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Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial
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Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial Nestor E Vain, Daniela S Satragno, Adriana N Gorenstein, Juan E Gordillo, Juan P Berazategui, M Guadalupe Alda, Luis M Prudent
Summary Background Delayed cord clamping allows for the passage of blood from the placenta to the baby and reduces the risk of iron deficiency in infancy. To hold the infant for more than 1 min at the level of the vagina (as is presently recommended), on the assumption that gravity affects the volume of placental transfusion, is cumbersome, might result in low compliance, and interferes with immediate contact of the infant with the mother. We aimed to assess whether gravity affects the volume of placental transfusion
Published Online April 17, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60197-5
Methods We did a multicentre non-inferiority trial at three university-affiliated hospitals in Argentina. We obtained informed consent from healthy mothers with normal term pregnancies admitted early in labour. Vigorous babies born vaginally were randomly assigned in a 1:1 ratio by computer-generated blocks and sequentially numbered sealed opaque envelopes to be held for 2 min before clamping the umbilical cord, at the level of the vagina (introitus group) or on the mother’s abdomen or chest (abdomen group). Newborn babies were weighed immediately after birth and after cord clamping. The primary outcome was the difference in weight (as a proxy of placental transfusion volume). The prespecified non-inferiority margin was 18 g (20%). We used t test and χ² test for group comparison, and used a multivariable linear regression analysis to control for covariables. This trial is registered with ClinicalTrials.gov, number NCT01497353.
School of Medicine, University of Buenos Aires, Buenos Aires, Argentina (Prof N E Vain MD); Foundation for Maternal and Child Health (FUNDASAMIN), Buenos Aires, Argentina (Prof N E Vain, D S Satragno MD, A N Gorenstein MD, J P Berazategui MD, Prof L M Prudent MD); Trinidad Palermo Private Hospital, Buenos Aires, Argentina (Prof N E Vain, A N Gorenstein, M G Alda MD); and Institute of Maternity Our Lady of Mercy, San Miguel de Tucumán, Argentina (J E Gordillo MD)
Findings Between Aug 1, 2011, and Aug 31, 2012, we allocated 274 newborn babies to the introitus group and 272 to the abdomen group. 77 newborn babies in the introitus group and 78 in the abdomen group were ineligible after randomisation (eg, caesarean section, forceps delivery, short umbilical cord or nuchal cord). Mean weight change was 56 g (SD 47, 95% CI 50–63) for 197 babies in the introitus group compared with 53 g (45, 46–59) for 194 babies in the abdomen group, supporting non-inferiority of the two approaches (difference 3 g, 95% CI −5∙8 to 12∙8; p=0·45). We did not note any serious adverse events during the study. Interpretation Position of the newborn baby before cord clamping does not seem to affect volume of placental transfusion. Mothers could safely be allowed to hold their baby on their abdomen or chest. This change in practice might increase obstetric compliance with the procedure, enhance maternal-infant bonding, and decrease iron deficiency in infancy.
See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(14)60411-6
Correspondence to: Prof Nestor E Vain, Foundation for Maternal and Child Health (FUNDASAMIN), Honduras 4160, Buenos Aires, Argentina [email protected]
Funding Foundation for Maternal and Child Health (FUNDASAMIN).
Introduction The ideal timing for umbilical cord clamping is controversial.1 Delayed cord clamping allows for passage of blood from the placenta to the baby (known as placental transfusion).2–5 When cord clamping is done after 60 s, newborn babies have a median birthweight 101 g higher than those born after early clamping (before 60 s),5 probably representing an average placental transfusion of 96 mL (1 mL of blood=1∙05 g).6 Delayed cord clamping increases haemoglobin in the neonatal period and decreases the risk of iron deficiency in infancy,5–8 a serious public health problem in lowincome9,10 and high-income countries.11–13 The procedure is included in the guidelines for delivery room management of newborn babies from several professional organisations,14–16 but compliance with the recommendation is low.17–20 This low compliance could be related to some published studies suggesting that delayed cord clamping is associated with maternal complications.1 However, results of a Cochrane meta-analysis5 clearly
show no increase in maternal haemorrhage, the use of uterotonics, or duration of the third stage of labour. On the assumption that gravity affects the volume of placental transfusion, recommendations suggest that newborn babies be held at or below the level of the vagina.19–21 This procedure is cumbersome, interferes with immediate contact with the mother, and might therefore contribute to low compliance. The effect of gravity on the volume of transfusion is based on the studies by Gunther and by Yao.2–4 Although those studies were not randomised trials and were done 35 years ago, they had rigorous methods. If gravity plays a small or negligible part in placental transfusion, then most infants born after vaginal delivery could be placed immediately on the mother’s abdomen or chest before clamping the umbilical cord. Depending on the position of the mother (lying down, semi-sitting, or sitting), the newborn baby would be above the vaginal level by about 30 cm. In view of the scarce evidence of the effect of gravity,22 we aimed to assess whether, provided
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We did this multicentre, non-inferiority, randomised controlled trial at three university-affiliated hospitals in Argentina (Trinidad Palermo Private Hospital, Buenos Aires [centre one], Maternal Infant Hospital Carlos Gianantonio, San Isidro, Buenos Aires [centre two], and Institute of Maternity Our Lady of Mercy, San Miguel de Tucumán [centre three]). The institutional review board of each participating centre approved the protocol and consent form. Mothers were approached and gave written consent upon admittance to hospital for labour (mothers admitted in advanced labour were not approached because insufficient time would be available to obtain an ethically valid consent). Eligible mothers were those with a normal pregnancy, admitted at term, during the first stage of labour and in whom a vaginal uncomplicated delivery was expected. We included vigorous term newborn babies born by vaginal delivery. Exclusion criteria for mothers were history of placenta praevia or postpartum haemorrhage, multiple gestation, intrauterine growth restriction, major congenital malformations diagnosed before delivery, maternal diseases (eg, eclampsia, Rh incompatibility, congestive heart failure), and request by the parents for cord blood banking. Newborn babies who needed resuscitation were delivered by caesarean section or forceps, and those with a short umbilical cord or a tight nuchal cord preventing the placement of the newborn baby according to the group to which they were assigned although initially randomised were not studied nor included in the analyses.
procedure and maternal acceptance. After informed parental consent was obtained early in labour, we randomly assigned newborn babies to the introitus or abdomen group and the obstetric team was notified of the assigned intervention. All newborn babies were weighed immediately after birth at the level of the vagina with an electronic 1 g precision scale (STW - 6 BB, Electronic Balanzas CAM, Buenos Aires, Argentina) with a coefficient of variation of 0·0006 g. A reliable weight can usually be obtained within the first 15 s. The delivery of the infants’ shoulders was considered time zero, and using a stopwatch (SH-688 STAR, Fuego, China) a nurse notified the 1 min time for determining the Apgar score and the 2 min time to clamp the umbilical cord. During the first 2 min before clamping, newborn babies randomly assigned to the introitus group were held by the investigator at the vaginal level and those assigned to the abdomen group were placed on the mother’s abdomen or chest, depending mainly on the length of the umbilical cord. In all newborn babies care was taken to avoid compression of the umbilical vessels. At 2 min, the cord was clamped and cut in newborn babies of both groups, and they were weighed again on the same scale. Previous studies have estimated the volume of placental transfusion by the difference in weight.2,23,24 Venous haematocrit and bilirubin values were obtained at 36–48 h simultaneously with routine neonatal screening. Additionally, we noted the position of the mother during delivery up to the time the cord was clamped and the effect of the use of early oxytocin on the increment in weight of the newborn baby. Positions were defined as semi-sitting and sitting if an angle of more than 30° with the horizontal surface of the bed was estimated, and horizontal if the estimated angle was between 0 and 30°. Prophylactic oxytocin use was defined as the intramuscular or intravenous administration of 10 IU of oxytocin to the mother within 1 min after birth.
Randomisation and masking
Outcomes
Eligible newborn babies were randomly assigned in a 1:1 ratio to the introitus group or the abdomen group with computer-generated allocation sequence in block sizes of four to eight (created by a statistician who was not involved again in the trial until statistical analysis of the results). Allocation was concealed by sequentially numbered sealed opaque envelopes. The nature of the intervention prevented us from masking the study.
The primary outcome was the difference between weight of the newborn baby obtained immediately after birth and that at 2 min after clamping of the umbilical cord. Secondary outcomes were haematocrit and bilirubin concentrations, incidence of polycythaemia, need for phototherapy, mother’s position, and use of oxytocin. We analysed the association between the weight increment and birthweight.
Procedures
Statistical analysis
We did a pilot study in 2009, at centre one to assess safety and feasibility in 32 mothers and babies. Patients who participated in the pilot study were not included in the analysis of the trial. We found that the first weight was always obtained in the first 15 s after the delivery of the shoulders, and we were able to adjust technical details such as stability and height of the weight scale. We also noticed good compliance of the obstetricians with the
On the basis of results of a recent study,24 we assumed a difference of 90 g between the weight immediately after birth and that at 2 min and a standard deviation of 60 g. To assess non-inferiority, we compared the upper limit of the 95% CIs for the difference between the means of both groups with a prespecified non-inferiority margin of 18 g (20%). Assuming no differences in the weight increment between groups, for 80% power and a
umbilical cord clamping was delayed for 2 min, the volume of placental transfusion in newborn babies placed on the maternal abdomen or chest would not be inferior to that of those held at the level of the introitus.
Methods Study design and participants
For the trial protocol see http://fundasamin.org.ar/ newsite/?p=2720
2
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significance level of 5%, 170 newborn babies per group were needed. We used t test and χ² test for group comparison, and used a multivariable linear regression analysis to control for co-variables. Data were analysed per protocol with SPSS (version 17.0). An external data and safety monitoring committee (three experienced investigators who worked at different hospitals; one paediatrician, one neonatologist, and one obstetrician) was notified of any adverse events (classified as cause death, threaten life, cause transient or definitive disability, or cause an extension of the length of hospital stay) throughout the study, and did a planned interim analysis after the inclusion of the first 100 patients of the estimated population of the study to ensure safety and to assess the need for a re-estimation of the sample size. The committee concluded that it was safe to continue with the study and the sample size did not need adjusting. Investigators were not aware of any partial results until recruitment was completed. This study is registered with ClinicalTrials.gov, number NCT01497353.
688 newborn babies met inclusion criteria
142 excluded 142 declined to participate
546 randomly assigned
274 assigned to introitus group
272 assigned to abdomen group
77 not eligible for primary analysis 42 caesarean section or forceps 19 short umbilical cord or nuchal cord 7 need for resuscitation 6 team became unavailable 2 weight scale malfunctioned 1 parent withdrew consent
78 not eligible for primary analysis 41 caesarean section or forceps 16 short umbilical cord or nuchal cord 10 need for resuscitation 7 team became unavailable 2 weight scale malfunctioned 2 parents withdrew consent
197 included in primary analysis
194 included in primary analysis
Figure: Study profile
Role of the founding source The sponsor of the study had no role in the study design, data collection, data analysis, and data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results Between Aug 18, 2011, and Aug 31, 2012, 688 newborn babies fulfilled inclusion criteria, but 142 mothers refused consent. After informed consent was obtained from mothers, some newborn babies could not be studied: 83 were delivered by caesarean section or forceps, 35 had a short umbilical cord or a tight nuchal cord, 17 needed resuscitation, and 20 were excluded for other reasons. 197 newborn babies randomly assigned to the introitus group and 194 to the abdomen group were included in the primary analysis (figure). We recorded no serious adverse event during the study. Table 1 shows baseline characteristics. Mothers were mainly in their twenties and the mean gestational age for newborn babies was 39 weeks. Agpar scores in both groups were roughly 8·5 at 1 min after birth and 9·5 at 5 min. Table 2 shows data for the primary outcome and associations of weight gain with the mother’s position during delivery. The weight gain for newborn babies placed on the mother’s abdomen or chest was not inferior to those placed at the level of the introitus. Position of the mother during delivery did not notably affect these findings (table 2). We obtained venous bilirubin and haematocrit concentrations at 36–48h in 344 (88%) of 391 study newborn babies. The bilirubin concentration was 8∙4 mg
Introitus group (n=197) Maternal age (years) Pregnancy order
27 (6·8)
Abdomen group (n=194) 26·9 (6·9)
1·3 (1·6)
1·4 (1·7)
1 min
8·5 (0·5)
8·4 (0·5)
5 min
9·5 (0·5)
9·4 (0·5)
39·1 (0·9)
39·1 (0·9)
Apgar score
Gestational age (weeks) Birthweight (g) Female Admitted to the neonatal intensive care unit
3415 (396)
3378 (356)
92 (46%)
101 (49%)
1 (0·5%)
1 (0·5%)
Data are mean (SD) or n (%).
Table 1: Baseline characteristics of mothers and newborn babies
(SD 3) in the introitus group compared with 8∙7 mg (SD 3) in the abdomen group (p=0∙35). Haematocrit values were 56% in the introitus group and 55% in the abdomen group (p=0∙18). 16 newborn babies in the introitus group and ten in the abdomen group had haematocrit values higher than 65%, and, one in the introitus group and five in the abdomen group of them higher than 70%. We noted no significant association between birthweight and the volume of placental transfusion. With regards to effect of centre on primary outcome, we recorded no differences in the weight gain between newborn babies in both groups within each centre, but weight gain differed significantly between centres. Newborn babies in hospital one gained much less weight than did those in hospital three (28 g vs 71 g, p<0·0001; table 3).
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All women Semi-sitting or sitting position Lying down position
Introitus group
Abdomen group
n
Mean weight change, g (SD, 95% CI)
n
Difference, g (mean, 95% CI) p value
197
56 (47, 50–63)
194
53 (45, 46–59
3 (–5·8 to 12·8)
0·45
81
52 (48, 42–62)
74
54 (47, 43–65)
1·6 (-16·0 to 13·0)
0·82
114
59 (48, 50–68)
120
52 (45, 44–60)
6·7 (–5·0 to 18·0)
0·27
Mean weight change, g (SD, 95% CI)
Data are mean (SD), 95% CI.
Table 2: Weight increase in the first 2 min after birth and mother’s position during delivery
Overall n
Weight gain (g)
Introitus group
Abdomen group
n
n
Weight gain (g)
p value
Weight gain (g)
Centre one
129
28*
69
28 (44)
60
29 (51)
0·94
Centre two
38
49*
22
55 (59)
16
40 (54)
0·42
Centre three
224
71*
106
75 (37)
118
67 (34)
0·09
Data are n, mean, or mean (SD). *p<0·001.
Table 3: Weight increase, by centre
In univariate analysis, newborn babies whose mothers received oxytocin in the first minute after birth gained 62 g (SD 44) compared with 34 g (SD 45) for mothers who did not (p<0∙0001 ). However, after controlling by centre in the multivariable linear regression model, we recorded no significant differences in the weight increments in newborn babies whose mothers received early oxytocin and those who did not.
Discussion When cord clamping is delayed for 2 min after birth, the volume of placental transfusion for newborn babies held on the mother’s abdomen or chest is not inferior to that of newborn babies held at or below the level of the introitus (panel). Several randomised controlled trials5,8,25 have confirmed that delayed cord clamping contributes to decreased iron deficiency in newborn babies and children, which is a serious public health problem in low-income countries,9,10 but also prevalent in countries with sufficient resources from North America and western Europe.11 In the USA, up to 20% of preschool children have depleted iron stores and up to 8% have iron deficiency anaemia.12 Findings of a 2001 study13 in 11 European countries showed that 7∙2% of infants were iron deficient. Although delayed cord clamping is recommended by leading professional organisations,14–16 compliance is low.17,18,20 Notwithstanding the paucity of information about the effect of gravity,22 one reason for this low compliance could be the recommendation that newborn babies should be held at or below the level of the vagina until the cord is clamped.21 However, this position is uncomfortable for the person holding the baby and impedes early skin to skin contact and bonding with the mother.26 Mothers would probably also prefer to hold 4
their newborn baby on top of the abdomen or chest, but we did not assess this aspect in our trial. Data from several small studies published more than 35 years ago suggested gravity has a role in the volume of placental transfusion.2,4 In a non-randomised study, Yao and colleagues4 noted that the placental residual blood volume was lower in newborn babies held below the introitus than in infants held above. Our findings might differ from those of the study by Yao and coworkers for several reasons. First, in one group of newborn babies in Yao’s study, the babies were held vertically, 40 cm above the placenta. Although we have not measured the real vertical distance, newborn babies in the abdomen group were held by the mother on her abdomen or chest, about 30 cm above the level of the introitus, which most likely represents a vertical distance from the placenta lower than 40 cm. Second, as with many biological processes, the volume of placental transfusion varies greatly dependent on several physiological events. This finding can be recognised by the large standard deviations noted by Farrar and colleagues,24 and those from our own trial. The few babies in each group of Yao’s study might have led to an overestimation of the effect of gravity. Furthermore, the method of measurement of residual blood volume left at the placenta could have been a source of error. Finally, the study by Yao and colleagues was not randomised, which makes it vulnerable to other sources of bias too. With regards to the position of the mother (table 2), newborn babies of mothers who were sitting or semisitting who were placed at least 30 cm above the level of the vagina and had a weight increment of about 54 g, whereas in those placed at the level of the introitus the increment was about 52 (p=0∙82). Although the women’s behaviour and not randomisation established
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the position, and that the subgroup analysis is underpowered, data strongly suggest that gravity does not produce a negative effect in newborn babies managed this way. Haematocrit and bilirubin concentrations did not differ between groups. As in the trial by Ceriani and colleagues,7 we noted no newborn babies with symptomatic polycythaemia or other potential complications of delayed cord clamping. The volume of placental transfusion varies widely,24 and can be the result of several factors, in particular the spontaneous breathing efforts of the newborn baby and the forces of uterine contraction in temporal relation to the time of clamping the cord. In the first few seconds after birth, pulmonary vascular resistance drops rapidly, which causes decreased flow through the ductus arteriosus and the descending aorta to the placenta.27,28 Blood return from the placenta is the result of high pressure at the level of the umbilical vein generated by uterine contractions.2 Variation in the timing of the fall in pulmonary vascular resistance and the frequency and intensity of uterine contractions are biological variables that affect the volume of placental transfusion in individual newborn babies. Additionally, the size of the umbilical vessels and the relative time of when oxytocin is given in relation to the time of birth might have an effect. Some technical problems might have affected measurements of the weight increments. Findings of a previous study with a model similar to ours recorded a large increase in weight gain in the initial seconds associated with the first uterine contractions after birth.2 A limitation of our investigation is that we did not record the time between birth and the first registered weight. We had previously done a pilot study at one of the centres to assess safety and feasibility in 32 mothers and babies. The time to obtain the first weight was less than 15 s in all infants. However, we might have measured weight in some of our babies later than 15 s, which could have caused us to miss part of the volume of transfusion generated by the first postpartum uterine contractions and therefore underestimate the total volume of placental transfusion. In this situation, the effect would have been similar for newborn babies held at the introitus and those placed at the level of the abdomen. Technical problems might have accounted for the significant differences in the weight increments recorded between centres (table 3). At hospital one (a private hospital) all study participants were delivered under epidural anaesthesia, whereas in the other two centres (public hospitals) no mothers received anaesthesia. Epidural anaesthesia might change uterine activity,29,30 but we are unaware of data suggesting that it affects the volume of placental transfusion. Newborn babies whose mothers received oxytocin within the first minute after birth had larger weight gain
Panel: Research in context Systematic review To develop the protocol we searched PubMed without language or time restriction with the terms “delayed cord clamping”, “placental transfusion”, “gravity”, “position”, and “delivery”, and various combinations of those words. We also searched abstracts from the Pediatric Academic Societies annual meetings up to June 1, 2011. We found several studies2-4,22 comparing the volume of placental transfusion in relation to infant position at birth, but no randomised controlled trials. In August, 2010, a Cochrane systematic review22 was published on alternative positions for the baby at birth before clamping the umbilical cord. This review was updated in 2012, but added no additional publications to our databases search. Although several of the studies suggested an effect of gravity on the volume of placental transfusion, they did not include many study participants or allow for the management of the infant immediately after delivery. We concluded from these searches that a randomised controlled trial assessing the effect of gravity on the volume of placental transfusion in a pragmatic way was needed. Interpretation Data from our study suggest that when umbilical cord clamping is delayed for 2 min, the volume of placental transfusion is similar for infants held on the mothers’ abdomen or chest and those held at the level of the vagina. Therefore, and because of the potential of enhanced bonding between mother and baby and increased success of breastfeeding and the compliance with the procedure, holding the infant by the mother immediately after birth should be strongly recommended.
than did those with mothers who did not. However, following centre practices, the frequency of administration of the drug in mothers included in the study was 48 of 122 (39%) in centre one, 34 of 38 (89%) in centre two, and 214 of 222 (96%) in centre three. When we corrected by centre in the multivariable linear regression model, we found no significant differences in the weight increments in newborn babies whose mothers received early oxytocin and those who did not. We have not recorded the exact timing of injection, and because oxytocin increases the frequency and intensity of uterine contractions, the effect of its administration in the first moments after birth on the volume of placental transfusion deserves further investigation. Although the frequency of clinical jaundice is not increased, more newborn babies with delayed cord clamping receive phototherapy.5 53 babies had jaundice in this study; 15 of those treated with phototherapy. Therefore, a strict follow-up of these babies after discharge from hospital is mandatory and, in situations when follow-up is not feasible or treatment for jaundice is not readily available, the risk benefits of this practice should be carefully assessed. We conclude that delayed umbilical cord clamping for 2 min provides a clinically relevant placental transfusion to most newborn babies, and that placement of a vigorous, vaginally delivered, full term baby on the mother’s abdomen or chest before clamping the umbilical cord results in identical amounts of placental transfusion as would holding the baby during the same period at the level of vaginal introitus. Therefore, we recommend that mothers be allowed to hold their baby
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for 2 min before the cord is clamped to increase obstetric compliance with delayed cord clamping enhance maternal–infant bonding, and decrease iron deficiency in infancy. Contributors NEV was responsible for the idea of the study and organised the study methods. NEV, DSS, LMP, and ANG developed the protocol and managed the project. NEV and DSS coordinated the study and did data analysis. DSS reviewed study methods and data collection procedures. JEG and MGA participated in data management. DSS and ANG trained staff. NEV, DSS, LMP, and ANG wrote the report, which was reviewed by JEG. JPB and MGA organised and coordinated the pilot feasibility trial. Declaration of interests We declare that we have no competing interests. Acknowledgments The study was funded partly by Fundación para la Salud Materno Infantil, and by a donation from Juan Navarro. Manrique Hnos SRL donated the weight scales. We thank all study participant’s families and the chairs and staff of the participating centres; Gustavo Goldsmit, Fernando Ferrero, and Hugo Krupitski for their participation as members of the Data Safety Monitoring Committee; Ariel Fernández for database development and management; Leandro Kovalevski for statistical advice and analysis; José María Diaz-Rossello for assistance with the model to assess volume of placental transfusion; Cecilia García, Marcelo Decaro, and Lionel Cracco for their participation in the pilot study; and Fernando Althabe and M Jeffrey Maisels for thoughtful review of the report. We also thank the nurses and physicians who helped to recruit patients at Trinidad Palermo Private Hospital, Buenos Aires, Argentina (centre one, principal investigator Adriana Gorenstein): Edith Martínez, Graciela Roppel, Graciela Orieta, María Méndez, Gabriela Di Maria, Gladys de la Cruz, Noemí Jacobi, Florencia Chiarelli, Carolina Cerúsico, Laura García, Graciela Corral; Maternal Infant Hospital Carlos Gianantonio, San Isidro, Buenos Aires, Argentina (centre two, principal investigator Blanca C Senra): Leonardo Augusto Graf, Nelson Facundo Herrera, Lucia Fedorowicz, Yesica Leiro, Alicia Ponce, Susana Maligne; and Institute of Maternity Our Lady of Mercy, San Miguel de Tucumán, Argentina (centre three, principal investigator Juan Esteban Gordillo): Natalia Corbalan, Gerardo Murga, Veronica Zavalsa, Eliana Soria, Marcela Rocha, Mabel Saracho, Anabella Gimenez Osorio, Natalia Rodriguez, Gabriela Teseira, Daniel Solorzano, Fernando Lizarraga, Patricia Gonzales, Susana Caceres, Etel Sanchez, Noemi Brizuela, Andrea Calderon, and Claudia Albarracin. References 1 Prendiville WJ, Harding JE, Elbourne DR, Stirrat GM. The Bristol third stage trial: active versus physiological management of third stage of labour. BMJ 1988; 297: 1295–300. 2 Gunther M. The transfer of blood between baby and placenta in the minutes after birth. Lancet 1957; 272: 1277–80. 3 Yao AC, Lind J. Placental transfusion. Am J Dis Child 1974; 127: 128–41. 4 Yao AC, Lind J. Effect of gravity on placental transfusion. Lancet 1969; 2: 505–08. 5 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: CD004074. 6 Trudnowski RJ, Rico RC. Specific gravity of blood and plasma at 4 and 37 degrees C. Clin Chem 1974; 20: 615–16. 7 Ceriani Cernadas JM, Carroli G, Pellegrini L, et al. The effect of timing of cord clamping on neonatal venous hematocrit values and clinical outcome at term: a randomized, controlled trial. Pediatrics 2006; 117: e779–86. 8 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: 1997–2004. 9 Durán P, Mangialavori G, Biglieri A, Kogan L, Abeyá Gilardon E. Nutrition status in Argentinean children 6 to 72 months old: results from the National Nutrition and Health Survey (ENNyS). Arch Argent Pediatr 2009; 107: 397–404 (in Spanish).
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Nojilana B, Norman R, Dhansay MA, Labadarios D, van Stuijvenberg ME, Bradshaw D, and the South African Comparative Risk Assessment Collaborating Group. Estimating the burden of disease attributable to iron deficiency anaemia in South Africa in 2000. S Afr Med J 2007; 97: 741–46. 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. Eden AN, Sandoval C. Iron deficiency in infants and toddlers in the United States. Pediatr Hematol Oncol 2012; 29: 704–09. Male C, Persson LA, Freeman V, Guerra A, van’t Hof MA, Haschke F, and the Euro-Growth Iron Study Group. Prevalence of iron deficiency in 12-mo-old infants from 11 European areas and influence of dietary factors on iron status (Euro-Growth study). Acta Paediatr 2001; 90: 492–98. Perlman JM, Wyllie J, Kattwinkel J, et al, and the Neonatal Resuscitation Chapter Collaborators. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010; 122 (suppl 2): S516–38. Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Committee Opinion No.543: Timing of umbilical cord clamping after birth. Obstet Gynecol 2012; 120: 1522–26. Sweet DG, Carnielli V, Greisen G, et al, and the European Association of Perinatal Medicine. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants: 2010 update. Neonatology 2010; 97: 402–17. Hutchon DJ. Why do obstetricians and midwives still rush to clamp the cord? BMJ 2010; 341: c5447. Raju TN, Singhal N. Optimal timing for clamping the umbilical cord after birth. Clin Perinatol 2012; 39: 889–900. van Rheenen P. Delayed cord clamping and improved infant outcomes. BMJ 2011; 343: d7127. Zapata Barrios J, Albornoz G, Musante G, Pedraza A, Prudent L. Timing of umbilical cord clamping of term infants in a large maternity center in Buenos Aires. [Abstract 374]. J Perinat Med 2011; 39: 386. Royal College of Obstetricians and Gynaecologists. Clamping of the umbilical cord and placental transfusion. Scientific Impact Paper 14. May, 2009. http://www.rcog.org.uk/clamping-umbilical-cordand-placental-transfusion (accessed Feb 17, 2014). Airey RJ, Farrar D, Duley L. Alternative positions for the baby at birth before clamping the umbilical cord. Cochrane Database Syst Rev 2010; 6: CD007555. Caldeyro-Barcia R, Poseiro JJ. Physiology of the uterine contraction. Clin Obstet Gynecol 1960; 3: 386–410. Farrar D, Airey R, Law GR, Tuffnell D, Cattle B, Duley L. Measuring placental transfusion for term births: weighing babies with cord intact. BJOG 2011; 118: 70–75. Ceriani Cernadas JM, Carroli G, Pellegrini L, et al. The effect of early and delayed umbilical cord clamping on ferritin levels in term infants at six months of life: a randomized, controlled trial. Arch Argent Pediatr 2010; 108: 201–08 (in Spanish). Moore ER, Anderson GC, Bergman N, Dowswell T. Early skin-toskin contact for mothers and their healthy newborn infants. Cochrane Database Syst Rev 2012; 5: CD003519. 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: 2113–26. Gleason CA, Devaskar SU. Embryology and physiology of the cardiovascular system. In: Avery’s diseases of the newborn. 9th edn. Philadelphia, PA, USA: Saunders Elsevier, 2012: 711−12. Alexander JM, Lucas MJ, Ramin SM, McIntire DD, Leveno KJ. The course of labor with and without epidural analgesia. Am J Obstet Gynecol 1998; 178: 516–20. Incerti M, Locatelli A, Ghidini A, et al. Prediction of duration of active labor in nulliparous women at term. Am J Perinatol 2008; 25: 85–89.
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Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial Nestor E Vain, Daniela S Satragno, Adriana N Gorenstein, Juan E Gordillo, Juan P Berazategui, M Guadalupe Alda, Luis M Prudent
Summary Background Delayed cord clamping allows for the passage of blood from the placenta to the baby and reduces the risk of iron deficiency in infancy. To hold the infant for more than 1 min at the level of the vagina (as is presently recommended), on the assumption that gravity affects the volume of placental transfusion, is cumbersome, might result in low compliance, and interferes with immediate contact of the infant with the mother. We aimed to assess whether gravity affects the volume of placental transfusion
Published Online April 17, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60197-5
Methods We did a multicentre non-inferiority trial at three university-affiliated hospitals in Argentina. We obtained informed consent from healthy mothers with normal term pregnancies admitted early in labour. Vigorous babies born vaginally were randomly assigned in a 1:1 ratio by computer-generated blocks and sequentially numbered sealed opaque envelopes to be held for 2 min before clamping the umbilical cord, at the level of the vagina (introitus group) or on the mother’s abdomen or chest (abdomen group). Newborn babies were weighed immediately after birth and after cord clamping. The primary outcome was the difference in weight (as a proxy of placental transfusion volume). The prespecified non-inferiority margin was 18 g (20%). We used t test and χ² test for group comparison, and used a multivariable linear regression analysis to control for covariables. This trial is registered with ClinicalTrials.gov, number NCT01497353.
School of Medicine, University of Buenos Aires, Buenos Aires, Argentina (Prof N E Vain MD); Foundation for Maternal and Child Health (FUNDASAMIN), Buenos Aires, Argentina (Prof N E Vain, D S Satragno MD, A N Gorenstein MD, J P Berazategui MD, Prof L M Prudent MD); Trinidad Palermo Private Hospital, Buenos Aires, Argentina (Prof N E Vain, A N Gorenstein, M G Alda MD); and Institute of Maternity Our Lady of Mercy, San Miguel de Tucumán, Argentina (J E Gordillo MD)
Findings Between Aug 1, 2011, and Aug 31, 2012, we allocated 274 newborn babies to the introitus group and 272 to the abdomen group. 77 newborn babies in the introitus group and 78 in the abdomen group were ineligible after randomisation (eg, caesarean section, forceps delivery, short umbilical cord or nuchal cord). Mean weight change was 56 g (SD 47, 95% CI 50–63) for 197 babies in the introitus group compared with 53 g (45, 46–59) for 194 babies in the abdomen group, supporting non-inferiority of the two approaches (difference 3 g, 95% CI −5∙8 to 12∙8; p=0·45). We did not note any serious adverse events during the study. Interpretation Position of the newborn baby before cord clamping does not seem to affect volume of placental transfusion. Mothers could safely be allowed to hold their baby on their abdomen or chest. This change in practice might increase obstetric compliance with the procedure, enhance maternal-infant bonding, and decrease iron deficiency in infancy.
See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(14)60411-6
Correspondence to: Prof Nestor E Vain, Foundation for Maternal and Child Health (FUNDASAMIN), Honduras 4160, Buenos Aires, Argentina [email protected]
Funding Foundation for Maternal and Child Health (FUNDASAMIN).
Introduction The ideal timing for umbilical cord clamping is controversial.1 Delayed cord clamping allows for passage of blood from the placenta to the baby (known as placental transfusion).2–5 When cord clamping is done after 60 s, newborn babies have a median birthweight 101 g higher than those born after early clamping (before 60 s),5 probably representing an average placental transfusion of 96 mL (1 mL of blood=1∙05 g).6 Delayed cord clamping increases haemoglobin in the neonatal period and decreases the risk of iron deficiency in infancy,5–8 a serious public health problem in lowincome9,10 and high-income countries.11–13 The procedure is included in the guidelines for delivery room management of newborn babies from several professional organisations,14–16 but compliance with the recommendation is low.17–20 This low compliance could be related to some published studies suggesting that delayed cord clamping is associated with maternal complications.1 However, results of a Cochrane meta-analysis5 clearly
show no increase in maternal haemorrhage, the use of uterotonics, or duration of the third stage of labour. On the assumption that gravity affects the volume of placental transfusion, recommendations suggest that newborn babies be held at or below the level of the vagina.19–21 This procedure is cumbersome, interferes with immediate contact with the mother, and might therefore contribute to low compliance. The effect of gravity on the volume of transfusion is based on the studies by Gunther and by Yao.2–4 Although those studies were not randomised trials and were done 35 years ago, they had rigorous methods. If gravity plays a small or negligible part in placental transfusion, then most infants born after vaginal delivery could be placed immediately on the mother’s abdomen or chest before clamping the umbilical cord. Depending on the position of the mother (lying down, semi-sitting, or sitting), the newborn baby would be above the vaginal level by about 30 cm. In view of the scarce evidence of the effect of gravity,22 we aimed to assess whether, provided
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We did this multicentre, non-inferiority, randomised controlled trial at three university-affiliated hospitals in Argentina (Trinidad Palermo Private Hospital, Buenos Aires [centre one], Maternal Infant Hospital Carlos Gianantonio, San Isidro, Buenos Aires [centre two], and Institute of Maternity Our Lady of Mercy, San Miguel de Tucumán [centre three]). The institutional review board of each participating centre approved the protocol and consent form. Mothers were approached and gave written consent upon admittance to hospital for labour (mothers admitted in advanced labour were not approached because insufficient time would be available to obtain an ethically valid consent). Eligible mothers were those with a normal pregnancy, admitted at term, during the first stage of labour and in whom a vaginal uncomplicated delivery was expected. We included vigorous term newborn babies born by vaginal delivery. Exclusion criteria for mothers were history of placenta praevia or postpartum haemorrhage, multiple gestation, intrauterine growth restriction, major congenital malformations diagnosed before delivery, maternal diseases (eg, eclampsia, Rh incompatibility, congestive heart failure), and request by the parents for cord blood banking. Newborn babies who needed resuscitation were delivered by caesarean section or forceps, and those with a short umbilical cord or a tight nuchal cord preventing the placement of the newborn baby according to the group to which they were assigned although initially randomised were not studied nor included in the analyses.
procedure and maternal acceptance. After informed parental consent was obtained early in labour, we randomly assigned newborn babies to the introitus or abdomen group and the obstetric team was notified of the assigned intervention. All newborn babies were weighed immediately after birth at the level of the vagina with an electronic 1 g precision scale (STW - 6 BB, Electronic Balanzas CAM, Buenos Aires, Argentina) with a coefficient of variation of 0·0006 g. A reliable weight can usually be obtained within the first 15 s. The delivery of the infants’ shoulders was considered time zero, and using a stopwatch (SH-688 STAR, Fuego, China) a nurse notified the 1 min time for determining the Apgar score and the 2 min time to clamp the umbilical cord. During the first 2 min before clamping, newborn babies randomly assigned to the introitus group were held by the investigator at the vaginal level and those assigned to the abdomen group were placed on the mother’s abdomen or chest, depending mainly on the length of the umbilical cord. In all newborn babies care was taken to avoid compression of the umbilical vessels. At 2 min, the cord was clamped and cut in newborn babies of both groups, and they were weighed again on the same scale. Previous studies have estimated the volume of placental transfusion by the difference in weight.2,23,24 Venous haematocrit and bilirubin values were obtained at 36–48 h simultaneously with routine neonatal screening. Additionally, we noted the position of the mother during delivery up to the time the cord was clamped and the effect of the use of early oxytocin on the increment in weight of the newborn baby. Positions were defined as semi-sitting and sitting if an angle of more than 30° with the horizontal surface of the bed was estimated, and horizontal if the estimated angle was between 0 and 30°. Prophylactic oxytocin use was defined as the intramuscular or intravenous administration of 10 IU of oxytocin to the mother within 1 min after birth.
Randomisation and masking
Outcomes
Eligible newborn babies were randomly assigned in a 1:1 ratio to the introitus group or the abdomen group with computer-generated allocation sequence in block sizes of four to eight (created by a statistician who was not involved again in the trial until statistical analysis of the results). Allocation was concealed by sequentially numbered sealed opaque envelopes. The nature of the intervention prevented us from masking the study.
The primary outcome was the difference between weight of the newborn baby obtained immediately after birth and that at 2 min after clamping of the umbilical cord. Secondary outcomes were haematocrit and bilirubin concentrations, incidence of polycythaemia, need for phototherapy, mother’s position, and use of oxytocin. We analysed the association between the weight increment and birthweight.
Procedures
Statistical analysis
We did a pilot study in 2009, at centre one to assess safety and feasibility in 32 mothers and babies. Patients who participated in the pilot study were not included in the analysis of the trial. We found that the first weight was always obtained in the first 15 s after the delivery of the shoulders, and we were able to adjust technical details such as stability and height of the weight scale. We also noticed good compliance of the obstetricians with the
On the basis of results of a recent study,24 we assumed a difference of 90 g between the weight immediately after birth and that at 2 min and a standard deviation of 60 g. To assess non-inferiority, we compared the upper limit of the 95% CIs for the difference between the means of both groups with a prespecified non-inferiority margin of 18 g (20%). Assuming no differences in the weight increment between groups, for 80% power and a
umbilical cord clamping was delayed for 2 min, the volume of placental transfusion in newborn babies placed on the maternal abdomen or chest would not be inferior to that of those held at the level of the introitus.
Methods Study design and participants
For the trial protocol see http://fundasamin.org.ar/ newsite/?p=2720
2
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significance level of 5%, 170 newborn babies per group were needed. We used t test and χ² test for group comparison, and used a multivariable linear regression analysis to control for co-variables. Data were analysed per protocol with SPSS (version 17.0). An external data and safety monitoring committee (three experienced investigators who worked at different hospitals; one paediatrician, one neonatologist, and one obstetrician) was notified of any adverse events (classified as cause death, threaten life, cause transient or definitive disability, or cause an extension of the length of hospital stay) throughout the study, and did a planned interim analysis after the inclusion of the first 100 patients of the estimated population of the study to ensure safety and to assess the need for a re-estimation of the sample size. The committee concluded that it was safe to continue with the study and the sample size did not need adjusting. Investigators were not aware of any partial results until recruitment was completed. This study is registered with ClinicalTrials.gov, number NCT01497353.
688 newborn babies met inclusion criteria
142 excluded 142 declined to participate
546 randomly assigned
274 assigned to introitus group
272 assigned to abdomen group
77 not eligible for primary analysis 42 caesarean section or forceps 19 short umbilical cord or nuchal cord 7 need for resuscitation 6 team became unavailable 2 weight scale malfunctioned 1 parent withdrew consent
78 not eligible for primary analysis 41 caesarean section or forceps 16 short umbilical cord or nuchal cord 10 need for resuscitation 7 team became unavailable 2 weight scale malfunctioned 2 parents withdrew consent
197 included in primary analysis
194 included in primary analysis
Figure: Study profile
Role of the founding source The sponsor of the study had no role in the study design, data collection, data analysis, and data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results Between Aug 18, 2011, and Aug 31, 2012, 688 newborn babies fulfilled inclusion criteria, but 142 mothers refused consent. After informed consent was obtained from mothers, some newborn babies could not be studied: 83 were delivered by caesarean section or forceps, 35 had a short umbilical cord or a tight nuchal cord, 17 needed resuscitation, and 20 were excluded for other reasons. 197 newborn babies randomly assigned to the introitus group and 194 to the abdomen group were included in the primary analysis (figure). We recorded no serious adverse event during the study. Table 1 shows baseline characteristics. Mothers were mainly in their twenties and the mean gestational age for newborn babies was 39 weeks. Agpar scores in both groups were roughly 8·5 at 1 min after birth and 9·5 at 5 min. Table 2 shows data for the primary outcome and associations of weight gain with the mother’s position during delivery. The weight gain for newborn babies placed on the mother’s abdomen or chest was not inferior to those placed at the level of the introitus. Position of the mother during delivery did not notably affect these findings (table 2). We obtained venous bilirubin and haematocrit concentrations at 36–48h in 344 (88%) of 391 study newborn babies. The bilirubin concentration was 8∙4 mg
Introitus group (n=197) Maternal age (years) Pregnancy order
27 (6·8)
Abdomen group (n=194) 26·9 (6·9)
1·3 (1·6)
1·4 (1·7)
1 min
8·5 (0·5)
8·4 (0·5)
5 min
9·5 (0·5)
9·4 (0·5)
39·1 (0·9)
39·1 (0·9)
Apgar score
Gestational age (weeks) Birthweight (g) Female Admitted to the neonatal intensive care unit
3415 (396)
3378 (356)
92 (46%)
101 (49%)
1 (0·5%)
1 (0·5%)
Data are mean (SD) or n (%).
Table 1: Baseline characteristics of mothers and newborn babies
(SD 3) in the introitus group compared with 8∙7 mg (SD 3) in the abdomen group (p=0∙35). Haematocrit values were 56% in the introitus group and 55% in the abdomen group (p=0∙18). 16 newborn babies in the introitus group and ten in the abdomen group had haematocrit values higher than 65%, and, one in the introitus group and five in the abdomen group of them higher than 70%. We noted no significant association between birthweight and the volume of placental transfusion. With regards to effect of centre on primary outcome, we recorded no differences in the weight gain between newborn babies in both groups within each centre, but weight gain differed significantly between centres. Newborn babies in hospital one gained much less weight than did those in hospital three (28 g vs 71 g, p<0·0001; table 3).
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All women Semi-sitting or sitting position Lying down position
Introitus group
Abdomen group
n
Mean weight change, g (SD, 95% CI)
n
Difference, g (mean, 95% CI) p value
197
56 (47, 50–63)
194
53 (45, 46–59
3 (–5·8 to 12·8)
0·45
81
52 (48, 42–62)
74
54 (47, 43–65)
1·6 (-16·0 to 13·0)
0·82
114
59 (48, 50–68)
120
52 (45, 44–60)
6·7 (–5·0 to 18·0)
0·27
Mean weight change, g (SD, 95% CI)
Data are mean (SD), 95% CI.
Table 2: Weight increase in the first 2 min after birth and mother’s position during delivery
Overall n
Weight gain (g)
Introitus group
Abdomen group
n
n
Weight gain (g)
p value
Weight gain (g)
Centre one
129
28*
69
28 (44)
60
29 (51)
0·94
Centre two
38
49*
22
55 (59)
16
40 (54)
0·42
Centre three
224
71*
106
75 (37)
118
67 (34)
0·09
Data are n, mean, or mean (SD). *p<0·001.
Table 3: Weight increase, by centre
In univariate analysis, newborn babies whose mothers received oxytocin in the first minute after birth gained 62 g (SD 44) compared with 34 g (SD 45) for mothers who did not (p<0∙0001 ). However, after controlling by centre in the multivariable linear regression model, we recorded no significant differences in the weight increments in newborn babies whose mothers received early oxytocin and those who did not.
Discussion When cord clamping is delayed for 2 min after birth, the volume of placental transfusion for newborn babies held on the mother’s abdomen or chest is not inferior to that of newborn babies held at or below the level of the introitus (panel). Several randomised controlled trials5,8,25 have confirmed that delayed cord clamping contributes to decreased iron deficiency in newborn babies and children, which is a serious public health problem in low-income countries,9,10 but also prevalent in countries with sufficient resources from North America and western Europe.11 In the USA, up to 20% of preschool children have depleted iron stores and up to 8% have iron deficiency anaemia.12 Findings of a 2001 study13 in 11 European countries showed that 7∙2% of infants were iron deficient. Although delayed cord clamping is recommended by leading professional organisations,14–16 compliance is low.17,18,20 Notwithstanding the paucity of information about the effect of gravity,22 one reason for this low compliance could be the recommendation that newborn babies should be held at or below the level of the vagina until the cord is clamped.21 However, this position is uncomfortable for the person holding the baby and impedes early skin to skin contact and bonding with the mother.26 Mothers would probably also prefer to hold 4
their newborn baby on top of the abdomen or chest, but we did not assess this aspect in our trial. Data from several small studies published more than 35 years ago suggested gravity has a role in the volume of placental transfusion.2,4 In a non-randomised study, Yao and colleagues4 noted that the placental residual blood volume was lower in newborn babies held below the introitus than in infants held above. Our findings might differ from those of the study by Yao and coworkers for several reasons. First, in one group of newborn babies in Yao’s study, the babies were held vertically, 40 cm above the placenta. Although we have not measured the real vertical distance, newborn babies in the abdomen group were held by the mother on her abdomen or chest, about 30 cm above the level of the introitus, which most likely represents a vertical distance from the placenta lower than 40 cm. Second, as with many biological processes, the volume of placental transfusion varies greatly dependent on several physiological events. This finding can be recognised by the large standard deviations noted by Farrar and colleagues,24 and those from our own trial. The few babies in each group of Yao’s study might have led to an overestimation of the effect of gravity. Furthermore, the method of measurement of residual blood volume left at the placenta could have been a source of error. Finally, the study by Yao and colleagues was not randomised, which makes it vulnerable to other sources of bias too. With regards to the position of the mother (table 2), newborn babies of mothers who were sitting or semisitting who were placed at least 30 cm above the level of the vagina and had a weight increment of about 54 g, whereas in those placed at the level of the introitus the increment was about 52 (p=0∙82). Although the women’s behaviour and not randomisation established
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the position, and that the subgroup analysis is underpowered, data strongly suggest that gravity does not produce a negative effect in newborn babies managed this way. Haematocrit and bilirubin concentrations did not differ between groups. As in the trial by Ceriani and colleagues,7 we noted no newborn babies with symptomatic polycythaemia or other potential complications of delayed cord clamping. The volume of placental transfusion varies widely,24 and can be the result of several factors, in particular the spontaneous breathing efforts of the newborn baby and the forces of uterine contraction in temporal relation to the time of clamping the cord. In the first few seconds after birth, pulmonary vascular resistance drops rapidly, which causes decreased flow through the ductus arteriosus and the descending aorta to the placenta.27,28 Blood return from the placenta is the result of high pressure at the level of the umbilical vein generated by uterine contractions.2 Variation in the timing of the fall in pulmonary vascular resistance and the frequency and intensity of uterine contractions are biological variables that affect the volume of placental transfusion in individual newborn babies. Additionally, the size of the umbilical vessels and the relative time of when oxytocin is given in relation to the time of birth might have an effect. Some technical problems might have affected measurements of the weight increments. Findings of a previous study with a model similar to ours recorded a large increase in weight gain in the initial seconds associated with the first uterine contractions after birth.2 A limitation of our investigation is that we did not record the time between birth and the first registered weight. We had previously done a pilot study at one of the centres to assess safety and feasibility in 32 mothers and babies. The time to obtain the first weight was less than 15 s in all infants. However, we might have measured weight in some of our babies later than 15 s, which could have caused us to miss part of the volume of transfusion generated by the first postpartum uterine contractions and therefore underestimate the total volume of placental transfusion. In this situation, the effect would have been similar for newborn babies held at the introitus and those placed at the level of the abdomen. Technical problems might have accounted for the significant differences in the weight increments recorded between centres (table 3). At hospital one (a private hospital) all study participants were delivered under epidural anaesthesia, whereas in the other two centres (public hospitals) no mothers received anaesthesia. Epidural anaesthesia might change uterine activity,29,30 but we are unaware of data suggesting that it affects the volume of placental transfusion. Newborn babies whose mothers received oxytocin within the first minute after birth had larger weight gain
Panel: Research in context Systematic review To develop the protocol we searched PubMed without language or time restriction with the terms “delayed cord clamping”, “placental transfusion”, “gravity”, “position”, and “delivery”, and various combinations of those words. We also searched abstracts from the Pediatric Academic Societies annual meetings up to June 1, 2011. We found several studies2-4,22 comparing the volume of placental transfusion in relation to infant position at birth, but no randomised controlled trials. In August, 2010, a Cochrane systematic review22 was published on alternative positions for the baby at birth before clamping the umbilical cord. This review was updated in 2012, but added no additional publications to our databases search. Although several of the studies suggested an effect of gravity on the volume of placental transfusion, they did not include many study participants or allow for the management of the infant immediately after delivery. We concluded from these searches that a randomised controlled trial assessing the effect of gravity on the volume of placental transfusion in a pragmatic way was needed. Interpretation Data from our study suggest that when umbilical cord clamping is delayed for 2 min, the volume of placental transfusion is similar for infants held on the mothers’ abdomen or chest and those held at the level of the vagina. Therefore, and because of the potential of enhanced bonding between mother and baby and increased success of breastfeeding and the compliance with the procedure, holding the infant by the mother immediately after birth should be strongly recommended.
than did those with mothers who did not. However, following centre practices, the frequency of administration of the drug in mothers included in the study was 48 of 122 (39%) in centre one, 34 of 38 (89%) in centre two, and 214 of 222 (96%) in centre three. When we corrected by centre in the multivariable linear regression model, we found no significant differences in the weight increments in newborn babies whose mothers received early oxytocin and those who did not. We have not recorded the exact timing of injection, and because oxytocin increases the frequency and intensity of uterine contractions, the effect of its administration in the first moments after birth on the volume of placental transfusion deserves further investigation. Although the frequency of clinical jaundice is not increased, more newborn babies with delayed cord clamping receive phototherapy.5 53 babies had jaundice in this study; 15 of those treated with phototherapy. Therefore, a strict follow-up of these babies after discharge from hospital is mandatory and, in situations when follow-up is not feasible or treatment for jaundice is not readily available, the risk benefits of this practice should be carefully assessed. We conclude that delayed umbilical cord clamping for 2 min provides a clinically relevant placental transfusion to most newborn babies, and that placement of a vigorous, vaginally delivered, full term baby on the mother’s abdomen or chest before clamping the umbilical cord results in identical amounts of placental transfusion as would holding the baby during the same period at the level of vaginal introitus. Therefore, we recommend that mothers be allowed to hold their baby
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for 2 min before the cord is clamped to increase obstetric compliance with delayed cord clamping enhance maternal–infant bonding, and decrease iron deficiency in infancy. Contributors NEV was responsible for the idea of the study and organised the study methods. NEV, DSS, LMP, and ANG developed the protocol and managed the project. NEV and DSS coordinated the study and did data analysis. DSS reviewed study methods and data collection procedures. JEG and MGA participated in data management. DSS and ANG trained staff. NEV, DSS, LMP, and ANG wrote the report, which was reviewed by JEG. JPB and MGA organised and coordinated the pilot feasibility trial. Declaration of interests We declare that we have no competing interests. Acknowledgments The study was funded partly by Fundación para la Salud Materno Infantil, and by a donation from Juan Navarro. Manrique Hnos SRL donated the weight scales. We thank all study participant’s families and the chairs and staff of the participating centres; Gustavo Goldsmit, Fernando Ferrero, and Hugo Krupitski for their participation as members of the Data Safety Monitoring Committee; Ariel Fernández for database development and management; Leandro Kovalevski for statistical advice and analysis; José María Diaz-Rossello for assistance with the model to assess volume of placental transfusion; Cecilia García, Marcelo Decaro, and Lionel Cracco for their participation in the pilot study; and Fernando Althabe and M Jeffrey Maisels for thoughtful review of the report. We also thank the nurses and physicians who helped to recruit patients at Trinidad Palermo Private Hospital, Buenos Aires, Argentina (centre one, principal investigator Adriana Gorenstein): Edith Martínez, Graciela Roppel, Graciela Orieta, María Méndez, Gabriela Di Maria, Gladys de la Cruz, Noemí Jacobi, Florencia Chiarelli, Carolina Cerúsico, Laura García, Graciela Corral; Maternal Infant Hospital Carlos Gianantonio, San Isidro, Buenos Aires, Argentina (centre two, principal investigator Blanca C Senra): Leonardo Augusto Graf, Nelson Facundo Herrera, Lucia Fedorowicz, Yesica Leiro, Alicia Ponce, Susana Maligne; and Institute of Maternity Our Lady of Mercy, San Miguel de Tucumán, Argentina (centre three, principal investigator Juan Esteban Gordillo): Natalia Corbalan, Gerardo Murga, Veronica Zavalsa, Eliana Soria, Marcela Rocha, Mabel Saracho, Anabella Gimenez Osorio, Natalia Rodriguez, Gabriela Teseira, Daniel Solorzano, Fernando Lizarraga, Patricia Gonzales, Susana Caceres, Etel Sanchez, Noemi Brizuela, Andrea Calderon, and Claudia Albarracin. References 1 Prendiville WJ, Harding JE, Elbourne DR, Stirrat GM. The Bristol third stage trial: active versus physiological management of third stage of labour. BMJ 1988; 297: 1295–300. 2 Gunther M. The transfer of blood between baby and placenta in the minutes after birth. Lancet 1957; 272: 1277–80. 3 Yao AC, Lind J. Placental transfusion. Am J Dis Child 1974; 127: 128–41. 4 Yao AC, Lind J. Effect of gravity on placental transfusion. Lancet 1969; 2: 505–08. 5 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: CD004074. 6 Trudnowski RJ, Rico RC. Specific gravity of blood and plasma at 4 and 37 degrees C. Clin Chem 1974; 20: 615–16. 7 Ceriani Cernadas JM, Carroli G, Pellegrini L, et al. The effect of timing of cord clamping on neonatal venous hematocrit values and clinical outcome at term: a randomized, controlled trial. Pediatrics 2006; 117: e779–86. 8 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: 1997–2004. 9 Durán P, Mangialavori G, Biglieri A, Kogan L, Abeyá Gilardon E. Nutrition status in Argentinean children 6 to 72 months old: results from the National Nutrition and Health Survey (ENNyS). Arch Argent Pediatr 2009; 107: 397–404 (in Spanish).
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www.thelancet.com Published online April 17, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60197-5