 fewer]). {Dong 2016 635; Gokmen 2011 323; McDonnell 1997 308; Oh 2011 S68; Rabe 2000 775; Ruangkit 2019 156}

For the important outcome of lowest mean arterial blood pressure in the first 12 hours after birth, evidence of low certainty (downgraded for risk of bias and imprecision) from 7 trials involving 374 infants showed benefit from later cord clamping compared to early cord clamping (MD 1.79mmHg, 95% CI 0.53 to 3.05mmHg; I² = 0%). {Baenziger 2007 455; Finn 2019 121; Gokmen 2011 323; Kugelman 2007 307; Mercer 2003 466; Mercer 2006 1235; Ruangkit 2019 156}

For the important outcome of receiving transfusion of packed red blood cells, evidence of low certainty (downgraded for risk of bias and inconsistency) from 12 trials involving 2910 infants showed fewer infants received blood transfusions from later cord clamping compared to early cord clamping (RR 0.83, 95% CI 0.77 to 0.90; RD -0.07, 95% CI -0.11 to -0.04; NNTB 14, 95% CI 9 to 25; I² = 36%; 71/1000 fewer infants received any blood transfusions when later cord clamping was intended than when early cord clamping was intended, [95% CI, 40 fewer to 111 fewer per 1000). {Armanian 2017 4909; Das 2018 496; Dipak 2017 112; Dong 2016 635; Duley 2018 F6; Finn 2019 121; Kugelman 2007 307; Mercer 2006 1235; Rabe 2000 775; Rana 2018 655; Ruangkit 2019 156; Tarnow-Mordi 2017 2445}

Comparison 2: Intact-cord milking compared to early cord clamping

The systematic review identified 13 trials (1170 infants). {Alan 2014 c493; Elimian 2014 1075; El-Naggar 2019 F145; Finn 2019 121; Hosono 2008 F14; Katheria 2014 1045; Kilicdag 2016 615; Leal 2018 1; Li 2018 184; March 2013 763; Mercer 2016 50; Silahli 2018 1560; Song 2017 527}

For the critical outcome of survival to discharge, the evidence of moderate certainty (downgraded for imprecision) from 10 trials involving 945 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 1.02, 95% CI 0.98 to 1.06; I² = 24%). {Alan 2014 c493; Elimian 2014 1075; El-Naggar 2019 F145; Hosono 2008 F14; Katheria 2014 1045; Li 2018 184; March 2013 763; Mercer 2016 50; Silahli 2018 1560; Song 2017 527}

For the critical outcome of mortality to discharge, the evidence of moderate certainty (downgraded for imprecision) from 10 trials involving 945 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 0.77, 95% CI 0.49 to 1.23; I² = 24%); (post hoc sensitivity analysis of mortality). {Alan 2014 c493; Elimian 2014 1075; El-Naggar 2019 F145; Hosono 2008 F14; Katheria 2014 1045; Li 2018 184; March 2013 763; Mercer 2016 50; Silahli 2018 1560; Song 2017 527}

For the critical outcome of moderate to severe neurodevelopmental impairment in early childhood, the evidence of very low certainty (downgraded for imprecision and indirectness) from 1 trial involving 26 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 0.75, 95% CI 0.21 to 2.71). {Hosono 2008 F14}

For the critical outcome of cerebral palsy, the evidence of very low certainty (downgraded for imprecision and indirectness) from 1 trial involving 161 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 2.65, 95% CI 0.88 to 7.97). {Mercer 2016 50}

For the critical outcome of severe intraventricular hemorrhage (IVH, ultrasound diagnosis grade III, IV), the evidence of low certainty (downgraded for very serious imprecision) from 10 trials involving 889 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 0.72, 95% CI 0.44 to 1.19; I² = 0%). {Alan 2014 c493; Elimian 2014 1075; El-Naggar 2019 F145; Finn 2019 121; Hosono 2008 F14; Katheria 2014 1045; Li 2018 184; March 2013 763; Mercer 2016 50; Song 2017 527}

For the critical outcome of chronic lung disease (supplemental oxygen at 36 weeks' postmenstrual age), the evidence of low certainty (downgraded for inconsistency and imprecision) from 7 trials involving 685 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 1.02, 95% CI 0.63 to 1.65; I² = 50%; random effects). {Alan 2014 c493; Elimian 2014 1075; El-Naggar 2019 F145; Hosono 2008 F14; Katheria 2014 1045; March 2013 763; Mercer 2016 50}

For the critical outcome of necrotizing enterocolitis (Bell staging greater than or equal to stage 2), the evidence of moderate certainty (downgrade for imprecision) from 9 trials involving 843 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 0.80, 95% CI 0.55 to 1.18; I² = 0%). {Alan 2014 c493; Elimian 2014 1075; El-Naggar 2019 F145; Finn 2019 121; Kilicdag 2016 615; Li 2018 184; March 2013 763; Mercer 2016 50; Song 2017 527}

For the important outcome of hyperbilirubinemia treated with phototherapy, the evidence of high certainty from 5 trials involving 480 infants showed that a large effect of benefit or harm was unlikely from intact-cord milking compared to early cord clamping (RR 1.04, 95% CI 0.94 to 1.16; I² = 10%; RD 0.03, 95% CI -0.04 to 0.10). {Elimian 2014 1075; El-Naggar 2019 F145; Finn 2019 121; Li 2018 184; March 2013 763}

For the important outcome of hemoglobin concentrations within the first 24 hours after birth, the evidence of moderate certainty (downgraded for inconsistency) from 10 trials involving 914 infants showed higher hemoglobin from intact-cord milking compared to early cord clamping (MD 1.18g/dL, 95% CI 0.65 to 1.71g/dL; I² = 71%; random effects). {Elimian 2014 1075; El-Naggar 2019 F145; Finn 2019 121; Hosono 2008 F14; Kilicdag 2016 615; Li 2018 184; March 2013 763; Mercer 2016 50; Silahli 2018 1560; Song 2017 527}

For the important outcome of hematocrit within the first 24 hours after birth, the evidence of moderate certainty (downgraded for inconsistency) from 7 trials involving 774 infants showed higher hematocrit from intact-cord milking compared to early cord clamping (MD 3.04%, 95% CI 1.28 to 4.80%; I² = 69%; random effects). {Elimian 2014 1075; Katheria 2014 1045; Kilicdag 2016 615; Li 2018 184; March 2013 763; Mercer 2016 50; Silahli 2018 1560}

For the important outcome of hemoglobin concentrations within the first 7 days after birth, the evidence of low certainty (downgrade for indirectness and imprecision) from 1 trial involving 54 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (MD 0.60g/dL, 95% CI -0.57 to 1.77g/dL). {Kilicdag 2016 615}

For the important outcome of hematocrit within the first 7 days after birth, the evidence of low certainty (downgrade for indirectness and imprecision) from 1 trial involving 54 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (MD 1.00%, 95% CI -2.32 to 4.32%). {Kilicdag 2016 615}

For the critical (maternal) outcomes of severe postpartum hemorrhage (≥1000ml), the evidence of very low certainty (downgraded for risk of bias and very serious imprecision) from 2 trials involving 266 mothers could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 2.83, 95% CI 0.12 to 67.01, I² not applicable as one trial reported zero events). {Elimian 2014 1075; Song 2017 527}

For the critical (maternal) outcome of maternal blood transfusion, the evidence of very low certainty (downgraded for indirectness and very serious imprecision) from 1 trial involving 66 mothers could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 2.83, 95% CI 0.12 to 67.01). {Song 2017 527}

Post hoc GRADE evaluations:

For the important outcome of respiratory support after birth (mechanical ventilation or CPAP), the evidence of low certainty (downgraded for risk of bias and imprecision) from 6 trials involving 373 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (RR 0.96, 95% CI 0.87 to 1.07; I² = 24%). {El-Naggar 2019 F145; Finn 2019 121; Kilicdag 2016 615; March 2013 763; Silahli 2018 1560; Song 2017 527}

For the important outcome of infants receiving inotropic support for hypotension within the first 24 hours after birth, the evidence of moderate certainty (downgraded for risk of bias) from 5 trials involving 439 infants showed benefit with fewer infants receiving inotropic support after intact-cord milking compared to early cord clamping (RR 0.61, 95% CI 0.44 to 0.84; RD -0.12, 95% CI -0.19 to -0.05; NNTB 8, 95% CI 5 to 20; I² = 0%; 125/1000 fewer infants received inotropic support for hypotension within the first 24 hours after birth when intact-cord milking was intended than when early cord clamping was intended, [95% CI, 50 fewer to 200 fewer per 1000]). {Elimian 2014 1075; El-Naggar 2019 F145; Hosono 2008 F14; Katheria 2014 1045; Song 2017 527}

For the important outcome of lowest mean arterial blood pressure in the first 12 hours after birth, the evidence of very low certainty (downgraded for risk of bias, inconsistency, indirectness, and imprecision) from 5 trials involving 431 infants could not exclude benefit or harm from intact-cord milking compared to early cord clamping (MD 0.58mmHg, 95% CI -0.79 to 1.94mmHg; I² = 0%). {El-Naggar 2019 F145; Finn 2019 121; Katheria 2014 1045; Mercer 2016 50; Song 2017 527}

For the important outcome of receiving a transfusion of packed red blood cells, the evidence of very low certainty (downgraded for risk of bias, inconsistency, and imprecision) from 7 trials involving 545 infants showed benefit with fewer infants receiving blood transfusions with intact-cord milking compared to early cord clamping (RR 0.73, 95% CI 0.56 to 0.94; RD -0.17, 95% CI -0.30 to -0.04; NNTB 6, 95% CI 3 to 25; I² = 54%; random effects; 167/1000 fewer infants received any blood transfusions when intact-cord milking was intended than when early cord clamping was intended [95% CI, 40 fewer to 333 fewer per 1000). {Alan 2014 c493; Elimian 2014 1075; Finn 2019 121; Hosono 2008 F14; Katheria 2014 1045; Li 2018 184; March 2013 763}

Comparison 3: Cut-cord milking compared to early cord clamping (based on timing of delay clamping <30 seconds)

Only one study was identified in this group with 60 subjects. {Ram Mohan 2018 88}

For the critical outcome of survival to discharge, the evidence of very low certainty (downgraded for indirectness and very serious imprecision) from 1 trial involving 60 infants could not exclude benefit or harm from cut-cord milking compared to early cord clamping (RR 1.00, 95% CI 0.94 to 1.07). {Ram Mohan 2018 88}

For the critical outcome of severe intraventricular hemorrhage (IVH, ultrasound diagnosis grade III, IV), the evidence of very low certainty (downgraded for indirectness and very serious imprecision) from 1 trial involving 60 infants could not exclude benefit or harm from cut-cord milking compared to early cord clamping (RR 0.33, 95% CI 0.01 to 7.87). {Ram Mohan 2018 88}

For the critical outcome of chronic lung disease (supplemental oxygen at 36 weeks' postmenstrual age), the evidence of very low certainty (downgraded for inconsistency and very serious imprecision) from 1 trial involving 60 infants could not exclude benefit or harm from cut-cord milking compared to early cord clamping (RR 1.00, 95% CI 0.07 to 15.26). {Ram Mohan 2018 88}

For the critical outcome of necrotizing enterocolitis (Bell staging greater than or equal to stage 2), the evidence of very low certainty (downgraded for indirectness and very serious imprecision) from 1 trial involving 60 infants could not exclude benefit or harm from cut-cord milking compared to early cord clamping (RR 0.50, 95% CI 0.05 to 5.22). {Ram Mohan 2018 88}

For the important outcome of hematocrit in the first 24 hours after birth, the evidence of low certainty from 1 trial involving 60 infants showed higher hematocrit from cut-cord milking compared to early cord clamping (MD 3.34%, 95% CI 0.60 to 6.08%). {Ram Mohan 2018 88}

Comparison 4: Later (delayed) cord clamping (≥30 seconds) compared to intact-cord milking

The systematic review identified 7 trials (1073 infants). {Finn 2019 208; Katheria 2015 61; Katheria 2019 1877; Krueger 2015 394.e1; Pratesi 2018 364; Rabe 2011 205; Shirk 2019 482.e1} Data are presented with intervention 1 (later (delayed) clamping) as the intervention and intervention 2 (intact-cord milking) as the comparison.

For the critical outcome of survival to discharge, the evidence of moderate certainty (downgraded for imprecision) from 5 trials involving 1000 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (RR 0.99, 95% CI 0.95 to 1.02; I² = 14%). {Katheria 2015 61; Katheria 2019 1877; Krueger 2015 394.e1; Rabe 2011 205; Shirk 2019 482.e1}

For the critical outcome of mortality prior to discharge, the evidence of moderate certainty (downgraded for imprecision) from 5 trials involving 1000 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (RR 1.21, 95% CI 0.76 to 1.94; I² = 14%). This was a post hoc sensitivity analysis of mortality prior to discharge. {Katheria 2015 61; Katheria 2019 1877; Krueger 2015 394.e1; Rabe 2011 205; Shirk 2019 482.e1}

For the critical outcome of cerebral palsy, the evidence of low certainty (downgraded for very serious imprecision) from 2 trials involving 193 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (RR 0.36, 95% CI 0.01 to 8.65; I² not applicable as one trial reported zero events). {Katheria 2015 61; Rabe 2011 205}

For the critical outcome of severe intraventricular hemorrhage (IVH, ultrasound diagnosis grade III, IV), the evidence of moderate certainty (downgraded for imprecision) from 4 trials involving 761 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (RR 0.60, 95% CI 0.32 to 1.12; I² = 23%). {Finn 2019 208; Katheria 2015 61; Katheria 2019 1877; Rabe 2011 205}

For the critical outcome of chronic lung disease (supplemental oxygen at 36 weeks' postmenstrual age), the evidence of moderate certainty (downgrade for imprecision) from 4 trials involving 734 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (RR 0.91, 95% CI 0.67 to 1.25; I² = 0%). {Katheria 2015 61; Katheria 2019 1877; Krueger 2015 394.e1; Rabe 2011 205;}

For the critical outcome of necrotizing enterocolitis (Bell staging greater than or equal to stage 2), the evidence of moderate certainty (downgrade for imprecision) from 5 trials involving 922 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (RR 1.57, 95% CI 0.83 to 2.97; I² = 0%). {Finn 2019 208; Katheria 2015 61; Katheria 2019 1877; Rabe 2011 205; Shirk 2019 482.e1}

For the important outcome of hyperbilirubinemia receiving phototherapy, the evidence of moderate certainty (downgrade for inconsistency) from 2 trials involving 236 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (RR 1.05, 95% CI 0.90 to 1.24; I² = 43%; random effects). {Finn 2019 208; Shirk 2019 482.e1}

For the important outcome of hemoglobin concentrations at 24 hours after birth, the evidence of moderate certainty (downgrade for inconsistency) from 6 trials involving 941 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (MD -0.02g/dL, 95% CI -0.56 to 0.53g/dL, I² = 52%; random effects). {Finn 2019 208; Katheria 2015 61; Katheria 2019 1877; Rabe 2011 205; Shirk 2019 482.e1}

For the important outcome of hematocrit at 24 hours after birth, the evidence of moderate certainty (downgraded for inconsistency) from 5 trials involving 841 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (MD -0.18%, 95% CI -1.90 to 1.54%; I² = 51%; random effects). {Katheria 2019 1877; Krueger 2015 394.e1; Pratesi 2018 364; Rabe 2011 205; Shirk 2019 482.e1}

Comparison 5: Later (delayed) cord clamping (≥30 seconds) compared to cut-cord milking

No studies met inclusion criteria for this comparison.

Comparison 6: Intact-cord milking compared to cut-cord milking

No studies met inclusion criteria for this comparison.

Comparison 7: Later (delayed) cord clamping ≥60 seconds versus later (delayed) cord clamping (≥30 and <60 seconds)

No studies met inclusion criteria for this comparison.

Comparison 8: Later (delayed) cord clamping (≥30 seconds) versus physiological approach

No studies met inclusion criteria for this comparison.

SUBGROUP ANALYSES

The number of pre-specified subgroup analyses was large and was multiplied by the number of comparisons. The p-values were not adjusted for multiple comparisons. As a consequence, GRADE evaluations were not done for all subgroup analyses. Instead, post hoc GRADE evaluations were requested for important outcomes that might influence our justification, values and preferences statements.

We assessed the influence of key prognostic factors on the intervention effect using a test of interaction, including gestation (<30 weeks vs. ≥30 to <34 weeks), resource setting, respiratory support given with intact- or cut-cord, and time to clamping. We planned to test for subgroup interactions within and between studies where appropriate. We noted whether randomization was stratified by the characteristic of interest. If subgroup data were not available, we performed subgroup analyses according to study characteristics, where applicable. These subgroup analyses are exploratory and must be interpreted with caution, especially for interaction tests between studies and by strata that were not used in randomization.

Subgroup Comparison: Later (delayed) cord clamping versus early cord clamping (based on gestational age)

For the critical outcome of survival to discharge the evidence of moderate certainty from 3 trials involving 1639 infants <30 weeks gestational age showed improved survival or no difference from later (delayed) clamping (≥30s) compared to early cord clamping (<30s) (RR 1.03, 95% CI 1.00 to 1.06; RD 0.03, 95% CI 0.00 to 0.05; I² = 0%). {Backes 2016 35; Oh 2011 S68; Tarnow-Mordi 2017 2445} The evidence of low certainty from 1 trial involving 461 infants from 30 to 34 weeks gestation could not exclude benefit or harm from later (delayed) clamping (≥30s) compared to early cord clamping (<30s) (RR 0.96, 95% CI 0.89 to 1.04). {Das 2018 496} The evidence of moderate certainty from 12 trials involving 846 infants from both gestational age strata showed improved survival or no difference from later (delayed) clamping (≥30s) compared to early cord clamping (<30s) (RR 1.03, 95% CI 1.00 to 1.06; RD 0.03, 95% CI 0.00 to 0.06; NNTB 33, 95% CI 17 to >1,000; I² 28%). {Armanian 2017 4909; Baenziger 2007 455; Duley 2018 F6; Hofmeyr 1988 104; Hofmeyr 1993 110; Kinmond 1993 172; Kugelman 2007 307; McDonnell 1997 308; Mercer 2003 466; Mercer 2006 1235; Rabe 2000 775; Ruangkit 2019 156} The p-value for interaction between subgroups was 0.26; I² = 27%.

Subgroup Comparison: Later (delayed) cord clamping compared to early cord clamping (based on

setting defined according to World Bank country classifications)

For the critical outcome of survival to discharge the evidence of high certainty from 9 trials involving 633 infants from high-income countries showed increased survival from later (delayed) clamping (≥30s) compared to early cord clamping (<30s) (RR 1.06, 95% CI 1.02 to 1.11; RD 0.06, 95% CI 0.02 to 0.10; NNTB 17, 95% CI 10 to 50; I² = 0%; 59/1000 more infants survived in the subgroup sampled from high-income countries when later cord clamping was intended than when early cord clamping was intended, [95% CI 20 more to 100 more per 1000]).{Backes 2016 35; Baenziger 2007 455; Duley 2018 F6; Kinmond 1993 172; Kugelman 2007 307; McDonnell 1997 308; Mercer 2003 466; Mercer 2006 1235; Oh 2011 S68} The evidence of low certainty from 5 trials involving 749 infants from low-and-middle-income countries could not exclude benefit or harm from later (delayed) clamping (≥30s) compared to early cord clamping (<30s) (RR 0.97, 95% CI 0.92 to 1.01; I² = 39%). {Armanian 2017 4909; Das 2018 496; Hofmeyr 1988 104; Hofmeyr 1993 110; Ruangkit 2019 156} The evidence of moderate certainty from 2 trials involving 1606 infants from mixed settings or from studies in which settings were not reported showed improved survival or no difference from later (delayed) clamping (≥30s) compared to early cord clamping (<30s) (RR 1.03, 95% CI 1.00 to 1.06; RD 0.03, 95% CI 0.00 to 0.05; NNTB 33, 95% CI 20 to >1,000; I² = 0%; 30/1000 more infants survived in the subgroup sampled from mixed settings when later cord clamping was intended than when early cord clamping was intended, [95% CI, 0 more to 50 more per 1000]). {Rabe 2000 775; Tarnow-Mordi 2017 2445} The p-value for interaction between subgroups was 0.01; I² = 77%.

Subgroup Comparison: Intended management in the late cord clamping group if resuscitation required - resuscitation before cord clamping vs clamping and cutting of cord followed by resuscitation.

For the critical outcome of survival to discharge the evidence of low certainty from 1 trial involving 270 infants with cord intact during respiratory support could not exclude benefit or harm from later (delayed) clamping (≥30s) compared to early cord clamping (<30s) (RR 1.07, 95% CI 0.99 to 1.15). {Duley 2018 F6} The evidence of moderate certainty from 5 trials involving 331 infants with cord cut prior to respiratory support could not exclude benefit or harm from later (delayed) clamping (≥30s) compared to early cord clamping (<30s) (RR 1.02, 95% CI 0.99 to 1.06; I² = 0%). {Hofmeyr 1993 110; Mercer 2003 466; Mercer 2006 1235; Rabe 2000 775; Ruangkit 2019 156} The evidence of moderate certainty from 10 trials involving 2174 infants from studies that were unclear about whether respiratory support was given with intact cord or cut cord could not exclude benefit or harm from later (delayed) clamping (≥ 30s) compared to early cord clamping (<30s) (RR 1.01, 95% CI 0.99 to 1.04; I² = 9%). {Armanian 2017 4909; Backes 2016 35; Baenziger 2007 455; Das 2018 496; Hofmeyr 1988 104; Kinmond 1993 172; Kugelman 2007 307; McDonnell 1997 308; Oh 2011 S68; Tarnow-Mordi 2017 2445} The p-value for interaction between subgroups was 0.43; I² = 0%.

Subgroup Comparison: Later (delayed) cord clamping compared to early cord clamping (based on duration of clamping (30-<60s; 60-120s; >120s)

For the critical outcome of survival to discharge the evidence of moderate certainty from 12 trials involving 1075 infants could not exclude benefit or harm from later (delayed) clamping (30-<60s) compared to early cord clamping (<30s) (RR 1.00, 95% CI 0.97 to 1.04; I² = 0%). {Armanian 2017 4909; Backes 2016 35; Das 2018 496; Hofmeyr 1993 110; Kinmond 1993 172; Kugelman 2007 307; McDonnell 1997 308; Mercer 2003 466; Mercer 2006 1235; Oh 2011 S68; Rabe 2000 775; Ruangkit 2019 156} The evidence of low certainty from 3 trials involving 1643 infants showed improved survival or no difference from later (delayed) clamping (60-120s) compared to early cord clamping (<30s) (RR 1.03, 95% CI 1.00 to 1.10; I² = 40%). {Baenziger 2007 455; Hofmeyr 1988 104; Tarnow-Mordi 2017 2445} The evidence of low certainty from 1 trial involving 270 infants could not exclude benefit or harm from later (delayed) clamping (>2 minutes) compared to early cord clamping (<30s) (RR 1.07, 95% CI 0.99 to 1.15). {Duley 2018 F6} The p-value for interaction between subgroups was 0.27; I² = 23%.

Treatment Recommendations

In infants born at less than 34+0 weeks’ gestational age who do not require immediate resuscitation after birth, we suggest deferring clamping the cord for at least 30 seconds (weak recommendation, low certainty of evidence).

In infants born at 28+0 to 33+6 weeks’ gestational age who do not require immediate resuscitation after birth, we suggest intact-cord milking as a reasonable alternative to deferring cord-clamping (weak recommendation, moderate certainty of evidence).

We suggest against intact cord milking for infants born at less than 28+0 weeks’ gestational age (weak recommendation; very low certainty of evidence).

In infants born at less than 34+0 weeks’ gestational age who require immediate resuscitation, there is insufficient evidence to make a recommendation with respect to cord management.

There is also insufficient evidence to make recommendations on cord management for maternal, fetal, or placental conditions that were considered exclusion criteria in many studies (in particular multiple fetuses, congenital anomalies, placental abnormalities, alloimmunization and/or fetal anemia, fetal compromise, and maternal illness). In these situations, we suggest individualized decisions based on severity of the condition and assessment of maternal and neonatal risk (weak recommendation; very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

Justification

Our suggestions/recommendations were based on several inferences that included the following:

1. The critical outcome of survival with later (delayed) clamping versus early clamping suggests benefit or neutrality from delaying clamping.
2. There are no significant differences in other critical outcomes for all comparisons.
3. There is improvement in important cardiovascular (blood pressure), therapeutic (inotropic support and/or transfusions), and hematological outcomes with later (delayed) clamping and/or intact-cord milking versus early clamping.
4. There are no significant differences between later (delayed) clamping and intact-cord milking (except for the presence of a “signal for harm” from intact-cord milking in infants born at <28 weeks’ gestational age in a single large study).
5. Only one small study was available for cut-cord milking.
6. Post hoc and subgroup analyses did not conflict with our suggestions or recommendations.
7. There is a paucity of evidence available to make recommendations for cord management in the preterm infant needing immediate resuscitation.

1: Survival with later (delayed) clamping versus early clamping

This analysis was based on the preference of ILCOR to use survival to discharge as the primary outcome rather than mortality. It showed that later (delayed) cord clamping for 30s or more in infants who do not require immediate resuscitation may have a survival benefit or make no difference when compared to early clamping (moderate certainty evidence, RR 1.02 and lower confidence interval just reaching 1.00). However, for mortality, the confidence intervals were wider and crossed 1.00.

When calculating confidence intervals around a relative risk, events that occur frequently (such as survival) will result in a narrower confidence interval than events that occur infrequently (in this case, mortality). In the included studies, survival was much more common than mortality. As a result, we anticipated that the confidence interval around survival and mortality would appear to have different precision. For transparency, we included the estimate for both outcomes. As a consequence of the wider confidence intervals, a post hoc analysis of mortality was unable to exclude benefit or harm (RR 0.80, 95% CI 0.63 to 1.02).

Our inference is that delayed cord clamping is safe and may be beneficial when compared to early clamping in infants born at <34 weeks who do not require immediate resuscitation. With a 2% increase in survival, the number needed to benefit is 50 (confidence interval 25 to >1000).

Overall, we interpret the data to suggest that later (delayed) cord clamping is likely to be safe and may have a benefit whether the outcome is described as survival or mortality.

2: No significant differences in other critical outcomes with any other comparison

With the exception of survival to discharge when later (delayed) clamping and early cord clamping were compared, no comparisons showed significant benefit or harm for any critical neonatal (or maternal) outcomes including severe intraventricular hemorrhage, chronic lung disease, necrotizing enterocolitis, neurodevelopment and maternal postpartum hemorrhage and infection.

3: Possible benefits in important outcomes with later (delayed) clamping or intact-cord milking versus early clamping.

Although there were no significant effects for all but one critical neonatal outcome, there were significant effects on some important outcomes. Later cord clamping and intact-cord milking resulted in fewer infants receiving inotropic support, higher hemoglobin and hematocrit by 24 hours and 7 days, and fewer infants receiving blood transfusions. There were no significant effects on use of respiratory support after birth or use of phototherapy.

Together with the potential benefit for the critical outcome of survival to discharge, they influenced us to suggest either later (delayed) cord clamping or intact-cord milking (in the case of infants born at 28 to <34 weeks’ gestational age) over early clamping, despite the lack of evidence for benefit for other critical outcomes.

4: Lack of significant differences between later (delayed) clamping and intact-cord milking

The analysis, with moderate certainty, showed no significant differences in outcomes between later (delayed) clamping and intact-cord milking.

We noted that one large clinical trial comparing intact-cord milking with later (delayed) cord clamping closed recruitment before completion because of an increased rate of severe intraventricular hemorrhage in infants born at <28 weeks gestational age who received intact-cord milking. {Katheria 2019 1877} However, meta-analysis of 4 trials involving 761 infants could not exclude benefit or harm from later (delayed) cord clamping compared to intact-cord milking (RR 0.60, 95% CI 0.32 to 1.12; I² = 23%). {Finn 2019 208; Katheria 2015 61; Katheria 2019 1877; Rabe 2011 205}

These findings influenced us to suggest intact-cord milking as a reasonable alternative to delayed cord clamping for infants born at ≥28 weeks’ gestational age.

5: Cut-cord milking

Only one study was included in this comparison (60 infants). Given the small numbers and nonsignificant findings, this comparison was not considered in our suggestions or recommendations. {Ram Mohan 2018 88}

6: Post hoc and subgroup analyses and GRADE evaluations

Subgroup analyses are exploratory and must be interpreted with caution.

The p-values for interaction did not suggest important influences of gestational age (p = 0.26 for interaction) or duration of deferral of cord clamping (p = 0.27 for interaction) on survival to discharge.

There was some evidence that the effect of later cord clamping on survival to discharge may be influenced by setting, with treatment effect being apparent only in studies performed in high-income countries (p= 0.01 for interaction; studies in high-income countries: RR 1.06, 95% CI 1.02 to 1.11; I² = 0%; studies in low-and-middle income countries: RR 0.97, 95% CI 0.92 to 1.01; I² = 39%). We caution that the difference in effect direction, size and significance between low-and-middle- and high- income countries could be a result of variation in resources available to individual participating hospitals within each country.

We do not have sufficient confidence in these findings to make separate recommendations for cord management by country income, by gestational age, or interval from birth to cord clamping (beyond 30s). We consider that the beneficial effect of delayed clamping in high-income countries is likely to be widely generalizable and should therefore be offered in all settings.

7: Cord management when immediate resuscitation is required

There is insufficient evidence to make any recommendation for cord management in preterm infants who require immediate resuscitation.

Overall justification:

In 2015, the ILCOR Neonatal Task Force stated: “We suggest delayed umbilical cord clamping for preterm infants not requiring immediate resuscitation after birth (weak recommendation, very-low-quality evidence). There is insufficient evidence to recommend an approach to cord clamping for preterm infants who receive resuscitation immediately after birth, because many infants who were at high risk of requiring resuscitation were excluded from or withdrawn from the studies.” An updated review of the evidence does not substantially change this recommendation.

As all critical outcomes but one (survival to discharge with later (delayed) cord clamping versus early clamping) did not show either benefit or harm, we drew our conclusions from that one outcome and the important neonatal outcomes of fewer infants receiving inotropic support, higher hemoglobin and hematocrit concentrations, fewer blood transfusions, and otherwise no evidence of harm for the mother or neonate. Limited subgroup analyses were non-contributory but did not contradict the results of critical or important comparisons.

Two previous systematic reviews {Fogarty 2018 1; Rabe 2019 CD003248} suggest benefits from later (delayed) clamping over early clamping in preterm infants for survival and other outcomes. The systematic review that informed this statement of Consensus on Science with Treatment Recommendations {Seidler 2021 in press} included an additional 11 studies, while removing studies with substantial late preterm populations. All three reviews are in general accord in suggesting that benefits outweigh harms of later (delayed) cord clamping in preterm infants resembling those enrolled in the included trials. A large systematic review derived from individual patient data is underway and may improve the certainty of evidence for some critical and important outcomes. {Seidler 2020 e034595}

It should be noted that in many studies, infants randomized to later (delayed) clamping may have received early clamping if they were thought to require resuscitation. For example, in the largest study {Tarnow-Mordi 2017 2445}, 19.5% (146 of 748) of infants in the later cord clamping group had non-adherence to their allocated study arm because of clinical concern about infant well-being. This is less likely to be the case with intact-cord milking, where the baby is more likely to have received a placental transfusion before the need for resuscitation was determined. We await the results of studies that are underway or planned that examine resuscitation with the cord intact, which may help determine the optimal umbilical cord management for infants at highest risk for mortality and neonatal morbidity.

With respect to the upper limit of duration of later (delayed) cord clamping, it should be noted that 20 out of 23 studies in comparison 1 intended clamping between 30 and 90 seconds, and 3 studies used a longer time frame of 120 seconds or more.

There is currently insufficient evidence to make a recommendation with respect to cord management for preterm infants who require immediate resuscitation. There is also uncertainty regarding the optimal cord management strategy in deliveries complicated by multiple pregnancies, infants who have major congenital abnormalities, fetal anemia, or other conditions that may impact maternal or fetal well-being at the time of birth. There is also uncertainty regarding optimal cord management in the setting of placental problems including abruption, incision through an anterior placenta, placenta previa, or abnormalities of placental vasculature or insertion. Until more data are available for specific situations such as these, decisions about cord management in the presence of maternal, placental, or fetal complications need to be individualized, based on severity of presentation and clinical assessment of risk to the mother or baby.

The uncertainty of the updated evidence (including its generalisability to infants at highest risk for adverse outcomes) influences the decision to continue to make a ‘weak’ recommendation.

Values, Preferences, and Task Force Insights: Values-preferences-and-task-force-insights

Knowledge Gaps

We identified the following knowledge gaps:

• There are insufficient data on long-term neurodevelopment outcomes, or any other post-discharge outcomes.
• There are insufficient data on cord management as a public health strategy to impact child health and development
• There are insufficient data for cord management among preterm infants who require immediate resuscitation.
• There are insufficient data for cord management among preterm infants with specific conditions, such as congenital heart or lung disease.
• The long-term neurodevelopmental outcomes of intact-cord milking in extremely preterm infants is uncertain.
• The optimal timing of cord clamping is not known, nor is how it should be determined with different maternal or fetal conditions.
• There are limited numbers of studies of cut-cord milking as a management strategy
• The impact of cord management on vertical transmission of infectious diseases is uncertain
• There is a need for widely agreed nomenclature and definition of different interventions including “delayed”, “deferred”, “later”, “optimal”, and “physiological” cord clamping, as well as “milking”, “stripping”, “intact-cord”, and “cut-cord”

Attachments

NLS-787-Preterm-Cord-Management-Et D-table

References

Preterm-cord-management-references