The Effect of Timing of Cord Clamping on Neonatal

Venous Hematocrit Values and Clinical Outcome at

Term: A Randomized, Controlled Trial

 

Jose´ M. Ceriani Cernadas,  Guillermo Carroli,  Liliana Pellegrini,  Lucas Otano, Marina Ferreira,  Carolina Ricci,  Ofelia Casas,  Daniel Giordano, Jaime Lardiza´ bal,

 

Pediatrics 2006;117;779-786;

 

ABSTRACT

BACKGROUND. The umbilical cord is usually clamped immediately after birth. There is

no sound evidence to support this approach, which might deprive the newborn of

some benefits such as an increase in iron storage.

OBJECTIVES.We sought to determine the effect of timing of cord clamping on neonatal

venous hematocrit and clinical outcome in term newborns and maternal postpartum

hemorrhage.

METHODS. This was a randomized, controlled trial performed in 2 obstetrical units in

Argentina on neonates born at term without complications to mothers with

uneventful pregnancies. After written parental consents were obtained, newborns

were randomly assigned to cord clamping within the first 15 seconds (group 1), at

1 minute (group 2), or at 3 minutes (group 3) after birth. The infants’ venous

hematocrit value was measured 6 hours after birth.

RESULTS. Two hundred seventy-six newborns were recruited. Mean venous hematocrit

values at 6 hours of life were 53.5% (group 1), 57.0% (group 2), and 59.4%

(group 3). Statistical analyses were performed, and results were equivalent among

groups because the hematocrit increase in neonates with late clamping was within the

prespecified physiologic range. The prevalence of hematocrit at _45% (anemia) was

significantly lower in groups 2 and 3 than in group 1. The prevalence of hematocrit at

_65% was similar in groups 1 and 2 (4.4% and 5.9%, respectively) but significantly

higher in group 3 (14.1%) versus group 1 (4.4%). There were no significant differences

in other neonatal outcomes and in maternal postpartum hemorrhage.

CONCLUSIONS. Delayed cord clamping at birth increases neonatal mean venous hematocrit

within a physiologic range. Neither significant differences nor harmful

effects were observed among groups. Furthermore, this intervention seems to

reduce the rate of neonatal anemia. This practice has been shown to be safe and

should be implemented to increase neonatal iron storage at birth.

TIMING OF UMBILICAL cord clamping has been and still

is a highly controversial issue.1–4 The current obstetric

approach in Western medicine is to clamp the cord

within the first 10 to 15 seconds after birth. However,

there has been no sound evidence in favor of this approach

in comparison to the millennial practice of

clamping the cord between 1 and 3 minutes after birth.5,6

In some studies,7–9 it was observed that delayed cord

clamping could contribute to preventing iron-deficiency

anemia in the first year of life. A recent systematic

review confirms the benefit of delayed cord clamping.10

The reason for this effect is based on the fact that after

birth the newborn is delivered with a placental transfusion

of _80 mL of blood at 1 minute after birth and 100

mL at 3 minutes after birth.6,11–17 This volume will supply

40 to 50 mg/kg of extra iron to the _75 mg/kg of body

iron that newborn term infants have, reaching a total of

115 to 120 mg/kg, which might prevent iron deficiency

in the first year of life.4,8 Iron deficiency early in life may

have pronounced central nervous system effects such as

cognitive impairment18; iron deficiency is also the main

cause of anemia, one of the most serious conditions in

childhood, especially in developing countries.19

Conversely, some observational studies suggest that

delayed umbilical cord clamping puts newborns at

higher risk of suffering from polycythemia, respiratory

symptoms, hyperbilirubinemia, and other neonatal disorders.

14,20–24 However, there have been no randomized,

controlled trials showing the risk of these harmful effects

on the newborn.

In view of the above considerations, we performed a

prospective randomized, controlled clinical trial to determine

the benefits and risks of delayed cord clamping.

Our hypothesis was that delayed cord clamping (at 1

or 3 minutes after birth) in healthy term newborns

increases hematocrit within physiologic ranges without

causing any harmful effects. Umbilical cord clamping at

1 minute of life increases hematocrit in no more than 8

points compared with cord clamping in the first 15 seconds

after birth. Cord clamping at 3 minutes increases

neonatal hematocrit to a level no more than 8 points

compared with cord clamping at 1 minute after birth.

Our primary objective of the study was to determine

the effect of timing of umbilical cord clamping on venous

hematocrit in term neonates 6 hours after birth. Our

secondary objectives were to assess the effect of timing of

umbilical cord clamping on neonatal outcomes and on

the presence of unwanted effects in the newborn while

in the maternity ward and during the first month of life.

Venous hematocrit and plasma bilirubin levels at 24 to

48 hours of life and maternal postpartum blood loss

were measured also.

METHODS

This was a randomized, controlled trial performed in the

Hospital Italiano of Buenos Aires and Maternidad Martin

of Rosario; Centro Rosarino de Estudios Perinatales was

the coordinating center. The trial was approved by the

ethics committees of both hospitals (Hospital Italiano de

Buenos Aires, protocol number: 681/2002).

Women were eligible if they had uneventful cephalic

vaginal or cesarean section delivery with the following

characteristics: singleton pregnancy at term; no evidence

of clinical disease (diabetes, preeclampsia, hypertension)

or any other complications; and no evidence of congenital

malformations or intrauterine growth restriction (estimated

fetal weight _10th percentile).

Interventions

Three interventions for the newborns were compared:

early umbilical cord clamping (within the first 15 seconds

after birth), umbilical cord clamping at 1 minute

after birth, and at 3 minutes after birth. The latter 2

groups were regarded as delayed cord clamping. The

cord-clamping technique used in the 3 groups was similar.

The assigned intervention was considered as accomplished

if early cord clamping was performed within the

first 20 seconds after birth, delayed 1-minute cord clamping

at 45 to 75 seconds of life, and delayed 3-minute cord

clamping at _150 seconds after birth.

For vaginal deliveries, newborns assigned to delayed

cord clamping were held by mothers in their arms while

waiting for the cord to be clamped. In the case of cesarean

sections, newborns were placed on their mother’s

laps and swaddled to prevent heat loss. No additional

interventions were performed.

Newborns without spontaneous breathing during the

first 10 seconds of life, with major congenital malformations

diagnosed at birth, with estimated neonatal birth

weight _10th percentile, and/or with tight nuchal cord

were subjected to early cord clamping based on physician

discretion regardless of the assigned intervention.

Outcome Measures

The primary outcome measure was the newborn venous

hematocrit value 6 hours after birth. Secondary outcome

measures were neonatal hematocrit at 24 to 48 hours of

age, plasma bilirubin level at 24 to 48 hours of age, early

neonatal morbidity and mortality (tachypnea, respiratory

grunting, respiratory distress, jaundice, seizures,

sepsis, necrotizing enterocolitis, neonatal death), admission

to the NICU, newborn length of hospital stay, any

neonatal disease that occurred between birth and 1

month of age, weight and type of feeding at 1 month of

age, postpartum maternal blood-loss volume, and maternal

hematocrit value 24 hours after delivery. Pediatricians

assessing the outcomes were unaware of the

assigned interventions.

There is a general consensus that a venous hematocrit

level of _3.5 g/dL or 40% in the umbilical cord blood is

a synonym of anemia.25,26 However, taking into account

that in the first hours of life venous hematocrit and

hemoglobin values increase _10%, it was considered

clinically appropriate to define anemia as a venous hematocrit

level of _45% at 6 hours after birth. Polycythemia

in the newborn is defined as a venous hematocrit

of _65%.27

Procedures

Venous hematocrit in the newborn was measured in

blood drawn from the antecubital vein. Blood was collected

in 2 tubes sealed at one end with modeling clay.

Both tubes were filled up and centrifuged for 5 minutes.

Hematocrit was measured in an “ad hoc” graded scale

provided by the centrifuge manufacturer. Bilirubin was

measured following the Malloy and Evelyn technique.28

Every newborn included in the study was scheduled

to be followed up at 7, 14, and 28 days of life. During

these visits, neonates were followed up based on the

standard clinical approach; growth and development

were evaluated, and feeding patterns were recorded

also.

For the measurement of maternal blood loss, all vaginal

blood was collected immediately after the infant’s

delivery by placing a pan and pad under the woman’s

buttocks until she was transferred to the postpartum

ward. Collected blood was poured in a graded jar, and

blood volume was determined.

Sample Size

The average neonatal hematocrit level at 6 hours is

known to be _50% (SD: 7%) when the cord is clamped

early after birth and _55% (SD: 7%) when the cord is

clamped at 1 minute after birth. Sample sizes were calculated

to show that the hematocrit level when cord

clamping at 1 minute of life is within 8 U of the hematocrit

level obtained with early clamping. In that case, the

2 groups will be considered as equivalent. Similar calculations

were made assuming a mean neonatal hematocrit

level at 6 hours of _60% (SD: 7%) when the cord is

clamped at 3 minutes after birth, an equivalent limit of 8

U was used for the comparison with the group assigned

to cord clamping at 1 minute after birth. Using an _ error

of 5% and a statistical power (1 _ _) of 80%, the

number of patients to be studied is 70 in each group, for

a total of 210 newborn infants.

Statistical Analysis

The information collected through the data forms was

entered in a database by different operators using the

double-entry technique. These operators also checked

for and validated inconsistencies. Case charts were reviewed

whenever a flaw was detected. Means and SDs

were used as descriptive measures for continuous variables

with normal distributions, and medians and quartiles

were used when the normality assumption was not

acceptable. Frequencies and percentages were reported

for categorical variables. Hematocrit levels were compared

among groups by using confidence intervals (CIs)

for differences in averages.29 The Bonferroni method was

used for multiple comparison adjustments. The normality

assumption for the distribution of hematocrit levels

within groups was checked by using the Shapiro-Wilk

test.30 Categorical variables were compared among

groups by using relative risks (RRs), and the Fisher’s

exact test was used to assess that statistical significance of

comparisons. Continuous secondary outcomes were

compared among groups by using the Kruskal-Wallis

test.31 SAS 8 (SAS Institute, Inc, Cary, NC) was used to

perform all calculations.

Analyses were made on an intention-to-treat basis.

Assignment

Randomization

Randomization was conducted by Centro Rosarino de

Estudios Perinatales (the center responsible for the study

coordination) through a sequence of computer-generated

random numbers (SAS 8). The randomization was

stratified by hospital, and in turn, in each institution

stratification was based on the mode of delivery (vaginal

or cesarean section). Variable-length blocks were used

for the randomization process. Sealed opaque sequentially

numbered envelopes that contained the assigned

intervention were used to conceal the allocation. The

envelopes were placed in a box from which only 1

envelope could be drawn at a time. The staff responsible

for the random generation and the allocation-concealment

process was not involved in the recruitment phase

of the trial.

Implementation

At 36 weeks of gestational age, eligible women were

invited to take part in the trial by the physician in charge

of antenatal care. If they agreed to participate, both

parents signed an informed consent during the following

visit. If at the time of delivery the woman was still

considered eligible for the trial, enrollment took place,

and an envelope was drawn and opened accordingly in

the delivery room. Enrollment was made by a physician

of the trial (working in this area but not in charge of the

delivery), who read to the obstetrician assisting the delivery

the assigned intervention. After completion of

these procedures, a third physician used a timekeeper to

check the time at which clamping was effectively accomplished.

Labor and delivery were performed following

the standard practice of care.

Masking

Given the characteristics of the intervention, the physician

in charge of the intervention (umbilical cord clamping)

could not be blinded. However, health professionals

who made the neonatal evaluations after birth were not

the ones present when infants were delivered and were

not aware of the approach to which the delivery had

been assigned. The personnel in charge of biochemical

tests also were not aware of the approach used.

RESULTS

Recruitment was conducted from November 2, 2002, to

April 28, 2003. Invited to take part in the study were 312

eligible women. At the time of random assignment, 21 of

the total number of women did not meet the inclusion

criteria. Fifteen of the remaining 291 eligible women

either did not agree to participate or were not enrolled in

the trial for operative reasons. The remaining 276 patients

were randomly assigned to the 3 approaches described

for umbilical cord clamping (Fig 1).

Compliance with the allocated intervention was

94.6% (88 of 93) in the early-cord-clamping group,

91.2% (83 of 91) in the 1-minute cord-clamping group,

and 90.2% (83 of 92) in the 3-minute cord-clamping

group. Cases and reasons for protocol deviations are

shown on Fig 1.

Average clamping time for each group was 12.7 seconds

in the early-cord-clamping group, 59.8 seconds in

the 1-minute cord-clamping group, and 169.5 seconds in

the 3-minute cord-clamping group.

Study groups were similar with respect to demographic

and clinical variables (Table 1).

Compliance with evaluation standards of the first and

second neonatal hematocrit determinations and bilirubin

level was checked. No differences were found among

groups when these tests were performed.

Statistical analyses among groups showed equivalence

within the prespecified ranges, because hematocrit

increase in neonates assigned to cord clamping at 1

minute was not higher than 8 points compared with the

hematocrit value recorded in the group with early cord

clamping (mean difference: _3.52; 95% CI: _5.79 to

_1.26). Also, equivalence is shown in the comparison

between cord-clamping groups at 1 and 3 minutes, respectively

(mean difference: _2.39; 95%CI: _4.64 to

_0.13) (Fig 2).

The prevalence of newborn infants with a hematocrit

level of _45% at 6 hours was significantly higher in the

early-cord-clamping group (8.9%) versus groups with

cord clamping at 1 or 3 minutes (1% and 0%, respectively)

(Table 3).

There were no differences regarding the percentage of

neonates with a hematocrit level of _65% (polycythemia)

between groups 1 and 2 (4.4% and 5.5%, respectively),

but this was significantly higher in group 3 than

in group 1 (14.1% vs 4.4%) (Table 3). None of the

polycythemic newborns developed symptoms; hence,

partial exchange transfusion was not required.

Venous hematocrit values at 24 to 48 hours were

51.14% in the early-cord-clamping group, 53.62% in

the 1-minute cord-clamping group, and 56.41% in the

3-minute cord-clamping group (Table 4).

The prevalence of newborn infants with a hematocrit

level of _45% at 24 to 48 hours was significantly higher

in the early-cord-clamping group (16.8%) compared

with groups assigned to cord clamping at 1 minute

(2.2%) and 3 minutes (3.3%), respectively (Table 4).

No significant differences were observed in the groups

concerning the rate of neonates with a hematocrit level

of _65% at 24 to 48 hours (Table 4).

Plasma bilirubin values at 24 to 48 hours of age were

similar among the 3 groups. No significant differences

were observed in neonatal adverse-event rates. There

were no cases of necrotizing enterocolitis or seizures.

Only 1 case of neonatal sepsis was found in the group

subjected to cord clamping at 1 minute. There was only

a slight and statistically not significant increase in respiratory

distress, tachypnea, and grunting rates in the

groups subjected to clamping at 1 or 3 minutes after

birth in comparison to the group assigned to early cord

clamping (Table 5). No significant differences were

found in the admission rate to the NICU (Table 5) or

length of hospital stay (Table 5).

The clinical course after discharge during the first

month of life was similar in the 3 groups, and at 30 days

no differences in relation to the infant’s weight or frequency

of exclusive breastfeeding were observed (Table

5). No neonatal deaths were observed in the population

under study.

Regarding maternal outcomes, no differences were

observed among the groups with respect to postpartum

blood-loss volume, postpartum hemorrhage, and maternal

hematocrit level 24 hours after birth. The median

maternal blood loss was 265 mL (first-third quartiles:

150–510 mL) in the early-cord-clamping group, 250 mL

(first-third quartiles: 150–400 mL) in the 1-minute

cord-clamping group, and 300 mL (first-third quartiles:

200–500 mL) in the 3-minute cord-clamping group.

Postpartum hemorrhage (blood loss _500 mL) was

26.8% in the early-cord-clamping group, 22.2% in the

1-minute cord-clamping group, and 25.4% in the

3-minute cord-clamping group. Severe postpartum

hemorrhage (blood loss _1000 mL) was 3.6%, 5.6%,

and 3.2% in each group, respectively. The maternal

hematocrit at 24 hours postpartum was 29.9% (SD: 3.5)

in group 1, 30.9% (SD: 4.5) in group 2, and 30.6% (SD:

3.6) in group 3.

DISCUSSION

Although well-designed randomized, controlled trials

have not shown any harmful effects related to delayed

cord clamping, immediate clamping is still the common

practice. However, its value is highly controversial, especially

because the newborn is deprived from a large

quantity of blood, iron, and other benefits. Iron stores at

birth are variable and are correlated to each infant with

stores at 6, 9, and 12 months of age.8 Iron content in the

diet is only one of the factors influencing the “iron

status” during the first year of life.32 These considerations

have led to the question that, if an elevated iron deposit

at birth is associated with an adequate iron status at 12

months of age, then why not attempt to increase iron

content in the newborn?4

This prospective randomized, controlled study evaluated

the potential placental transfusion effects on the

newborn and the mother at 3 different cord-clamping

time intervals. This study was designed to demonstrate

that in late cord clamping (at 1 or 3 minutes after birth)

there is an increase in venous hematocrit within physiologic

ranges and without harmful effects in comparison

to early cord clamping. We found that the mean venous

hematocrit of the newborn at 6 hours of life, the primary

outcome of this study, remained within physiologic

ranges without significant differences among groups,

thereby confirming our hypothesis and previous observations.

13,33 There is a correlation between cord-clamping

time and the slight increase observed in the hematocrit

value.

As described in other studies,10,13,34 no polycythemiarelated

harmful effects were observed, and all polycythemic

newborns were free of symptoms. Furthermore,

we observed a remarkable increase of anemia in the

group with early cord clamping, both at 6 and 24 to 48

hours of life. This finding, also reported by others, is

significant, especially considering its likely impact on the

prevalence of anemia in the first months of life.34 In the

other neonatal variables evaluated in our study, no differences

were found among the 3 groups. Respiratory

disorders were transient, and there was no need to supplement

oxygen beyond 24 hours of life. Plasma bilirubin

values as well as hyperbilirubinemia rates were similar

in the 3 groups, which goes along with other

authors’ observations.10,34,35

Likewise, another benefit of delayed clamping would

be the increase of hematopoietic stem cells transfused to

the newborn, which might play a role on different blood

disorders and immune conditions.36

With respect to maternal variables, no harmful effects

were observed. Blood loss after delivery and hematocrit

variations between delivery and at 24 hours after birth

were similar among the 3 groups. These data are in

agreement with what other authors have reported35,37

and in disagreement with the belief that late clamping is

associated with greater postpartum bleeding.38

CONCLUSIONS

In term newborn infants, cord clamping at 1 or 3 minutes

after birth resulted in an increase of venous hematocrit

levels measured at 6 hours, within physiologic

ranges, and a decreased prevalence of neonatal anemia

without any harmful effect in newborns or mothers.

Thus, this intervention seems to be safe and effective and

could be implemented easily. The advantages of umbilical

cord clamping at least at 1 minute after birth could

decrease the prevalence of iron-deficiency anemia in the

first year of life, especially in populations with limited

access to health care. This trial was focused mainly on

cord-clamping timing and its effect on the newborn,

particularly in the first hours and days of life. We have

shown our hypothesis to be true and additionally proved

the protective effect of late cord clamping on neonatal

anemia at birth. However, bearing in mind the significance

of the consequences of this intervention on iron

stores during the first months of life, we followed up the

infants until 6 months of age. Follow-up controlled studies

should focus on the relationship between delayed

cord clamping and the presence of anemia and iron

status in infants.

ACKNOWLEDGMENTS

This trial was supported by United Nations Children’s

Fund (UNICEF) Argentina. The Hospital Italiano de Buenos

Aires Department of Pediatrics (via the “Carlos

Gianantonio Foundation”) was guarantor of the study.

We thank Marı´a del Carmen Morasso, MD, from

UNICEF Argentina for constant support that made this

study possible; Daniel Wodjyla, MSc, for statistical advice;

the nurses, physicians, and biochemists of the participating

hospitals who contributed with dedication to

the accomplishment of this study; and the parents who,

with generosity, gave their consent.

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