Cord management of non-vigorous term and late preterm (≥34 weeks’ gestation) infants: NLS 5050(b) TF SR

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
• The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees:
  • Peter Davis and Stuart Hooper are authors of the BabyDUCC study {Badurdeen 2022 e1004029} and were excluded from study selection and bias assessment
  • Anup Katheria and Walid El-Naggar are authors of the MINVI study {Katheria 2023 217.e1} and were excluded from study selection and bias assessment
  • Peter Davis, Susan Niemeyer and Walid El-Naggar were authors of the previous ILCOR systematic review on the topic of umbilical cord management at term and late preterm birth. {Gomersall 2021 e2020015404}

CoSTR Citation

Davis PG, El-Naggar W, Ibarra Rios D, Soraisham A, Fawke J, Niermeyer S, Katheria A, Hooper S, Ozawa Y. Cord management of non-vigorous term and late preterm (≥34 weeks’ gestation) infants Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Neonatal Life Support Task Force, 2024 xxx . Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

A systematic review conducted for ILCOR by the Cochrane Collaboration found substantial evidence to support a recommendation suggesting that deferred cord clamping for>60 seconds is the preferred strategy.{Wyckoff 2021 229} Because of a paucity of evidence at the time, this recommendation excluded an important group of infants at increased risk of death or long-term neurodevelopmental impairment i.e., those who are non-vigorous at birth. These infants appear apneic, hypotonic and pale and require early assistance, commonly in the form of assisted ventilation. Treatment of these infants has traditionally involved immediate clamping of the umbilical cord and transfer to a resuscitation trolley for the commencement of assisted ventilation. Based on an improved understanding of the physiological changes occurring at delivery, alternative strategies were developed. Therefore, this review was initiated following a priority list from the ILCOR NLS TF. The continuous evidence evaluation process for the creation of Consensus of Science and Treatment Recommendations (CoSTR) started with a systematic review (PROSPERO 2024 CRD42024562012) The review was led by a group of TF members.

Systematic Review

Webmaster to insert the Systematic Review citation and link to Pubmed using this format when it is available if published

Davis PG, El-Naggar W, Ibarra Rios D, Soraisham A, Fawke J, Niermeyer S, Katheria A, Hooper S, Ozawa Y, Weiner G, Liley HG; on behalf of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. Cord management of non-vigorous term and late preterm (≥34 weeks’ gestation) infants. To be submitted.

PICOST

Population: Term and late preterm infants (≥34 weeks’ gestation) who are not vigorous at birth

Intervention: Any cord management strategy designed to improve the fetal to neonatal cardiorespiratory transition:

• Deferred (delayed/later) cord clamping (DCC) for any time >60 seconds, before respiratory support (high flow, CPAP, intermittent positive pressure ventilation)

• Deferred (delayed/later) cord clamping (DCC) for any time >60 seconds with concurrent respiratory support (high flow, CPAP, intermittent positive pressure ventilation)

• Intact umbilical cord milking (UCM)

• Cut-cord umbilical cord milking (UCM)

Comparator: Immediate cord clamping (ICC), without cord milking or initiation of respiratory support at ≤60 seconds or as defined by the trialist (compared to the above interventions).

Between-intervention comparisons (e.g., DCC vs. UCM)

Outcomes:

Primary outcome: Neonatal mortality (critical)

Secondary outcomes:

Infant

• Moderate to severe neurodevelopmental impairments at 18-24 months (critical)

Any component of neurodevelopmental impairment at 18-24 months (critical)

a) cerebral palsy

b) significant mental developmental delay (Bayley Scales of Infant Development Mental Developmental Index < 70)

c) legal blindness as defined by WHO (< 20/200 visual acuity) or the author’s definition.

d) hearing deficit (aided or < 60 dB on audiometric testing)

Moderate to severe hypoxic ischemic encephalopathy (Sarnat 2 or greater) (critical)

Proportion of infants receiving cardiac compressions in DR (important)

Admission to a neonatal intensive care unit (important)

Jaundice: treated with exchange transfusion (critical) or phototherapy (important)

Peak hemoglobin or hematocrit concentration during hospital admission (important)

Anemia/iron deficiency as determined by hemoglobin or hematocrit levels at 4-6 months (important) or ferritin concentration at 4-6 months (important)

Unintended hypothermia within the first hour of life

Mother

Postpartum hemorrhage, estimated as at least 1000 mL (critical)

Postpartum infection (critical)

Death or severe morbidity (composite), major surgery, organ failure, intensive care

unit (ICU) admission, or as defined by trial authors (critical)

Outcomes ratings using the GRADE classifications of critical or important were decided

according to a consensus for international neonatal resuscitation guidelines.{Strand 2020 }

Study Design: Randomized controlled trials (RCTs) and nonrandomized studies (non-RCTs,

interrupted time series, controlled before-and-after studies, and cohort studies) were

eligible for inclusion. Case series, case reports, animal studies and unpublished studies

(conference abstracts, trial protocols) were excluded.

PROSPERO Registration CRD42024562012

Risk of Bias:

We used the GRADE approach {Guyatt 2008 924} to determine the certainty of evidence for each outcome deemed critical or important with the relevant risk of bias instrument: Cochrane risk of bias tool 2 for RCTs. {Sterne 2019 l4898}

Consensus on Science

Two literature searches were conducted using Medline (Ovid and PubMed), CINAHL, Embase and Cochrane CENTRAL, one for randomized controlled trials since the previous search, {Gomersall 2021 e2020015404} and the other for non-randomized trials across all dates. A total of 1016 articles were retrieved in the RCT search, of which four were considered eligible. {Andersson 2019 15, Badurdeen 2022 e1004029, Katheria 2023 217.e1, Raina 2023 54} Two included studies subsequently published prespecified longer term outcomes and these were also included. {Isacson 2021 465, Katheria 2024 e2416870} Two interventions were identified, intact-cord milking and intact cord resuscitation. These were analyzed separately.

The detailed search strategy is explained in the Appendix

A total of 771 non-randomized studies were screened, of which two were considered eligible. {Blank 2018 1, Lefebvre 2017 20}

Randomized trials

Intact umbilical cord milking (I-UCM) compared to early cord clamping (ECC)

One eligible trial, with follow-up at two years of age was identified. {Katheria 2023 217.e1, Katheria 2024 e2416870} This study was a cluster randomized crossover study comparing I-UCM with ECC within 60 seconds of birth in 1730 infants born at ≥35 weeks’ gestation. Infants were eligible if in the first 15 seconds after birth, their obstetrical provider noted that they had poor tone, pallor or lack of breathing despite stimulation. For infants allocated to cord milking, the provider milked 20 cm of cord over two seconds, repeating three additional times. The median (IQR) clamping time was 29 (29-30) and 20 (10-30) in the cord milking and early clamping groups respectively.

Where the authors reported analyses accounting for the cluster-randomized study design as modelled odds ratios (ORs) or modelled mean differences (MD), these are used. Otherwise, unadjusted risk ratios (RRs) and risk differences (RDs) are reported.

For the critical primary outcome of mortality, clinical benefit or harm could not be excluded, (RR 0.11, 95% CI 0.01 to 2.01), low certainty evidence (downgraded for imprecision) from one clinical trial including 1730 participants. Rates of mortality were very low (4/1730), all occurred in the early cord clamping group. {Katheria 2023 217.e1}

For the critical outcome of moderate-to-severe encephalopathy, there was possible clinical benefit for I-UCM [anticipated absolute risk difference 15 fewer per thousand (22 fewer to 1 fewer)], moderate certainty evidence from 1634 infants included in one RCT. {Katheria 2023 217.e1} This was associated with a reduction in the rate of infants receiving therapeutic hypothermia in the cord milking group (an outcome included post hoc).

For the important outcome of admission to NICU, clinical benefit or harm could not be excluded, moderate certainty evidence, modelled OR 0.69 (0.14, 1.14) from one RCT including 1730 infants. {Katheria 2023 217.e1}

For the important outcome of hemoglobin at 24 hours of age, there was possible clinical benefit for intact cord milking [modelled mean difference 0.7g/L (0.3 higher to 1.1 higher)] moderate certainty evidence from one RCT including 1730 infants. {Katheria 2023 217.e1}

For the critical outcome of survival with typical development, clinical benefit or harm could not be excluded, [modelled OR 0.76 (0.54 to 1.08)] low certainty evidence from one RCT from which follow-up results were available for 971 of 1730 infants (56%). {Katheria 2024 e2416870}

For the important outcome of rate of cardiac compressions, clinical benefit or harm could not be excluded, [RR 1.27 (0.47 to 3.38)] low certainty evidence from one RCT including 1730 infants. {Katheria 2023 217.e1}

For the important outcome of jaundice treated with phototherapy, clinical benefit or harm could not be excluded, [RR 1.16 (0.87 to 1.54)] low certainty evidence from one RCT for which this outcome was available for 1219 of 1730 infants (70.6%)

Intact cord resuscitation

Three eligible studies were included. {Andersson 2019 15, Badurdeen 2022 e1004029, Raina 2023 54} One had two-year follow-up data available. {Isacson 2021 465} In two studies, the intervention group received respiratory support if required with the umbilical cord intact, aiming for at least 180 seconds before cord clamping.{Andersson 2019 15}, {Raina 2023 54} In the third, infants in the intervention group had umbilical cord clamping deferred until ≥2 minutes after birth and until ≥60 seconds after change in color of a carbon dioxide detector placed between the face mask and T-Piece. {Badurdeen 2022 e1004029}

For the critical primary outcome of mortality (in hospital), clinical benefit or harm could not be excluded (Relative risk (RR); 0.39 (0.03, 4.73); very low certainty evidence from 516 infants in 3 RCTs. {Andersson 2019 15, Badurdeen 2022 e1004029, Raina 2023 54} The evidence was downgraded for imprecision and high risk of bias (evidence that randomization before birth may have altered management of enrolled infants in one trial).

For the critical outcome of moderate or severe hypoxic ischemic encephalopathy, clinical benefit or harm could not be excluded (RR 0.47 (0.11, 1.96); very low certainty evidence from 285 infants in 2 RCTs. {Badurdeen 2022 e1004029, Raina 2023 54} The evidence was downgraded for imprecision and evidence that randomization before birth may have altered management of enrolled infants in one trial.

For the important outcome of received cardiac compressions, clinical benefit or harm could not be excluded (RR 0.26 (0.01, 5.24); very low certainty evidence from 285 infants in 2 RCTs. The evidence was downgraded for imprecision. {Badurdeen 2022 e1004029, Raina 2023 54}

For the important outcome of admission to NICU, clinical benefit or harm could not be excluded (RR 0.88 (0.53, 1.48); very low certainty evidence from 516 infants in 3 RCTs. {Andersson 2019 15, Badurdeen 2022 e1004029, Raina 2023 54} The evidence was downgraded for imprecision and evidence that randomization before birth may have altered management of enrolled infants in one trial.

For the important outcome of neurodevelopment at two years of age, clinical benefit or harm could not be excluded, 138 infants in one RCT. {Isacson 2021 465} Analysis was not attempted because of low follow-up rates (59.7%), wide age range at time of assessment, instrument used (Indicators of Infant and Young Child Development which was still under development), and threshold used (15^th centile) to define high risk.

For the important outcome of jaundice treated with phototherapy, clinical benefit or harm could not be excluded (RR 1.30 (0.88, 1.90); low certainty evidence from 285 infants in 3 RCTs. {Andersson 2019 15, Badurdeen 2022 e1004029, Raina 2023 54} The evidence was downgraded for imprecision.

For the important outcome of maternal postpartum haemorrhage (>1L), clinical benefit or harm could not be excluded (RR 0.95 (0.29, 3.12); low certainty evidence from 123 infants in 1RCT. {Badurdeen 2022 e1004029} The evidence was downgraded for imprecision.

Non-randomized trials

Intact cord resuscitation

Based on the prespecified PICOST criteria, only two studies were included. {Blank 2018 1, Lefebvre 2017 20} Both were small feasibility studies.

Blank et al examined the feasibility of the Baby-Directed Umbilical Cord Clamping (Baby-DUCC) technique (feasibility of monitoring and providing respiratory support prior to cord clamping, until the physiology endpoint is reached- primary outcome) in infants ≥ 32 weeks’ gestation. Vigorous infants (n=32) received deferred cord clamping (DCC) for ≥ 2 min while non-vigorous infants (n=12) received cord clamping ≥ 60 sec after respiratory support was initiated and gas exchange was confirmed (exhaled CO₂ detection). Uterotonic medication was administered after cord clamping. Eleven non-vigorous infants completed the study protocol. The median time of DCC was 138 seconds in non-vigorous infants. All heart rate values were >100 bpm by 80 sec after birth. None of the infants received intubation or chest compression. Except for the time to first cry which was longer in the non-vigorous infants, there were no statistically significant differences in Apgar scores, body temperature, admission to nursery or maternal blood loss after Baby-DUCC in the non-vigorous infants compared to DCC in vigorous infants, very low certainty evidence downgraded for risk of bias and very serious imprecision and indirectness. Although the study doesn’t provide evidence for clinical benefits from Baby-DUCC, the authors concluded that the approach was feasible in both vaginal and cesarean births.

The second study was a single-center prospective feasibility study that compared intact cord resuscitation (ICR), including intubation and assisted ventilation until cardiorespiratory stabilization, in 20 infants with congenital diaphragmatic hernia (CDH) to 20 CDH historical controls who received immediate cord clamping (ICC) before intubation and resuscitation.{Lefebvre 2017 20} Uterotonic medication was administered after cord clamping. ICR was achieved without significant increase in maternal blood loss or neonatal adverse events. Apgar scores, blood gases in the first hour, mean blood pressure and hematocrit concentration were significantly higher in the ICR group than the ICC group. Mean body temperature on admission to NICU was low (35.3C and 35.7C) but not significantly different between the two groups. Chest compression, epinephrine administration, pre- and post-ductal SpO₂, duration of supplemental O₂, duration of mechanical ventilation, extracorporeal membrane oxygenation (ECMO), survival to discharge and age at discharge home were not significantly different between ICR and ICC group, very low certainty evidence downgraded for risk of bias and very serious imprecision and indirectness.

It is worth noting that one of the reviewed studies reported that stimulation of non-crying neonates with the cord intact (n=671) resulted in increased rate of breathing (81% vs. 69%, p < 0.01), decreased use of bag and mask ventilation (18% vs. 32%, p <0.01), and fewer Apgar scores ≤ 3 (8% vs. 11%, p <01) compared to those who were stimulated after cord clamping (n= 1892). Neonates with intact cords had 84% increased odds of spontaneous breathing compared with those with cord clamped (adjusted OR, 1.84; 95% CI:1.48 to 2.29). {Kc 2021 e001207} The study was excluded from our review because the intervention was stimulation rather than cord management.

Treatment Recommendations

Only evidence from RCTs was used to derive treatment recommendations because of the low numbers of infants recruited and very low certainty of evidence from the non-randomized trials.

Intact cord milking

In term and late preterm infants who remain non-vigorous despite stimulation, we suggest intact cord milking in preference to early cord clamping (weak recommendation, low certainty evidence).

Intact cord resuscitation

There is currently insufficient evidence to recommend either for or against intact cord resuscitation for term and late preterm infants who are non-vigorous at birth (weak recommendation, low certainty evidence).

We refer to the following treatment recommendation in relation to tactile stimulation and suggest that this should apply immediately after birth regardless of the method of umbilical cord management:

We suggest it is reasonable to apply tactile stimulation in addition to routine handling with measures to maintain temperature in newborn infants with absent, intermittent, or shallow respirations during resuscitation immediately after birth (weak recommendation, with very low certainty due to risk of bias, indirectness, and imprecision). Tactile stimulation should not delay the initiation of positive pressure ventilation for newborns who continue to have absent, intermittent, or shallow respirations after birth.{Wyckoff 2022 }

Justification and Evidence to Decision Framework Highlights

Intact cord milking:

Certainty of evidence was low to moderate for most outcomes (downgraded for imprecision); although large by neonatal standards the included trial did not reach optimal information size for any outcome. Evidence relating to long-term follow-up was of low certainty due to follow-up rates <90% and imprecision.

The balance of effects favors cord milking as there is no evidence of short-term or long-term harm and some evidence of benefit from this approach. A single, large cluster randomized trial (n=1730) provided moderate certainty evidence of a benefit in terms of a reduction in the rate of moderate-to-severe hypoxic ischemic encephalopathy. The choice of a weak recommendation based on low quality evidence was influenced by the lack of replication of evidence obtained from the single published trial. Implementation of its results should be restricted to infants similar to those enrolled in the trial i.e. those with poor tone, pallor or lack of breathing despite stimulation in the first 15 seconds after birth. Likewise, the protocol used in the trial should be followed i.e. 20 cm of cord milked over two seconds, repeating three additional times.

The practice of stimulation of the infant before implementing a cord management strategy used in the included study {Katheria 2023 217.e1} is supported by evidence from a systematic review {Guinsburg 2022 10.1542/peds.2021-055067} and an observational study.{Kc 2021 e001207}

Cord milking does not require additional equipment or manpower.

Quantitating the cost effectiveness of the intervention is difficult because no economic outcomes are reported. However, it seems likely that the benefits experienced by infants undergoing the intervention and the lack of additional costs for the technique mean that cost effectiveness probably favors cord milking. The reduction of rates of moderate-to-severe hypoxic ischemic encephalopathy appears to translate into a reduction in the need for therapeutic hypothermia with its attendant additional staffing and equipment costs.

Intact cord resuscitation:

The certainty of evidence for neonatal outcomes is low to very low due to 1) the relatively small sample sizes of the three included studies, which fall well below optimal sample size for all outcomes and 2) randomization before birth potentially leading to infants in the two allocated groups having different baseline risks of poor outcome in one study. The allocated intervention was followed in <50% in the intact cord group and 100% in the early cord clamping group in one study. {Andersson 2019 15}

Resuscitation of babies still attached to the umbilical cord can be done using a variety of techniques. Some centers use a purpose-built table to allow operators to resuscitate the baby close to the mother on a stable base and with the provision of warmth. They may be used for vaginal or caesarean section deliveries. These add considerable cost to that of conventional resuscitation equipment. Less expensive arrangements may be used, particularly for vaginal deliveries where strict asepsis is less critical.

Quantitating the cost effectiveness of the intervention is difficult because no economic outcomes are reported. Since there were no important benefits of the intervention demonstrated, cost effectiveness is assumed to be greater in the less expensive control group.

Some centers in the developed world are currently practicing intact cord resuscitation, many with purpose-built resuscitation trolleys. They may wish to continue to use this technique based on the physiological benefits demonstrated in studies performed in animal models. Other centers will await more robust evidence supporting or refuting this approach.

Further evidence is required to justify widespread use of intact cord resuscitation. If proven safe and effective, more work is required to ascertain the range of equipment that should be used to enable its practice outside the context of a clinical trial.

Knowledge Gaps

• Large multicenter RCTs evaluating both intact cord milking and intact cord resuscitation are required
• High quality follow-up studies with formal assessment of cognition, motor development, hearing and vision are required
• Comparison of different devices to support resuscitation with an intact cord should be undertaken
• Economic analyses are required, especially to determine the feasibility of providing resuscitation with an intact cord in resource limited settings
• Other techniques to facilitate placental transfusion including cut cord milking should be tested in adequately powered RCTs

ETD summary table: NLS 5050b Umbilical cord management non vigorous term TF Sys Rev Et D1; NLS 5050b Umbilical cord management non vigorous term TF Sys Rev 2024 Et D2

References

Andersson O, Rana N, Ewald U, Malqvist M, Stripple G, Basnet O, et al. Intact cord resuscitation versus early cord clamping in the treatment of depressed newborn infants during the first 10 minutes of birth (Nepcord III) - a randomized clinical trial. Maternal health, neonatology and perinatology. 2019;515.

Badurdeen S, Davis PG, Hooper SB, Donath S, Santomartino GA, Heng A, et al. Physiologically based cord clamping for infants ≥32+0 weeks gestation: A randomised clinical trial and reference percentiles for heart rate and oxygen saturation for infants ≥35+0 weeks gestation. PLoS Medicine. 2022;19(6).

Blank DA, Badurdeen S, Omar FKC, Jacobs SE, Thio M, Dawson JA, et al. Baby-directed umbilical cord clamping: A feasibility study. Resuscitation. 2018;1311-7.

Gomersall J, Berber S, Middleton P, McDonald SJ, Niermeyer S, El-Naggar W, et al. Umbilical Cord Management at Term and Late Preterm Birth: A Meta-analysis. Pediatrics. 2021;147(3).

Guinsburg R, de Almeida MFB, Finan E, Perlman JM, Wyllie J, Liley HG, et al. Tactile Stimulation in Newborn Infants With Inadequate Respiration at Birth: A Systematic Review. Pediatrics. 2022;149(4).

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Bmj. 2008;336(7650)924-6.

Isacson M, Gurung R, Basnet O, Andersson O, Ashish KC. Neurodevelopmental outcomes of a randomised trial of intact cord resuscitation. Acta Paediatrica, International Journal of Paediatrics. 2021;110(2)465-472.

Katheria AC, Clark E, Yoder B, Schmölzer GM, Yan Law BH, El-Naggar W, et al. Umbilical cord milking in nonvigorous infants: a cluster-randomized crossover trial. American journal of obstetrics and gynecology. 2023;228(2)217.e1‐217.e14.

Katheria AC, El Ghormli L, Clark E, Yoder B, Schmolzer GM, Law BHY, et al. Two-Year Outcomes of Umbilical Cord Milking in Nonvigorous Infants: A Secondary Analysis of the MINVI Randomized Clinical Trial. JAMA network open. 2024;7(7)e2416870.

Katheria AC, El Ghormli L, Clark E, Yoder B, Schmölzer GM, Law BHY, et al. Two-Year Outcomes of Umbilical Cord Milking in Nonvigorous Infants: A Secondary Analysis of the MINVI Randomized Clinical Trial. JAMA Netw Open. 2024;7(7)e2416870.

Kc A, Budhathoki SS, Thapa J, Niermeyer S, Gurung R, Singhal N. Impact of stimulation among non-crying neonates with intact cord versus clamped cord on birth outcomes: observation study. BMJ Paediatr Open. 2021;5(1)e001207.

Lefebvre C, Rakza T, Weslinck N, Vaast P, Houfflin-Debarge V, Mur S, et al. Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH). Resuscitation. 2017;12020-25.

Raina JS, Chawla D, Jain S, Khurana S, Sehgal A, Rani S. Resuscitation with Intact Cord Versus Clamped Cord in Late Preterm and Term Neonates: A Randomized Controlled Trial. The Journal of pediatrics. 2023;25454-60.e4.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj. 2019;366l4898.

Strand ML, Simon WM, Wyllie J, Wyckoff MH, Weiner G. Consensus outcome rating for international neonatal resuscitation guidelines. Arch Dis Child Fetal Neonatal Ed. 2020;105(3)328-330.

Wyckoff MH, Greif R, Morley PT, Ng KC, Olasveengen TM, Singletary EM, et al. 2022 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces. Circulation. 2022;146(25)e483-e557.

Wyckoff MH, Singletary EM, Soar J, Olasveengen TM, Greif R, Liley HG, et al. 2021 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Neonatal Life Support; Education, Implementation, and Teams; First Aid Task Forces; and the COVID-19 Working Group. Resuscitation. 2021;169229-311.

Appendix: Search Strategy

• This is an update of this review.
• The searching for that review was done on July 26, 2019. Peter has confirmed he would like the RCT searches (Search 1) run back to Jan 2019.
• For the update, two searches were requested:
  • Rerun the previous RCT searches back to the previous search date
  • Make a version of the previous searches with added nonvigorous concept, and cohort studies/case series. Peter has confirmed to run these searches across all dates
• For the methods section of the new review these statements or something similar could be made:
  • Including the previous review PubMed has been searched for RCTs from 2018/06/01 to the present
  • The previous review's searches were translated directly to identify RCTs for this review. The only modification made was to the terms used to exclude animal studies for Embase, which were made more inclusive of potential studies

Search 1 for RCTs: umbilical cord + management + newborns + RCTs

Ovid MEDLINE ALL

(exp Umbilical Cord/ OR (cord or cords or umbilicus or umbilical or navel-string).mp.)

AND

(exp Constriction/ OR exp Ligation/ OR (clamp or clamping or clamped or milking or milked or stripping or stripped or ligation or ligature or constrict*).mp. OR ((cord or cords) adj3 management).mp. OR (DCC or ICC or ECC or LCC).ti,ab. OR exp Placental Circulation/ OR

((placental or placenta or placentofetal or placentofoetal) adj2 (transfusion* or circulation)).mp.)

AND

(exp infant, newborn/ OR (newborn* or new born or new borns or newly born or baby* or babies or infant or infants or infantile or infancy or neonat*).ti,ab.)

AND
(randomized controlled trial.pt. OR controlled clinical trial.pt. OR randomized.ab. OR placebo.ab. OR drug therapy.fs. OR randomly.ab. OR trial.ab. OR groups.ab.)

NOT (exp animals/ not humans.sh.)

AND (2019* or 2020* or 2021* or 2022* or 2023* or 2024*).dt.

PubMed

(“Umbilical Cord”[Mesh] OR cord[TW] OR cords[TW] OR umbilicus[TW] OR umbilical[TW] OR navelstring[TW])
AND

(“Constriction”[Mesh] OR “Ligation”[Mesh] OR clamp[TW] OR clamping[TW] OR clamped[TW] OR milking[TW] OR milked[TW] OR stripping[TW] OR stripped[TW] OR ligation[TW] OR ligature[TW] OR constrict*[TW] OR ((cord[TW] OR cords[TW]) AND management[TW]) OR DCC[TIAB] OR ICC[TIAB] OR ECC[TIAB] OR LCC[TIAB] OR “Placental Circulation”[Mesh] OR ((placental[TW] OR placenta[TW] OR placentofetal[TW] OR placentofoetal[TW]) AND (transfusion*[TW] OR circulation[TW])))
AND
(infant,newborn[MeSH] OR newborn*[TIAB] OR “new born”[TIAB] OR “new borns”[TIAB] OR “newly born”[TIAB] OR baby*[TIAB] OR babies[TIAB] OR infant[TIAB] OR infants[TIAB] OR infantile[TIAB] OR infancy[TIAB] OR neonat*[TIAB])
AND
(randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab])
NOT (animals[mh] NOT humans[mh])
AND 2019/01/01:2024/12/31 [crdt]

CINAHL (via EBSCOHost)

(cord or cords or umbilicus or umbilical or navel-string)
AND

(clamp or clamping or clamped or milking or milked or stripping or stripped or ligation or ligature or constrict* OR ((cord or cords) AND management) OR ((placental or placenta or placentofetal or placentofoetal) AND (transfusion* or circulation)))

AND

(infant or infants or infantile or infancy or newborn* or “new born” or “new borns” or “newly born” or neonat* or baby* or babies)

AND

(randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical

trials as topic OR randomly OR trial OR PT clinical trial)

AND EM 20190101-

Embase (via Embase.com)

('umbilical cord'/exp OR (cord OR cords OR umbilicus OR umbilical OR navel-string))

AND

(ligation/exp OR

(clamp OR clamping OR clamped OR milking OR milked OR stripping OR stripped OR ligation OR ligature OR constrict*) OR

'umbilical cord clamp'/exp OR

((cord OR cords ) NEAR/3 management) OR

(DCC OR ICC OR ECC OR LCC):ti,ab OR

'placenta circulation'/exp OR

((placental OR placenta OR placentofetal OR placentofoetal) NEAR/2 (transfusion* OR circulation)))

AND

(infant/exp OR (newborn* OR 'new born' OR 'new borns' OR 'newly born' OR baby* OR babies OR infant OR infants OR infantile OR infancy OR neonat*):ti,ab)

AND

('randomized controlled trial' OR 'controlled clinical trial' OR randomized OR placebo OR 'clinical trials as topic' OR randomly OR trial OR 'clinical trial' )

NOT (('animal experiment'/de OR animal/exp) NOT ('human experiment'/de OR 'human'/exp))
AND [01-01-2019]/sd

Cochrane CENTRAL (via the Cochrane Library)

([mh "Umbilical Cord"] OR cord:ti,ab,kw OR cords:ti,ab,kw OR umbilicus:ti,ab,kw OR umbilical:ti,ab,kw OR navelstring:ti,ab,kw)

AND

(

[mh Constriction] OR [mh Ligation] OR clamp:ti,ab,kw OR clamping:ti,ab,kw OR clamped:ti,ab,kw OR milking:ti,ab,kw OR milked:ti,ab,kw OR stripping:ti,ab,kw OR stripped:ti,ab,kw OR ligation:ti,ab,kw OR ligature:ti,ab,kw OR constrict*:ti,ab,kw OR

((cord:ti,ab,kw OR cords:ti,ab,kw) NEAR/4 management:ti,ab,kw) OR

DCC:ti,ab OR ICC:ti,ab OR ECC:ti,ab OR LCC:ti,ab OR [mh "Placental Circulation"] OR ((placental:ti,ab,kw OR placenta:ti,ab,kw OR placentofetal:ti,ab,kw OR placentofoetal:ti,ab,kw) NEAR/4 (transfusion*:ti,ab,kw OR circulation:ti,ab,kw))

)

AND

([mh "infant, newborn"] OR newborn*:ti,ab OR "new born":ti,ab OR "new borns":ti,ab OR "newly born":ti,ab OR baby*:ti,ab OR babies:ti,ab OR NICU:ti,ab OR infant:ti,ab OR infants:ti,ab OR infantile:ti,ab OR infancy:ti,ab OR neonat*:ti,ab)

Limited by 'Date added to CENTRAL trials database' to 01/01/2019 to 31/12/2024

Search 2 for cohort studies/case series: umbilical cord + management + newborns + nonvigorous + cohort studies/case series

Note: the terms used to identify cohort studies and case studies were based on the Scottish Intercollegiate Guidelines Network (SIGN) observational studies filter, MEDLINE version (SIGN, n.d.). Modifications were made based on this paper, these search terms, and the MEDLINE cohort, case-control, and case series strategy here.

Ovid MEDLINE ALL

(exp Umbilical Cord/ OR (cord or cords or umbilicus or umbilical or navel-string).mp.)

AND

(exp Constriction/ OR exp Ligation/ OR (clamp or clamping or clamped or milking or milked or stripping or stripped or ligation or ligature or constrict*).mp. OR ((cord or cords) adj3 management).mp. OR (DCC or ICC or ECC or LCC).ti,ab. OR exp Placental Circulation/ OR

((placental or placenta or placentofetal or placentofoetal) adj2 (transfusion* or circulation)).mp.)

AND

(exp infant, newborn/ OR (newborn* or new born or new borns or newly born or baby* or babies or infant or infants or infantile or infancy or neonat*).ti,ab.)

AND
("Epidemiologic studies"/ OR "Case Reports".pt. OR exp "case control studies"/ OR exp "cohort studies"/ OR "Observational Study".pt. OR "case control".tw. OR cohort.tw. OR "follow up stud*".tw. OR "observational stud*".tw. OR longitudinal.tw. OR retrospective.tw. OR prospective.tw. OR "cross sectional".tw. OR "Cross-sectional studies"/ OR "case series".tw. OR "case report*".tw. OR "case stud*".tw. OR "case presentation*".tw.)
AND
(nonvigorous.mp. OR non-vigorous.mp. OR depressed.mp. OR "requiring resuscitation".mp. OR resuscitated.mp. OR inactive.mp. OR atonic.mp. OR unresponsive.mp. OR nonresponsive.mp. OR non-responsive.mp. OR floppy.mp. OR hypotonic.mp. OR hypotonia.mp. OR non-reactive.mp. OR nonreactive.mp. OR "at risk".mp. OR "not breathing".mp. OR non-breathing.mp. OR "not crying".mp. OR non-crying.mp. OR "meconium stain*".mp. OR "meconium aspiration".mp. OR apnea.mp. OR apnoea.mp. OR asphyxia.mp. OR bradycardia.mp. OR

((low.mp. OR lower.mp. OR poor*.mp. OR weak.mp. OR decreased.mp.) AND ("apgar score*".mp. OR "heart rate".mp. OR "muscle tone".mp. OR "respiratory effort".mp.)))

NOT (exp animals/ NOT humans.sh.)

PubMed

(“Umbilical Cord”[Mesh] OR cord[TW] OR cords[TW] OR umbilicus[TW] OR umbilical[TW] OR navelstring[TW])
AND

(
“Constriction”[Mesh] OR “Ligation”[Mesh] OR clamp[TW] OR clamping[TW] OR clamped[TW] OR milking[TW] OR milked[TW] OR stripping[TW] OR stripped[TW] OR ligation[TW] OR ligature[TW] OR constrict*[TW] OR
((cord[TW] OR cords[TW]) AND management[TW]) OR
DCC[TIAB] OR ICC[TIAB] OR ECC[TIAB] OR LCC[TIAB] OR “Placental Circulation”[Mesh] OR ((placental[TW] OR placenta[TW] OR placentofetal[TW] OR placentofoetal[TW]) AND (transfusion*[TW] OR circulation[TW]))
)
AND
(infant, newborn[MeSH] OR newborn*[TIAB] OR “new born”[TIAB] OR “new borns”[TIAB] OR “newly born”[TIAB] OR baby*[TIAB] OR babies[TIAB] OR infant[TIAB] OR infants[TIAB] OR infantile[TIAB] OR infancy[TIAB] OR neonat*[TIAB])
AND
("Epidemiologic studies"[Mesh:NoExp] OR "Case Reports" [Publication Type] OR "case control studies"[Mesh] OR "cohort studies"[Mesh] OR "Observational Study" [Publication Type] OR "case control"[tiab] OR cohort[tiab] OR "follow up stud*"[tiab] OR "observational stud*"[tiab] OR longitudinal[tiab] OR retrospective[tiab] OR prospective[tiab] OR "cross sectional"[tiab] OR "Cross-sectional studies"[Mesh:NoExp] OR "case series"[tiab] OR "case report*"[tiab] OR "case stud*"[tiab] OR "case presentation*"[tiab])

AND
(nonvigorous[TW] OR non-vigorous[TW] OR depressed[TW] OR “requiring resuscitation” [TW] OR resuscitated[TW] OR inactive[TW] OR atonic[TW] OR unresponsive[TW] OR nonresponsive[TW] OR non-responsive[TW] OR floppy[TW] OR hypotonic[TW] OR hypotonia[TW] OR non-reactive[TW] OR nonreactive[TW] OR "at risk"[TW] OR "not breathing"[TW] OR "non-breathing"[TW] OR "not crying"[TW] OR "non-crying"[TW] OR "meconium stain*"[TW] OR "meconium aspiration"[TW] OR apnea[TW] OR apnoea[TW] OR asphyxia[TW] OR bradycardia[TW] OR
((low[TW] OR lower[TW] OR poor*[TW] OR weak[TW] OR decreased[TW]) AND ("apgar score*"[TW] OR "heart rate"[TW] OR "muscle tone"[TW] OR "respiratory effort"[TW])))

NOT (animals[mh] NOT humans[mh])

CINAHL (via EBSCOhost)

(cord or cords or umbilicus or umbilical or navel-string)
AND

(clamp or clamping or clamped or milking or milked or stripping or stripped or ligation or ligature or constrict* OR ((cord or cords) AND management) OR ((placental or placenta or placentofetal or placentofoetal) AND (transfusion* or circulation)))

AND

(infant or infants or infantile or infancy or newborn* or “new born” or “new borns” or “newly born” or neonat* or baby* or babies)

AND

(MH "Case Studies" OR MH "Epidemiological Research" OR MH "Case Control Studies+" OR MH "Prospective Studies+" OR PT "Case Study" OR MH "Correlational Studies" OR TI "case control" OR AB "case control" OR TI cohort OR AB cohort OR TI "follow up stud*" OR AB "follow up stud*" OR TI "observational stud*" OR AB "observational stud*" OR TI longitudinal OR AB longitudinal OR TI retrospective OR AB retrospective OR TI prospective OR AB prospective OR TI "cross sectional" OR AB "cross sectional" OR MH "Cross Sectional Studies" OR TI "case series" OR AB "case series" OR TI "case report*" OR AB "case report*" OR TI "case stud*" OR AB "case stud*" OR TI "case presentation*" OR AB "case presentation*")
AND
(nonvigorous OR non-vigorous OR depressed OR "requiring resuscitation" OR resuscitated OR inactive OR atonic OR unresponsive OR nonresponsive OR non-responsive OR floppy OR hypotonic OR hypotonia OR non-reactive OR nonreactive OR "at risk" OR "not breathing" OR non-breathing OR "not crying" OR non-crying OR "meconium stain*" OR "meconium aspiration" OR apnea OR apnoea OR asphyxia OR bradycardia OR
((low OR lower OR poor* OR weak OR decreased) AND ("apgar score*" OR "heart rate" OR "muscle tone" OR "respiratory effort")))

Embase (via Embase.com)
('umbilical cord'/exp OR (cord OR cords OR umbilicus OR umbilical OR navel-string))
AND
(ligation/exp OR
(clamp OR clamping OR clamped OR milking OR milked OR stripping OR stripped OR ligation OR ligature OR constrict*) OR
'umbilical cord clamp'/exp OR
((cord OR cords ) NEAR/3 management) OR
(DCC OR ICC OR ECC OR LCC):ti,ab OR
'placenta circulation'/exp OR
((placental OR placenta OR placentofetal OR placentofoetal) NEAR/2 (transfusion* OR circulation)))
AND
(infant/exp OR (newborn* OR 'new born' OR 'new borns' OR 'newly born' OR baby* OR babies OR infant OR infants OR infantile OR infancy OR neonat*):ti,ab)
AND
('case control study'/exp OR 'cohort analysis'/exp OR 'observational study'/exp OR 'panel study'/exp OR 'case report'/exp OR 'case study'/exp OR 'prospective study'/exp OR 'retrospective study'/exp OR 'case control':ti,ab OR cohort:ti,ab OR 'follow up stud*':ti,ab OR 'observational stud*':ti,ab OR longitudinal:ti,ab OR retrospective:ti,ab OR prospective:ti,ab OR 'cross sectional':ti,ab OR 'cross-sectional study'/exp OR 'case series':ti,ab OR 'case report*':ti,ab OR 'case stud*':ti,ab OR 'case presentation*':ti,ab)

AND

(nonvigorous OR non-vigorous OR depressed OR 'requiring resuscitation' OR resuscitated OR inactive OR atonic OR unresponsive OR nonresponsive OR non-responsive OR floppy OR hypotonic OR hypotonia OR non-reactive OR nonreactive OR 'at risk' OR 'not breathing' OR non-breathing OR 'not crying' OR non-crying OR 'meconium stain*' OR 'meconium aspiration' OR apnea OR apnoea OR asphyxia OR bradycardia OR

((low OR lower OR poor* OR weak OR decreased) AND ('apgar score*' OR 'heart rate' OR 'muscle tone' OR 'respiratory effort')))

NOT (('animal experiment'/de OR animal/exp) NOT ('human experiment'/de OR 'human'/exp))

Cochrane CENTRAL (via the Cochrane Library)

As search 2 is intended to find cohort and case studies, CENTRAL was not searched as it is a database of controlled trials