Research
Original Investigation
Effect of Delayed vs Early Umbilical Cord Clamping on Iron Status and Neurodevelopment at Age 12 Months A Randomized Clinical Trial Ola Andersson, MD, PhD; Magnus Domellöf, MD, PhD; Dan Andersson, MD, PhD; Lena Hellström-Westas, MD, PhD
IMPORTANCE Prevention of iron deficiency in infancy may promote neurodevelopment.
Journal Club Slides at jamapediatrics.com
Delayed cord clamping (DCC) can prevent iron deficiency during the first 6 months of life. However, no data are available on long-term effects on infant outcomes in relation to time for umbilical cord clamping.
CME Quiz at jamanetworkcme.com and CME Questions page 591
OBJECTIVE To investigate effects of DCC, as compared with early cord clamping (ECC), on infant iron status and neurodevelopment at age 12 months in a European setting. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 382 full-term infants born after a low-risk pregnancy at a Swedish county hospital. Follow-up at 12 months included evaluation of iron status (ferritin level, transferrin saturation, transferrin receptor level, reticulocyte hemoglobin level, and mean cell volume) and parental assessment of neurodevelopment by the Ages and Stages Questionnaire, second edition (ASQ). INTERVENTIONS Infants were randomized to DCC (ⱖ180 seconds after delivery) or ECC (ⱕ10 seconds after delivery). MAIN OUTCOMES AND MEASURES The main outcome was iron status at age 12 months; the secondary outcome was ASQ score. RESULTS In total, 347 of 382 infants (90.8%) were assessed. The DCC and ECC groups did not differ in iron status (mean ferritin level, 35.4 vs 33.6 ng/mL, respectively; P = .40) or neurodevelopment (mean ASQ total score, 229.6 vs 233.1, respectively; P = .42) at age 12 months. Predictors of ferritin levels were infant sex and ferritin in umbilical cord blood. Predictors of ASQ score were infant sex and breastfeeding within 1 hour after birth. For both outcomes, being a boy was associated with lower results. Interaction analysis showed that DCC was associated with an ASQ score 5 points higher among boys (mean [SD] score, 229 [43] for DCC vs 224 [39] for ECC) but 12 points lower among girls (mean [SD] score, 230 [39] for DCC vs 242 [36] for ECC), out of a maximum of 300 points (P = .04 for the interaction term). CONCLUSIONS AND RELEVANCE Delayed cord clamping did not affect iron status or neurodevelopment at age 12 months in a selected population of healthy term-born infants. However, it may not be possible to demonstrate minor effects on neurodevelopment with the size of the study population and the chosen method for assessment. The current data indicate that sex may influence the effects on infant development after DCC in different directions. The magnitude and biological reason for this finding remain to be investigated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01245296
JAMA Pediatr. 2014;168(6):547-554. doi:10.1001/jamapediatrics.2013.4639 Published online April 21, 2014.
Author Affiliations: Department of Pediatrics, Hospital of Halland, Halmstad, Sweden (O. Andersson, D. Andersson); Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden (O. Andersson, Hellström-Westas); Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden (Domellöf). Corresponding Author: Ola Andersson, MD, PhD, Department of Women’s and Children’s Health, Uppsala University, SE-751 85 Uppsala, Sweden (ola.andersson @kbh.uu.se).
547
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Research Original Investigation
Cord Clamping, Iron Status, and Neurodevelopment
I
mmediately after birth, the newborn infant still shares its blood circulation with the placenta and umbilical cord. As the arteries in the umbilical cord start to constrict, uterine contractions contribute with a net inflow of blood from the placenta into the newborn, totaling approximately 30% extra blood volume.1 This transfusion will be impaired if immediate or early cord clamping (ECC) is performed, while a delay in clamping for 2 to 3 minutes will allow for a full transfusion. This placental transfusion has been shown to result in an increased hemoglobin (Hb) level and hematocrit in the neonatal period.2 During the last decade, several studies have shown that the increased blood volume after delayed cord clamping (DCC) also contributes to higher ferritin levels at 4 to 6 months of life and possibly also helps to prevent infant iron deficiency (ID).3,4 In animal models, ID has repeatedly been shown to affect dopamine metabolism, myelination, and energy metabolism.5,6 In infancy, ID has also been associated with impaired neurodevelopment, including both gross motor function and fine motor development, and adverse behavior.7 Iron supplementation to populations with increased risk for ID improves psychomotor outcome in infancy and reduces behavioral problems.8,9 We previously demonstrated in a randomized clinical trial that DCC, as compared with ECC, is associated with a higher neonatal Hb level and a lower rate of neonatal anemia as well as a higher ferritin level and less ID at age 4 months.10 No adverse effects of the intervention were found.10,11 At age 4 months, the infants in the 2 groups had a comparable incidence of symptoms of infection and similar neurodevelopment.12 We hypothesized that DCC after delivery has long-lasting effects and that it improves iron status and neurodevelopment at age 12 months.
Methods This study is a secondary analysis of a randomized clinical trial conducted at the Hospital of Halland, Halmstad, Sweden. The trial was approved by the Regional Ethical Review Board of Lund University. In short, pregnant women were considered eligible if they were nonsmoking, healthy, and carrying a lowrisk singleton pregnancy with an expected vaginal delivery at term, as previously described.10 They were informed about the study at antenatal care units in the area around Halmstad. After written informed parental consent was obtained and when delivery was imminent, 400 newborn infants were randomized to DCC at 180 seconds or more after delivery or to ECC before or at 10 seconds after birth, as previously described (Figure).10 Neither the mother giving birth nor the midwife performing the intervention could be blinded, but all staff involved in collection or analyses of blood samples or administration of the Ages and Stages Questionnaire, second edition (ASQ) were blinded to the allocation group. Early cord clamping was the standard method at the hospital during the inclusion period between April 16, 2008, and May 22, 2009. Infants were scheduled for follow-up visits at ages 4 and 12 months. 548
Outcomes The primary outcome of this randomized clinical trial was the ferritin level at age 4 months, as previously reported.10 For the 12-month follow-up, the following outcomes were prespecified: Hb level, iron status (as assessed by ferritin level, transferrin saturation [TS], soluble transferrin receptor [sTfR] level, and mean cell volume [MCV]), and neurodevelopment (as assessed by the ASQ [ASQ total score and scores on 5 subdomains: communication, gross motor, fine motor, problem solving, and personal-social]). As a post hoc outcome, we also analyzed determinants present at birth or age 4 months for ferritin and ASQ score at age 12 months.
12-Month Follow-up The follow-up visit included blood sampling, weight measurement, and length measurement. Venous blood sampling was performed after application of a local anesthetic (lidocaine, 2.5%, and prilocaine, 2.5%). One month before the planned 12month visit, parents received a letter with the ASQ and a 3-day food diary.
Blood Samples Blood samples were analyzed for the following: complete blood cell count (Hb level, hematocrit, and MCV), iron status (serum ferritin level, TS, and sTfR level), and C-reactive protein (CRP) level. Blood samples for complete blood cell counts were collected in ethylenediaminetetraacetic acid (EDTA) tubes (BD Vacutainer) and analyzed using the automated hematology analyzer Sysmex XE 2100 (Sysmex). Iron status indicators and CRP were collected in serum separator tubes (BD Vacutainer) and analyzed using a Cobas 6000 analyzer (Roche Diagnostics). Anemia was defined as an Hb level lower than 11.0 g/dL (to convert to grams per liter, multiply by 10.0). Low MCV, ferritin level, and TS were defined as MCV lower than 70 fL, ferritin level lower than 12 ng/mL (to convert to picomoles per liter, multiply by 2.247), and TS less than 10%, respectively.13 We defined the upper reference limit for sTfR (5.9 mg/L) by the mean value plus 2 SDs of the values from the 330 study participants with no anemia and normal MCV, ferritin level, and TS. Iron deficiency was defined as at least 2 of 4 iron store indicators (ferritin level, TS, sTfR level, MCV) outside reference values. Iron deficiency anemia was defined as anemia in combination with ID. 14 As inflammation is known to influence iron status markers,15 blood samples with a CRP concentration of 10 mg/L or greater (to convert to nanomoles per liter, multiply by 9.524) were excluded from analysis.
Ages and Stages Questionnaire The ASQ16 was used to assess parent-reported infant development. Permission was obtained from Paul H. Brookes Publishing Co to translate the ASQ 12-month questionnaire to Swedish for use in the study. We created cutoff scores according to the ASQ manual, ie, by subtracting the mean score with 2 SDs. If the ASQs were not completely answered, scores were adjusted according to the ASQ manual.
JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Birmingham User on 05/30/2015
jamapediatrics.com
Cord Clamping, Iron Status, and Neurodevelopment
Original Investigation Research
Figure. Trial Profile 1992 Assessed for eligibility
1592 Excluded 929 Not meeting inclusion criteria 663 Declined to participate
400 Randomized Allocation 200 Allocated to early clamping (≤10 s) 8 Excluded 1 Data not recorded 7 Inclusion criteria not followed 166 Received allocated intervention 26 Did not receive allocated intervention
200 Allocated to delayed clamping (≥180 s) 4 Excluded 4 Inclusion criteria not followed 168 Received allocated intervention 28 Did not receive allocated intervention
Follow-up at 2 d 3 Lost to follow-up 3 Family decided to stop participating
3 Lost to follow-up 3 Family decided to stop participating
Follow-up at 4 mo 9 Lost to follow-up 9 Family decided to stop participating
8 Lost to follow-up 8 Family decided to stop participating
180 With Ages and Stages Questionnaire 157 Received allocated intervention 176 With blood sample 154 Received allocated intervention
185 With Ages and Stages Questionnaire 160 Received allocated intervention 181 With blood sample 149 Received allocated intervention
Follow-up at 12 mo 10 Lost to follow-up 10 Family decided to stop participating
8 Lost to follow-up 8 Family decided to stop participating
168 With Ages and Stages Questionnaire 147 Received allocated intervention 163 With blood sample 144 Received allocated intervention
172 With Ages and Stages Questionnaire 149 Received allocated intervention 174 With blood sample 150 Received allocated intervention
3-Day Food Diary Parents were asked to record, in detail, all food and beverages the child was given during 3 days, in weight (grams) or volume (milliliters). The diary and instructions were included in the letter sent 1 month before the 4- and 12-month visits.
Sample Size The sample size for the primary outcome at 4 months was estimated to find a difference of 29% in geometric mean serum ferritin level between the 2 randomization groups with a power of 80% and a significance level of P < .05. A post hoc analysis of the 12-month data showed that a difference between the 2 groups of 7.5% in geometric mean ferritin level and a 12-point difference in the ASQ total score were needed to reach statistical significance (with a type I error rate of .05 and power of 80%).
Statistical Analysis Data were analyzed both according to intention to treat and per protocol. For comparisons, t test, Mann-Whitney U test, and Fisher exact test were used as appropriate. For 95% confidence interval across groups, the Hodges-Lehmann estima-
Flow diagram adapted to the CONSORT flow diagram.
tor was used. Ferritin was log10 transformed for analysis. We used SPSS for Windows, version 18.0 (SPSS Inc). Relative risks and 95% confidence intervals were calculated by the webbased JavaStat calculator.17 Calculations of Spearman rank correlation coefficient (ρ) were used to determine neonatal and 4-month variables that were associated with outcomes at 12 months (ferritin level and ASQ total score). Variables with a correlation significance of P < .05 for each outcome were then entered into a linear regression model and analyzed by stepwise backward selection, leaving only variables with P < .05 in the model.
Results At 12 months, 347 of 382 infants (90.8%) returned for blood sampling and/or were assessed by the ASQ. Blood samples were collected from 337 of 382 infants (88.2%), of whom 174 of 193 (90.2%) belonged to the DCC group and 163 of 189 (86.2%) to the ECC group (P = .27) at a mean (SD) age of 366 (8) days in the DCC group and 366 (7) days in the ECC group (P = .92) (Figure).
jamapediatrics.com
JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
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549
Research Original Investigation
Cord Clamping, Iron Status, and Neurodevelopment
Table 1. Baseline and Background Characteristics by Intervention Group and Correlations Between These Characteristics, Intervention Group, and Ferritin and Ages and Stages Questionnaire Total Score Outcomes at Age 12 Monthsa Outcome at 12 mo, Spearman ρ (P Value)
Cord Clampingb Delayed Characteristic
Value
Early Participants, No.
Value
Participants, No.
Spearman ρ (P Value)
ASQ Total Score
Ferritin
Maternal data, mean (SD) Weight, kg
67.4 (12.3)
177
66.6 (12.2)
167
Hb at first antenatal visit, g/dL
12.9 (1.1)
177
12.8 (0.9)
163
Newborn data Male, No. (%)
81 (45.8)
177
85 (50.0)
170
Apgar score at 5 min, mean (SD)
9.8 (0.6)
177
9.8 (0.7)
170
3.62 (0.46)
177
3.53 (0.50)
170
15.9 (1.8)
151
16.3 (1.6)
146
170
190 (118.5-285.0)
165
54.8 (16.4)
162
52.4 (17.0)
123 (73.7)
167
118 (73.3)
161
6.81 (0.86)
180
6.86 (0.84)
176
78.1 (3.0)
168
0.142 (.01)
0.234 (
Original Investigation
Effect of Delayed vs Early Umbilical Cord Clamping on Iron Status and Neurodevelopment at Age 12 Months A Randomized Clinical Trial Ola Andersson, MD, PhD; Magnus Domellöf, MD, PhD; Dan Andersson, MD, PhD; Lena Hellström-Westas, MD, PhD
IMPORTANCE Prevention of iron deficiency in infancy may promote neurodevelopment.
Journal Club Slides at jamapediatrics.com
Delayed cord clamping (DCC) can prevent iron deficiency during the first 6 months of life. However, no data are available on long-term effects on infant outcomes in relation to time for umbilical cord clamping.
CME Quiz at jamanetworkcme.com and CME Questions page 591
OBJECTIVE To investigate effects of DCC, as compared with early cord clamping (ECC), on infant iron status and neurodevelopment at age 12 months in a European setting. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 382 full-term infants born after a low-risk pregnancy at a Swedish county hospital. Follow-up at 12 months included evaluation of iron status (ferritin level, transferrin saturation, transferrin receptor level, reticulocyte hemoglobin level, and mean cell volume) and parental assessment of neurodevelopment by the Ages and Stages Questionnaire, second edition (ASQ). INTERVENTIONS Infants were randomized to DCC (ⱖ180 seconds after delivery) or ECC (ⱕ10 seconds after delivery). MAIN OUTCOMES AND MEASURES The main outcome was iron status at age 12 months; the secondary outcome was ASQ score. RESULTS In total, 347 of 382 infants (90.8%) were assessed. The DCC and ECC groups did not differ in iron status (mean ferritin level, 35.4 vs 33.6 ng/mL, respectively; P = .40) or neurodevelopment (mean ASQ total score, 229.6 vs 233.1, respectively; P = .42) at age 12 months. Predictors of ferritin levels were infant sex and ferritin in umbilical cord blood. Predictors of ASQ score were infant sex and breastfeeding within 1 hour after birth. For both outcomes, being a boy was associated with lower results. Interaction analysis showed that DCC was associated with an ASQ score 5 points higher among boys (mean [SD] score, 229 [43] for DCC vs 224 [39] for ECC) but 12 points lower among girls (mean [SD] score, 230 [39] for DCC vs 242 [36] for ECC), out of a maximum of 300 points (P = .04 for the interaction term). CONCLUSIONS AND RELEVANCE Delayed cord clamping did not affect iron status or neurodevelopment at age 12 months in a selected population of healthy term-born infants. However, it may not be possible to demonstrate minor effects on neurodevelopment with the size of the study population and the chosen method for assessment. The current data indicate that sex may influence the effects on infant development after DCC in different directions. The magnitude and biological reason for this finding remain to be investigated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01245296
JAMA Pediatr. 2014;168(6):547-554. doi:10.1001/jamapediatrics.2013.4639 Published online April 21, 2014.
Author Affiliations: Department of Pediatrics, Hospital of Halland, Halmstad, Sweden (O. Andersson, D. Andersson); Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden (O. Andersson, Hellström-Westas); Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden (Domellöf). Corresponding Author: Ola Andersson, MD, PhD, Department of Women’s and Children’s Health, Uppsala University, SE-751 85 Uppsala, Sweden (ola.andersson @kbh.uu.se).
547
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Birmingham User on 05/30/2015
Research Original Investigation
Cord Clamping, Iron Status, and Neurodevelopment
I
mmediately after birth, the newborn infant still shares its blood circulation with the placenta and umbilical cord. As the arteries in the umbilical cord start to constrict, uterine contractions contribute with a net inflow of blood from the placenta into the newborn, totaling approximately 30% extra blood volume.1 This transfusion will be impaired if immediate or early cord clamping (ECC) is performed, while a delay in clamping for 2 to 3 minutes will allow for a full transfusion. This placental transfusion has been shown to result in an increased hemoglobin (Hb) level and hematocrit in the neonatal period.2 During the last decade, several studies have shown that the increased blood volume after delayed cord clamping (DCC) also contributes to higher ferritin levels at 4 to 6 months of life and possibly also helps to prevent infant iron deficiency (ID).3,4 In animal models, ID has repeatedly been shown to affect dopamine metabolism, myelination, and energy metabolism.5,6 In infancy, ID has also been associated with impaired neurodevelopment, including both gross motor function and fine motor development, and adverse behavior.7 Iron supplementation to populations with increased risk for ID improves psychomotor outcome in infancy and reduces behavioral problems.8,9 We previously demonstrated in a randomized clinical trial that DCC, as compared with ECC, is associated with a higher neonatal Hb level and a lower rate of neonatal anemia as well as a higher ferritin level and less ID at age 4 months.10 No adverse effects of the intervention were found.10,11 At age 4 months, the infants in the 2 groups had a comparable incidence of symptoms of infection and similar neurodevelopment.12 We hypothesized that DCC after delivery has long-lasting effects and that it improves iron status and neurodevelopment at age 12 months.
Methods This study is a secondary analysis of a randomized clinical trial conducted at the Hospital of Halland, Halmstad, Sweden. The trial was approved by the Regional Ethical Review Board of Lund University. In short, pregnant women were considered eligible if they were nonsmoking, healthy, and carrying a lowrisk singleton pregnancy with an expected vaginal delivery at term, as previously described.10 They were informed about the study at antenatal care units in the area around Halmstad. After written informed parental consent was obtained and when delivery was imminent, 400 newborn infants were randomized to DCC at 180 seconds or more after delivery or to ECC before or at 10 seconds after birth, as previously described (Figure).10 Neither the mother giving birth nor the midwife performing the intervention could be blinded, but all staff involved in collection or analyses of blood samples or administration of the Ages and Stages Questionnaire, second edition (ASQ) were blinded to the allocation group. Early cord clamping was the standard method at the hospital during the inclusion period between April 16, 2008, and May 22, 2009. Infants were scheduled for follow-up visits at ages 4 and 12 months. 548
Outcomes The primary outcome of this randomized clinical trial was the ferritin level at age 4 months, as previously reported.10 For the 12-month follow-up, the following outcomes were prespecified: Hb level, iron status (as assessed by ferritin level, transferrin saturation [TS], soluble transferrin receptor [sTfR] level, and mean cell volume [MCV]), and neurodevelopment (as assessed by the ASQ [ASQ total score and scores on 5 subdomains: communication, gross motor, fine motor, problem solving, and personal-social]). As a post hoc outcome, we also analyzed determinants present at birth or age 4 months for ferritin and ASQ score at age 12 months.
12-Month Follow-up The follow-up visit included blood sampling, weight measurement, and length measurement. Venous blood sampling was performed after application of a local anesthetic (lidocaine, 2.5%, and prilocaine, 2.5%). One month before the planned 12month visit, parents received a letter with the ASQ and a 3-day food diary.
Blood Samples Blood samples were analyzed for the following: complete blood cell count (Hb level, hematocrit, and MCV), iron status (serum ferritin level, TS, and sTfR level), and C-reactive protein (CRP) level. Blood samples for complete blood cell counts were collected in ethylenediaminetetraacetic acid (EDTA) tubes (BD Vacutainer) and analyzed using the automated hematology analyzer Sysmex XE 2100 (Sysmex). Iron status indicators and CRP were collected in serum separator tubes (BD Vacutainer) and analyzed using a Cobas 6000 analyzer (Roche Diagnostics). Anemia was defined as an Hb level lower than 11.0 g/dL (to convert to grams per liter, multiply by 10.0). Low MCV, ferritin level, and TS were defined as MCV lower than 70 fL, ferritin level lower than 12 ng/mL (to convert to picomoles per liter, multiply by 2.247), and TS less than 10%, respectively.13 We defined the upper reference limit for sTfR (5.9 mg/L) by the mean value plus 2 SDs of the values from the 330 study participants with no anemia and normal MCV, ferritin level, and TS. Iron deficiency was defined as at least 2 of 4 iron store indicators (ferritin level, TS, sTfR level, MCV) outside reference values. Iron deficiency anemia was defined as anemia in combination with ID. 14 As inflammation is known to influence iron status markers,15 blood samples with a CRP concentration of 10 mg/L or greater (to convert to nanomoles per liter, multiply by 9.524) were excluded from analysis.
Ages and Stages Questionnaire The ASQ16 was used to assess parent-reported infant development. Permission was obtained from Paul H. Brookes Publishing Co to translate the ASQ 12-month questionnaire to Swedish for use in the study. We created cutoff scores according to the ASQ manual, ie, by subtracting the mean score with 2 SDs. If the ASQs were not completely answered, scores were adjusted according to the ASQ manual.
JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Birmingham User on 05/30/2015
jamapediatrics.com
Cord Clamping, Iron Status, and Neurodevelopment
Original Investigation Research
Figure. Trial Profile 1992 Assessed for eligibility
1592 Excluded 929 Not meeting inclusion criteria 663 Declined to participate
400 Randomized Allocation 200 Allocated to early clamping (≤10 s) 8 Excluded 1 Data not recorded 7 Inclusion criteria not followed 166 Received allocated intervention 26 Did not receive allocated intervention
200 Allocated to delayed clamping (≥180 s) 4 Excluded 4 Inclusion criteria not followed 168 Received allocated intervention 28 Did not receive allocated intervention
Follow-up at 2 d 3 Lost to follow-up 3 Family decided to stop participating
3 Lost to follow-up 3 Family decided to stop participating
Follow-up at 4 mo 9 Lost to follow-up 9 Family decided to stop participating
8 Lost to follow-up 8 Family decided to stop participating
180 With Ages and Stages Questionnaire 157 Received allocated intervention 176 With blood sample 154 Received allocated intervention
185 With Ages and Stages Questionnaire 160 Received allocated intervention 181 With blood sample 149 Received allocated intervention
Follow-up at 12 mo 10 Lost to follow-up 10 Family decided to stop participating
8 Lost to follow-up 8 Family decided to stop participating
168 With Ages and Stages Questionnaire 147 Received allocated intervention 163 With blood sample 144 Received allocated intervention
172 With Ages and Stages Questionnaire 149 Received allocated intervention 174 With blood sample 150 Received allocated intervention
3-Day Food Diary Parents were asked to record, in detail, all food and beverages the child was given during 3 days, in weight (grams) or volume (milliliters). The diary and instructions were included in the letter sent 1 month before the 4- and 12-month visits.
Sample Size The sample size for the primary outcome at 4 months was estimated to find a difference of 29% in geometric mean serum ferritin level between the 2 randomization groups with a power of 80% and a significance level of P < .05. A post hoc analysis of the 12-month data showed that a difference between the 2 groups of 7.5% in geometric mean ferritin level and a 12-point difference in the ASQ total score were needed to reach statistical significance (with a type I error rate of .05 and power of 80%).
Statistical Analysis Data were analyzed both according to intention to treat and per protocol. For comparisons, t test, Mann-Whitney U test, and Fisher exact test were used as appropriate. For 95% confidence interval across groups, the Hodges-Lehmann estima-
Flow diagram adapted to the CONSORT flow diagram.
tor was used. Ferritin was log10 transformed for analysis. We used SPSS for Windows, version 18.0 (SPSS Inc). Relative risks and 95% confidence intervals were calculated by the webbased JavaStat calculator.17 Calculations of Spearman rank correlation coefficient (ρ) were used to determine neonatal and 4-month variables that were associated with outcomes at 12 months (ferritin level and ASQ total score). Variables with a correlation significance of P < .05 for each outcome were then entered into a linear regression model and analyzed by stepwise backward selection, leaving only variables with P < .05 in the model.
Results At 12 months, 347 of 382 infants (90.8%) returned for blood sampling and/or were assessed by the ASQ. Blood samples were collected from 337 of 382 infants (88.2%), of whom 174 of 193 (90.2%) belonged to the DCC group and 163 of 189 (86.2%) to the ECC group (P = .27) at a mean (SD) age of 366 (8) days in the DCC group and 366 (7) days in the ECC group (P = .92) (Figure).
jamapediatrics.com
JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Birmingham User on 05/30/2015
549
Research Original Investigation
Cord Clamping, Iron Status, and Neurodevelopment
Table 1. Baseline and Background Characteristics by Intervention Group and Correlations Between These Characteristics, Intervention Group, and Ferritin and Ages and Stages Questionnaire Total Score Outcomes at Age 12 Monthsa Outcome at 12 mo, Spearman ρ (P Value)
Cord Clampingb Delayed Characteristic
Value
Early Participants, No.
Value
Participants, No.
Spearman ρ (P Value)
ASQ Total Score
Ferritin
Maternal data, mean (SD) Weight, kg
67.4 (12.3)
177
66.6 (12.2)
167
Hb at first antenatal visit, g/dL
12.9 (1.1)
177
12.8 (0.9)
163
Newborn data Male, No. (%)
81 (45.8)
177
85 (50.0)
170
Apgar score at 5 min, mean (SD)
9.8 (0.6)
177
9.8 (0.7)
170
3.62 (0.46)
177
3.53 (0.50)
170
15.9 (1.8)
151
16.3 (1.6)
146
170
190 (118.5-285.0)
165
54.8 (16.4)
162
52.4 (17.0)
123 (73.7)
167
118 (73.3)
161
6.81 (0.86)
180
6.86 (0.84)
176
78.1 (3.0)
168
0.142 (.01)
0.234 (
