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Timing of cord clamping in very preterm infants: more evidence is needed

Published:March 31, 2014DOI:https://doi.org/10.1016/j.ajog.2014.03.055
      In December 2012, the American College of Obstetricians and Gynecologists published a Committee Opinion entitled “Timing of umbilical cord clamping after birth.” It stated that “evidence exists to support delayed cord clamping in preterm infants, when feasible. The single most important benefit for preterm infants is the possibility for a nearly 50% reduction in IVH.” However, the Committee Opinion added that the ideal timing of umbilical cord clamping has yet to be determined and recommended that large clinical trials be conducted in the most preterm infants. Published randomized controlled trials include <200 infants of <30 weeks' gestation, with assessments of neurodevelopmental outcome in less than one-half of the children. This is a major gap in the evidence. Without reliable data from randomized controlled trials that optimally include childhood follow-up evaluations, we will not know whether delayed cord clamping may do more overall harm than good. Ongoing trials of delayed cord clamping plan to report childhood outcomes in >2000 additional very preterm infants. Current recommendations may need to change when these results become available. Greater international collaboration could accelerate resolution of whether this promising intervention will improve disability-free survival in about 1 million infants who will be born very preterm globally each year.

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      In December 2012, the American College of Obstetricians and Gynecologists (ACOG) published a Committee opinion entitled “Timing of umbilical cord clamping after birth.” It stated that “Several systematic reviews have suggested that clamping the umbilical cord...should be delayed for at least 30-60 seconds...because of the associated neonatal benefits, including increased blood volume, reduced need for blood transfusion, (and) decreased incidence of intracranial hemorrhage in preterm infants...Evidence exists to support delayed cord clamping in preterm infants, when feasible. The single most important benefit for preterm infants is the possibility for a nearly 50% reduction in IVH.”
      Committee on Obstetric Practice, American College of Obstetricians and Gynecologists
      Committee Opinion no. 543: Timing of umbilical cord clamping after birth.
      Consistent with this opinion, delayed cord clamping (DCC) is increasingly being advocated for the routine care of preterm infants.
      • Niermeyer S.
      • Velaphi S.
      Promoting physiologic transition at birth: re-examining resuscitation and the timing of cord clamping.
      • Raju T.N.
      • Singhal N.
      Optimal timing for clamping the umbilical cord after birth.
      It has been claimed that failure to implement this procedure may represent an unnecessary harm for vulnerable neonates.
      • McAdams R.M.
      Time to implement delayed cord clamping.
      In light of the evidence reviewed by the ACOG Committee, which has been summarized in 2 systematic reviews, can clinicians and institutional review boards continue to support trials of DCC in very preterm infants?
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      • Rabe H.
      • Reynolds G.
      • Diaz-Rossello J.
      A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants.
      The answer is clearly “yes” (Video clip). The ACOG Committee Opinion added the disclaimer that it “should not be construed as dictating an exclusive course of treatment or procedure to be followed.”
      Committee on Obstetric Practice, American College of Obstetricians and Gynecologists
      Committee Opinion no. 543: Timing of umbilical cord clamping after birth.
      Further, the effects on severe intracranial hemorrhage and neurodevelopmental outcome in very preterm infants remain unclear. The Committee Opinion continued “the ideal timing for umbilical cord clamping has yet to be established” and “large clinical trials are needed to investigate the effect of delayed cord clamping on infants delivered at less than 28 weeks gestation.”
      Committee on Obstetric Practice, American College of Obstetricians and Gynecologists
      Committee Opinion no. 543: Timing of umbilical cord clamping after birth.

      European consensus guidelines for preterm infants

      The recent European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants
      • Sweet D.G.
      • Carnielli V.
      • Greisen G.
      • et al.
      European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants: 2013 update.
      reviewed the same evidence that was available to the ACOG Committee.
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      • Rabe H.
      • Reynolds G.
      • Diaz-Rossello J.
      A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants.
      In contrast to the ACOG Committee Opinion, the European guidelines made a formal recommendation: “If possible delay clamping of the umbilical cord for at least 60 s with the baby held below the mother to promote placentofetal transfusion.”
      • Sweet D.G.
      • Carnielli V.
      • Greisen G.
      • et al.
      European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants: 2013 update.
      The guidelines noted that a large multicenter trial is underway to determine whether this practice genuinely improves short- and long-term outcome.

      Tarnow-Mordi W. Australian Placental Transfusion Study. Available at: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335752. Accessed March 12, 2014.

      However, the guidelines did not mention the current lack of evidence as to whether DCC improves or worsens survival or neurosensory disability. Despite these major gaps in the evidence, the advice to delay clamping of the cord in preterm infants was graded A, which suggests the highest level of evidence to support the recommendation.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.

      Potential mechanisms, benefits and risks

      Enhancing placental transfusion by DCC might benefit the very preterm infant by increasing neonatal blood volume,
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      • Ghavam S.
      • Batra B.
      • Mercer J.
      • et al.
      Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.
      thereby potentially improving perfusion and reducing organ injury.
      • Kluckow M.
      • Evans N.
      Low superior vena cava flow and intraventricular haemorrhage in preterm infants.
      • Hunt R.W.
      • Evans N.
      • Rieger I.
      • Kluckow M.
      Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants.
      • Sommers R.
      • Stonestreet B.S.
      • Oh W.
      • et al.
      Hemodynamic effects of delayed cord clamping in premature infants.
      • Miletin J.
      • Dempsey E.M.
      Low superior vena cava flow on day 1 and adverse outcome in the very low birthweight infant.
      DCC may also allow more time for spontaneous breathing to begin before the umbilical cord is clamped, achieving a smoother transition of the cardiopulmonary and cerebral circulation
      • Bhatt S.
      • Alison B.J.
      • Wallace E.M.
      • et al.
      Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs.
      and reducing the risk of invasive and potentially injurious resuscitation.
      • Allison B.J.
      • Crossley K.J.
      • Flecknoe S.J.
      • et al.
      Ventilation of the very immature lung in utero induces injury and BPD-like changes in lung structure in fetal sheep.
      DCC may also increase iron stores,
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      • Ghavam S.
      • Batra B.
      • Mercer J.
      • et al.
      Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.
      reduce childhood anaemia,
      • Lozoff B.
      • Jimenez E.
      • Wolf A.W.
      Long-term developmental outcome of infants with iron deficiency.
      and increase the transfer of stem cells, which may have anti-inflammatory, neurotrophic and neuroprotective effects.
      • Jensen A.
      • Vaihinger H.M.
      • Meier C.
      Perinatal brain damage: from neuroprotection to neuroregeneration using cord blood stem cells.
      • Vendrame M.
      • Gemma C.
      • de Mesquita D.
      • et al.
      Anti-inflammatory effects of human cord blood cells in a rat model of stroke.
      However, DCC may increase the incidence and severity of jaundice and hypothermia and its long-term effects are unknown. Also, if DCC delays urgently needed resuscitation, it may cause net long-term harm.
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      • Ghavam S.
      • Batra B.
      • Mercer J.
      • et al.
      Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.
      • Reynolds G.J.
      Beyond sweetness and warmth: transition of the preterm infant.

      How have others interpreted current evidence?

      Authors of systematic reviews and consensus statements have drawn varying conclusions from the available evidence.
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      • Sweet D.G.
      • Carnielli V.
      • Greisen G.
      • et al.
      European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants: 2013 update.
      • Ghavam S.
      • Batra B.
      • Mercer J.
      • et al.
      Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.

      Abalos E. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes: RHL commentary. The WHO Reproductive Health Library website. Available at: http://apps.who.int/rhl/pregnancy_childbirth/childbirth/. Accessed Dec. 17, 2012.

      Importantly, few have noted that conclusions may need to change in the light of results from ongoing randomized controlled trials (RCTs),

      Tarnow-Mordi W. Australian Placental Transfusion Study. Available at: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335752. Accessed March 12, 2014.

      • Pushpa-Rajah A.
      • Duley L.
      CORD Pilot Trial
      Immediate cord clamping versus deferred cord clamping for preterm birth before 32 weeks gestation: a pilot randomised trial ISRCTN21456601 in World Health Organization International Clinical Trials Registry Platform.
      which could enroll >10 times as many very preterm infants as those on which current advice is based.

      Trials in infants at <37 weeks' gestation

      The most recent Cochrane Review synthesized evidence from 15 RCTs in 738 infants who were born at <37 weeks' gestation, an average of only 49 infants per trial, or about 25 infants per study arm in each trial.
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      The number born at <30 weeks' gestation could not be ascertained. Also, several studies were at risk of bias, with missing data for several outcomes. The trials compared early cord clamping, in <20 seconds, with strategies to enhance placental transfusion. These were DCCs for 30-120 seconds or, in 1 RCT,
      • Hosono S.
      • Mugishima H.
      • Fujita H.
      • et al.
      Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks' gestation: a randomised controlled trial.
      cord milking. The 4 primary outcomes were death, severe (grade 3 or 4) intraventricular hemorrhage (IVH), periventricular leukomalacia, and neurodevelopment in early childhood. Increased placental transfusion appeared to protect against the secondary outcome of IVH (all grades). Among 534 infants, the risk ratio (RR) was 0.59 (95% confidence interval [CI], 0.41–0.85; P = .0048). However, the clinical significance of this was unclear because there were too few data about the primary outcomes of severe (grades 3 or 4) IVH (n = 305; RR, 0.68; 95% CI, 0.23–1.96; P = .20) and neurodevelopment at age 2-3 years (n = 0). There were no differences in development in 58 children 7 months after discharge from hospital. The authors concluded that “there were insufficient data for reliable conclusions about the comparative effects on any of the primary outcomes for this review.”
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      DCC also improved other short-term outcomes, including necrotizing enterocolitis, transfusions for anemia, use of inotropes, late onset sepsis, and increased peak bilirubin. However, the Cochrane authors concluded that “larger multicentre studies are essential and demand international collaboration …. Future studies should include more data … on long term neurodevelopmental outcome at two years of age. …”
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.

      Trials in infants at <30 weeks' gestation

      In a systematic review, Ghavam et al
      • Ghavam S.
      • Batra B.
      • Mercer J.
      • et al.
      Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.
      evaluated neurodevelopmental outcome at 18-24 months in RCTs of very low birthweight (<1000 g) preterm infants of <30 weeks' gestation. Infants were assigned randomly either to early clamping or to enhanced placental transfusion by DCC or milking. Trial authors were contacted for additional information. In 10 eligible RCTs, 199 infants were enrolled, which was an average of 20 per trial or approximately 10 per study arm in each trial. Information on the primary outcome of neurodevelopment at 18-24 months could be obtained for just 96 infants, from just 3 of the 10 trials.
      • Hosono S.
      • Mugishima H.
      • Fujita H.
      • et al.
      Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks' gestation: a randomised controlled trial.
      • Mercer J.S.
      • Vohr B.R.
      • McGrath M.M.
      • Padbury J.F.
      • Wallach M.
      • Oh W.
      Delayed cord clamping in very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized, controlled trial.
      • Oh W.
      • Fanaroff A.A.
      • Carlo W.A.
      • et al.
      Effects of delayed cord clamping in very-low-birth-weight infants.
      No difference was found in rates of disability or death between early clamping and enhanced placental transfusion in these 3 trials.
      Two RCTs followed 42 children at 18-24 months but used different developmental scales and were inconclusive.
      • Hosono S.
      • Mugishima H.
      • Fujita H.
      • et al.
      Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks' gestation: a randomised controlled trial.
      • Oh W.
      • Fanaroff A.A.
      • Carlo W.A.
      • et al.
      Effects of delayed cord clamping in very-low-birth-weight infants.
      Short-term benefits in all 10 trials included improved blood pressure and hemoglobin concentration, fewer blood transfusions, late-onset sepsis, and a trend (P = .08) to reduced IVH of all grades.
      • Ghavam S.
      • Batra B.
      • Mercer J.
      • et al.
      Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.
      The authors concluded that, for very low birthweight infants of <30 weeks' gestation, “paucity of data on neurodevelopmental outcomes and safety concerns tempers enthusiasm for these interventions. Appropriately designed RCTs to assess short-term and long-term outcomes are needed.”

      Need for adequate power and follow up

      Adequate sample size and power are critical in perinatal trials.
      • Tarnow-Mordi W.
      • Brocklehurst P.
      Randomised controlled trials in perinatal medicine: 1. the need for studies of mortality and major morbidity with adequate power.
      • Tarnow-Mordi W.
      • Kumar P.
      • Kler N.
      Neonatal trials need thousands, not hundreds, to change global practice.
      Recent neonatal oxygen-targeting trials underline the need for studies to be powered to detect reliably the incidence of substantive outcomes such as death.
      • Carlo W.A.
      • Finer N.N.
      • Walsh M.C.
      • et al.
      Target ranges of oxygen saturation in extremely preterm infants.
      • Stenson B.
      • Brocklehurst P.
      • Tarnow-Mordi W.
      Increased 36-week survival with high oxygen saturation target in extremely preterm infants.
      • Stenson B.J.
      • et al.
      BOOST II United Kingdom Collaborative Group; BOOST II Australia Collaborative Group; BOOST II New Zealand Collaborative Group
      Oxygen saturation and outcomes in preterm infants.
      Childhood follow-up evaluation is also critical. Many interventions in pregnancy and the newborn infant have suggested short-term benefit, but longer term evidence has been inconclusive or indicated harm. Several examples underline the need for caution.

      High-dose postnatal steroids

      Toward the end of last century, many babies at risk of chronic lung disease were treated with high-dose steroids soon after birth. Early trials had suggested short-term benefits (eg, less oxygen dependence and chronic lung disease), so high-dose steroids were increasingly adopted world-wide. Follow-up studies did not show improved survival, and some studies showed an increase in cerebral palsy.
      Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants.
      • Halliday H.L.
      • Ehrenkranz R.A.
      • Doyle L.W.
      Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.

      Antenatal antibiotics and antenatal thyrotropin-releasing hormone

      The Overview of the Role of Antibiotics in Curtailing Labour and Early delivery (ORACLE) trial of antibiotics in women who were at risk of preterm birth suggested the hypothesis, in 2226 singleton infants who were born to women with preterm rupture of membranes, that antibiotics reduced major cerebral abnormality in infants before discharge.
      • Kenyon S.L.
      • Taylor D.J.
      • Tarnow-Mordi W.
      Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group.
      Despite this, there was no improvement in functional impairment in 7-year-old children.
      • Kenyon S.
      • Pike K.
      • Jones D.R.
      • et al.
      Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial.
      Furthermore, 2 antibiotics that were given to women in preterm labor with intact membranes increased the risk of cerebral palsy by 60-90%.
      • Kenyon S.
      • Pike K.
      • Jones D.R.
      • et al.
      Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial.
      Early trials of antenatal thyrotropin-releasing hormone in women who were at risk of preterm birth suggested that thyrotropin-releasing hormone reduced neonatal chronic lung disease
      • Ballard R.A.
      • Ballard P.L.
      • Creasy R.K.
      • et al.
      Respiratory disease in very-low-birthweight infants after prenatal thyrotropin-releasing hormone and glucocorticoid: TRH Study Group.
      and hospital deaths.
      • Knight D.B.
      • Liggins G.C.
      • Wealthall S.R.
      A randomized, controlled trial of antepartum thyrotropin-releasing hormone and betamethasone in the prevention of respiratory disease in preterm infants.
      However, 2 more RCTs, in >4 times as many women, found no benefit for neonatal chronic lung disease
      • Crowther C.A.
      • Hiller J.E.
      • Haslam R.R.
      • Robinson J.S.
      Australian Collaborative Trial of Antenatal Thyrotropin-Releasing Hormone: adverse effects at 12-month follow-up: ACTOBAT Study Group.
      or hospital death
      • Crowther C.A.
      • Hiller J.E.
      • Haslam R.R.
      • Robinson J.S.
      Australian Collaborative Trial of Antenatal Thyrotropin-Releasing Hormone: adverse effects at 12-month follow-up: ACTOBAT Study Group.
      but found an increased risk of motor delay at 12 months
      • Crowther C.A.
      • Hiller J.E.
      • Haslam R.R.
      • Robinson J.S.
      Australian Collaborative Trial of Antenatal Thyrotropin-Releasing Hormone: adverse effects at 12-month follow-up: ACTOBAT Study Group.
      and of mental delay at 12 and 24 months.
      • Briet J.M.
      • van Sonderen L.
      • Buimer M.
      • Boer K.
      • Kok J.H.
      Neurodevelopmental outcome of children treated with antenatal thyrotropin-releasing hormone.

      Oxygen, severe retinopathy, and survival

      Perhaps the most dramatic example of the necessity for childhood follow-up evaluation in RCTs is described by Silverman.
      • Silverman W.A.
      A cautionary tale about supplemental oxygen: the albatross of neonatal medicine.
      An early RCT of liberal vs restricted oxygen therapy in preterm infants suggested that oxygen curtailment did not increase mortality rates but did reduce retinopathy with cicatricial eye disease, which is a major cause of blindness, by two thirds.
      • Silverman W.A.
      A cautionary tale about supplemental oxygen: the albatross of neonatal medicine.
      • Kinsey V.E.
      • Hemphill F.M.
      Etiology of retrolental fibroplasia and preliminary report of cooperative study of retrolental fibroplasia.
      Restriction of oxygen therapy to concentrations <40% rapidly became routine practice, regardless of the presence of hypoxia. Survivors in this RCT never received followed-up evaluation.
      • Silverman W.A.
      A cautionary tale about supplemental oxygen: the albatross of neonatal medicine.
      Later, widespread excesses in the incidence of spastic diplegia and death were attributed to hypoxic respiratory failure because of arbitrary, inappropriate oxygen restriction. It was estimated that “every sighted infant gained may have cost some 16 deaths.”
      • Bolton D.P.
      • Cross K.W.
      Further observations on cost of preventing retrolental fibroplasia.
      These examples suggest that, despite promising short-term evidence of benefit, without studies that are powered to detect changes in mortality rates and without long-term data we cannot exclude the possibility that DCC may do more harm than good.

      Is IVH a reliable surrogate for childhood impairment?

      It is unclear whether isolated, low-grade (grades 1 and 2) IVH without white matter damage or ventricular dilation increases the risk of adverse developmental outcome in childhood.
      • Papile L.A.
      • Munsick-Bruno G.
      • Schaefer A.
      Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps.
      • Whitaker A.H.
      • Feldman J.F.
      • Van Rossem R.
      • et al.
      Neonatal cranial ultrasound abnormalities in low birth weight infants: relation to cognitive outcomes at six years of age.
      • Whitaker A.H.
      • Van Rossem R.
      • Feldman J.F.
      • et al.
      Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrasound abnormalities.
      • Costello A.M.
      • Hamilton P.A.
      • Baudin J.
      • et al.
      Prediction of neurodevelopmental impairment at four years from brain ultrasound appearance of very preterm infants.
      • Dyet L.E.
      • Kennea N.
      • Counsell S.J.
      • et al.
      Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment.
      • O'Shea T.M.
      • Allred E.N.
      • Kuban K.C.
      • et al.
      Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants.
      • Payne A.H.
      • Hintz S.R.
      • Hibbs A.M.
      • et al.
      Neurodevelopmental outcomes of extremely low-gestational-age neonates with low-grade periventricular-intraventricular hemorrhage.
      Of 3 recent cohort studies, 1 study concluded that, except when accompanied or followed by a white matter lesion, isolated IVH is associated with no more than a mild increase (and possibly no increase) in adverse developmental outcome.
      • O'Shea T.M.
      • Allred E.N.
      • Kuban K.C.
      • et al.
      Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants.
      Another study found that, at 18-22 months, neurodevelopmental outcomes of very low gestational-age infants with isolated low-grade IVH did not differ significantly from those without IVH.
      • Payne A.H.
      • Hintz S.R.
      • Hibbs A.M.
      • et al.
      Neurodevelopmental outcomes of extremely low-gestational-age neonates with low-grade periventricular-intraventricular hemorrhage.
      A third concluded that infants with isolated grades 1 and 2 IVH had a 50% increase in moderate-severe neurosensory impairment in early childhood.
      • Bolisetty S.
      • Dhawan A.
      • Abdel-Latif M.
      • et al.
      Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants.
      By contrast, lesions often referred to as severe (grade 3 or 4) IVH, but which are more properly described as evidence of white matter damage,
      • Leviton A.
      • Paneth N.
      White matter damage in preterm newborns–an epidemiologic perspective.
      • Paneth N.
      • Rudelli R.
      • Kazam E.
      • Monte W.
      Brain damage in the preterm infant.
      • Paneth N.
      Classifying brain damage in preterm infants.
      • Leviton A.
      • Kuban K.
      • Paneth N.
      Intraventricular haemorrhage grading scheme: time to abandon?.
      clearly are associated with greater risk of neurodevelopmental impairment and psychiatric disorder.
      • Papile L.A.
      • Munsick-Bruno G.
      • Schaefer A.
      Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps.
      • Whitaker A.H.
      • Feldman J.F.
      • Van Rossem R.
      • et al.
      Neonatal cranial ultrasound abnormalities in low birth weight infants: relation to cognitive outcomes at six years of age.
      • Whitaker A.H.
      • Van Rossem R.
      • Feldman J.F.
      • et al.
      Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrasound abnormalities.
      • Costello A.M.
      • Hamilton P.A.
      • Baudin J.
      • et al.
      Prediction of neurodevelopmental impairment at four years from brain ultrasound appearance of very preterm infants.
      • Dyet L.E.
      • Kennea N.
      • Counsell S.J.
      • et al.
      Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment.
      • O'Shea T.M.
      • Allred E.N.
      • Kuban K.C.
      • et al.
      Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants.
      White matter damage is thus a better surrogate of important brain injury than IVH of all grades, but evaluation of outcomes in childhood provides still more reliable evidence. In the Trial of Indomethacin Prophylaxis in Preterms, indomethacin prophylaxis reduced the odds of severe (grade 3 or 4) IVH in extremely low birthweight infants by 30% compared with placebo, but there was no difference in long-term outcome.
      • Schmidt B.
      • Davis P.
      • Moddeman D.
      • et al.
      Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants.

      Criteria for new standards of care

      Clinical trials with surrogate endpoints do not provide an appropriate basis for long-term clinical policy in any specialty.
      • McNeil J.J.
      • Nelson M.R.
      • Tonkin A.M.
      Public funding of large-scale clinical trials in Australia.
      We suggest that a new standard of perinatal care will require (1) reliable, relevant evidence of net clinical benefit, informed by (2) data on survival and childhood outcome that show no appreciable evidence of harm and (3) the perspectives of parents, professionals, and the community.

      What is net clinical benefit?

      For many, no other outcome in very preterm infants is as important as survival,
      • Streiner D.L.
      • Saigal S.
      • Burrows E.
      • Stoskopf B.
      • Rosenbaum P.
      Attitudes of parents and health care professionals toward active treatment of extremely premature infants.
      so this usually outweighs short-term morbidity or childhood disability when considering net clinical benefit. For the most severely disabled children, some professionals, parents, and communities may consider survival worse than death.
      • Saigal S.
      • Stoskopf B.L.
      • Feeny D.
      • et al.
      Differences in preferences for neonatal outcomes among health care professionals, parents, and adolescents.
      • Boyle M.H.
      • Torrance G.W.
      • Sinclair J.C.
      • Horwood S.P.
      Economic evaluation of neonatal intensive care of very-low-birth-weight infants.
      However, few trials have sufficient power to show any impact on this risk.
      When there is no appreciable evidence of harm in terms of survival or childhood disability, reliable evidence of improvements in short-term morbidity would indicate net clinical benefit. The numbers of patients needed to infer “no appreciable harm” is a matter of judgment. However, the number of very preterm infants (n = 96) in whom neurodevelopment in childhood currently is reported
      • Ghavam S.
      • Batra B.
      • Mercer J.
      • et al.
      Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.
      is clearly inadequate to make such a judgment.

      What constitutes reliable relevant evidence?

      Much depends on the quality of the evidence and the size and setting of the population in which the evidence has been obtained and the impact of the intervention. A rigorously conducted RCT that shows a treatment difference in 300 patients, with a probability value of < .05, is less convincing than a trial of equal rigor that shows a similar treatment difference with the same probability value in 3000 patients. Similarly, an intervention in which the number needed to treat to prevent 1 extra death is 10 is likely to have greater impact than an intervention for which number needed to treat is 100. The impact of DCC in very preterm infants on survival or childhood disability is currently unknown.

      Implications for clinical practice, guidelines and research

      Implications for clinical practice

      What options are open to practitioners and parents of very preterm infants? Some may opt for DCC (or milking) because of the short-term evidence of benefit. However, milking disrupts the fetoplacental circulation and does not allow time to facilitate a smooth transition of the cardiopulmonary and cerebral circulation or to avoid potentially unnecessary resuscitation; therefore, it may risk different adverse effects than DCC. Others may opt for early clamping because of the potential harms of delayed resuscitation and uncertainty about long-term outcome. Others, if they have the opportunity, may wish to contribute to RCTs to resolve the uncertainties, as recommended by various authorities.
      • Rabe H.
      • Diaz-Rossello J.L.
      • Duley L.
      • Dowswell T.
      Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
      • Ghavam S.
      • Batra B.
      • Mercer J.
      • et al.
      Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.
      Each of these options is reasonable.

      Implications for clinical guidelines

      When evidence falls short of reliably showing net clinical benefit, it is important that clinical guidelines do not inhibit future research inadvertently.
      • Ambalavanan N.
      • Whyte R.K.
      The mismatch between evidence and practice: common therapies in search of evidence.
      Two ways to reduce this risk are to ensure that published guidelines emphasize, in the text and the abstract, (1) the need for further research and (2) that advice may change when further evidence is available.

      Implications for research and international collaboration

      It may require thousands, rather than hundreds, of patients to show net clinical benefit (or harm) reliably.
      • Tarnow-Mordi W.
      • Brocklehurst P.
      Randomised controlled trials in perinatal medicine: 1. the need for studies of mortality and major morbidity with adequate power.
      • Tarnow-Mordi W.
      • Kumar P.
      • Kler N.
      Neonatal trials need thousands, not hundreds, to change global practice.
      • Roberts I.
      • Yates D.
      • Sandercock P.
      • et al.
      Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial.
      • Roberts I.
      • Shakur H.
      • et al.
      CRASH-2 Collaborators
      The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.
      • Shakur H.
      • Roberts I.
      • et al.
      CRASH-2 trial collaborators
      Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
      Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.
      ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group.
      For example, to demonstrate a moderate, but clinically important, reduction in death from 25-21% with 90% power and a2-tailed probability value < .05 requires >4800 subjects. To show this with a 2-tailed probability value < .01, and similar power, requires about 8300 subjects.
      • Tarnow-Mordi W.
      • Kumar P.
      • Kler N.
      Neonatal trials need thousands, not hundreds, to change global practice.
      However, larger differences require smaller samples.
      If death and disability are affected in opposing directions, a composite outcome that uses both outcomes will reduce the power of a trial. If that is likely, it may be appropriate to prespecify (1) an evaluation for a difference in mortality rates, then (2) an examination of survivors for risk of disability (ie, to undertake 2 consecutive analyses after a single randomization). Each of these analyses may have greater power than an analysis of the 2 opposing outcomes combined, because noise in 1 will not obscure signal in the other.
      Also, as outcomes improve, the numbers of patients that are needed to demonstrate additional improvement will increase in all specialties. In high-income countries, preterm infants of <30 weeks' gestation may number approximately 5-fold fewer than patients with serious trauma
      • Roberts I.
      • Yates D.
      • Sandercock P.
      • et al.
      Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial.
      • Roberts I.
      • Shakur H.
      • et al.
      CRASH-2 Collaborators
      The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.
      • Shakur H.
      • Roberts I.
      • et al.
      CRASH-2 trial collaborators
      Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
      and 10-fold fewer than patients with myocardial infarction.
      Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.
      ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group.
      As with trials in those specialties, perinatal trials will require increasing international collaboration and a culture of continuous quality improvement in which supporting trials and acquisition of other rigorous evidence is an integral part of routine care.
      • Horbar J.D.
      • Soll R.F.
      • Edwards W.H.
      The Vermont Oxford Network: a community of practice.

      Australian Placental Transfusion study and United Kingdom CORD trial

      The Australian Placental Transfusion study is an international, multicentre pragmatic RCT to test the hypothesis that, in 1600 infants of <30 weeks' gestation, compared with immediate clamping of the umbilical cord within 10 seconds of delivery, DCC for ≥60 seconds will reduce deaths or major morbidity at 36 weeks corrected gestation and deaths or major disability at 3 years.

      Tarnow-Mordi W. Australian Placental Transfusion Study. Available at: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335752. Accessed March 12, 2014.

      As of March 2014, the study has recruited >650 infants, which makes it the largest study of its kind to date.
      The UK CORD trial is planned as a randomized comparison in very preterm infants of early clamping of the cord at <20 seconds vs DCC for at least 2 minutes.
      • Pushpa-Rajah A.
      • Duley L.
      CORD Pilot Trial
      Immediate cord clamping versus deferred cord clamping for preterm birth before 32 weeks gestation: a pilot randomised trial ISRCTN21456601 in World Health Organization International Clinical Trials Registry Platform.
      However, in those babies allocated to DCC, resuscitation or stabilization will commence at once at the mothers' bedside, and this generally should permit the cord to remain intact well in excess of 2 minutes. The CORD trial will contribute to an international collaborative individual patient metaanalysis
      • Askie L.M.
      • Brocklehurst P.
      • Darlow B.A.
      • et al.
      NeOProM: Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol.
      of similar trials of enhanced placental transfusion, including the Australian Placental Transfusion trial.
      • Lloyd C.
      • Duley L.
      • Yang M.
      • Askie L.
      Cord clamping and placental transfusion at preterm birth prospective meta-analysis in PROSPERO International prospective register of systematic reviews.
      Altogether, these trials are expected to enroll 2000-5000 very preterm infants, like the Neonatal Oxygenation Prospective Metaanalysis collaboration of neonatal oxygen-targeting trials (NeOProM), which will enhance the precision of comparisons of survival and neurodevelopment in childhood.
      • Askie L.M.
      • Brocklehurst P.
      • Darlow B.A.
      • et al.
      NeOProM: Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol.

      Implications for government and funding agencies

      An incentive for governments and funding agencies to consider is that funding large-scale, international trials of low-cost perinatal interventions like placental transfusion may save considerably more than the cost of the trials themselves. In another specialty, it has been estimated that a lack of data from large scale, public-good trials on the cost-effective management of hypertension led to unnecessary costs to Australian taxpayers of between $45 million and $108 million in 1998.
      • McNeil J.J.
      • Nelson M.R.
      • Tonkin A.M.
      Public funding of large-scale clinical trials in Australia.
      This equates, by extension, to a cost to US taxpayers of between one-half and 1 billion dollars.

      Comment

      Perinatal medicine is replete with examples of promising interventions the short-term benefits of which did not translate into long-term benefit, including some that caused harm. Through international collaboration, obstetricians, midwives, neonatal clinicians, parents, and policymakers can ensure that randomized trials of DCC with childhood follow-up evaluation are completed as rapidly as possible to provide reliable evidence of the safety and effectiveness in the short and longer term. This could improve morbidity, disability, or survival in approximately 1 million infants who are born very preterm globally each year.
      • Blencowe H.
      • Cousens S.
      • Oestergaard M.Z.
      • et al.
      National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.

      Supplementary data

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      Linked Article

      • Delayed cord clamping?
        American Journal of Obstetrics & GynecologyVol. 212Issue 6
        • Preview
          I congratulate Tarnow-Mordi et al1 on their excellent scientific analysis of delayed cord clamping. I would like to inquire regarding the authors’ views on the terminology itself. The term, delayed, is generally not a good thing and often denotes a maloccurrence. The technique of delayed cord clamping is delayed only when compared with the current common practice, which might best be described as immediate or accelerated. The delay proposed is generally sooner than would occur compared with physiological cord occlusion from vasoconstriction.
        • Full-Text
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      • Immediate versus delayed cord clamping
        American Journal of Obstetrics & GynecologyVol. 212Issue 6
        • Preview
          I read with interest the Clinical Opinion by Tarnow-Mordi et al entitled “Timing of cord clamping in very preterm infants: more evidence is needed” in the August 2014 issue of the Journal. The authors were quite correct in their comment section that “perinatal medicine is replete with examples of promising interventions, the short-term benefits of which did not translate into long-term benefit, including some that caused harm.”1
        • Full-Text
        • PDF