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Abstract

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 (≥180 seconds after delivery) or early clamping (≤60 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.
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 (180 seconds
after delivery) or early clamping (60 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
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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.
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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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... 23 Delayed cord clamping has shown to be beneficial for term and preterm newborns, 24 with increased Hb levels after birth and iron stores in the first few months of life. 25,26 In a 2017 study, delayed cord clamping was shown to reduce anemia at 8 months and 12 months of age, which could have a positive impact on health in high-risk infants. 26 Additionally, in 2010, the American Academy of Pediatrics issued a recommendation that newborns exclusively breastfed at 4 months of life be given routine iron supplementation to promote cognitive development. ...
... 25,26 In a 2017 study, delayed cord clamping was shown to reduce anemia at 8 months and 12 months of age, which could have a positive impact on health in high-risk infants. 26 Additionally, in 2010, the American Academy of Pediatrics issued a recommendation that newborns exclusively breastfed at 4 months of life be given routine iron supplementation to promote cognitive development. 27 Although this recommendation has been called into question, it remains standard of care at this time. ...
Article
Iron deficiency anemia is the most prevalent form of anemia worldwide. In the United States, clinicians routinely screen for iron deficiency anemia upon initiation of prenatal care, at the start of the third trimester, and prior to birth. Treatment of iron deficiency anemia generally begins with oral supplementation of elemental iron, which is associated with adverse gastrointestinal effects. These adverse effects can decrease adherence, leading to subtherapeutic treatment. Newer evidence highlights the benefits of early screening for iron deficiency before the onset of anemia, as well as the use of intravenous iron to expedite the treatment of iron deficiency anemia. More research is needed on the potential consequences of over‐supplementation and iron deficiency without anemia to guide treatment. This article reviews the evidence for best practices for screening, treatment, and continued monitoring of iron deficiency anemia during pregnancy and postpartum. Maternal, fetal, and neonatal implications are reviewed, as well as the risks and benefits of treatment options. Finally, an evidence‐based algorithm is proposed to guide clinicians on continued monitoring after treatment.
... By delaying cord clamping (CC) for 3-5 minutes, term infants receive a placental transfusion of 25%-35% of their total blood volume. 1,2 Beneficial effects after delayed CC include reduced iron deficiency at 3-8 months, improved neurodevelopment at 12 and 48 months, [3][4][5][6][7] and improved brain myelin content during infancy. 8,9 In preterm infants, delayed CC is associated with reduced mortality by approximately 30%. ...
... This further strengthens the recommendation to delay CC >3 minutes to give the infant short-term benefits such as improved oxygen levels immediately after birth 25,26 and positive long-term benefits such as less iron deficiency, improved brain myelin content, neurodevelopment, and reduction of infant anemia in low-resource settings. [3][4][5][6][7][8][9] Furthermore, the results suggest that the concerns about increased risk of phototherapy in conjunction with delayed CC should be abandoned. However, longer CC time than evaluated in this study, for example extending CC time beyond placental delivery, could theoretically lead to reverse blood transfusion back to the placenta 29 and is not recommended. ...
Article
Full-text available
Background Delaying cord clamping (CC) for 3‐5 minutes reduces iron deficiency and improves neurodevelopment. Data on the effects of CC beyond 3 minutes in relation to short‐term neonatal outcomes and maternal risk of postpartum hemorrhage are scarce. Methods This was a prospective observational study performed in two delivery departments. Pregnant women with vaginal deliveries were included. Time to CC, estimated postpartum blood loss, and perinatal data were recorded. Spearman's correlation analysis and comparisons between newborns clamped before and after 3 minutes were performed. Results In total, 904 dyads were included. The mean gestational age ± standard deviation was 40.1 ± 1.2 weeks. CC was performed at a median time of 6 minutes (range 0‐23.5). Apgar scores at 5 and 10 minutes were positively correlated with time to CC (correlation coefficient .140, P < .001 and .161, < .001). There was no correlation between CC time and bilirubin level (correlation coefficient .021, P = .54). The median postpartum blood loss was 300 mL (70‐2550 mL), with a negative correlation between CC time and postpartum blood loss (−0.115, P = .001). The postpartum blood loss was larger in the group clamped at ≤3 minutes (median [interquartile range] 400 mL [300‐600] vs 300 mL [250‐450], [P = .003]]. Conclusions Umbilical CC times beyond 3 minutes in vaginal deliveries were not associated with negative short‐term outcomes in newborns and were associated with a smaller maternal postpartum blood loss. Although CC time as long as 6 minutes could be considered as safe, further research is needed to decide the optimal timing.
... This blood contains not only volume, but also 15-20 ml/kg of red blood cells, hundreds of millions to billions of stem cells, and 10-15 ml/kg of plasma. The amount of iron provided by the placental transfusions is enough for a term infant to last 3-8 months (11,12). The large amount of stem cells represents an autologous transplant, which is important in the development of organ systems, tissue repair, and immunocompetence, as well as lowering the infant's risk of neonatal and age-related diseases (13)(14)(15). ...
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Background The umbilical cord blood contains a high concentration of stem cells. There is not any published study evaluating the amount of stem cells that have the potential to be transferred to the infant through placental transfusion methods as delayed cord clamping (DCC) and umbilical cord milking (UCM). The aim of this study is to measure the concentrations of endothelial progenitor cell (EPC) and CD34+ hematopoietic stem cell (HSC) in the placental residual blood volume (PRBV), and evaluate the delivery room adaptation and cerebral oxygenation of these infants. Methods Infants with ≥36 gestational weeks were randomized to receive DCC (120 s), UCM, or immediate cord clamping (ICC). EPC and CD34+ HSC were measured by flow cytometry from the cord blood. PRBV was collected in the setup. The cord blood gas analysis and complete blood count were performed. The heart rate (HR), oxygen saturation (SpO2), and cerebral regional oxygen saturation (crSO2) were recorded. Results A total of 103 infants were evaluated. The amount of PRBV (in ml and ml/kg) was higher in the ICC group ( p < 0.001). The number of EPCs in the PRBV content (both ml and ml/kg) were the highest in the ICC group ( p = 0.002 and p = 0.001, respectively). The number of CD34+ HSCs in PRBV content (ml and ml/kg) was similar in all groups, but nonsignificantly higher in the ICC group. The APGAR scores at the first and fifth min were lower in the ICC group ( p < 0.05). The mean crSO2 values were higher at the 3rd and 10th min in the DCC group ( p = 0.042 and p = 0.045, respectively). cFOE values were higher at the 3rd and 10th min in the ICC group ( p = 0.011 and p < 0.001, respectively). Conclusion This study showed that placental transfusion methods, such as DCC and UCM, provide both higher blood volume, more stem cells transfer to the infant, and better cerebral oxygenation in the first minutes of life, whereas many lineages of stem cells is lost to the placenta by ICC with higher residual blood volume. These cord management methods rather than ICC do not require any cost or technology, and may be a preemptive therapeutic source for diseases of the neonatal period.
... Our study had some limitations. Data were unavailable for other evidence-based practices such as use of surfactant within 2 h of birth and early nasal continuous positive airway pressure [22], deferred cord clamping [23], and umbilical cord milking [24]. There were 960 cases with missing information on one of the 4 practices and 965 cases with missing information on the outcome. ...
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Introduction: Very preterm infants are at high risk of early death or severe brain injury, with potential for impaired long-term neurodevelopmental function and physical health. There are evidence-based healthcare practices that can reduce the incidence. Materials and methods: Infants born at 24-316 weeks gestational age and admitted within 24 h to NICUs participating in the Chinese Neonatal Network in 2019 were included. We examined the association between 4 evidence-based practices: inborn (born in a tertiary hospital in the Chinese Neonatal Network), ACS (any antenatal corticosteroid), MgSO4 (prenatal magnesium sulfate), and NT (normothermic temperature [36.0-37.5°C] at admission) and early death and/or severe brain injury in the study population. Results: Of 6,035 eligible infants, the incidence of early death and/or severe brain injury was 10.6%. Exposure to ACS only was associated with significant lower incidence of death and/or severe brain injury than none (aOR, 0.71; 95% CI: 0.57-0.88), but not MgSO4 only (aOR, 0.97; 95% CI: 0.81-1.17), NT only (aOR, 0.91; 95% CI: 0.76-1.08), or inborn only (aOR, 0.91; 95% CI: 0.72-1.15). The association between number of practices and incidence of early death and/or severe brain injury is as follows: none = 23% (31/138), any 1 = 14% (84/592), any 2 = 12% (185/1,538), any 3 = 9% (202/2,285), and all 4 = 9% (140/1,482). Discussion/conclusion: More comprehensive use of evidence-based practices was associated with improved survival without severe brain injury among very preterm infants born at <32 weeks gestational age.
... Adequately powered trials are needed to investigate the non-hematological benefits and risks of iron supplementation in this patient population. As an alternative to iron supplementation, measures to increase iron stores at birth among infants so as to provide them with adequate iron until late infancy, such as delayed cord clamping, have been reported [34]. ...
Article
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Background: Infants' feeding practices in the first 6 months of life and their association with iron status and hematologic parameters has not been well studied. We aim to evaluate this association. Methods: In a retrospective chart review, we identified 403 infants who received laboratory screening for anemia at 6-month visits. Infants were categorized into four groups according to feeding practices. Hematologic parameters and incidence of anemia, iron deficiency (ID), and iron deficiency anemia (IDA) were compared. Results: In total, 105 infants were breastfed (BF), 78 were breastfed with iron supplementation starting at 4 months (BI), 109 were mixed-fed (breast milk and formula) with or without iron supplementation (MF), and 111 were formula-fed (FF). The BF group had the highest incidence of anemia (38.1%), ID (28.6%), and IDA (17.1%) when compared with the other groups (p < 0.001). In multivariate logistic regression, BI, MF, and FF infants had 90.4%, 97.5%, and 96.9% decreased risk of IDA, respectively, with BF infants as a reference group. Conclusion: The incidence of anemia, ID, and IDA at age 6 months was higher in BF than FF or MF infants. However, iron supplements in BF infants starting at 4 months significantly reduced their ID and IDA incidence.
... Delayed cord clamping is important for the mother and for term and preterm infants [52,121,241]. Late cord clamping is improving iron status in infant in the first 6 to 12 months, which is decreasing the incidence of anemia and better neurodevelopmental outcome in term infants, while blood transfusions, necrotizing enterocolitis, and intracranial hemorrhage are less frequent in premature infants [102]. Risk of postpartum hemorrhage and anemia in mother are not increased [185]. ...
... Delayed cord clamping is important for the mother and for term and preterm infants [52,121,241]. Late cord clamping is improving iron status in infant in the first 6 to 12 months, which is decreasing the incidence of anemia and better neurodevelopmental outcome in term infants, while blood transfusions, necrotizing enterocolitis, and intracranial hemorrhage are less frequent in premature infants [102]. Risk of postpartum hemorrhage and anemia in mother are not increased [185]. ...
Chapter
Unlike other species in the nature, the human offspring and the birthing mother are protected institutionally by the whole society. This protection has to be in line with the natural rules and laws as much as possible in order to preserve natural evolutionary potentials of the human race. This means that the human race should make efforts to remain the part of the natural circle throughout the life cycle. Caring for the normal healthy newborn is particularly important on that track. Caregivers should use as much as possible the intrinsic potential of the mother and her newborn baby to preserve their health, with salutogenic approach and by strengthening their resilience. In this chapter you will find some answers connecting prenatal environment with postnatal life, with influence of birthing process on the neonate and its transition from intrauterine to extrauterine life, with initiation of breastfeeding immediately after birth. The importance of microbiome for human health is discussed and emphasized. Postnatal assessment of the newborn should enable one to find what may interfere with the natural process of transition. This approach includes provision of care minimizing medicalization and iatrogenic intervention, with the promotion and enhancement of positive state of health.
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Gelişmiş Cerrahi Sonrası İyileşme (ERAS) programları, 2000’li yılların başından beri birçok cerrahi uzmanlık dalında operasyon sonuçlarını iyileştirmiştir. Bu multidisipliner standart bakım programı, cerrahi hastalarının preoperatif, intraoperatif, postoperatif bakımını optimize etmeyi amaçlamıştır. Yeni yayınlar ERAS protokollerinin sezaryen doğumlarda başarıyla uygulandığını göstermiştir. Sezaryen doğumda ERAS programının temel öğeleri; antenatal eğitim/danışmanlık, cerrahi öncesi tıbbi optimizasyon, anestezi öncesi medikasyon, sınırlı açlık süresi, karbonhidrat suplementasyonu, intraoperatif anestezi yönetimi, cerrahi alan enfeksiyon profilaksisi, normotermi ve övoleminin sürdürülmesi, uygun cerrahi teknik, yenidoğan bakımı, postoperatif analjezi, bulantı ve kusmanın önlenmesi, erken beslenme, erken mobilizasyon, tromboembolizm profilaksisi, glukoz yönetimi, idrar yönetimi ve taburculuk danışmanlığıdır. Bu öğelerin uygulanması, maternal /neonatal sonuçların iyileşmesi ve hastanede kalış süresinin azalması ile sonuçlanmıştır. Bununla birlikte, bu konudaki mevcut literatür sezaryen doğum için standartlaştırılmış, küresel olarak uygulanan bir ERAS protokolü geliştirmek için yeterli değildir. Bakım programını ve önerileri geliştirmek için daha fazla çalışmaya ihtiyaç vardır.
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Breastfeeding and human milk are the normative standards for infant feeding and nutrition. The short- and long-term medical and neurodevelopmental advantages of breastfeeding make breastfeeding, or the provision of human milk, a public health imperative. The American Academy of Pediatrics (AAP) recommends exclusive breastfeeding for approximately 6 months after birth. Furthermore, the AAP supports continued breastfeeding, along with appropriate complementary foods introduced at about 6 months, as long as mutually desired by mother and child for 2 years or beyond. These recommendations are consistent with those of the World Health Organization (WHO). Medical contraindications to breastfeeding are rare. The AAP recommends that birth hospitals or centers implement maternity care practices shown to improve breastfeeding initiation, duration, and exclusivity. The Centers for Disease Control and Prevention (CDC) and The Joint Commission monitor breastfeeding practices in US hospitals. Pediatricians play a critical role in hospitals, their practices, and communities as advocates of breastfeeding and, thus, need to be trained about the benefits of breastfeeding for mothers and children and in managing breastfeeding.
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It is important to focus on preconception care in the well woman because prevention is better than treatment, and interventions commenced in pregnancy may have limited benefit. A lower socioeconomic status is associated with poorer maternal and neonatal outcomes, including gestational diabetes mellitus (GDM), preterm birth (PTB), pre‐eclampsia (PET), and small‐for‐gestational‐age babies. Poor nutrition contributes to epigenetic dysregulation, which can alter gene expression and effect phenotypic change. A healthy diet during pregnancy, high in grains and vegetables, may help to reduce the risk of obesity, GDM, cardiovascular disease, hypertension, PET, and maternal anaemia; the benefits to the fetus include the prevention of low birthweight, macrosomia, PTB and stillbirth. The minimum amount of aerobic activity recommended during the preconception and pregnancy period is either 150 minutes of moderate intensity activity per week, or 30 minutes of activity per day, or 75 minutes of intense activity per week. Alcohol is a teratogen that can cause fetal growth restriction and facial malformations, learning and behavioural challenges and impairment to the central nervous system. Smoking in pregnancy can lead to impaired fetal growth and adverse effects on the immune system. To understand the importance of the preconception period. To evaluate key nutritional requirements in the preconception period. To critically evaluate the benefits and disadvantages of vaccination in the preconception period.
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Background: Delayed cord clamping at birth has shown to benefit neonates with increased placental transfusion leading to higher haemoglobin concentrations, additional iron stores and less anaemia later in infancy, higher red blood cell flow to vital organs and better cardiopulmonary adaptation. As iron deficiency in infants even without anaemia has been associated with impaired development, delayed cord clamping seems to benefit full term infants also in regions with a relatively low prevalence of iron deficiency anaemia. In Nepal, there is a high anaemia prevalence among children between 6 and 17 months (72-78 %). The objective of the proposed study is to evaluate the effects of delayed and early cord clamping on anaemia (and haemoglobin level) at 8 and 12 months, ferritin at 8 and 12 months, bilirubin at 2-3 days, admission to Neonatal Intensive Care Unit (NICU) or special care nursery, and development at 12 and 18-24 months of age. Methods/design: A randomized, controlled trial comparing delayed and early cord clamping will be implemented at Paropakar Maternity and Women's Hospital in Kathmandu, Nepal. Pregnant woman of gestational age 34-41 weeks who deliver vaginally will be included in the study. The interventions will consist of delayed clamping of the umbilical cord (≥180 s after delivery) or early clamping of the umbilical cord (≤60 s). At 8 and 12 months of age, infant's iron status and developmental milestones will be measured. Discussion: This trial is important to perform because, although strong indications for the beneficial effect of delayed cord clamping on anaemia at 8 to 12 months of age exist, it has not yet been evaluated by a randomized trial in this setting. The proposed study will analyse both outcome as well as safety effects. Additionally, the results may not only contribute to practice in Nepal, but also to the global community, in particular to other low-income countries with a high prevalence of iron deficiency anaemia. Trial registration: Clinical trial.gov NCT02222805 . Registered August 19 2014.
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Background/objectives: Iron deficiency anemia is a widespread public health problem, particularly in low- and middle-income countries. Maternal iron status around and during pregnancy may influence infant iron status. We examined multiple biomarkers to determine the prevalence of iron deficiency and anemia among breastfed infants and explored its relationship with maternal and infant characteristics in Bhaktapur, Nepal. Subjects/methods: In a cross-sectional survey, we randomly selected 500 mother-infant pairs from Bhaktapur municipality. Blood was analyzed for hemoglobin, ferritin, total iron-binding capacity, transferrin receptors and C-reactive protein. Results: The altitude-adjusted prevalence of anemia was 49% among infants 2-6-month-old (hemaglobin (Hb) <10.8 g/dl) and 72% among infants 7-12-month-old (Hb <11.3 g/dl). Iron deficiency anemia, defined as anemia and serum ferritin <20 or <12 μg/l, affected 9 and 26% of infants of these same age groups. Twenty percent of mothers had anemia (Hb <12.3 g/dl), but only one-fifth was explained by depletion of iron stores. Significant predictors of infant iron status and anemia were infant age, sex and duration of exclusive breastfeeding and maternal ferritin concentrations. Conclusions: Our findings suggest that iron supplementation in pregnancy is likely to have resulted in a low prevalence of postpartum anemia. The higher prevalence of anemia and iron deficiency among breastfed infants compared with their mothers suggests calls for intervention targeting newborns and infants.European Journal of Clinical Nutrition advance online publication, 2 December 2015; doi:10.1038/ejcn.2015.199.
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Prevention of iron deficiency in infancy may promote neurodevelopment. Delayed umbilical cord clamping (CC) prevents iron deficiency at 4 to 6 months of age, but long-term effects after 12 months of age have not been reported. To investigate the effects of delayed CC compared with early CC on neurodevelopment at 4 years of age. Follow-up of a randomized clinical trial conducted from April 16, 2008, through May 21, 2010, at a Swedish county hospital. Children who were included in the original study (n = 382) as full-term infants born after a low-risk pregnancy were invited to return for follow-up at 4 years of age. Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and Movement Assessment Battery for Children (Movement ABC) scores (collected between April 18, 2012, and July 5, 2013) were assessed by a blinded psychologist. Between April 11, 2012, and August 13, 2013, parents recorded their child's development using the Ages and Stages Questionnaire, Third Edition (ASQ) and behavior using the Strengths and Difficulties Questionnaire. All data were analyzed by intention to treat. Randomization to delayed CC (≥180 seconds after delivery) or early CC (≤10 seconds after delivery). The main outcome was full-scale IQ as assessed by the WPPSI-III. Secondary objectives were development as assessed by the scales from the WPPSI-III and Movement ABC, development as recorded using the ASQ, and behavior using the Strengths and Difficulties Questionnaire. We assessed 263 children (68.8%). No differences were found in WPPSI-III scores between groups. Delayed CC improved the adjusted mean differences (AMDs) in the ASQ personal-social (AMD, 2.8; 95% CI, 0.8-4.7) and fine-motor (AMD, 2.1; 95% CI, 0.2-4.0) domains and the Strengths and Difficulties Questionnaire prosocial subscale (AMD, 0.5; 95% CI, >0.0-0.9). Fewer children in the delayed-CC group had results below the cutoff in the ASQ fine-motor domain (11.0% vs 3.7%; P = .02) and the Movement ABC bicycle-trail task (12.9% vs 3.8%; P = .02). Boys who received delayed CC had significantly higher AMDs in the WPPSI-III processing-speed quotient (AMD, 4.2; 95% CI, 0.8-7.6; P = .02), Movement ABC bicycle-trail task (AMD, 0.8; 95% CI, 0.1-1.5; P = .03), and fine-motor (AMD, 4.7; 95% CI, 1.0-8.4; P = .01) and personal-social (AMD, 4.9; 95% CI, 1.6-8.3; P = .004) domains of the ASQ. Delayed CC compared with early CC improved scores in the fine-motor and social domains at 4 years of age, especially in boys, indicating that optimizing the time to CC may affect neurodevelopment in a low-risk population of children born in a high-income country. clinicaltrials.gov Identifier: NCT01581489.
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Background: Low haemoglobin concentrations and anaemia are important risk factors for the health and development of women and children. We estimated trends in the distributions of haemoglobin concentration and in the prevalence of anaemia and severe anaemia in young children and pregnant and non-pregnant women between 1995 and 2011. Methods: We obtained data about haemoglobin and anaemia for children aged 6–59 months and women of childbearing age (15–49 years) from 257 population-representative data sources from 107 countries worldwide. We used health, nutrition, and household surveys; summary statistics from WHO's Vitamin and Mineral Nutrition Information System; and summary statistics reported by other national and international agencies. We used a Bayesian hierarchical mixture model to estimate haemoglobin distributions and systematically addressed missing data, non-linear time trends, and representativeness of data sources. We quantified the uncertainty of our estimates. Findings: Global mean haemoglobin improved slightly between 1995 and 2011, from 125 g/L (95% credibility interval 123–126) to 126 g/L (124–128) in non-pregnant women, from 112 g/L (111–113) to 114 g/L (112–116) in pregnant women, and from 109 g/L (107–111) to 111 g/L (110–113) in children. Anaemia prevalence decreased from 33% (29–37) to 29% (24–35) in non-pregnant women, from 43% (39–47) to 38% (34–43) in pregnant women, and from 47% (43–51) to 43% (38–47) in children. These prevalences translated to 496 million (409–595 million) non-pregnant women, 32 million (28–36 million) pregnant women, and 273 million (242–304 million) children with anaemia in 2011. In 2011, concentrations of mean haemoglobin were lowest and anaemia prevalence was highest in south Asia and central and west Africa. Interpretation: Children's and women's haemoglobin statuses improved in some regions where concentrations had been low in the 1990s, leading to a modest global increase in mean haemoglobin and a reduction in anaemia prevalence. Further improvements are needed in some regions, particularly south Asia and central and west Africa, to improve the health of women and children and achieve global targets for reducing anaemia. Funding: Bill & Melinda Gates Foundation, Grand Challenges Canada, and the UK Medical Research Council.
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The optimal timing for cord clamping, early versus delayed, in the third stage of labour is a controversial subject. Issues surrounding the timing of cord clamping include gestational age and maternal and neonatal considerations. Delayed cord clamping (DCC) has been shown to increase placental transfusion, leading to an increase in neonatal blood volume at birth of approximately 30%. In the term infant, although this may result in an increase in iron stores, thereby decreasing the risk of anemia, it may adversely increase the risk of jaundice and the need for phototherapy. In the preterm infant, DCC (or even milking of the cord) decreases the need for blood transfusions for anemia, the number of such transfusions, and the risks of intraventricular hemorrhage and late-onset sepsis. Advantages of DCC also include a reduction in alloimmunization in Rh-negative women, although this advantage is theoretical and unproven.
Article
When the umbilical cord is clamped immediately after birth, over 100 cc. of blood can usually be obtained from the placental end of the cord.1 This blood normally flows into the infant if clamping is delayed until the placenta begins to descend into the vagina.2 During the neonatal period the infant's total blood volume is about 10 per cent of the body weight,3 and the average weight at birth is about 3.2 Kg.; therefore it is possible that the blood contained in the placenta and its surface vessels is equivalent to a third of the blood volume of the newborn infant. We have shown previously that depriving the infant of the placental blood results in a significant decrease in the erythrocyte count and the hemoglobin content of the blood and an increase in the reticulocytes during the first week of life.2c Further observations have indicated that
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Background: Policies for timing of cord clamping vary, with early cord clamping generally carried out in the first 60 seconds after birth, whereas later cord clamping usually involves clamping the umbilical cord more than one minute after the birth or when cord pulsation has ceased. The benefits and potential harms of each policy are debated. Objectives: To determine the effects of early cord clamping compared with late cord clamping after birth on maternal and neonatal outcomes Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013). Selection criteria: Randomised controlled trials comparing early and late cord clamping. Data collection and analysis: Two review authors independently assessed trial eligibility and quality and extracted data. Main results: We included 15 trials involving a total of 3911 women and infant pairs. We judged the trials to have an overall moderate risk of bias. Maternal outcomes: No studies in this review reported on maternal death or on severe maternal morbidity. There were no significant differences between early versus late cord clamping groups for the primary outcome of severe postpartum haemorrhage (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.65 to 1.65; five trials with data for 2066 women with a late clamping event rate (LCER) of ~3.5%, I(2) 0%) or for postpartum haemorrhage of 500 mL or more (RR 1.17 95% CI 0.94 to 1.44; five trials, 2260 women with a LCER of ~12%, I(2) 0%). There were no significant differences between subgroups depending on the use of uterotonic drugs. Mean blood loss was reported in only two trials with data for 1345 women, with no significant differences seen between groups; or for maternal haemoglobin values (mean difference (MD) -0.12 g/dL; 95% CI -0.30 to 0.06, I(2) 0%) at 24 to 72 hours after the birth in three trials. Neonatal outcomes: There were no significant differences between early and late clamping for the primary outcome of neonatal mortality (RR 0.37, 95% CI 0.04 to 3.41, two trials, 381 infants with a LCER of ~1%), or for most other neonatal morbidity outcomes, such as Apgar score less than seven at five minutes or admission to the special care nursery or neonatal intensive care unit. Mean birthweight was significantly higher in the late, compared with early, cord clamping (101 g increase 95% CI 45 to 157, random-effects model, 12 trials, 3139 infants, I(2) 62%). Fewer infants in the early cord clamping group required phototherapy for jaundice than in the late cord clamping group (RR 0.62, 95% CI 0.41 to 0.96, data from seven trials, 2324 infants with a LCER of 4.36%, I(2) 0%). Haemoglobin concentration in infants at 24 to 48 hours was significantly lower in the early cord clamping group (MD -1.49 g/dL, 95% CI -1.78 to -1.21; 884 infants, I(2) 59%). This difference in haemoglobin concentration was not seen at subsequent assessments. However, improvement in iron stores appeared to persist, with infants in the early cord clamping over twice as likely to be iron deficient at three to six months compared with infants whose cord clamping was delayed (RR 2.65 95% CI 1.04 to 6.73, five trials, 1152 infants, I(2) 82%). In the only trial to report longer-term neurodevelopmental outcomes so far, no overall differences between early and late clamping were seen for Ages and Stages Questionnaire scores. Authors' conclusions: A more liberal approach to delaying clamping of the umbilical cord in healthy term infants appears to be warranted, particularly in light of growing evidence that delayed cord clamping increases early haemoglobin concentrations and iron stores in infants. Delayed cord clamping is likely to be beneficial as long as access to treatment for jaundice requiring phototherapy is available.
Article
Historically, in midwifery and obstetric care, the umbilical cord was not usually clamped until all pulsation of the cord had ceased. This is now referred to as delayed cord clamping or DCC (not clamping umbilical cord before two minutes of life). During the last one hundred years with changes in the ways women give birth, especially the shift toward hospital based birth in the Western world, it became commonplace for the cord to be clamped within 20 -30 seconds of birth (immediate cord clamping or ICC). Authors have postulated various reasons for this shift in timing of umbilical cord clamping to include a possible decreased risk of postpartum hemorrhage, the need for resuscitation of the newborn and sampling of cord blood for stem cells and cord blood analysis. Recent evidence suggests that newborns (particularly in low-resourced settings) would benefit greatly from a policy of DCC with decreased risks of childhood anemia, subsequent seque-lae and the need for supplementation. This systematic review examined recent literature from the last eight years using commonly used academic search engines with associated keywords. The re-sults were carefully collated into a table of findings and outcomes.
Article
Iron deficiency (ID) is the most common micronutrient deficiency worldwide and young children are a special risk group since their rapid growth leads to high iron requirements. Risk factors associated with a higher prevalence of iron deficiency anemia (IDA) include low birth weight, high cow's milk intake, low intake of iron-rich complementary foods, low socioeconomic status and immigrant status.The aim of this position paper is to review the field and provide recommendations regarding iron requirements in infants and toddlers, including those of moderately or marginally low birth weight.There is no evidence that iron supplementation of pregnant women improves iron status in their offspring in a European setting. Delayed cord clamping reduces the risk of iron deficiency. There is insufficient evidence to support general iron supplementation of healthy, European infants and toddlers of normal birth weight. Formula-fed infants up to 6 months of age should receive iron fortified infant formula, with an iron content of 4-8 mg/L (0.6-1.2 mg/kg/d). Marginally low birth weight infants (2000-2500 g) should receive iron supplements of 1-2 mg/kg/d. Follow-on formulas should be iron-fortified. However, there is not enough evidence to determine the optimal iron concentration in follow-on formula. From the age of 6 months, all infants and toddlers should receive iron-rich (complementary) foods including meat products and/or iron fortified foods. Unmodified cow's milk should not be fed as the main milk drink to infants before the age of 12 months and intake should be limited to <500 mL daily in toddlers. It is important to ensure that this dietary advice reaches high risk groups such as socioeconomically disadvantaged families and immigrant families.