There’s a cord attached:Delayed Cord Clamping & MilkingKelli D Barbour, MD MSc MA

Assistant Professor, Maternal fetal Medicine & Global Women’s Health

Division of Maternal Fetal Medicine

Department of Obstetrics & Gynecology

Baylor College of Medicine

Disclosure

I developed the Delayed Cord Clamping protocol at TCH with Dr. Nathan Sundgren

Objectives

Discuss the evidence in favor of Delayed Cord Clamping (DCC) for preterm and term infants

Be familiar with outcomes for infants for DCC versus umbilical cord milking

Know the Consensus Statements on DCC Be familiar with an algorithm for when/how to do DCC List factors affecting the decision to do DCC

Outline

The Evidence for DCC Preterm

Term

Evidence for Cord Milkin Preterm

Consensus Statements WHO

ACOG

ACP

Performing DCC

What is the purpose of manipulating the cord? Who can be it be done in?

Placental Transfusion?Stable Transition to Ex-Utero Life?Term vs Preterm?

Rationale for DCC

thought to be associated with increased autotransfusion from the placenta to the neonate, resulting in increased blood volume

decreased anemia (and its sequelae)decreased hypoxia

aiding time for physiologic transition - ensuring adequate cardiac output, oxygenation, and arterial blood pressure until respiration is established

DCC for Preterm Infants

Jan 2018 Systemic Review and Meta-analysis

18 RCTs, 2834 preterm infants, at least 30 seconds of DCC, excluded studies looking at UCM (Fogarty, 2018, AJOG): delayed cord clamping reduced the primary outcome of all-cause (hospital) mortality (RR 0.68, 95% CI

0.52-0.90; risk difference -0.03, 95% CI -0.05-0.01; for a number needed to benefit of 33, 95% CI 20-100); similar result for <28 weeks

reduced incidence of low one-minute APGARs

increased the peak hematocrit by 2.37 percentage points (95% CI 1.94-3.52, p<0.00001).

Reduced proportion of infants receiving a blood transfusion by 10% (95% CI 6-13%, p<0.00001); a similar result for <28 weeks

incidence of polycythemia was increased (RR 2.65, 95% CI 1.61-4.37), but there was no impact on the use of partial exchange transfusion for polycythemia

increased peak bilirubin, but there was no difference in the use of exchange transfusion

2018 SR/MA

No differences were seen in mortality by type of delivery, where the infant was held in relation to the introitus/incision, or duration of cord clamping

maternal outcomes, there was no difference in the number of women with postpartum hemorrhage or requiring blood transfusion. The study does not report on long-term outcomes.

Australian Placental Transfusion Study (APTS)

Tarnow-Mordi et al, 2017, NEJM largest RCT included in the meta-analysis (1634), <30 weeks gestation, DCC for at least 60

seconds Primary outcome = composite of death and major morbidity (severe brain injury, severe

retinopathy, necrotizing enterocolitis, late-onset sepsis, chronic lung disease). No difference in the composite primary outcome (37.0% for DCC versus 37.2 for early/immediate cord

clamping (RR 1.00, 95% CI 0.88-1.13, P= 0.096) unadjusted univariate analysis, mortality in the DCC group was decreased (6.4% versus 9.0%, RR 0.69,

95% CI 0.49-0.97) When adjusted post-hoc for multiple comparisons, the difference was no longer significant (p=0.39).

No difference in secondary outcomes Long-term outcomes not reported

9/2019 Cochrane Review

15 RCTs: 738 infants, 24-36 weeks, max delay in cord clamping 180 seconds (Rabe, 2019, Cochrane) fewer infants requiring transfusions for anaemia (7 trials, 392 infants; risk ratio (RR) 0.61, 95%

confidence interval (CI) 0.46 to 0.81) less intraventricular haemorrhage (ultrasound diagnosis all grades) 10 trials, 539 infants (RR 0.59,

95% CI 0.41 to 0.85) lower risk for necrotising enterocolitis (5 trials, 241 infants, RR 0.62, 95% CI 0.43 to 0.90) peak bilirubin concentration was higher for infants allocated to delayed cord clamping (7 trials,

320 infants, mean difference 15.01 mmol/L, 95% CI 5.62 to 24.40) Outcome at discharge from hospital was reported for one small study: no significant differences

between the groups in mean Bayley II scores at age seven months (corrected for gestation at birth (58 children)).

Effect on cord gases

limited studies

no change or a small decrease in pH (0.03)

not known how DCC affects umbilical artery pH in non-vigorous infants.

Effect on blood banking

associated with decreased volume and nucleated cell counts in cord blood donations (sufficient collection in 17% of DCC cases compared to 39% of early CC cases

DCC in Multifetal pregnancies

insufficient evidence to recommend or avoid DCC in multiple gestations, especially in monochorionic pregnancies

DCC in IUGR

In a sub-analysis of the IUGR/SGA preterm infants at Brown University (Wang, et al, 2018, Journal of Pediatrics) noted to be safe

associated with a higher admission temperature and lower risk of suspected NEC (but not confirmed NEC)

*20% of patients had UCM

Long-term outcomes

Very limited data

Unanswered questions

How generalizable the meta-analysis is to all groups of premature infants is unclear

There is insufficient data for or against DCC in infants with growth restriction and abnormal umbilical blood flow

Long-term outcomes

DCC in Preterm Infants: Conclusions

appears to be safe

may decrease the risk of death, improve one-minute APGARs, and decrease the number of infants requiring a transfusion

maternal adverse events are not increased by DCC.

DCC for Term Infants

2013 Systemic Review and Meta-analysis

15 RCTs with a total of 3911 dyads (McDonald et al, 2013, Cochrane) did not reduce the primary outcome of mortality (RR 0.37, 95% CI 0.04-3.41; 2 trials)

Mean birth weight was higher (101g difference, 95% CI 45-157g; 12 trials).

Need for phototherapy was decreased in the early CC group (RR 0.62, 95% CI 0.41-0.96; 7 trials)

Hemoglobin concentrations at 24-48 hours were lower in the early CC group (MD -1.49 g/dL, 95% CI -1.78- 1.21), but did not differ at subsequent assessments

2013 SR/MA

Infants in the early CC group were more likely to be iron deficient at 3-6 months of age (RR 2.65, 95% CI 1.04-6.73; 5 trials)

Only one trial reported on longer-term neurodevelopment outcomes and did not show a difference in the Ages and Stages Questionnaire scores

No studies reported on maternal deaths or severe maternal morbidity

No significant difference in severe postpartum hemorrhage (RR 1.04, 95% CI 0.65-1.65; 5 trials) or postpartum hemorrhage (RR 1.17, 95% CI 0.94-1, which can be adapted.44; 5 trials)

DCC in CHD

Pilot RCT of 30 singleton neonates with congenital heart defects, designed to test safety and feasibility, randomized infants to ECC (<10 sec) versus DCC (>120 sec). (Backes et al, 2015, Journal of Perinatology) No difference in safety measures (polycythemia, peak bilirubin, phototherapy, 5-minute Apgar,

pre-operative mortality) or surgical parameters

No difference in neonatal morbidities

Hematocrits were higher within the first 72 hours for infants; no difference seen later in the hospitalization.

Less likelihood of needing a blood transfusion (7% versus 43%, p=0.02)

DCC in LGA

51 term LGA infants were randomized in Turkey to ICC (<15 sec) versus DCC (>=60 sec) (Vural et al, 2018, J Paediatr Child Health)

No difference in Apgar scores and cord gas pH

No difference in two-hour hematocrit nor 24-hour bilirubin nor in the incidence of polycythemia

Maternal outcomes

97 term singleton pregnancies were randomized to ECC (<10c) versus DCC (>2 min). (De Paco et al, 2016, Eur J Obstet Gynecol Reprod Biol) no differences in length of second stage, blood indices, or umbilical cord parameters

113 women randomized to ECC vs DCC (60 seconds) at time of cesarean (Purish, 2019, JAMA) no significant difference in a mean hemoglobin change of -1.90 g/dL and -1.78 g/dL (mean

difference, 0.12 g/dL [95% CI, -0.22 to 0.46]; P = .49)

1 unplanned hysterectomy in each group.

Long-term outcomes

Andersson followed up iron status and neonatal developmental outcomes in 382 infants in Sweden; follow up data was available in 90.8% of participants. (Andersson et al, 2014 & 2015, JAMA Pediatrics) Using the Ages and Stages Questionnaire, scores were 5 points higher in male infants in the DCC arm,

but 12 points lower in girls in the same arm. Iron status and hematologic studies did not differ between the arms. At 4 years of age, 263 infants (68.8% of the original cohort) were assessed for neurodevelopment

outcomes. No differences were noted in IQ (as measured by WPPSI-II). Higher adjusted mean differences (AMDs) in ASQ in personal-social (2.8; 95%CI, 0.8-4.7) and fine-motor

(2.1, 95% CI 0.2-4.0) Fewer fell below the cutoff in the ASQ fine motor domain (11.0%vs 3.7%; P = .02) and Movement ABC

bicycle trail task (12.9% vs 3.8%; P = .02).. In male children having received DCC had significantly higher AMDs in the WPPSI-III processing-speed

quotient (4.2; 95%CI, 0.8-7.6; P = .02), as well as higher AMDs in movement ABC bicycle-trail task (0.8; 95%CI, 0.1-1.5; P = .03), and fine-motor (4.7; 95%CI, 1.0-8.4; P = .01) and personal-social (4.9; 95%CI, 1.6-8.3; P = .004) domains of the ASQ.

Long-term outcomes

6-month hematologic indices were investigated in Pakistan (Nesheli et al, 2014, Journal of Pakistan Medical Association) Higher hemoglobin, hematocrit, and transferrin saturation

No differences in polycythemia, hyperbilirubinemia, tachypnea, or in maternal hemorrhage

44 infants had followup at 4 months of age. (Mercer, 2018, The Journal of Pediatrics) Higher ferritin levels (96.4 ng/ml versus 65.3, p=0.03)

Greater myelin content in the internal capsule and other maturing brain regions

No differences in the Mullen score for neurodevelopment or in hematocrit

Unanswered questions

How generalizable is the meta-analysis and RCTs is to all groups of term?

Insufficient data for or against DCC in infants with growth restriction and abnormal umbilical blood flow

Long-term outcomes?

DCC in Term Infants: Conclusion

appears to be safe

may decrease the risk of iron deficiency

maternal adverse events are not increased by DCC, but these have not been studied extensively.

Cord Milking/Stripping

What is Umbilical Cord Milking?

Umbilical cord milking (UCM): Milking or stripping is done by pinching the cord between fingers with the hand moving toward the infant

Goal is to move blood from the cord into the infant quickly Approximately 20 cm of the umbilical cord is vigorously milked towards the umbilicus two or three

times before clamping the cord over ~ 2 seconds

= Bolus of blood over short period of time

Rationale for UMC

Seems like a solution for babies that need resuscitation in order to get placental transfusion.

Animal data shows cord milking is superior at affecting placental transfusion.

DCC vs. UCM in Preterm Infants

Katheria A et al, 2015, Pediatrics Randomized trial of DCC (30 secs+) vs UCM

<32 weeks GA, 197 infants

Several CV, hematologic, and renal measures better for UCM Katheria A et al, J Peds 2017

Neurodevelopmental follow up of above trial

22-26 month, 69% follow up

UCM less likely to have Cognitive or Language score <85

DCC vs. UCM in Preterm Infants

15 RCTs: 738 infants, 24-36 weeks, max delay in cord clamping 180 seconds (Rabe, 2019, Cochrane) Only 1 trial compares DCC vs UCM ((Hosono et al, 2008, Archives of Disease in Childhood. Fetal

and Neonatal Edition)

No clear differences in primary outcomes

Higher haemoglobin at birth

Better blood pressure

Less need for donor blood transfusion

DCC vs. UCM in Preterm Infants

11/2019 noninferiority RCT of DCC vs. UCM: planned 1500 infants randomized, 23-31 weeks – stopped at 474 due to concern for safety 12% (29/236) of UCM died or developed severe intraventricular hemorrhage compared with 8%

(20/238) of DCC (risk difference, 4%[95%CI, −2%to 9%]; P = .16)

Severe intraventricular hemorrhage was statistically significantly higher in the UCM (8%[20/236] vs 3%[8/238]; risk difference, 5%[95%CI, 1% to 9%]; P = .02)

Among infants born at 23 to 27 weeks’ gestation, severe intraventricular hemorrhage was statistically significantly higher with UCM (22%[20/93] vs 6%[5/89], risk difference, 16%[95%CI, 6%to 26%]; P = .002)

Consensus statements

WHO recommendations

DCC should be performed during the provision of essential neonatal care for at least 60 seconds.

Recommendations apply equally to preterm and term births.When newborn require PPV, cord should be clamped and cut to

allow effective ventilation to be performed.

ACOG Recommendations 2017

Recommends a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30–60 seconds after birth.

Delayed umbilical cord clamping does not increase the risk of postpartum hemorrhage.

ACOG Committee Opinion No. 684: Delayed Umbilical Cord Clamping After Birth.

AAP and NRP

AAP endorsed ACOG guidelines (2017)NRP (2015) recommendations:In vigorous preterm DCC for at least 30-60 seconds“By carefully coordinating with the OB providers, the

initial steps of newborn care, including clearing the airway and providing gentle stimulation, can be performed with UC intact.”

Royal College of Obstetricians and Gynecologists

Recommends DCC of at least 120 seconds in healthy preterm and term infant

American College of Nurse-Midwives

Recommends DCC for 2-5 minutes in term and preterm neonates.

Performing DCC

Is DCC right for this mom and this baby?

Each delivery is unique and the decision for DCC should be made after discussion between the delivering obstetrician, neonatologist, and resuscitation team taking maternal, placental, and fetal/neonatal factors into account

Contraindications Maternal - hemorrhage, hemodynamic instability

Placental - placental abruption, abnormal placentation, umbilical cord avulsion

Fetal - need for immediate resuscitation, IUGR with abnormal cord Doppler evaluation, monochorionic pregnancy

Logistics of DCC

How is DCC performed? DCC should not delay warming, drying, and stimulating of the neonate.

Immediate skin-to-skin contact can be done and the neonate can be cleaned with clean/warm blankets.

In a cesarean section, the infant can be held close to the wound. Secretions can be cleared if they are copious or if there is obstruction.

Cord Blood banking? If cord banking is planned, this can still be done, but the family should be counseled that inadequate

total volume and nucleated cells are likely to be encountered.

What about the 3rd stage of labor? Active management of the third stage of labor can continue, including the use of oxytocin and other

uterotonics.

DCC Algorithm & Checklist

Discussion with neonatology regarding plans for DCC

Decide on amount of planned DCC time Ensure room temperature is set to 75F Once the infant is delivered, place infant skin-to-

skin on the maternal abdomen (or on the surgical drapes near the surgical incision

Initiate warming, drying, and stimulating Bulb suction of the airway as needed Continuous assessment by Neonatology and

Obstetrics regarding infant status and need for earlier cord clamping

Cord clamp at goal DCC time or earlier if clinically indicated.

Questions

References

Fogarty M, Osborn DA, Askie L, Seidler AL, Hunter K, Lui K, et al. Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis. Am J Obstet Gynecol. Elsevier Inc; 2018 Jan 1;218(1):1–18.

Tarnow-Mordi W, Morris J, Kirby A, Robledo K, Askie L, Brown R, et al. Delayed versus Immediate Cord Clamping in Preterm Infants. N Engl J Med. 2017 Dec 21;377(25):2445–55.

Rabe H, Diaz-Rossello JL, 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. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD003248.

Wang M, Mercer JS, Padbury JF. Delayed Cord Clamping in Infants with Suspected Intrauterine Growth Restriction. The Journal of Pediatrics. 2018 Oct;201:264–8.

McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Pregnancy and Childbirth Group, editor. Cochrane Database of Systematic Reviews. 2013 Jul 11;5(4):319–96.

Backes CH, Huang H, Cua CL, Garg V, Smith CV, Yin H, et al. Early versus delayed umbilical cord clamping in infants with congenital heart disease: a pilot, randomized, controlled trial. J Perinatol. 2015 Jul 30;35(10):826–31.

Vural I, Ozdemir H, Teker G, Yoldemir T, Bilgen H, Ozek E. Delayed cord clamping in term large-for-gestational age infants: A prospective randomised study. J Paediatr Child Health. 2018 Oct 4.

De Paco C, Herrera J, Garcia C, Corbalán S, Arteaga A, Pertegal M, et al. Effects of delayed cord clamping on the third stage of labour, maternal haematological parameters and acid–base status in fetuses at term. Eur J Obstet GynecolReprod Biol. Elsevier Ireland Ltd; 2016 Dec 1;207:153–6.

Andersson O, Domellöf M, Andersson D, Hellström-Westas L. Effect of Delayed vs Early Umbilical Cord Clamping on Iron Status and Neurodevelopment at Age 12 Months. JAMA Pediatr. 2014 Jun 1;168(6):547–8.

Andersson O, Lindquist B, Lindgren M, Stjernqvist K, Domellöf M, Hellström-Westas L. Effect of Delayed Cord Clamping on Neurodevelopment at 4 Years of Age. JAMA Pediatr. 2015 Jul 1;169(7):631–8.

Nesheli HM, Esmailzadeh S, Med MHJP, 2014. Effect of late vs early clamping of the umbilical cord (on haemoglobin level) in full-term neonates. Journal of Pakistan Medical Association.

Mercer JS, Erickson-Owens DA, Deoni SCL, Dean DC, Collins J, Parker AB, et al. Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial. The Journal of Pediatrics. 2018 Dec;203:266–272.e2.

Purisch SE, Ananth CV, Arditi B, Mauney L, Ajemian B, Heiderich A, Leone T, Gyamfi-Bannerman C. Effect of Delayed vs Immediate Umbilical Cord Clamping on Maternal Blood Loss in Term Cesarean Delivery: A Randomized Clinical Trial. JAMA. 2019 Nov 19;322(19):1869-1876.

References

Katheria A, Truong G, Cousins L, Oshiro B, Finer N. Umbilical Cord Milking Versus Delayed Cord Clamping in Preterm Infants. Pediatrics. 2015 Jul;136(1):61-9.

Katheria A, Garey D, Truong G, Akshoomoff N, Steen J, Maldonado M, Poeltler D, Harbert M, Vaucher YE, Finer N. A Randomized Clinical Trial of Umbilical Cord Milking vs Delayed Cord Clamping in Preterm Infants: Neurodevelopmental Outcomes at 22-26 Months of Corrected Age. J Pediatr. 2018 Mar;194:76-80.

Katheria A; Reister F; Essers J; Mendler M; Hummler H; Subramaniam A; Carlo W; Tita A; Truong G; Davis-Nelson S; Schmölzer G; Chari R; Kaempf J; Tomlinson M; Yanowitz T; Beck S; Simhan H; Dempsey E; O'Donoghue, K; Bhat S; Hoffman M; Faksh A; Arnell K; Rich W; Finer N; Vaucher Y; Khanna, P; Meyers M; Varner M; Allman P; Szychowski J; Cutter G. Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants. JAMA, November 19, 2019, Vol.322(19), pp.1877-1886