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Guideline No. 424: Umbilical Cord Management in Preterm and Term Infants

      Abstract

      Objective

      To assess the impact of deferred (delayed) cord clamping (DCC) and umbilical cord milking in singleton and twin gestations on maternal and infant mortality and morbidity.

      Target Population

      People who are pregnant with preterm or term singletons or twins.

      Benefits, Harms, and Costs

      In preterm singletons, DCC for (ideally) 60 to 120 seconds, but at least for 30 seconds, reduces infant risk of mortality and morbidity. DCC in preterm twins is associated with some benefits. In term singletons, DCC for 60 seconds improves hematological parameters. In very preterm infants, umbilical cord milking increases risk for intraventricular hemorrhage.

      Evidence

      Searches of Medline, PubMed, Embase, and the Cochrane Library from inception to March 2020 were undertaken using Medical Subject Heading (MeSH) terms and key words related to deferred cord clamping and umbilical cord milking. This document represents an abstraction of the evidence rather than a methodological review.

      Validation Methods

      The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations).

      Intended Users

      Maternity and newborn care providers.

      RECOMMENDATIONS

      • For ease of implementation, recommendations for preterm versus term infants have been kept distinct. Note that as the preterm period progresses, the risks of prematurity decrease substantially, such that the absolute benefits of deferred (delayed) cord clamping also decrease.
      • 1.
        Singletons:
        • a.
          In both preterm (<37 weeks) and extremely preterm (<28 weeks) singletons, deferred (delayed) cord clamping is recommended for 60 to 120 seconds because it decreases newborn mortality and morbidity and improves hematological outcomes after the newborn period. When cord clamping cannot be deferred for a full 60 to 120 seconds, then deferred (delayed) cord clamping for at least 30 seconds is superior to immediate clamping. Deferred (delayed) cord clamping should be performed with the infant at or below the level of the introitus or at the level of the cesarean incision (strong, high).
        • b.
          In term singletons, deferred (delayed) cord clamping is recommended for 60 seconds because it improves hematological outcomes at birth and past the newborn period. Deferred (delayed) cord clamping beyond 60 seconds increases the risk of hyperbilirubinemia requiring phototherapy. Deferred (delayed) cord clamping can be performed with the infant at or below the level of the introitus, or at the level of the cesarean incision (strong, high), or on the mother’s abdomen (conditional, low).
      • 2.
        Stabilization or resuscitation with an intact cord for longer durations in preterm and term infants is feasible for centres with appropriate experience and equipment, although larger trials are needed to understand benefits and risks (strong, moderate).
      • 3.
        For maintenance of temperature during deferred (delayed) cord clamping:
        • a.
          Preterm infants should be placed in warm towels, medical grade plastic bags, or medical grade plastic wrap to maintain temperature (strong, high).
        • b.
          Term infants can be placed in warm towels or on the mother’s abdomen (conditional, low).
      • 4.
        Twins:
        • a.
          In preterm twins, deferred (delayed) cord clamping is associated with some benefits and should be considered, except when contraindicated (conditional, low).
        • b.
          In term twins, deferred (delayed) cord clamping may be considered based on presumed extrapolation of benefits in term singletons, except when contraindicated (conditional, low).
        • c.
          The evidence regarding optimal duration of deferred (delayed) cord clamping in twins is insufficient. Deferred (delayed) cord clamping for 30 to 60 seconds can be considered (conditional, low).
        • d.
          When deferred (delayed) cord clamping is performed, not delaying delivery of the second twin is recommended (conditional, low).
      • 5.
        Uterotonic medications increase uterine tone to prevent postpartum hemorrhage:
        • a.
          In preterm pregnancies, due to concerns about a potential bolus of blood to preterm infants, it is recommended that intravenous uterotonic medications be administered after clamping the cord (conditional, low).
        • b.
          In term pregnancies, with lower risk for bolus effects of blood, lower benefits of deferred cord clamping, and higher risk for maternal postpartum hemorrhage, it is recommended that intravenous uterotonic medications be administered with delivery of the anterior shoulder of the final infant (conditional, low).
      • 6.
        Absolute contraindications to deferred (delayed) cord clamping are few, and include (but are not limited to) fetal hydrops, the need for immediate resuscitation of mother or infant (except in centres with appropriate experience and equipment), disrupted utero-placental circulation (e.g., bleeding vasa previas), and known twin-to-twin transfusion syndrome or twin anemia polycythemia sequence (strong, high).
      • 7.
        Relative contraindications to deferred (delayed) cord clamping are few but include (in term infants) risk factors for significant hyperbilirubinemia (e.g., significant polycythemia, severe intrauterine growth restriction, pregestational diabetes), and cases where maternal antibody titres are high or when the first infant in a pair of monochorionic twins is delivered. In all these circumstances, immediate cord clamping should be considered. (conditional, low).
      • 8.
        Cautions regarding deferred (delayed) cord clamping are few but include (in preterm infants) risk factors for significant hyperbilirubinemia (e.g., significant polycythemia, severe intrauterine growth restriction, and cases where maternal antibody titres are high or when the first infant in a pair of monochorionic twins is delivered. In all these circumstances, discussion with the newborn’s care providers regarding benefits and risks and the duration of deferred (delayed) cord clamping is encouraged. The infant’s gestational age should be taken into account, with consideration of deferral for 30 seconds (conditional, low).
      • 9.
        Umbilical cord milking:
        • a.
          Umbilical cord milking is not recommended in very preterm infants <32 weeks, due to increased risk for severe intraventricular hemorrhage (strong, moderate).
        • b.
          In preterm and term infants, deferred (delayed) cord clamping should be performed instead of umbilical cord milking (strong, high).

      Keywords

      Abbreviations:

      DCC (deferred (delayed) cord clamping), GA (gestational age), ICC (immediate cord clamping), IVH (intraventricular hemorrhage), IUGR (intrauterine growth restriction), NEC (necrotizing enterocolitis), RCT (randomized controlled trial), SGA (small for gestational age), TAPS (twin anemia polycythemia sequence), TTTS (twin-to-twin transfusion syndrome), UCM (umbilical cord milking)

      The Rationale for Umbilical Cord Management

      Best practices for umbilical cord management enhance the transfer of blood from placenta to newborn. Deferred (delayed) cord clamping (DCC) involves waiting before clamping the cord, while umbilical cord milking (UCM) involves squeezing cord blood toward the infant one or more times.
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      The term ‘deferred cord clamping’ better expresses a choice of practice, and is used instead of ‘delayed cord clamping’ (which suggests being late to act) in this statement. DCC and UCM help to increase blood volume as the preterm infant’s lungs expand during the transition to extrauterine life.
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      ,
      WHO. Guideline
      Delayed umbilical cord clamping for improved maternal and infant health and nutrition outcomes.
      Both practices enhance oxygenation, blood pressure, and hemoglobin, and reduce risk for ischemia during the switch from placental to pulmonary circulation.
      • Bhatt S.
      • Polglase G.R.
      • Wallace E.M.
      • et al.
      Ventilation before umbilical cord clamping improves the physiological transition at birth.
      ,
      • Katheria A.C.
      Neonatal resuscitation with an intact cord: Current and ongoing trials.
      It is the Society of Obstetrician and Gynaecologists of Canada (SOGC) policy to review the content 5 years after publication, at which time the document may be revised to reflect new evidence or the document may be archived.
      This clinical practice guideline was prepared by the authors and overseen by the SOGC Clinical Practice – Obstetrics Committee and the Canadian Paediatric Society (CPS)’s Fetus and Newborn Committee. It was reviewed by the Association of Ontario Midwives; the Canadian Anesthesiologists’ Society; the Canadian Association of Perinatal and Women’s Health Nurses; members of the College of Family Physicians of Canada, Advisory Committee on Family Practice and the Maternal and Newborn Care Member Interest Group; the CPS’ Community Paediatrics Committee; the SOGC’s Maternal Fetal Medicine Committee; the SOGC’s Guideline Management and Oversight Committee and approved by the SOGC’s Board of Directors and CPS’ Board of Directors.
      SOGC Clinical Practice – Obstetrics Committee (2021): Douglas Black (Chair), Krista Cassell, Mélina Castonguay, Cynthia Chan, Elissa Cohen, Gina Colbourne, Christine Dallaire, Kirsten Duckitt, Sebastian Hobson, Amy Metcalfe, J. Larry Reynolds, Debbie Robinson, Marie-Ève Roy-Lacroix, Kristen Simone, Katherine Tyndall
      CPS Fetus and Newborn Committee (2020-2021): Gabriel Altit, Nicole Anderson, Heidi Budden, Leonora Hendson, Souvik Mitra, Michael R. Narvey, Eugene Ng, Nicole Radziminski, Vibhuti Shah
      Radha Chari (SOGC Liaison), James Cummings (Committee on Fetus and Newborn, American Academy of Pediatrics Liaison), William Ehman (College of Family Physicians of Canada Liaison), Danica Hamilton (Canadian Association of Neonatal Nurses Liaison), Chloë Joynt (CPS Neonatal-Perinatal Medicine Section Executive Liaison), Chantal Nelson (Public Health Agency of Canada Liaison)
      Acknowledgements: The authors would like to thank Kristen Viaje, MD, Hamilton, ON for her assistance with systematic reviews of the literature and drafting of the Figure.
      Weeks Gestation Notation: The authors follow the World Health Organization’s notation on gestational age: the first day of the last menstrual period is day 0 (of week 0); therefore, days 0 to 6 correspond to completed week 0, days 7 to 13 correspond to completed week 1, etc.
      Disclosures: Statements were received from all authors. No relationships or activities that could involve a conflict of interest were declared. All authors have indicated that they meet the journal’s requirements for authorship.
      KEY MESSAGE
      • 1.
        Deferred cord clamping benefits most infants, especially preterm infants, and is recommended best practice in most cases. Deferred cord clamping is advised for 60 to 120 seconds with preterm infants, and for 60 seconds with term infants. Umbilical cord milking is not recommended for very preterm infants (<32 weeks).
      (En français : Directive clinique no 424 : Prise en charge du cordon ombilical chez le nourrisson prématuré ou à terme)
      The English document is the original version. In the event of any discrepancy between the English and French content, the English version prevails.
      DEFINITIONS
      Preterm: ≤ 37 weeks’ gestational age
      Very Preterm: < 32 weeks’ gestational age
      Extremely Preterm: < 28 weeks’ gestational age
      Research has established that preterm singletons randomized to DCC have lower rates of mortality and morbidity (including intraventricular hemorrhage [IVH]) than newborns who receive early cord clamping.
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      ,
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      Knowledge and practice of DCC are increasing in Canada, but a minority of eligible infants <32 weeks received DCC in 2018.
      • Beltempo M.
      • Shah P.
      • Yoon E.W.
      • et al.
      Annual Report Review Committee. Annual Report 2018 / Le Réseau Néonatal Canadien 2018 Rapport Annuel.
      This statement was developed jointly by obstetric and paediatric experts, based on current best evidence (Figure), and updates cord management recommendations made by the Fetus and Newborn Committee of the Canadian Paediatric Society (CPS) in a statement published in 2019.
      • Ryan M.
      • Lacaze-Masmonteil T.
      • Mohammad K.
      Canadian Paediatric Society, Fetus and Newborn Committee. Neuroprotection from acute brain injury in preterm infants.
      Guidance includes maternal outcomes, contraindications, and facilitators to improve implementation of DCC and UCM for all infants—but especially preterm infants—in Canada.
      Figure thumbnail gr1
      FigureFlow chart for approach to deferred cord clamping
      Note: When DCC is performed with twins, it is suggested that the following 4 individuals be identified: 1) receiving Twin A; 2) monitoring status of Twin A and clamping cord; 3) delivering Twin B; 4) monitoring status of Twin B and clamping cord.
      aExcept in centres with appropriate experience and equipment.
      DCC: deferred cord clamping; ICC: immediate cord clamping; IV: intravenous; IM: Intramuscular; TTTS: twin-to-twin transfusion syndrome; TAPS: twin anemia polycythemia sequence.

      Method and approach

      A literature search was conducted to capture systematic randomized control trials (RCTs), reviews of RCTs, and observational studies. Searches of Medline, PubMed, Embase and the Cochrane Library from inception to March 2020 were undertaken using Medical Subject Heading (MeSH) terms and key words related to deferred/delayed cord clamping and umbilical cord milking. Guidance is informed by: 1) the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Evidence to Decision framework;
      • Alonso-Coello P.
      • Oxman A.D.
      • Moberg J.
      • et al.
      GRADE Evidence to Decision (EtD) frameworks: A systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines.
      2) the Appraisal of Guidelines for Research and Evaluation II Instrument (AGREE II) approach;
      • Brouwer E.
      • Knol R.
      • Vernooij A.S.
      • et al.
      Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: A feasibility study.
      and 3) the AGREE-Recommendation Excellence (AGREE-REX) tool, which evaluates clinical applicability, values and preferences, and implementability.
      AGREE-REX Research Team
      The Appraisal of Guidelines Research and Evaluation—Recommendation EXcellence (AGREE-REX).

      Benefits of Delayed Cord Clamping

      Preterm Singleton Births

      In the newborn period

      DCC decreases mortality by approximately 30% in both extremely preterm infants (gestational age [GA] ≤28 weeks) and preterm infants overall. Two recent meta-analyses of RCTs found a relative risk (RR) of 0.70; 95% confidence interval (CI) 0.51–0.95 for extremely preterm infants,
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      and an RR of 0.73; 95% CI 0.54–0.98 for preterm infants overall.
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      Although the reduction in RR is similar for extremely preterm and all preterm infants, the risks of prematurity decrease substantially over the course of the preterm period. Thus, the absolute benefits of DCC also decrease.
      Also, DCC was found to significantly reduce morbidities, including IVH (RR 0.83; 95% CI 0.70–0.99),
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      and necrotizing enterocolitis (NEC) (RR 0.59; 95% CI 0.37–0.94).
      • Garg B.D.
      • Kabra N.S.
      • Bansal A.
      Role of delayed cord clamping in prevention of necrotizing enterocolitis in preterm neonates: A systematic review.
      Infants randomized to DCC had significantly higher mean arterial blood pressure
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      and hematocrit values
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      than those after ICC. DCC also significantly reduced the need for interventions such as blood transfusion (RR 0.66; 95% CI 0.50–0.86), and inotropic pressure support (RR 0.37; 95% CI 0.17–0.81).
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      The few adverse side effects with DCC include increased peak bilirubin (mean difference [MD] 4.43 umol/L; 95% CI 1.15–7.71 umol/L), and polycythemia in preterm infants overall (RR 2.65; 95% CI 1.61–4.37).
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      However, the need for exchange transfusion
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      or partial exchange transfusion
      • Brouwer E.
      • Knol R.
      • Vernooij A.S.
      • et al.
      Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: A feasibility study.
      was not significantly increased.
      DCC has not been associated with hypothermia, either in systematic reviews of randomized data
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      ,
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      or in Canadian observational data.
      • Beltempo M.
      • Shah P.
      • Yoon E.W.
      • et al.
      Annual Report Review Committee. Annual Report 2018 / Le Réseau Néonatal Canadien 2018 Rapport Annuel.

      Beyond the newborn period

      DCC’s benefits for singletons extend beyond the neonatal period. A recent meta-analysis of RCTs found that 6 to 10 weeks after preterm birth, DCC slightly increased hematocrit (MD 1.09; 95% CI 0.72–1.47) and serum ferritin levels as well (MD 0.38; 95% CI 0.01– 0.74).
      • Zhao Y.
      • Hou R.
      • Zhu X.
      • et al.
      Effects of delayed cord clamping on infants after neonatal period: A systematic review and meta-analysis.
      Children born <32 weeks GA who been randomized to DCC for ≥120 seconds (versus ICC) had a reduced risk of death or adverse neurodevelopmental outcomes at 2 years of age (composite outcome, RR 0.61; 95% CI 0.39– 0.96).
      • Armstrong-Buisseret L.
      • Powers K.
      • Dorling J.
      • et al.
      Randomised trial of cord clamping at very preterm birth: Outcomes at 2 years.

      Term Singleton births

      In the newborn period

      The prevalence of hematocrit <45% (study threshold for anemia) has been shown to be significantly lower in infants randomized to receive either 60 or 180 seconds of DCC versus 15 seconds. However, the prevalence of a hematocrit of >65% (study threshold for polycythemia) was significantly higher at 180 seconds (14.1%) than at 15 seconds (4.4%), but not significantly higher than at 60 seconds (5.9%).
      • Cernadas J.M.C.
      • Carroli G.
      • Pellegrini L.
      • et al.
      The effect of timing of cord clamping on neonatal venous hematocrit values and clinical outcome at term: A randomized, controlled trial.
      The prevalence of neonatal intensive care unit (NICU) admission following 15 seconds, 60 seconds, and 180 seconds of DCC was not significantly different (4.3%, 5.5%, and 8.7%, respectively).
      • Cernadas J.M.C.
      • Carroli G.
      • Pellegrini L.
      • et al.
      The effect of timing of cord clamping on neonatal venous hematocrit values and clinical outcome at term: A randomized, controlled trial.
      Most RCTs of term infants have focused on longer durations of DCC.
      • McDonald S.J.
      • Middleton P.
      • Dowswell T.
      • et al.
      Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.
      A meta-analysis of RCTs noted that term newborns who were randomized to receive DCC up to 60 seconds (versus for longer than 60 seconds, until cessation of cord pulsation) did not experience either improved mortality or morbidity, including NICU admission, while infants receiving DCC up to 60 seconds had slightly lower hemoglobin concentrations (MD –1.49 g/dL; 95% CI –1.78 to –1.21 g/dL) and significantly lower risk of jaundice requiring phototherapy (RR 0.62; 95% CI 0.41–0.96.
      • McDonald S.J.
      • Middleton P.
      • Dowswell T.
      • et al.
      Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.

      Beyond the newborn period

      In term singletons, the benefits of DCC beyond the newborn period are demonstrated almost exclusively in RCTs of DCC beyond 60 seconds. These trials have shown significantly improved hemoglobin, iron, ferritin, and transferrin saturation with lower rates of iron deficiency at a variety of time points between 4 to 12 months (RR 0.68; 95% CI 0.49–0.94, in a meta-analysis of 20 RCTs).
      • Zhao Y.
      • Hou R.
      • Zhu X.
      • et al.
      Effects of delayed cord clamping on infants after neonatal period: A systematic review and meta-analysis.
      At 4 years of age, children randomized to DCC (≥180 s vs. ICC) demonstrated better fine-motor skills and social development scores, although there was no difference in intelligence quotient (IQ) or for 15 other outcomes.
      • Andersson O.
      • Lindquist B.
      • Lindgren M.
      • et al.
      Effect of delayed cord clamping on neurodevelopment at 4 years of age: A randomized clinical trial.

      Preterm Twin Births

      In the newborn period

      There are limited data on cord management in preterm twins, with only 1 small RCT
      • Ruangkit C.
      • Bumrunphuet S.
      • Panburana P.
      • et al.
      A randomized controlled trial of immediate versus delayed umbilical cord clamping in multiple-birth infants born preterm.
      (80 twins, of whom 55 were monochorionic twins) and 2 cohort studies.
      • Chiruvolu A.
      • Tolia V.N.
      • Qin H.
      • et al.
      Effect of delayed cord clamping on very preterm infants.
      ,
      • Liu L.Y.
      • Yee L.M.
      Delayed cord clamping in preterm dichorionic twin gestations.
      One meta-analysis found that none of the four trials that included twins stratified outcomes on this basis.
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      A Canadian observational study found some benefits for the 624 twins in total who received DCC, compared with a greater number who received ICC.
      • Grabovac M.
      • Beltempo M.
      • Lodha A.
      • et al.
      Impact of deferred cord clamping in twins: Severe neurologic injury in twins born at <30 weeks of gestation.
      Although DCC was not associated with a difference in death or severe brain injury occurrence (aOR 1.07; 95% CI 0.78–1.47), it was associated with a decrease in need for transfusion (adjusted coefficient -0.49; 95% CI –0.86 to –0.12). DCC was also associated in this study with reduced need for delivery room intubation (aOR 0.53; 95% CI 0.42–0.68), mechanical ventilation (adjusted OR 0.51; 95% CI 0.39–0.67), and NICU length of stay, (adjusted coefficient –4.17; 95% CI 8.15 to –0.19)
      • Grabovac M.
      • Beltempo M.
      • Lodha A.
      • et al.
      Impact of deferred cord clamping in twins: Severe neurologic injury in twins born at <30 weeks of gestation.
      although these findings may relate more to stable infants at birth receiving DCC. In a cohort of twins <32 weeks GA, DCC was associated with significantly lower rates of red blood cell transfusion and surfactant use.
      • Chiruvolu A.
      • Tolia V.N.
      • Qin H.
      • et al.
      Effect of delayed cord clamping on very preterm infants.
      No studies stratified outcomes based on whether the twin pregnancies were monochorionic or dichorinonic, although most did not exclude monochorionic twins.
      • Ruangkit C.
      • Bumrunphuet S.
      • Panburana P.
      • et al.
      A randomized controlled trial of immediate versus delayed umbilical cord clamping in multiple-birth infants born preterm.
      • Chiruvolu A.
      • Tolia V.N.
      • Qin H.
      • et al.
      Effect of delayed cord clamping on very preterm infants.
      • Liu L.Y.
      • Yee L.M.
      Delayed cord clamping in preterm dichorionic twin gestations.
      • Grabovac M.
      • Beltempo M.
      • Lodha A.
      • et al.
      Impact of deferred cord clamping in twins: Severe neurologic injury in twins born at <30 weeks of gestation.

      Term twin births

      Studies of term twins either have not exclusively focused on twins or did not stratify the data on twins when they were included.
      • McDonald S.J.
      • Middleton P.
      • Dowswell T.
      • et al.
      Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.

      Performance of Umbilical Cord Management

      Administering Uterotonics

      Uterotonic medications increase uterine tone to prevent postpartum hemorrhage. They are given prophylactically because they are critical to decreasing maternal morbidity and mortality. However, for preterm infants, there are concerns that using IV uterotonics to prevent postpartum hemorrhage may result in either a bolus effect of transfusion
      • Yao A.C.
      • Hirvensalo M.
      • Lind J.
      Placental transfusion-rate and uterine contraction.
      or, conversely, decreased blood flow secondary to uterine contraction.
      • Bhatt S.
      • Polglase G.R.
      • Wallace E.M.
      • et al.
      Ventilation before umbilical cord clamping improves the physiological transition at birth.
      ,
      • Begley C.M.
      • Gyte G.M.
      • Devane D.
      • et al.
      Active versus expectant management for women in the third stage of labour.
      Little is known about the impact of uterotonic medications on the infant. One study from the 1960s found that without these medications, blood transfusion to the infant increased from being ∼25% complete at 15 seconds, to ∼50% at 60 seconds, and ∼fully complete at 2 to 3 minutes.
      • Yao A.C.
      • Hirvensalo M.
      • Lind J.
      Placental transfusion-rate and uterine contraction.
      The optimal timing to administer prophylactic uterotonics in relation to DCC is not yet clear, ranging in trials from after delivery of the anterior shoulder to after cord clamping.
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      ,
      • McDonald S.J.
      • Middleton P.
      • Dowswell T.
      • et al.
      Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.
      One meta-analysis noted that the timing to administer oxytocin by various routes had no significant effect on maternal outcomes, but data remain scant.
      • Soltani H.
      • Hutchon D.R.
      • Poulose T.A.
      Timing of prophylactic uterotonics for the third stage of labour after vaginal birth.
      Subgroup analyses from two meta-analyses based on whether uterotonics were administered before or after DCC
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      ,
      • McDonald S.J.
      • Middleton P.
      • Dowswell T.
      • et al.
      Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.
      found no significant difference in neonatal mortality or morbidity in preterm
      • Beltempo M.
      • Shah P.
      • Yoon E.W.
      • et al.
      Annual Report Review Committee. Annual Report 2018 / Le Réseau Néonatal Canadien 2018 Rapport Annuel.
      and term
      • Garg B.D.
      • Kabra N.S.
      • Bansal A.
      Role of delayed cord clamping in prevention of necrotizing enterocolitis in preterm neonates: A systematic review.
      infants, but this result was based on limited data.
      Given the potential risk to preterm infants of a bolus effect from transfusion and the lack of adequately powered evidence to suggest optimal timing, prophylactic IV uterotonic medications should be held until after cord clamping in preterm pregnancies.
      • Duley L.
      • Dorling J.
      • Pushpa-Rajah A.
      • et al.
      Randomised trial of cord clamping and initial stabilisation at very preterm birth.
      Drug monographs for uterotonics refer to almost immediate onset of action when administered intravenously. It is therefore recommended to hold the administration of uterotonics until after the cord is clamped in preterm pregnancies.
      Food and Drug Adminstrition (U.S.)
      Pitocin. Reference I.D. 3638684.
      Because the onset of intramuscular oxytocin is slower, it may be reasonable to administer this medication without delay or to withhold until cord clamping has occurred, if there is not significant hemorrhage or risk thereof.
      Food and Drug Adminstrition (U.S.)
      Pitocin. Reference I.D. 3638684.
      For term births, when risk for maternal postpartum hemorrhage is greater and the benefits of DCC and the risk of a bolus effect are less, uterotonics should not be deferred, but administered with the anterior shoulder of the final infant delivered.

      Duration of Delayed Cord Clamping

      Preterm Infants

      The optimal duration of DCC has not yet been determined, although it is most commonly performed for “at least 60 seconds”,
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      ,
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      and can range up to 180 seconds.
      • Ultee C.A.
      • van der Deure J.
      • Swart J.
      • et al.
      Delayed cord clamping in preterm infants delivered at 34–36 weeks’ gestation: A randomised controlled trial.
      In preterm infants, one recent Cochrane meta-analysis of 25 RCTs found that deferral ranged from 30 to 59 seconds (10 trials), 60 to 120 seconds (6 trials), greater than 120 seconds (3 trials), and mixed or unknown protocols in 6 trials.
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      For the few trials where DCC was longest, durations were described as beyond 120 seconds in 30 to 36 week GA infants,
      • Ranjit T.
      • Nesargi S.
      • Suman Rao P.N.
      • et al.
      Effect of early versus delayed cord clamping on hematological status of preterm infants at 6 wk of age.
      120 to 180 seconds in infants 29 to 42 weeks GA (mean 38 weeks GA),
      • Tiemersma S.
      • Heistein J.
      • Ruijne R.
      • et al.
      Delayed cord clamping in South African neonates with expected low birthweight: A randomised controlled trial.
      and 180 seconds in 34 to 36 week GA infants.
      • Ultee C.A.
      • van der Deure J.
      • Swart J.
      • et al.
      Delayed cord clamping in preterm infants delivered at 34–36 weeks’ gestation: A randomised controlled trial.
      Despite meta-analysis, an optimal duration for DCC could not be identified.
      Ongoing large trials will likely determine whether preterm infants requiring stabilization can benefit from longer durations before clamping. Small studies have demonstrated the feasibility of stabilizing preterm infants with an intact placental circulation for >4 minutes,
      • Brouwer E.
      • Knol R.
      • Vernooij A.S.
      • et al.
      Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: A feasibility study.
      along with similar outcomes on many parameters compared with DCC for 30 to 60 seconds. However, the longer time frame resulted in lower umbilical pH,
      • Knol R.
      • Brouwer E.
      • van den Akker T.
      • et al.
      Physiological-based cord clamping in very preterm infants—Randomised controlled trial on effectiveness of stabilisation.
      greater risk for hypothermia (48.6%), and much greater risk for hyperbilirubinemia requiring phototherapy (94.6%).
      • Brouwer E.
      • Knol R.
      • Vernooij A.S.
      • et al.
      Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: A feasibility study.

      Term Infants

      In one as meta-analysis of RCTs, term infants receiving DCC for up to 60 seconds (versus >60 seconds, until cord pulsation ceased) had a significantly lower risk of developing jaundice requiring phototherapy (RR 0.62; 95% CI 0.41–0.96).
      • McDonald S.J.
      • Middleton P.
      • Dowswell T.
      • et al.
      Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.
      For infants who requiring resuscitation, trials have established that providing resuscitation with an intact cord is feasible in both preterm
      • Brouwer E.
      • Knol R.
      • Vernooij A.S.
      • et al.
      Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: A feasibility study.
      ,
      • Pratesi S.
      • Montano S.
      • Ghirardello S.
      • et al.
      Placental Circulation Intact Trial (PCI-T) – Resuscitation with the placental circulation intact vs. cord milking for very preterm infants: A feasibility study.
      ,
      • Winter J.
      • Kattwinkel J.
      • Chisholm C.
      • et al.
      Ventilation of preterm infants during delayed cord clamping (VentFirst): A pilot study of feasibility and safety.
      and term
      • Blank D.A.
      • Badurdeen S.
      • Kamlin C.O.F.
      • et al.
      Baby-directed umbilical cord clamping: A feasibility study.
      infants. Oxygen saturation and heart rate improved significantly compared with ICC in a mix of late preterm and term infants experiencing respiratory depression at birth.
      • Andersson O.
      • Rana N.
      • Ewald U.
      • 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.
      Mean blood pressures and cerebral tissue oxygen saturation also improved when compared with infants who received DCC for 60 seconds without resuscitation on the cord.
      • Katheria A.C.
      • Brown M.K.
      • Faksh A.
      • et al.
      Delayed cord clamping in newborns born at term at risk for resuscitation: A feasibility randomized clinical trial.
      Larger trials of these findings are underway.

      Positioning of the Infant

      Due to low umbilical venous pressures, most trials have positioned the infant using gravity to enhance flow to the infant.
      • Bhatt S.
      • Polglase G.R.
      • Wallace E.M.
      • et al.
      Ventilation before umbilical cord clamping improves the physiological transition at birth.
      ,
      • Airey R.J.
      • Farrar D.
      • Duley L.
      Alternative positions for the baby at birth before clamping the umbilical cord.
      Studies have warned against elevating the infant, which can impede flow.
      • Yao A.C.
      • Lind J.
      Effect of gravity on placental transfusion.
      No trial has yet compared infant outcomes based on positioning.
      • Bhatt S.
      • Polglase G.R.
      • Wallace E.M.
      • et al.
      Ventilation before umbilical cord clamping improves the physiological transition at birth.
      ,
      • Airey R.J.
      • Farrar D.
      • Duley L.
      Alternative positions for the baby at birth before clamping the umbilical cord.

      Preterm Infants

      According to one Cochrane meta-analysis of 25 RCTs on DCC in preterm infants, most trials specified that DCC occurred with the infant at or below the level of the introitus or cesarean incision.
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      In another meta-analysis of 27 trials, subgroup analysis did not identify the best position, although numbers were limited.
      • Fogarty M.
      • Osborn D.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: A systematic review and meta-analysis.
      For maintenance of temperature, infants were placed in medical plastic bags, plastic wrap, or warm towels.
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      Preterm infants can be placed on a resuscitation trolley at the maternal bedside, with the cord intact.
      • Brouwer E.
      • Knol R.
      • Vernooij A.S.
      • et al.
      Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: A feasibility study.
      ,
      • Duley L.
      • Dorling J.
      • Pushpa-Rajah A.
      • et al.
      Randomised trial of cord clamping and initial stabilisation at very preterm birth.

      Term Infants

      In a meta-analysis of RCTs, the positioning of term infants during DCC varied from below the introitus to placenta level to on the mother’s abdomen, the last of which typically occurred with DCC ≥180 seconds.
      • McDonald S.J.
      • Middleton P.
      • Dowswell T.
      • et al.
      Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.
      No clear benefit emerged based on position.

      Mode of Birth

      The effectiveness of DCC after cesarean section has been questioned because uterine surgery can decrease placental transfusion, possibly due to reduced uterine tone.
      • Katheria A.
      • Hosono S.
      • El-Naggar W.
      A new wrinkle: Umbilical cord management (how, when, who).
      • Katheria A.C.
      • Truong G.
      • Cousins L.
      • Oshiro B.
      • Finer N.N.
      Umbilical cord milking versus delayed cord clamping in preterm infants.
      • Kleinberg F.
      • Dong L.
      • Phibbs R.H.
      Cesarean section prevents placenta-to-infant transfusion despite delayed cord clamping.
      However, tone is more likely to be an issue at term than in the preterm period. One study found that term infants delivered by cesarean section who received DCC did not experience significant reductions in residual placenta blood volume compared with those receiving ICC or delivered vaginally.
      • Kleinberg F.
      • Dong L.
      • Phibbs R.H.
      Cesarean section prevents placenta-to-infant transfusion despite delayed cord clamping.
      Nor did a meta-analysis of RCTs find subgroup differences in infant outcomes based on mode of birth in preterm infants, though data overall were scant.
      • Lee L.
      • Dy J.
      • Azzam H.
      Management of spontaneous labour at term in healthy women.

      Maternal Considerations

      There are very limited data on maternal outcomes. Cochrane meta-analyses found no significant differences in either transfusion need (in a single RCT including vaginal birth and cesarean section) or maternal blood loss (≥500 mL, in a single RCT of vaginal birth) after preterm DCC, compared with ICC
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      or term DCC for 60 seconds versus >60 seconds.
      • McDonald S.J.
      • Middleton P.
      • Dowswell T.
      • et al.
      Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.
      Data stratifying maternal outcomes by mode of birth are lacking. The same Cochrane review
      • Rabe H.
      • Gyte G.M.
      • Díaz-Rossello J.L.
      • et al.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      found a single RCT that focused on the effects of UCM on maternal blood loss ≥500 mL, but found no such events in either study arm.
      • Elimian A.
      • Goodman J.
      • Escobedo M.
      • et al.
      Immediate compared with delayed cord clamping in the preterm neonate: A randomized controlled trial.
      In twin gestations, there have been conflicting results regarding increased bleeding with DCC.
      • Liu L.Y.
      • Yee L.M.
      Delayed cord clamping in preterm dichorionic twin gestations.
      ,
      • Ruangkit C.
      • Leon M.
      • Hassen K.
      • et al.
      Maternal bleeding complications following early versus delayed umbilical cord clamping in multiple pregnancies.

      Contraindications to DCC

      Most infants should receive DCC. In the literature, absolute contraindications to DCC are few but have included the following: fetal hydrops,
      • Rabe H.
      • Wacker A.
      • Hülskamp G.
      • et al.
      A randomised controlled trial of delayed cord clamping in very low birth weight preterm infants.
      certain fetal anomalies (e.g., diaphragmatic hernia at term),
      • Dipak N.K.
      • Nanavat R.N.
      • Kabra N.K.
      • et al.
      Effect of delayed cord clamping on hematocrit, and thermal and hemodynamic stability in preterm neonates: A randomized controlled trial.
      need for immediate resuscitation of mother or infant
      • Rabe H.
      • Wacker A.
      • Hülskamp G.
      • et al.
      A randomised controlled trial of delayed cord clamping in very low birth weight preterm infants.
      (except in centres with appropriate experience and equipment to perform resuscitation with an intact cord), or disruption of the placental circulation (e.g., bleeding vasa previa or placenta previa, placental transection or abruption).
      • Dipak N.K.
      • Nanavat R.N.
      • Kabra N.K.
      • et al.
      Effect of delayed cord clamping on hematocrit, and thermal and hemodynamic stability in preterm neonates: A randomized controlled trial.
      ,
      • Mercer J.S.
      • McGrath M.M.
      • Hensman A.
      • et al.
      Immediate and delayed cord clamping in infants born between 24 and 32 weeks: A pilot randomized controlled trial.
      Two trials excluded known cases of twin-to-twin transfusion syndrome, and one excluded monochorionic twins.
      • Duley L.
      • Dorling J.
      • Pushpa-Rajah A.
      • et al.
      Randomised trial of cord clamping and initial stabilisation at very preterm birth.
      ,
      • Tarnow-Mordi W.
      • Morris J.
      • Kirby A.
      • et al.
      Delayed versus immediate cord clamping in preterm infants.
      Some, but not all trials excluded cases of IUGR, likely due to an association with polycythemia.
      • Elimian A.
      • Goodman J.
      • Escobedo M.
      • et al.
      Immediate compared with delayed cord clamping in the preterm neonate: A randomized controlled trial.
      ,
      • Kramer M.S.
      • Olivier M.
      • McLean F.H.
      • et al.
      Impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcome.
      • Snijders R.
      • Abbas A.
      • Melby O.
      • et al.
      Fetal plasma erythropoietin concentration in severe growth retardation.
      • Deorari A.
      • Agarwal R.
      • Paul V.K.
      Management of infants with intra-uterine growth restriction.
      Relative contraindications to DCC are few, but include (in term infants) risk factors for significant hyperbilirubinemia (e.g., polycythemia, severe IUGR, pre-gestational diabetes), and cases where maternal antibody titres are high or when the first infant in a pair of monochorionic twins is delivered. In all these circumstances, immediate cord clamping should be considered.
      Recent Canadian data for SGA infants <10% and <33 weeks GA have found DCC associated with reduced mortality and severe morbidity (aOR mortality or severe morbidity 0.60; 95% CI 0.42–0.86), intubation at birth (aOR 0.29; 95% CI 0.16–0.52), inotropic support (aOR 0.47; 95% CI 0.23–0.97), IVH (aOR 0.70; 95% CI 0.52–0.92), and bronchopulmonary dysplasia (aOR 0.61; 95% CI 0.45–0.82).
      • Brown B.E.
      • Shah P.S.
      • Afifi J.K.
      • et al.
      Delayed cord clamping in small for gestational age preterm infants.
      In a study that did not use DCC, risk for polycythemia increased with the severity of growth restriction (term, non-IUGR infants 6.2%, mild IUGR 8.25%, moderate IUGR 12.5%, severe IUGR 36.2%).
      • Kramer M.S.
      • Olivier M.
      • McLean F.H.
      • et al.
      Impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcome.

      Umbilical Cord Milking

      Preterm infants

      One meta-analysis of 5 RCTs found a significant increase in severe IVH in infants ≤326 weeks GA with UCM versus DCC (RR 1.95; 95% CI 1.01–3.76).
      • Balasubramanian H.
      • Ananthan A.
      • Jain V.
      • et al.
      Umbilical cord milking in preterm infants: A systematic review and meta-analysis.
      This effect was hypothesized to be related to rapid changes in blood volume.

      Term infants

      One meta-analysis found only 2 studies comparing UCM to DCC. Both defined DCC as clamping “at or within 30 seconds”.
      • Al-Wassia H.
      • Shah P.S.
      Efficacy and safety of umbilical cord milking at birth: A systematic review and meta-analysis.
      Data are lacking that compare UCM with typically defined DCC in term infants.

      Implementation Initiatives in Canada

      In 2018, the Canadian Preterm Birth Network (CPTBN) and a large, multidisciplinary group of stakeholders (comprising maternal-fetal medicine specialists, obstetricians, neonatologists, paediatricians, nurses, administrators and parents) established a consensus protocol for preterm infants which has informed this statement (see Figure). The literature was reviewed and an unpublished draft consensus protocol was created focusing on DCC practice and implementation.

      Evidence for Improving DCC Implementation

      Care teams interested in implementing DCC can be informed by a recent systematic review that evaluated strategies, barriers, and facilitators to best practice.
      • Devin J.
      • Larkin P.
      Delayed cord clamping in term neonates: attitudes and practices of midwives in irish hospitals.
      The key implementation strategy was to use multidisciplinary “quality improvement approaches” involving “protocols, policies, or toolkits”, education (e.g., rounds, didactic teaching), simulations, and reminders (e.g., signs, newsletters). Occasionally, teams used champions and post-event feedback and debriefing formats.
      • Anton O.
      • Jordan H.
      • Rabe H.
      Strategies for implementing placental transfusion at birth: A systematic review.
      Barriers that teams may need to address include:
      • Anton O.
      • Jordan H.
      • Rabe H.
      Strategies for implementing placental transfusion at birth: A systematic review.
      • 1.
        General change management factors (e.g., lack of staff awareness, resistance to change),
      • 2.
        Obstetrical care provider concerns (e.g., risk of hemorrhage),
      • 3.
        Paediatrician concerns (e.g., duration of deferral, polycythemia), and
      • 4.
        Environmental factors (e.g., bags to minimize infant hypothermia).
      Strategies that teams may be able to leverage include:
      • Devin J.
      • Larkin P.
      Delayed cord clamping in term neonates: attitudes and practices of midwives in irish hospitals.
      • Perrone B.
      • Ghirardello S.
      Placental transfusion strategies in Italy: A nationwide survey of tertiary-care delivery wards.
      • Oddie S.
      • Rhodes P.
      Very Preterm Birth Qualitative Collaborative Group. Barriers to deferred cord clamping in preterm infants.
      • Beard M.M.
      PL. 65 Deferred clamping of the umbilical cord: Neural programming in the surgeon as a barrier to change.
      • 1.
        Guidelines
        • Devin J.
        • Larkin P.
        Delayed cord clamping in term neonates: attitudes and practices of midwives in irish hospitals.
        ,
        • Perrone B.
        • Ghirardello S.
        Placental transfusion strategies in Italy: A nationwide survey of tertiary-care delivery wards.
        or protocols,
        • Oddie S.
        • Rhodes P.
        Very Preterm Birth Qualitative Collaborative Group. Barriers to deferred cord clamping in preterm infants.
      • 2.
        Knowledge of benefits,
        • Devin J.
        • Larkin P.
        Delayed cord clamping in term neonates: attitudes and practices of midwives in irish hospitals.
        ,
        • Perrone B.
        • Ghirardello S.
        Placental transfusion strategies in Italy: A nationwide survey of tertiary-care delivery wards.
      • 3.
        Team communication,
        • Perrone B.
        • Ghirardello S.
        Placental transfusion strategies in Italy: A nationwide survey of tertiary-care delivery wards.
        and
      • 4.
        Reminders.
        • Beard M.M.
        PL. 65 Deferred clamping of the umbilical cord: Neural programming in the surgeon as a barrier to change.

      Conclusion

      For preterm singletons, DCC reduces risks for mortality and morbidity. For term singletons, DCC improves hematologic parameters. In preterm twins, observational data suggest some benefits. In very preterm infants, UCM doubles the risk of IVH when compared with DCC. There are limited data on preterm twins (with some benefit suggested) and maternal outcomes (no significant reported adverse outcomes). Standardized implementation of DCC practices by a multidisciplinary team should occur for most infants because contraindications to DCC are few. Best practices can be facilitated by reminders, protocols, and team communication. Areas warranting further study include slow UCM, DCC in twins, the timing of uterotonics administration, and the stabilization of preterm infants and resuscitation of preterm or term infants on an intact umbilical cord.

      Appendix A

      Table 1Key to Grading of Recommendations, Assessment, Development and Evaluation Quality of Evidence
      GradeDefinition
      Strength of recommendation
       StrongHigh level of confidence that the desirable effects outweigh the undesirable effects (strong recommendation for) or the undesirable effects outweigh the desirable effects (strong recommendation against)
       Conditional
      Do not interpret conditional recommendations to mean weak evidence or uncertainty of the recommendation.
      Desirable effects probably outweigh the undesirable effects (weak recommendation for) or the undesirable effects probably outweigh the desirable effects (weak recommendation against)
      Quality of evidence
       HighHigh level of confidence that the true effect lies close to that of the estimate of the effect
       ModerateModerate confidence in the effect estimate:

      The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
       LowLimited confidence in the effect estimate:

      The true effect may be substantially different from the estimate of the effect
       Very lowVery little confidence in the effect estimate:

      The true effect is likely to be substantially different from the estimate of effect
      Adapted from GRADE Handbook (2013), Table 5.1.
      a Do not interpret conditional recommendations to mean weak evidence or uncertainty of the recommendation.
      Table 2Implications of Strong and Conditional recommendations, by guideline user
      Perspective
      • Strong Recommendation
      • “We recommend that…”
      • “We recommend to not…”
      • Conditional (Weak) Recommendation
      • “We suggest…”
      • “We suggest to not…”
      AuthorsThe net desirable effects of a course of action outweigh the effects of the alternative course of action.It is less clear whether the net desirable consequences of a strategy outweigh the alternative strategy.
      PatientsMost individuals in the situation would want the recommended course of action, while only a small proportion would not.The majority of individuals in the situation would want the suggested course of action, but many would not.
      CliniciansMost individuals should receive the course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.Recognize that patient choices will vary by individual and that clinicians must help patients arrive at a care decision consistent with the patient’s values and preferences.
      PolicymakersThe recommendation can be adapted as policy in most settings.The recommendation can serve as a starting point for debate with the involvement of many stakeholders.
      Adapted from GRADE Handbook (2013), Table 6.1.

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