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Copyright 2016 American Medical Association. All rights reserved.
Effects of Delayed Umbilical Cord Clamping vs Early Clamping
on Anemia in Infants at 8 and 12 Months
A Randomized Clinical Trial
Ashish KC, MD, PhD; Nisha Rana, RN, MPH; Mats Målqvist, MD, PhD; Linda Jarawka Ranneberg, MD;
Kalpana Subedi, MD; Ola Andersson, MD, PhD
IMPORTANCE Delayed umbilical cord clamping has been shown to improve iron stores in
infants to 6 months of age. However, delayed cord clamping has not been shown to prevent
iron deficiency or anemia after 6 months of age.
OBJECTIVE To investigate the effects of delayed umbilical cord clamping, compared with
early clamping, on hemoglobin and ferritin levels at 8 and 12 months of age in infants at high
risk for iron deficiency anemia.
DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial included 540 late preterm
and term infants born vaginally at a tertiary hospital in Kathmandu, Nepal, from October 2 to
November 21, 2014. Follow-up included blood levels of hemoglobin and ferritin at 8 and 12
months of age. Follow-up was completed on December 11, 2015. Analysis was based on
intention to treat.
INTERVENTIONS Infants were randomized to delayed umbilical cord clamping (ⱖ180 seconds
after delivery) or early clamping (ⱕ60 seconds after delivery).
MAIN OUTCOMES AND MEASURES Main outcomes included hemoglobin and anemia levels at
8 months of age with the power estimate based on the prevalence of anemia. Secondary
outcomes included hemoglobin and anemia levels at 12 months of age and ferritin level, iron
deficiency, and iron deficiency anemia at 8 and 12 months of age.
RESULTS In this study of 540 infants (281 boys [52.0%] and 259 girls [48.0%]; mean [SD]
gestational age, 39.2 [1.1] weeks), 270 each were randomized to the delayed and early
clamping groups. At 8 months of age, 212 infants (78.5%) from the delayed group and 188
(69.6%) from the early clamping group returned for blood sampling. After multiple
imputation analysis, infants undergoing delayed clamping had higher levels of hemoglobin
(10.4 vs 10.2 g/dL; difference, 0.2 g/dL; 95% CI, 0.1 to 0.4 g/dL). Delayed cord clamping also
reduced the prevalence of anemia (hemoglobin level <11.0 g/dL) at 8 months in 197 (73.0%)
vs 222 (82.2%) infants (relative risk, 0.89; 95% CI, 0.81-0.98; number needed to treat
[NNT], 11; 95% CI, 6-54). At 8 months, the risk for iron deficiency was reduced in the delayed
clamping group in 60 (22.2%) vs 103 (38.1%) patients (relative risk, 0.58; 95% CI, 0.44-0.77;
NNT, 6; 95% CI, 4-13). At 12 months, delayed cord clamping still resulted in a hemoglobin level
of 0.3 (95% CI, 0.04-0.5) g/dL higher than in the early cord clamping group and a relative risk
for anemia of 0.91 (95% CI, 0.84-0.98), resulting in a NNT of 12 (95% CI, 7-78).
CONCLUSIONS AND RELEVANCE Delayed cord clamping reduces anemia at 8 and 12 months of
age in a high-risk population, which may have major positive effects on infants’ health and
development.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02222805
JAMA Pediatr. doi:10.1001/jamapediatrics.2016.3971
Published online January 17,2017.
Supplemental content
Author Affiliations: International
Maternal and Child Health,
Department of Women’s and
Children’s Health, Uppsala University,
Uppsala, Sweden (KC, Rana, Målqvist,
Andersson); Health Section, United
Nations Children’s Fund(UNICEF ),
Lalitpur, Nepal (KC);Paropakar
Maternity and Women’s Hospital,
Kathmandu, Nepal (KC, Rana,
Subedi); Department of Pediatrics,
Hospital of Halland, Halmstad,
Sweden (Jarawka Ranneberg).
Corresponding Author: Ola
Andersson, MD, PhD, International
Maternal and Child Health,
Department of Women’s and
Children’s Health, Uppsala University,
SE-75185 Uppsala, Sweden
(ola.andersson@kbh.uu.se).
Research
JAMA Pediatrics | Original Investigation
(Reprinted) E1
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Globally,43% of children younger than 5 years (approxi-
mately 273 million persons) have anemia, which is at-
tributable to iron deficiency in approximately 42%.
1
Children with anemia and iron deficiency have associated im-
paired neurodevelopment, affecting their cognitive,motor, and
behavioral abilities.
2,3
Food fortification and iron supplemen-
tation is currently used for treatment, and delayed umbilical
cord clamping has been proposed as a low-cost intervention
to reduce the risk for iron deficiency anemia.
4-6
After delivery, fetoplacental blood is transfused to the new-
born, augmenting the infant’s blood volume by 30% to 40%
(roughly 25-30 mL/kg), if early cord clamping is avoided.
7,8
Neonatal benefits include better cardiopulmonary adapta-
tion and higher hemoglobin concentrations to 2 to 3 months
of age.
9-11
The blood transfused can contribute with 75 mg of
iron and has been shown to increase iron stores and prevent
iron deficiency in early infancy, to 6 months of life.
10-13
In theory, this increased store of iron could help to pre-
vent iron deficiency and iron deficiency anemia later in in-
fancy. This possibility was not shown in a randomized clini-
cal trial among infants aged 12 months in Sweden,
14
whereas
an observational trial performed in Peru
15
found a 16% reduc-
tion in anemia at 8 months after a hospital policy change. Con-
vincing evidence is still lacking regarding the effect of de-
layed cord clamping on infants’ iron stores after 6 months of
age. The aim of this randomized clinical trial was to explore
whether delayed cord clampingafter 3 minutes, compared with
clamping the cord before 60 seconds, would reduce anemia
and iron deficiency at 8 and 12 months of age in a low-income
country with a high prevalence of anemia.
Methods
Study Design
This randomized clinical trial was conducted in Nepal at the
Paropakar Maternity and Women’sHospital, Kathmandu, a ter-
tiary center for obstetric and gynecologic service with a birth
rate of 22 000 per year. The trial design included 2 parallel
groups (1:1 ratio) randomized to delayed cord clamping (≥180
seconds) and early cord clamping (≤60 seconds). The cutoff
for early cord clamping was based on an observational study
in the hospital, which showed a mean (SD) umbilical cord
clamping time of 61 (33) seconds (Viktoria Nelin, MS, A.K., O.A.,
N.R., M.M.; unpublished data; September 28, 2013). The in-
stitutional review board of the hospital and the ethical re-
view board of Nepal Health Research Council approved the
study.The study protocol is available in Supplement 1 and has
been published elsewhere.
16
Written consent was obtained af-
ter assignment to the Maternal and Neonatal Service Centre
(MNSC) of Paropakar Maternity and Women’sHospital from the
women who were eligible and willing to participate.
Study Population
Paropakar Maternity and Women’sHospital has 2 delivery de-
partments, a high-risk labor room and the low-risk MNSC. The
hospital criteria for admission to the MNSC included uncom-
plicated pregnancies, no complication at admission, and
healthy mothers (no clinical history of hypertension, infec-
tion, diabetes, or any chronic medical condition), expected
vaginal delivery, gestational age of 34 to 41 weeks, and single-
ton pregnancy.Women were eligible to participate in the study
if they were assigned to the MNSC. The exclusion criteria were
predefined as serious congenital malformations or congeni-
tal disease that could affect the outcome measures.
Randomization and Masking
One of us (O.A.) prepared a list using the random digit genera-
tor in the Excel program (Microsoft Corporation). Sequen-
tially numbered, opaque envelopes were prepared holding
cards with details of the allocated group. These envelopes were
kept at the research office and were broughtto the delivery unit
before randomization.
Randomization occurred when delivery was imminent.
The surveillance officer opened the next consecutively num-
bered envelope and informed the nurse-midwife of the allo-
cation. The details of sequence generation and allocation con-
cealment were limited to the investigator (O.A.), who had no
clinical involvement in the trial but participated in data analy-
sis after the trial had ended. The surveillance officer and nurse-
midwife did not inform the mother of the allocated treat-
ment. However, the mother might have noticed the nature of
intervention. The outcome assessors were blinded to the al-
location, as were the members of the research team who
obtained the outcome measurements.
Procedures
At all deliveries, a surveillance officer measured the time from de-
livery of the infant’sshoulder to cord clamping using a stopwatch.
The nurse-midwife put the infant on the mother’s abdomen until
the cord was clamped. In the early clamping group, the surveil-
lance officer informed the nurse-midwife when 60 seconds
approached and that cord should be clamped if not performed
earlier. In the delayedclamping group, the surveillance officer in-
formed the nurse-midwife when 180 seconds had passed and the
cord should be clamped. If the nurse-midwife recognized that the
mother or the infant needed attention, the umbilical cord could
be clamped and cut regardless of the treatment allocation.
Information on maternal age and parity, gestational age,
Apgar scores, and birth weight was recorded. The gestational
age was calculated based on the recall of each woman about
Key Points
Question Can delaying umbilical cord clamping for 3 minutes after
birth reduce anemia at 8 and 12 months of age?
Findings In this randomized clinical trial, 540 newborns were
randomized to delayed umbilical cord clamping (>3 minutes) or
early clamping no later than 1 minute. This delay resulted in a
significant reduction in the prevalence of anemia by 9% at 8
months or age and 8% at 12 months of age.
Meaning By extending umbilical cord clamping to longer than 3
minutes after birth, infants in low-resource settings experience
less anemia, which may have positive effects on health and
development.
Research Original Investigation Delayed vs Early Umbilical Cord Clamping and Anemia in Infants
E2 JAMA Pediatrics Published online January 17,2017 (Reprinted) jamapediatrics.com
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her last menstrual period. Birth weight was based on the weight
taken on an analog weighing scale.
At 8 and 12 months, laboratory staff collected a venous
blood sample (2 mL) from the infants with a needle of a 3-mL
syringe (Lifeline Services Pvt Ltd). The blood sample was trans-
ferred into an anticoagulant-treated vial (EDTA K3; Zhejiang
Gongdong Medical Technology Co, Ltd). Blood samples were
stored at room temperature and analyzed the same day. A he-
matology analyzer (ABX Pentra XL 80; Horiba Medical) was
used for hemoglobin analysis, and an immunoassay system
(ADVIA Centaur; Siemens Healthcare GmbH) was used for fer-
ritin analysis. At the 8- and 12-month visits, parents were in-
terviewed regarding the feeding habits of the infant (eg, what
type of food had been given and frequency of meals).
Outcomes
The primary outcome was prespecified as the hemoglobin level
at 8 months of age. Hemoglobin level was analyzed by com-
paring means and as a categorical variable, defining anemia
as a hemoglobin level of less than 11.0 g/dL (altitude cor-
rected) (to convert to grams per liter, multiply by 10.0). The
secondary outcomes included the following:
•Hemoglobin level at 12 months of age, analyzed by compar-
ing means and as a categorical variable with the same defi-
nition of anemia.
•Ferritin levels at 8 and 12 months of age, analyzed by com-
paring means and as categorical variables, with iron defi-
ciency defined as a ferritin level of less than 12 μg/L (to con-
vert to picomoles per liter, multiply by 2.247).
17
•Iron deficiency anemia at 8 and 12 months of age, defined as
ferritin and hemoglobin levels below the respective cutoffs.
•Other secondary outcomes that will be described in sepa-
rate reports are transcutaneous bilirubin level at discharge,
breast-feeding and morbidity during the first 6 monthsof life,
and psychomotor development at 12 months of age.
Altitude Correction
We used the Centersfor Disease Control and Prevention hemo-
globin adjustment method of −0.32 × (altitude × 0.0032808)
+ 0.22 × (altitude × 0.0032808).
2
The altitude of Kathmandu
of 1400 m was entered in the formula, resulting in a correction
of 0.32 g/dL, which was subtracted from each of the individual
hemoglobin results before making descriptive statistics and
group comparisons.
18
Statistical Analysis
Analysis was based on intention to treat. We based the sample
size calculation on examining the effect of cord clamping on
anemia at 8 months of age. The national prevalence of ane-
mia was 70% at 8 months.
19
To find a difference of 15% (from
70% to 55%) in prevalence between the treatment groups with
80% power and 0.05 type I error, 176 infants were needed in
each group, and after allowing for 35% attrition wedec ided to
allocate 270 in each treatment group.
We used an unpaired 2-tailed ttest for variables with nor-
mal distribution; categorical variables were compared be-
tween groups using the Fisher exact test. Ferritin concentra-
tion was log
10
transformed for analysis.
Consideration was taken for baseline or follow-updata that
were imbalanced between treatment groups and significantly
correlated with primary and secondary outcomes. We used mul-
tivariate analysis of variance (MANOVA) and logistic regres-
sion analysis, as appropriate, to control for this imbalance.
Owing to attrition rates at 8 and 12 months, we analyzed
data using the multiple imputation method in SPSS (version
22; IBM Corp). Variables included in the model as predictors
were time to clamping, mother’s age, previous pregnancies,
gestational age, birth weight, sex, and time from delivery to
discharge in hours. Age in days and hemoglobin and ferritin
levels at 8 months were entered as dependent and predictive
variables, whereas age and hemoglobin and ferritin levels at
12 months of age were entered as only dependent variables.
Imputation was performed 5 times.
Results
From October 2 to November 21, 2014, 540 women who were
admitted to MNSC agreed to participate in the study. After signed
consent was obtained and as birth was imminent, 270 women
were randomly assigned to cord clamping no later than 60 sec-
onds (early) and 270 to cord clamping after at least 3 minutes
(delayed) subsequent to the appearance of the infant’s shoul-
der. Of the 540 included newborns (281 boys [52.0%] and 259
girls [48.0%]; mean [SD] gestational age, 39.2 [1.1] weeks), 466
(86.3%) received the allocated intervention (Figure). For the
8-month follow-up,400 infants (74.1%) returned for blood sam-
pling from May 25 to August 4, 2015; for the 12-month follow-
up, 334 infants (61.9%) returned from September 6 to Decem-
ber 11, 2015. The median time to clamping the umbilical cord
was 192 (interquartile range, 185-199) seconds for the delayed
clamping group and 32 (interquartile range, 23-45) seconds for
the early clamping group (P< .001). We found no significant dif-
ferences between the delayed and early clamping groups with
respect to maternal characteristics or neonatal baseline data, ex-
cept for gestational age, which was 1.6 (95% CI, 0.3-3.0) days
greater in the delayed clamping group (P=.02)(Table 1).
Primary Outcome
At 8 postpartum months, 212 children (78.5%) returned in the
delayed clamping group and 188 (69.6%) in the early clamp-
ing group, at a mean (SD) age of 238 (8) days. Forunknown rea-
sons, the difference between groups in return rate was statis-
tically significant (P= .02). Mean hemoglobin level was 0.2
(95% CI, 0.1-0.4) g/dL higher in the delayed clamping group
(Table 2). Anemia was less prevalent in the delayed clamp-
ingd group (197 [73.0%] vs 222 [82.2%]), with a relative risk
of 0.89 (95% CI, 0.81-0.98) (Table 3).
Secondary Outcomes
At 8 months, the ferritin concentrationwas signific antlyhigher
in the delayed vs the early clamping groups (differencein geo-
metric mean ratio, 33%; 95% CI, 14%-56%) (Table 2). Iron de-
ficiency (60 [22.2%] vs 103 [38.1%] infants) and iron defi-
ciency anemia (52 [19.3%] vs 90 [33.3%] infants) were
significantly less prevalent in the delayed clamping group
Delayed vs Early Umbilical Cord Clamping and Anemia in Infants Original Investigation Research
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(Table 3). The relative risk for having iron deficiency was 0.58
(95% CI, 0.44-0.77) in the delayed group, with a number
needed to treat (NNT) of 6 (95% CI, 4-13); the relative risk for
having iron deficiency anemia was 0.58 (95% CI, 0.42-0.78),
with an NNT of 7 (95% CI, 5-6).
At the age of 12 months, 177 infants (65.6%) in the de-
layed group and 157 (58.1%) in the early group returned at a
mean (SD) age of 357 (17) days. Mean hemoglobin was 0.3 (95%
CI, 0.04- 0.5) g/dL higher in the delayed group (Table 2). Ane-
mia was less prevalent in the delayed clamping group, with a
relative risk of 0.91 (95% CI, 0.84-0.98), resulting in an NNT
of 12 (95% CI, 7-78) (Table 3). No difference was found in se-
rum ferritin level or prevalence of iron deficiency or iron de-
ficiency anemia between groups (Table 3).
Ancillary Analyses
At 8 months of age, all infants werepartially breast-fed. Wean-
ing foods were equally common between groups, except for
Figure. CONSORT Flow Diagram for RandomizedClinical Trial of Delayed vs Early Umbilical Cord Clamping
1775 Did not meet the eligible criteria
341 Complication during the pregnancy
552 Active stage of labor
65 Hypertensive disorder
130 Previous cesarean section
672 Complication during admission
15 Multiple-gestation pregnancy
273 Not eligible for randomization
(declined to participate)
540 Randomized
2588 Women admitted to the hospital
underwent screening for eligibility
criteria for admission in low-risk
delivery unit
813 Admitted to low-risk delivery unit
270 Randomized to early clamping
257 Received intervention as
randomized
13 Did not receive intervention
as randomized
6Delay in procedure
1Cord tightly around the
neck, delay in procedure
6Midwife-nurse chose to
not follow allocation
270 Randomized to delayed clamping
209 Received intervention as
randomized
61 Did not receive intervention
as randomized
10 Asphyxia
25 Poor cry
9Meconium stained
1Cyanosis
11 Cord tightly around
the neck
1Shoulder dystocia
4Midwife-nurse chose to
not follow allocation
188 Underwent analysis
179 Received allocated intervention
5Excluded from analysis
(laboratory staff failed to
collect blood samples)
212 Underwent analysis
164 Received allocated intervention
5Excluded from analysis
(laboratory staff failed to
collect blood samples)
31 Unavailable for follow-up at 12 mo
(declined to continue follow-up)
39 Unavailable for follow-up at 12 mo
(declined to continue follow-up)
157 Included in analysis
149 Received allocated intervention
5Excluded from analysis
(laboratory staff failed to
collect blood samples)
177 Included in analysis
136 Received allocated intervention
1Excluded from analysis
(laboratory staff failed to
collect blood samples)
77 Lost to or unavailable for
follow-up at 8-mo
3Deaths
31 Declined to continue
follow-up
43 Not reachable
53 Lost to or unavailable for
follow-up at 8-mo
4Deaths
30 Declined to continue
follow-up
19 Not reachable
Early clamping was defined as 60
seconds or less; delayed clamping,
180 seconds or longer.
Research Original Investigation Delayed vs Early Umbilical Cord Clamping and Anemia in Infants
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fruits that were given to 27 of 212 infants (12.7%) in the de-
layed clamping group and 48 of 188 infants(25.5%) in the early
clamping group (P= .003). We found no difference in occa-
sions of respective feedings per day between groups. At 12
months of age, 298 of 334 infants (89.2%) were still partially
breast-fed. The types of other kinds of food and occasion of
feeding did not differ between groups. The parents did not re-
port giving iron supplements to any infant.
Gestational age was not statistically balanced between
treatment groups (Table 1), and at 12 monthsthe mean (SD) age
of the infant at the time of blood sampling also differed sig-
nificantly between groups at 359 (17) days in the delayedclamp-
ing group vs 355 (17) days in the early group (P= .02). To con-
trol for this difference, we performed a MANOVA for the scale
variables and logistic regression for categorical variables, en-
tering gestational age as a covariate when analyzing variables
from the 8- and 12-month blood samples and adding age as a
covariate in the analyses of 12-month blood samples. The re-
sults from the MANOVA and logistic regression analysis did not
change the results’ significance.
We found a significant difference betweengroups regard-
ing protocol adherence, because 61 infants (22.6%) random-
ized to delayed cord clamping had their cord clamped before
180 seconds and 13 infants (4.8%) in the early clamping group
had their cords clamped after 60 seconds. To control for this
difference, we performed the analysis again including only in-
fants treated according to their assigned allocation group (per
protocol). This per-protocol analysis resulted in an overall more
pronounced effect difference between the delayed and early
clamping group, but did not change the results in a way that
would affect the conclusions of the study (eTables 1 and 2 in
Supplement 2).
Discussion
Previous studies of cord clamping have shown reduced iron
deficiency at 4 and 6 months of age.
12,13,20
As an advance-
ment to this knowledge, the present study resulted in im-
proved hemoglobin levels and reduced anemia in infants at 8
and 12 months of age after clamping the umbilical cord was de-
layed until at least 3 minutes after birth, compared with less
than or equal to 1 minute.
The improved iron stores at 3 to 6 months have been hy-
pothesized to protect against anemia later in infancy.
6,12,14
We
found 7 systematic reviews
10,11,21-25
regarding delayed vs early
umbilical cord clamping in term infants published during the
last decade. In summary, all conclude that delayed cord clamp-
ing after birth results in higher concentrations of hemoglobin
and hematocrit during the neonatal period, increased serum
ferritin levels, and a lower incidence of iron deficiency at 4 to
6 months of age.
Few studies on umbilical cord clamping are found in the
literature with follow-up after 6 months, and results are in-
conclusive. We have only identified 3 studies.
14,15,26
In 1941,
Wilson et al
26
compared 15 infants whose umbilical cords were
clamped immediately with 13 whose cords were clamped af-
ter the placenta began to descend into the vagina. The infants
in the delayed clamping group had significant higher mean cor-
puscular hemoglobin levels at 8 to 10 months of age (P= .007,
our calculation using data in the article), whereas the mean (SD)
hemoglobin concentration was higher, but not significantly
(11.8 [1.3] vs 10.8 [1.8]g /dL;P= .09, our calculation using data
in the article).
26
An observation study conducted by Gyorkos
et al
15
in Peru, a setting similar to Nepal, on the effect of a hos-
pital policy change toward delayed cord clamping resulted in
improved hemoglobin levels and significantly reduced ane-
mia at 8 postpartum months among 184 infants. A random-
ized clinical trial
14
comparing cord clamping after 180 sec-
onds with clamping before 10 seconds in 337 infants from
Sweden found no differences in hemoglobin or iron status at
12 months of age, most likely owing to an unexpected low
prevalence of anemia (11%-15%) and iron deficiency (3%-5%)
at that age.
Our randomized clinical trial shows a significant effect on
anemia at 8 months of age, with a risk reduction of 11% in the
delayed cord clamping group paired with a 42% risk reduc-
tion in iron deficiency. We had hypothesized that delayedcord
clamping would increase infant iron stores and hemoglobin lev-
els to 12 months of age. However, although anemia was less
prevalent and the mean hemoglobin concentration was higher
among the delayed cord clamping group at 12 months, the se-
rum ferritin level was not higher in the delayed clampinggroup
compared with the early clamping group, most probably ow-
ing to an increasing importance of complementary food as a
source of iron.
27
An additional important observation from our
results is that a relatively extended definition of early cord
clamping (≤60 seconds) still was inferior to delayedcord clamp-
ing after 180 seconds.
Strengths and Limitations
Some of the strengths and limitations of the study are corre-
lated with the advantages and difficulties associated with the
setting in a low-income country. Inclusion was performed dur-
ing a comparable short time (approximately 7 weeks), which
might prevent biases that could occur owing to a longer inclu-
Table 1. Baseline Characteristics of Mothers and NewbornInfants
Characteristic
Cord Clamping Group
a
Early
(n = 270)
Delayed
(n = 270)
Maternal
Age, mean (SD), y 23.8 (4.3) 23.4 (4.0)
Parity (excluding study child),
mean (SD)
0.64 (0.81) 0.66 (0.87)
Vaginal delivery
(noninstrumental), No. (%)
270 (100) 270 (100)
Infant
Gestational age, mean (SD), wk
b
39.0 (1.2) 39.3 (1.1)
Male, No. (%) 146 (54.1) 135 (50.0)
5-min Apgar score of 7-10, No. (%) 260 (96.3) 258 (95.6)
Birth weight, mean (SD), g 3015 (426) 3029 (405)
a
Early clamping was defined as 60 seconds or less; delayed clamping,
180 seconds or longer.
b
Data were missing for 4 infants in the early clamping group and 1 infant in the
delayed clamping group. Difference was 0.2(95% CI, 0.04-0.4) weeks
(P= .02).
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sion period. The study also compared a relatively late defini-
tion of early cord clamping (≤60 seconds) with 180 seconds or
more for delayed clamping. Attrition is a major limitation to
our study.We expected a high attrition rate of 35% at 8 months
owing to difficulties communicating with the included fami-
lies and powered the study accordingly. The actual attrition
rates included 140 infants (25.9%) at 8 and 206 infants(38.1%)
at 12 months. These numbers were close to the expected at-
trition rate but may be associated with bias in the results. To
adjust for attrition, results are presented after multiple impu-
tation analysis.
Furthermore, a high incidence of protocol deviation oc-
curred in the delayed cord clamping group. When analysis was
based on intention to treat, 22.6% of the infants in the de-
layed cord clamping group underwent clampingbefore 1 min-
ute, because the nurse-midwives perceived that early clamp-
ing against the allocation was required. An analysis of only
those cases that were handled per protocol showed similar re-
sults (eTables 1 and 2 in Supplement 2). Only women with rela-
tively low-risk pregnancies were included in the study, which
might impair the generalizability of the study, although the
rates of anemia in the study group were comparable with those
of earlier reports from Nepal.
28
Conclusions
This study shows that delayed cord clamping for 180 seconds
was an effective intervention to reduce anemia at 8 and 12
months of age in a high-risk population with minimal cost and
without apparent adverse effects. If the intervention was imple-
mented on a global scale, this could translate to 5 million fewer
infants with anemia at 8 months of age, with particular pub-
lic health significance in South Asia and Sub-Saharan Africa,
where the prevalence of anemia is the highest.
Children with anemia and iron deficiency are more likely
to experience stunting and delayed psychomotor
development.
2
One study has shown that delayed cord clamp-
Table 2. Laboratory Status at 8 and 12 Months of Age
a
Laboratory Status
Cord Clamping Group, Mean (SD)
Difference (95% CI) PValue
b
Early
(n = 270)
Delayed
(n = 270)
8-mo Follow-up
Time to umbilical cord clamping, s 35 (2) 159 (9) 125 (116 to 133) <.001
Hemoglobin level, g/dL
c
10.2 (0.9) 10.4 (0.9) 0.2 (0.1 to 0.4) .008
Ferritin level, μg/L
d
16.4 (2.2) 21.8 (2.1) 33 (14 to 56)
e
<.001
12-mo Follow-up
Hemoglobin level, g/dL
c
10.1 (1.0) 10.3 (0.9) 0.3 (0.04 to 0.5) .02
Ferritin level, μg/L
d
13.2 (2.2) 15.6 (2.4) 18 (−6 to 48)
e
.14
SI conversion factors: Toconvert ferritin to picomoles per liter, multiply by
2.247; hemoglobin to grams per liter, multiply by 10.0.
a
Results are presented after multiple imputation analysis. Data in multiple
imputation analysis were based on early cord clamping (n = 188) and delayed
cord clamping (n = 212) at 8 months and early cord clamping (n = 157) and
delayed cord clamping (n = 17 7) at 12 months. Early clampingwas defined as
60 seconds or less; delayed clamping, 180 seconds or longer.
b
Calculated using an unpaired 2-tailed ttest.
c
Corrected for altitude.
d
Presented as geometric mean (geometric SD).
e
Presented as geometric mean ratio in percentage.
Table 3. Proportion of InfantsWith Hemoglobin and Serum Ferritin Levels Outside Reference Limits at 8 and 12 Months of Age
a
Laboratory Status (Definition)
Cord Clamping Group, No. (%)
PValue
b
RR (95% CI)
NNT
(95% CI)
Early
(n = 270)
Delayed
(n = 270)
8-mo Follow-up
Anemia (hemoglobin level <11.0 g/dL)
c
222 (82.2) 197 (73.0) .01 0.89 (0.81-0.98) 11 (6-54)
Iron deficiency (ferritin level <12 μg/L) 103 (38.1) 60 (22.2) <.001 0.58 (0.44-0.77) 6 (4-13)
Iron deficiency anemia (hemoglobin level
<11.0 g/dL and ferritin level <12 μg/L)
90 (33.3) 52 (19.3) <.001 0.58 (0.42-0.78) 7 (5-16)
12-mo Follow-up
Anemia (hemoglobin level <11.0 g/dL)
c
232 (85.9) 210 (77.8) .02 0.91 (0.84-0.98) 12 (7-78)
Iron deficiency (ferritin level <12 μg/L) 116 (43.0) 96 (35.6) .09 0.83 (0.66-1.03) NA
Iron deficiency anemia (hemoglobin level
<11.0 g/dL and ferritin level <12 μg/L)
102 (37.8) 82 (30.4) .08 0.80 (0.63-1.03) NA
Abbreviations: NA, not applicable; NNT,number needed to treat;
RR, relative risk.
SI conversion factors: Toconvert ferritin to picomoles per liter, multiply by
2.247; hemoglobin to grams per liter, multiply by 10.0.
a
Results are presented after multiple imputation analysis. Data in multiple
imputation analysis were based on early cord clamping (n = 188) and delayed
cord clamping (n = 212) at 8 months and early cord clamping (n = 157) and
delayed cord clamping (n = 17 7) at 12 months.
b
Calculated using the Fisher exact test.
c
Hemoglobin level was corrected for altitude.
Research Original Investigation Delayed vs Early Umbilical Cord Clamping and Anemia in Infants
E6 JAMAPediatrics Published online January 17, 2017 (Reprinted) jamapediatrics.com
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ing compared with early cord clamping improved scores in
fine-motor and social domains at 4 years of age.
29
Further
follow-up studies will be required to evaluate the effect of
delayed cord clamping on neurodevelopmental milestones in
preschool and school children. Additional research may be
needed to evaluate whether the optimal timing of cord clamp-
ing may be even later than 180 seconds (ie, at the delivery of
the placenta).
ARTICLE INFORMATION
Accepted for Publication: October 10, 2016.
Published Online: January 17,2017.
doi:10.1001/jamapediatrics.2016.3971
Author Contributions: Drs KC and Andersson had
full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: KC,
Rana, Jarawka Ranneberg, Subedi.
Drafting of the manuscript: KC, Rana, Andersson.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Rana, Andersson.
Obtained funding: Målqvist, Andersson.
Administrative, technical, or material support: KC,
Rana, Målqvist, Jarawka Ranneberg, Subedi.
Study supervision: KC, Rana, Målqvist, Andersson.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by
grants from the Midwifery Society of Nepal, the
Swedish Society of Medicine, the Little Child’s
Foundation (Sweden), the Swedish Society of
Medical Research, and the United Nations
Children’s Fund.
Role of the Funder/Sponsor:The funding sources
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: Omkar Basnet, BBS,
Sabu Thapa, NHCM, and Shanshila Maharjan, PCLN,
Lifeline Nepal, helped collect the data. Majvi Alkass,
CNM, Hospital of Halland, Cecilia Andersson, CNM,
Hospital of Halland, and Birgitta Olsson Sharma,
CRNA, Hospital of Alingsås, supervised
randomization. Jageshwar Gautam, MD, Paropakar
Maternity and Women’s Hospital, Thapathali,
Sheela Verma, MD, Nepal Cancer Hospital,
Jawalakhel, Gehanath Baral, MD, MaiyaManandhar,
BN, and Amar Amatya, MEd, Paropakar Maternity
and Women's Hospital, Thapathali, contributed
with administrative and technical support for
acquisition of data. No financial compensation was
given.
REFERENCES
1. Stevens GA, Finucane MM, De-Regil LM, et al;
Nutrition Impact Model Study Group (Anaemia).
Global, regional, and national trends in
haemoglobin concentration and prevalence of total
and severe anaemia in children and pregnant and
non-pregnant women for 1995-2011: a systematic
analysis of population-representative data. Lancet
Glob Health. 2013;1(1):e16-e25.
2. Lozoff B, Beard J, Connor J, Barbara F, Georgieff
M, Schallert T.Long-lasting neural and behavioral
effects of iron deficiency in infancy. Nutr Rev.
2006;64(5 Pt 2):S34-S43.
3. Radlowski EC, Johnson RW. Perinatal iron
deficiency and neurocognitive development. Front
Hum Neurosci. 2013;7:585.
4. Bhutta ZA, Ahmed T, Black RE, et al; Maternal
and Child Undernutrition Study Group. What
works? interventions for maternal and child
undernutrition and survival. Lancet. 2008;371
(9610):417-440.
5. World Health Organization. Guideline: Delayed
Umbilical Cord Clamping for Improved Maternal and
Infant Health and Nutrition Outcomes. Geneva,
Switzerland: World Health Organization; 2014.
6. van Rheenen PF, Brabin BJ.A practical approach
to timing cord clamping in resource poor settings.
BMJ. 2006;333(7575):954-958.
7. Yao AC, Moinian M, Lind J. Distributionof blood
between infant and placenta after birth. Lancet.
1969;2(7626):871-873.
8. Farrar D, Airey R, Law GR, TuffnellD, Cattle B,
Duley L. Measuring placental transfusion for term
births: weighing babies with cord intact. BJOG.
2011;118(1):70-75.
9. Bhatt S, Alison BJ, Wallace EM, et al. Delaying
cord clamping until ventilation onset improves
cardiovascular function at birth in preterm lambs.
J Physiol. 2013;591(8):2113-2126.
10. Hutton EK, Hassan ES. Late vs early clamping of
the umbilical cord in full-term neonates: systematic
review and meta-analysis of controlled trials. JAMA.
2007;297(11):1241-1252.
11. McDonald SJ, Middleton P,Dowswell T, Morris
PS. Effect of timing of umbilical cord clamping of
term infants on maternal and neonatal outcomes.
Cochrane Database Syst Rev. 2013;7(7):CD004074.
12. Chaparro CM, Neufeld LM, Tena Alavez G,
Eguia-Líz Cedillo R, Dewey KG. Effect of timing of
umbilical cord clamping on iron status in Mexican
infants: a randomised controlled trial. Lancet.
2006;367(9527):1997-2004.
13. Andersson O, Hellström-Westas L, Andersson D,
Domellöf M. Effect of delayed versus early umbilical
cord clamping on neonatal outcomes and iron
status at 4 months: a randomised controlled trial.
BMJ. 2011;343:d7157.
14. Andersson O, Domellöf M, Andersson D,
Hellström-Westas L. Effect of delayedvs early
umbilical cord clamping on iron status and
neurodevelopment at age 12 months: a randomized
clinical trial. JAMA Pediatr. 2014;168(6):547-554.
15. Gyorkos TW, Maheu-Giroux M, Blouin B, et al.
A hospital policy change toward delayed cord
clamping is effective in improving hemoglobin
levels and anemia status of 8-month-old Peruvian
infants. J Trop Pediatr. 2012;58(6):435-440.
16. KC A, Målqvist M, Rana N, Ranneberg LJ,
Andersson O. Effect of timing of umbilical cord
clamping on anaemia at 8 and 12 months and later
neurodevelopment in late pre-term and term
infants; a facility-based, randomized-controlled trial
in Nepal. BMC Pediatr. 2016;16(1):35.
17. Dallman PR, Siimes MA, Stekel A. Iron
deficiency in infancy and childhood. Am J Clin Nutr.
1980;33(1):86-118.
18. Centers for Disease Control (CDC). CDC criteria
for anemia in children and childbearing-aged
women. MMWR Morb Mortal Wkly Rep. 1989;38
(22):400-404.
19. Ministry of Health & Population. New Era, ICF
Macro, USAID. Nepal Demographic and Health
Survey 2011. Kathmandu, Nepal: New Era; 2011.
20. van Rheenen P, de Moor L, Eschbach S, de
Grooth H, Brabin B. Delayed cord clamping and
haemoglobin levels in infancy: a randomised
controlled trial in term babies. Trop Med Int Health.
2007;12(5):603-616.
21. van Rheenen PF, Gruschke S, Brabin BJ. Delayed
umbilical cord clamping for reducing anaemia in low
birthweight infants: implications for developing
countries. Ann Trop Paediatr. 2006;26(3):157-167.
22. Arca G, Botet F, Palacio M, Carbonell-Estrany X.
Timing of umbilical cord clamping: new thoughts on
an old discussion. J Matern Fetal Neonatal Med.
2010;23(11):1274-1285.
23. Garofalo M, Abenhaim HA. Early vs delayed
cord clamping in term and preterm births: a review.
J Obstet Gynaecol Can. 2012;34(6):525-531.
24. Raju TN. Timing of umbilical cord clamping
after birth for optimizing placental transfusion. Curr
Opin Pediatr. 2013;25(2):180-187.
25. Houston J, Dillon L, Duvall A, McGuire M.
Bridging the gap between evidence and practice:
a systematic review—when is the best time to clamp
the infant’s umbilical cord in term low-risk women?
Open J Nurs. 2014;04(11):730-736.
26. Wilson EE, Windle WF, Alt HL. Deprivation of
placental blood as a cause of iron deficiency in
infants. AJDC. 1941;62(2):320-327.
27. Domellöf M, Braegger C, Campoy C, et al;
ESPGHAN Committee on Nutrition. Iron
requirements of infants and toddlers. J Pediatr
Gastroenterol Nutr. 2014;58(1):119-129.
28. Chandyo RK, Henjum S, Ulak M, et al. The
prevalence of anemia and iron deficiency is more
common in breastfed infants than their mothers in
Bhaktapur, Nepal. Eur J Clin Nutr. 2016;70(4):
456-462.
29. Andersson O, Lindquist B, Lindgren M,
Stjernqvist K, Domellöf M, Hellström-Westas L.
Effect of delayed cord clamping on
neurodevelopment at 4 years of age: a randomized
clinical trial. JAMA Pediatr. 2015;169(7):631-638.
Delayed vs Early Umbilical Cord Clamping and Anemia in Infants Original Investigation Research
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