OBJECTIVE. Our goal was to investigate the effect of placentofetal transfusion on cerebral oxygenation in preterm infants by near-infrared spectroscopy.

SUBJECTS. A total of 39 preterm infants with a median gestational age of 30.4 weeks were randomly assigned to an experiment group (*n* = 15) and a control group (*n* = 24).

INTERVENTIONS. The delivery of the infants in the experiment group was immediately followed by maternal administration of syntocinon, the infant was placed 15 cm below the placenta, and cord clamping was delayed by 60 to 90 seconds. The infants in the control group were delivered conventionally. At the ages of 4 and 24 hours, cerebral hemoglobin concentrations, cerebral blood volume, and regional tissue oxygenation were measured by near-infrared spectroscopy.

RESULTS. Cerebral blood volume was not different between the 2 groups at the age of 4 hours (6.1 vs 5.8 mL/100 g of tissue) nor at the age of 24 hours (6.2 vs 6.2 mL/100 g of tissue). Mean regional tissue oxygenation of the experiment group was higher at the ages of 4 hours (69.9% vs 65.5%) and of 24 hours (71.3% vs 68.1%).

CONCLUSION. Delayed clamping of the umbilical cord improves cerebral oxygenation in preterm infants in the first 24 hours.

Comments IconComments (1)To the editor:

We read with interest the article by Baenziger and colleagues entitled “Delayed Cord Clamping and Cerebral Oxygenation”, published in the March Edition of the

Pediatrics.[1] While the conclusion of the study is tantalizing (“delayed cord clamping increases cerebral oxygenation for the first 24 hours after birth”), it also generated a number of questions that mostly relate to basic statistics.It is undeniable that [brain] tissue oxygen saturation (StO

_{2}, also known as “TOSc”) was higher in the experimental versus the control group, as demonstrated by the p < 0.05 at both 4hrs and 24hrs (using Mann-Whitney U test). Nevertheless, we question whether it “clearly demonstrates a [clinically significant] higher cerebral tissue oxygenation in the experimental group.” As pointed out by Kain and MacLaren in the same Edition ofPediatricsin their enlightening article about p values, it is very important to determine “if the difference of primary end points between group is meaningful to a patient.”[2] The real question in this case, which relates to biological plausibility, is whether one expects that a 4-6% StO_{2}difference is enough to promote better outcomes (at 4hrs: 69.8% vs. 63.4%; at 24hrs: 71.4% vs. 67.1%)? The conclusion of the authors would obviously be considerably strengthened if they uncovered differences in short- and/or long-term neurological outcomes between the two groups.On this note, we were particularly intrigued by the fact that the standard deviations (SD) for StO

_{2}mentioned in the current article is much smaller than that published in previous reports by the same team, using similar technology (Critikon 2020 Cerebral RedOx Monitor) and methodology for StO_{2}measurements (‘Critikon algorithm’).[3] While the mean gestational ages (GA) were similar (29.9 wks vs. 30.5 wks), the GA ranges were slightly different (24-32 wks vs. 25-36 wks). The weighted estimate SD in the current study is 1.39% (see Table 1); we will use 1.5% hereafter to simplify calculations.Table 1

Article

Groups

StO2/TOSc (%)

SDs (%)

2007 (StO

_{2})Experiment (n = 15)

4 hours

69.81

1.53

24 hours

71.36

1.34

Control (n=24)

4 hours

63.37

1.46

24 hours

67.07

1.26

Weighted estimate SD from both groups

1.39

2000 (TOSc)

Experiment (n = 20)

64.7

7.2

For example, while the SD in the current report is 1.5% (n=39), the SD was in the order of 7.2% in another study published in 2000 (n=20).[3] Since the patient populations in both studies were comparable, it seems unlikely that a mere doubling in sample size would result in such dramatic improvement in SD. Although it is possible that the slightly tighter GA range in the current study may have resulted in less inter-patient variability, it seems implausible to explain the degree of change observed.

The simplest way to approach this interesting statistical conundrum is to use a formula designed to provide the expected impact of increasing the sample size on the SD: the SD is multiplied by 1/ (sq. root x), where x is the ratio of the sample size of the new study over that of the previous one. For our purpose, this would mean that doubling of the sample size (39/20) should reduce the SD by 1/(sq. root 2). Thus, if only the sample size is changed, and the patient population and methodology remained unaltered, we would have expected a reduction in the SD from 7% to about 5% (hereafter referred as the ‘expected SD’). This corresponds to the inherent variability change (in this case, a reduction) that one would predict from modification of the sample size alone.

An alternative way to analyze this situation is to calculate the actual variability reduction observed between both studies. Unfortunately, direct comparison of the SDs is an inadequate tool for this purpose since it does not take into account the relative sample sizes. However, comparison of the extent of data spread around the means should provide us with a close reflection of sampling variability. This is achieved by calculating the sums of squared deviations from the means [SUM (x - x

_{mean})^{2}] using the equations for variance and SD as follows:SD = sq. root variance

Variance = SUM (x - x

_{mean})^{2}/ n -1Where SUM (x - x

_{mean})^{2}computes the sum of the differences between each measurement and the mean (the difference is then squared to insure that there are no negative values), divided by n - 1 (where ‘n’ is the sample size).To get an estimate of the of sum of squared deviations from the means of each study, we solve the equation for SUM (x - x

_{mean})^{2}:SUM (x - x

_{mean})^{2}= SD^{2}x (n-1)As demonstrated in Table 2, an impressive 9-fold reduction in sampling variability is obtained from the numbers provided by the authors. Using the ‘expected SD’ calculated above, and feeding it in the same set of equations, we note that despite a reduction in SD of 2%, the sampling variability is unchanged since the ratio is near unity (0.98). This is precisely what one would expect if the same methodology is used since the built-in sources of error have not changed (but are more consistent owing to larger number of samples).

Table 2

n-1

SD

SD

^{2}SD

^{2}x (n-1)SUM (x - x

_{mean})^{2}_{2000}/ SUM (x - x_{mean})^{2}_{NEW}2000 study

19

7%

49

931

2007 study

38

1.5%

2.25

85.5

9.25

2000 vs. 2007

“Expected”

38

5%

25

950

0.98

2000 vs. expected

Unless the authors have made some unstated technical improvement is measuring StO

_{2}, it is unclear why such a remarkable reduction in sampling variability occurred. While we do not question the validity of the results presented, it is undeniable however that such significant reduction of the SD must translates into increased likelihood of obtaining statistically significant p values.This issue is particularly puzzling given the fact that the authors’ own conclusion in the previous study (2000) was that there was “a highly significant unexplained inter-patient variability, which is the major drawback of [the method].”[3] A recent review from 2003 corroborates that the “highly significant inter-patient variability” undermines the “clinical value of TOS measurements.”[4]

We would appreciate if the authors could comment on these issues.

Mathieu Lemaire, MDCM MSc

Pediatric Nephrology Fellow

Hospital for Sick Children

Toronto, Canada

References:

[1] Baenziger O et al. (2007) Delayed Cord Clamping and Cerebral Oxygenation. Pediatrics 119(3):455-459.

[2] Kain ZN & MacLaren J (2007) P less then .05. Pediatrics 119(3):608-610.

[3] Wolf M et al. (2000) Tissue oxygen saturation measured by near infrared spectrophotometry correlates with arterial oxygen saturation during induced oxygenation changes in neonates. Physiol Measur 21:481-491.

[4] Nicklin SE et al. (2003) The light still shines, but not that brightly? The current status of perinatal near infrared spectroscopy. Arch Dis Child 88(4):263-268.

## Conflict of Interest:

None declared