MANUSCRIPT CITATION

Armstrong-Buisseret L, Powers K, Dorling J, Bradshwa L, Johnson S, Mitchell E, Duley L. Randomised trial of cord clamping at very preterm birth: outcomes at 2 years. Arch Dis Child Fetal Neonatal Ed 2019, Aug 1; doi:10.1136/archdischild-2019-316912. PMID 31371434.

REVIEWED BY

Franziska Belling-Dierks, MD
University Children’s Hospital, University of Wuerzburg, Wuerzburg, Germany

Kirsten Glaser, MD
University Children’s Hospital, University of Wuerzburg, Wuerzburg, Germany

TYPE OF INVESTIGATION

Prevention, Treatment

QUESTION

In (P) preterm infants born to women expected to have a live birth before 32 weeks, does
(I) delayed cord clamping after at least 2 minutes  (C) compared to immediate clamping within 20 s (O) affect the composite outcome measure of death or adverse neurodevelopmental outcome (T) at two years corrected age?

METHODS

• Design: multi-center, randomized controlled trial. Trial registration number ISRCTN21456601.
• Allocation: Allocation concealed using opaque envelopes Sequence generation 1:1.
• Blinding: Unblinded
• Follow-up period: Infants were followed up to 2 years corrected age.
• Setting: Eight UK tertiary maternity units with a neonatal intensive care unit.
• Patients:
  • Inclusion criteria:
    • Preterm infants born to women expected to have a live birth before 32 weeks
    • Written informed consent prior to birth or two-stage consent pathway when birth was imminent (oral informed consent during labor or before caesarian section and written consent after birth)
  • Exclusion criteria:
    • Monochorionic twins
    • Triplets or higher-order multiple pregnancy
    • Known major congenital malformation
    • Withdrawn consent
    • Insufficient follow up data (e.g. loss to follow-up)
• Intervention:
  • Delayed cord clamping group: deferred cord clamping after at least 2 minutes and, if needed, immediate neonatal stabilization and resuscitation with cord intact.
  • Control group: immediate clamping within 20 seconds and, if needed, neonatal stabilization and resuscitation after clamping.
• Outcomes:
  • Primary outcome: composite of death or adverse neurodevelopmental outcome at 2 years corrected age.
  • Neurodevelopmental outcomes were classified using the Bayley-III scores (Bailey scales of Infant and Todler Development, Third Edition), if available, and/or the parent-completed Ages and Stages Questionnaire-3 (ASQ-3). If none of them were available, routine clinical data for 2-years outcomes were used.
  • Moderate or severe adverse neurodevelopmental outcome was defined as:
    • Bayley-III scores < 85, in any one of five functions: motor, cognitive, speech/language, hearing or vision, or
    • a total score > 2 standard deviations below the mean in any of the ASQ-3 domains hearing, vision and gross motor function.
  • Secondary outcomes: each individual component of the composite, meaning death or adverse neurodevelopmental outcome at 2 years corrected age
• Analysis and Sample Size: Initially created as a feasibility study. No formal sample size calculation done. All data were analyzed following an intention-to-treat protocol. After randomization of 261 women and exclusion of 6 babies due to birth after 36 weeks´ of gestational age each group comprised 135 infants.
• Patient follow-up: Primary outcome data were available for 218/270 enrolled infants (80.7%): 115/135 (85.2 %) children in the delayed cord clamping group and 103/135 (76.3 %) in the control group. 194 study patients were assessed at two years corrected age. Of these, Bayley-III data were obtained in 61.3 % of cases (119/194), with 20% of them being incomplete (24/119) leaving valid Bayley-III results in 48.9 % of cases (95/ 194). ASQ-3 data were available in 76.2% of children (148/194). In 39/194 children (20.1 %) only routine clinical data were obtained.

MAIN RESULTS

Baseline characteristics: The incidence of caesarean section was slightly higher in the delayed cord clamping group (64% vs. 54% in the immediate clamping group). Sepsis rates were minimally increased in the immediate cord clamping group (63% vs. 52% in the deferred clamping group). Demographic and neonatal outcome characteristics (including mother´s age at birth, gestational age (GA), sex, presence of high-grade intraventricular hemorrhage, periventricular leucomalacia, sepsis and duration of hospital stay) otherwise did not differ among the study groups. Median GA at birth was 29 weeks in both groups.

Primary outcome: Overall, 24/115 (21%) neonates allocated delayed clamping died or had an adverse neurodevelopmental outcome at 2 years corrected age compared with 35/103 ( 34%) infants allocated immediate clamping (risk difference -13%, [95% CI (-25 % to -1 %)]).

Primary outcome

Secondary outcomes: In the delayed clamping group, 8/115 neonates died compared to 16/103 in the immediate clamping group (risk difference -9 %,[95% CI (-17 % to -0 %)]). Of children alive at 2 years corrected age, 16/107 (15%) allocated deferred clamping had an adverse neurodevelopmental outcome versus 19/87 (22%) allocated immediate clamping (risk difference -5 %, [95% CI (-14 % to 5 %)]). Most common type of adverse outcome was speech/language and cognitive impairment.

Secondary outcomes

CONCLUSION

The authors conclude that delayed cord clamping may reduce the risk of death or adverse neurodevelopmental outcome at 2 years corrected age compared with immediate clamping. To confirm potential benefits and harms further studies are needed.

COMMENTARY

Delayed cord clamping (DCC) has already been established in healthy term infants (1), and there is growing evidence that DCC might also have beneficial effects in preterm infants (1-4). Current ERC guidelines recommend DCC for at least 30 seconds in preterm infants who do not need resuscitation (5). So far, approaches of incorporating DCC into stabilization or resuscitation of preterm infants have not been widely established. However, stabilization of preterm infants with umbilical cord intact, has been described in individual studies (2, 3, 6, 7) but long term followup data are scarce.

This prospective randomized trial compared DCC after at least 120 seconds and immediate neonatal care with cord intact, with prompt cord clamping within 20 seconds followed by neonatal care, evaluating the survival and neurodevelopmental outcome at two years corrected age. Short-term outcomes of enrolled infants were published separately (7). Initially created as a feasibility study, no formal sample size calculation was done. Neurodevelopmental outcome was assessed by means of Bayley-III Scale and/or parent-completed ASQ-3 questionnaire, if available; otherwise by routine clinical data.

Study design aimed at delaying cord clamping for at least 2 minutes and was achieved in 60% of patients (8). This time-based approach of cord clamping contrasts with studies favoring physiological-based cord clamping (PBCC), this fact highlighting the ongoing search for optimal time of clamping (1-3).

The study showed a non-significant decrease in the compound measure of mortality or adverse neurodevelopmental outcome in the DCC group. Regarding adverse neurodevelopmental outcome alone there were no differences between the two groups. Despite a tendency toward better outcome at 2 years corrected age in the DCC group, a higher loss to follow-up was observed in infants with poor outcome at discharge in the DCC group.

Strengths of the present study include its prospective character, the inclusion of preterm infants and its focus on long term neurodevelopmental follow up. However, median GA was 29 weeks in both groups, and only a minority of infants (13%) was born below 26 weeks’ GA (7). Heterogeneity of assessment and classification of neurodevelopmental outcome as well as missing data are important limitations of this study. Overall data were available in 80.7 % of cases; valid Bayley-III results exist in nearly half of all infants. The remaining data were assessed by means of ASQ-3 parents’ questionnaire potentially lacking objectivity, and in a minority of cases by means of routine clinical data. However, ASQ-3 questionnaires have been evaluated as a screening tool in neonatal neurodevelopmental follow-up(9).

In conclusion, this study reported neurodevelopmental outcome at 2 years corrected age in a large proportion of infants. However, assessment was heterogenous and the study was not sufficiently powered to allow for proper analyses of benefits and harms of DCC in preterm infants, thus hampering meaningful conclusions on outcome. Further randomized controlled trials adequately designed and powered to assess short-term and long-term outcomes are needed.

REFERENCES

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8. Te Pas AB. Timing is everything. Arch Dis Child Fetal Neonatal Ed. 2018; 103:F2-F3
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