MANUSCRIPT CITATION
Katheria AC, El Ghormli L, Clark E, Yoder B, Schmölzer GM, Law BHY, et al. Two-Year Outcomes of Umbilical Cord Milking in Nonvigorous Infants: A Secondary Analysis of the MINVI Randomized Clinical Trial. JAMA Netw Open. 2024 Jul 1;7(7):e2416870. doi: 10.1001/jamanetworkopen.2024.16870. PMID: 38949814; PMCID: PMC11217871.
REVIEWED BY
Dyanne Ifeoma Imo-Ivoke
Joanna Preece
TYPE OF INVESTIGATION
Prognosis
QUESTION
Among non-vigorous term and near-term newborns, does umbilical cord milking, compared with early cord clamping at birth, result in long term neurodevelopmental sequelae?
METHODS
• Design: Preplanned secondary analysis of a cluster randomised crossover trial.
• Allocation: Near-term and full-term infants aged 35 – 42 weeks gestational age (GA) at birth who were non-vigorous were allocated to Early Cord Clamping (ECM) or Umbilical Cord Milking (UCM) based on the hospital where they were born. Hospitals were allocated to ECC or UCM for a year and then crossed over.
• Blinding: None (Open Label).
• Follow-up period: 2 years.
• Ethics: The researchers had a waiver of informed consent for the primary trial. For the secondary analysis, consent was taken for long-term follow-up.
• Setting: The research took place in 10 medical centres in 3 countries (7 in the United States, 2 in Canada and 1 in Poland).
• Patients: 16,234 newborns were screened. 1730 were enrolled in the Milking in the Nonvigorous Infant (MINVI) trial. 1206 consented to follow-up. 971 babies were analysed in this secondary analysis (502 in UCM vs 469 in ECM).
• Eligible: 35–42 weeks’ gestation dated by best obstetrical estimate using earliest ultrasound or last menstrual period, and were non-vigorous at birth who had consented to long-term follow-up.
1. Inclusion: Non-vigorous, defined as poor tone, pale colour, or lack of breathing in the first 15 seconds after birth despite initial resuscitation efforts (stimulation, warmth, +/-suctioning) as per neonatal resuscitation program guidelines.
2. Exclusion: Babies were excluded if the following conditions were known before cord clamping: major fetal congenital or chromosomal anomalies; cardiac defects other than small ventricular septal defects; complete placental abruption or cutting through the placenta at the time of delivery; monochorionic multiples; cord anomalies, such as avulsion or true knots; the presence of a nonreducible nuchal cord, incomplete delivery data to determine eligibility or if delivered by an obstetric provider not trained in the study protocol.
• Intervention:
1. Umbilical cord milking, which is the milking of 20cm of cord over 2 seconds a total of 4 times (Intervention group)
2. Early cord clamping, which is the clamping of the umbilical cord within 60 seconds of birth (Control group)
• Outcomes:
1. Primary outcome: abnormal development scores on the Ages and Stages Questionnaires, 3rd edition (ASQ-3; range 0 – 300 points) and percentage of children with medium-to high-risk scores on the Modified Checklist for Autism in Toddlers, Revised / Follow-up )M-CHAT-R/F; range 0 – 20 points) at 2 years.
2. Secondary outcomes: None
• Analysis and Sample Size: A sample size of 1200 was estimated as necessary to test the efficacy of UCM versus ECC in the MINVI primary trial.
1. Descriptive statistics were used, with the Wilcoxon rank-sum test for continuous variables and the χ2 test for categorical variables.
2. The study was designed to provide at least a power of 80% to detect a small effect size
3. Analysis was conducted using a hierarchical generalised linear mixed model to account for the study design, with fixed treatment group effect, fixed period effect, random cluster effect, and random cluster x period effect.
4. All models also included adjustments for child sex and maternal educational level.
5. Least-square mean differences for the continuous outcome, odds ratios for the categorical outcome, and 95% CI were estimated.
6. Analysis was performed with the use of SAS software, version 9.4
• Patient follow-up (% included in the analysis): At 2 years, 971 participants (81% of MINVI trial babies consented to long-term follow-up) had ASQ-3 scores completed or died.
927 participants (77% of MINVI trial babies who consented to long-term follow-up) also had modified checklists for autism in toddlers.
MAIN RESULTS
Both groups had a median gestational age of 39 weeks (IQR, 38 – 49). There was no significant difference in the maternal and neonatal characteristics between the treatment and the control group.
Please Refer to Table 1 in the original manuscript
The 971 infants included in this secondary analysis were most likely to have been born by caesarean delivery, have older mothers, and have a higher maternal educational level compared with the 759 infants not evaluated for neurodevelopment. All other maternal and neonatal characteristics were similar between those included in the analysis and those excluded. Similar results were observed for the 927 infants included in the M-CHAT-R/F analysis.
The two groups had no significant differences in ASQ-3 subdomains and total scores. The Least squares mean difference in ASQ-3 total scores was -0.49 (95% CI, -6.36 to 5.37). In the infants ( 4% – 11%) with subnormal ASQ-3 scores across the subdomains (score > 2 SD below the mean), there was no significant difference between both groups.
There was also no significant difference in the percentage of infants with medium to high-risk M-CHAT-R scores at 2 years (9% in UCM vs 8% in ECC). The odds ratio for M-CHAT-R >2 points 1.08 (95% CI, 0.45 to 2.59).
CONCLUSION
The authors concluded that in late-term and full-term infants who are nonvigorous at birth, there was no significant difference in long term neurodevelopment sequelae. Additionally, the noted short-term benefits of UCM from the MINVI trial makes UCM a desirable and feasible intervention.
COMMENTARY
Close to term, about a third of the fetal blood volume is within the placenta at any time.(1) At birth, blood flow in the umbilical vessels continues for some minutes, allowing the transfusion of blood within the placenta bed to the baby. This can transfer 20 – 30% of additional blood volume to the baby at birth and can be achieved by delayed (deferred) cord clamping, DCC or umbilical cord milking. DCC, which is cutting the cord after 60 seconds, is the preferred cord management method in all newborns. UCM offers similar benefits and is recommended for babies over 28 weeks GA (2) (not recommended in <28 weeks due to concerns of intraventricular haemorrhage). DCC and UCM offer benefits such as increased haemoglobin levels, less delivery room cardiovascular support and lower incidence of moderate-severe hypoxic-ischaemic encephalopathy compared to early (immediate) cord clamping.
Most late preterm (GA between 34+0 and 36+6) and term babies are born in good condition and may only require an assisted transition. In some cases, babies may be born in poor condition, or the mother may require prompt lifesaving actions. In these cases, waiting for 60 seconds may not be possible, and the Resuscitation Council of UK supports milking the umbilical cord in babies >28 weeks GA.(3) The initial actions of drying and stimulating the baby, are parts of the newborn life support (NLS) and can be done while the baby is still attached to the cord. There is no clear evidence of the superiority of cord milking from an intact cord compared to the cut cord, but concerns exist about the effects of clamping the cord before the onset of respiration.(4)
While the short-term benefits of DCC and UCM are widely known, there is not enough data on the long-term sequelae. This study is the largest RCT showing the long-term safety of UCM in babies born at > 35 weeks GA and improves our knowledge of the long-term safety of UCM. Also, it has a high follow-up rate, is a multicentre cross-over trial, thereby limiting bias5, and includes babies born in North America and Europe, making it a desirable study.
This study has some limitations. Parental education plays a role in health outcomes and is variable in the population. However, most babies in this secondary analysis were born to parents with good school education, which can be a limitation when applying this to the general population. Waiver of consent for the primary trial but asking informed consent for the secondary analysis could have introduced some bias as most of the babies included in the secondary analysis had parents with higher educational level. Additionally, UCM is a low-cost intervention, and this study would be most beneficial to low-resource countries where more babies may be nonvigorous at birth due to poor antenatal care. With the study conducted in high-income academic centres where most mothers have sufficient prenatal care, applying this study to low-resource countries may be challenging as there may be different haemodynamic adaptations due to undetected chronic hypoxia.
REFERENCES
1. Linderkamp O. Placental transfusion: determinants and effects. Clin Perinatol. 1982 Oct;9(3):559-92. PMID: 6761038.
2. Katheria A, Reister F, Essers J, Mendler M, Hummler H, Subramaniam A, et al. Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants. JAMA. 2019 Nov 19;322(19):1877-1886. doi: 10.1001/jama.2019.16004. PMID: 31742630; PMCID: PMC6865839.
3. Fawke F, Cusack J, editors. Advanced Resuscitation of the Newborn Infant. 2nd Edition. London. Resuscitation Council of UK. 2021. Page 14.
4. Ersdal HL, Linde J, Mduma E, Auestad B, Perlman J. Neonatal outcome following cord clamping after onset of spontaneous respiration. Pediatrics. 2014 Aug;134(2):265-72. doi: 10.1542/peds.2014-0467. Epub 2014 Jul 14. PMID: 25022738.
5. Katheria AC, Clark E, Yoder B, Schmölzer GM, Yan Law BH, El-Naggar W, et al. Umbilical cord milking in nonvigorous infants: a cluster-randomized crossover trial. Am J Obstet Gynecol. 2023 Feb;228(2):217.e1-217.e14. doi: 10.1016/j.ajog.2022.08.015. Epub 2022 Aug 13. PMID: 35970202; PMCID: PMC9877105.
