Impact of Different Cord Clamping Strategies on Short Term Neuromonitoring Among Preterm Infants: A Randomized, Controlled Trial

Impact of Different Cord Clamping Strategies on Short Term Neuromonitoring Among Preterm Infants: A Randomized, Controlled Trial

Manuscript citation: Finn D, Ryan DH, Pavel A, O'Toole JM, Livingstone V, Boylan GB, et al. Clamping the Umbilical Cord in Premature Deliveries (CUPiD): Neuromonitoring in the Immediate Newborn Period in a Randomized, Controlled Trial of Preterm Infants Born at <32 Weeks of Gestation. The Journal of pediatrics. 2019 May; 208:121-6 e2.

Reviewed by:

Prashant Agarwal¹, Amit Sharma¹, Ahmad Farooqi², Girija Natarajan¹

¹Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Children’s Hospital of Michigan/Wayne State University, Detroit, MI, USA

²Children's Research Center of Michigan, Department of Pediatrics, Children’s Hospital of Michigan/Wayne State University, Detroit, MI, USA

Corresponding Author:

Prashant Agarwal

3901 Beaubien Street

Wayne State University School of Medicine/Children’s Hospital of Michigan, Detroit, MI

313-745-5638; [email protected]

Keywords: Cord clamping, premature, neuromonitoring, randomized trial
Type of investigation:  Interventional trial

Question:

Do premature infants (<32 weeks gestation) undergoing delayed cord clamping for 60 sec or cord milking (cord stripped 3 times) or immediate cord clamping have different 1-hour quantitative measurement of electroencephalogram (EEG) and near infrared spectroscopy (NIRS) at 6 and 12 hours of life

Methods:

Design: Single center, Prospective, Randomized, controlled clinical trial

Blinding: Intervention not blinded. EEG reader blinded to infant randomization

Setting: Single center, University NICU. Study period- December 2015 to September 2016

Patients:  Inclusion criteria: Gestational age <32 weeks. Exclusion criteria: Major congenital anomalies, bleeding from placenta previa, placental abruption or accrete, twin-to-twin transfusion syndrome, hydrops, and cord prolapse

Intervention: Infants were randomized into three groups: immediate cord clamping (within 20 seconds of delivery), umbilical cord milking (cord stripping 3 times), and delayed cord clamping (at 60 seconds after delivery with neonatal resuscitation in mobile resuscitation trolley). All infants underwent EEG and NIRS for the first 72 hours after birth.

Outcomes:

• Primary outcome: (1) Quantitative measures of median EEG and cerebral oxygenation values detected by cerebral NIRS, over 1- hour time frames at 6 and 12 hours of age , (2) Maternal hemoglobin at 24 to 36 hours post-partum
• Secondary outcome: Temperature on admission, hemoglobin at 12 hours of age, mean blood pressures, echocardiographic measurements of systemic blood flow, intraventricular hemorrhage, bronchopulmonary dysplasia.

Analysis and Sample size: Sample size calculation was not performed due to unavailability of previous data in preterm populations on EEG and NIRS monitoring with different cord clamping strategies. Forty-five infants were recruited during the study period. Kruskal-Wallis test was used for continuous variables and Fisher exact test was used for categorical variables. Multiple linear regression was performed to adjust for effect of gestational age on primary outcome. Linear mixed model was used to assess influence of different time points on outcome. Intention-to-treat analyses were conducted  

Main Results:

Table 1: Primary outcome – Quantitative measures of EEG and NIRS at 6 and 12 hours of age.

*Simple linear regression, independent variable – group

^¶ multiple linear regression, independent variables – group and gestational age

There was no difference in infant measures of EEG or NIRS at 6 or 12 hours of age, or in maternal hemoglobin among the groups. Also there was no difference among the groups in gestation age or other secondary outcomes.

Study Conclusion:

In this study of different cord management strategies among preterm infants, there were no differences in cerebral EEG activity and cerebral oxygenation at 6 and 12 hours of age.

Commentary:

The American College of Obstetricians and Gynecologists recommendation of a delay of 30-60 seconds in umbilical cord clamping for all vigorous preterm infants(1) was endorsed by the American Academy of Pediatrics in 2017. There is still uncertainty, though, about the best method of cord management in situations where the infant is non-vigorous and needs resuscitation. Mobile resuscitation trolleys, as used in the current study, allow for delayed cord clamping (DCC) to be done even among infants needing immediate resuscitation(2). Umbilical cord milking (UCM) is another technique that could allow for quick placental transfusion without delaying resuscitation and can be used as an alternate to DCC(3).

In the recently published Cochrane meta-analysis of umbilical cord management strategies among preterm infants, DCC was shown to probably decrease mortality before discharge when compared to immediate cord clamping (ICC)(4). DCC was also associated with slight reduction in any grade intraventricular hemorrhage (IVH), but little or no difference was seen in severe IVH, as compared to ICC. Data on neurodevelopment outcomes after DCC are inconsistent and less robust (5, 6). Since UCM allows for quick placental transfusion, it is considered as an alternative to DCC, However, a recent noninferiority randomized controlled trial assessing the difference in rates of death or IVH between DCC and UCM, was stopped early due to higher rate of death or IVH in the UCM group (8% vs 3%) (7).  

In the current study, the authors evaluate the impact of different cord clamping strategies on short term neurologic outcomes, by measuring cerebral activity and cerebral oxygenation. Sample size calculations were not performed, due to unavailability of similar previous data. However, relatively small number of infants in each of the three groups was one of the major limitations of this study, with only 3 infants in the entire cohort developing severe IVH. There were no statistically significant differences noted in hemoglobin levels or markers of systemic blood flow with different cord clamping strategies, although a Type 2 error was certainly possible. The under-powering was also compounded by multiple comparisons, unequal sample size in the three groups and the lack of adjustment for important differences between groups, most importantly the proportion of multiples. Mortality data were not reported in the current study. Another limitation of this study was lack of neuromonitoring in the delivery room. DCC and UCM increase placental transfusion, allow ventilation to be established before cord clamping, and improve cardiovascular transition after birth(8). Some studies have shown association of low delivery room cerebral oxygen tissue saturation with development of IVH in preterm infants(9) with no difference in cerebral oxygenation at later times(10). Delivery room neuromonitoring with different cord clamping strategies could provide more insight in the understanding of physiology leading to short term neuroprotection (decreased IVH risk) with DCC.

The strengths of the current study are the novel and detailed outcomes measures and the randomized controlled study design comparing three umbilical cord clamping strategies. Larger studies with neuromonitoring starting in the delivery room and continued for the first few days of life are needed to understand the physiologic effects of different cord clamping strategies. However, given the demonstrated significant benefits of delayed cord clamping, future trials with immediate cord clamping group might not be ethically feasible. Further studies comparing physiological effects of different durations of delayed cord clamping, and assisted ventilation prior to cord clamping are also needed.

EBM lesson: Linear mixed model

Mixed models are the type of regression models used to analyze the data that are correlated, e.g., multiple systolic blood pressure measurements taken from the same subjects at different periods of time. Mixed models are especially useful when working with a within-subject design, e.g., patients nested within the wards, or repeated measurements on each subject over time or space, or multiple related response measures at one point of time; this allows mixed models to systematically account for item-level variability (within subjects) and subject-level variability (within groups).  Mixed models provides a general, flexible approach in these situations, because it allows a wide variety of correlation patterns such as linear or curvilinear correlations, to be explicitly modeled and incorporate both fixed and random effects in the same analysis. Linear mixed model is useful when repeated measurements are made on the same individual or cluster and allows for the incorporation of random effects to account for the correlation among repeated measures. It is to be noted that, subject effects are usually random effects, as they represent the general variability among the subjects, while treatment levels and other variables besides the treatment can be considered as fixed effects telling us how unknown population means differ between any set of treatments.

In this study, linear regression and linear mixed model were used to evaluate the difference among the groups along with the influence of different time points (6hr and 12 hr), on group differences for EEG and NIRS. Gestational age, age at evaluation, group, and group-by-time interaction were set as fixed effects, while the infant was a random effect.

Acknowledgment:  

The Journal club is a collaboration between the American Academy of Pediatrics- Section of Neonatal Perinatal medicine and the International Society of Evidence- based neonatology (EBNEO.org)

Conflict of Interest: None declared

References:

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