Effects of timing of umbilical cord clamping for mother and newborn: a narrative review

Objective This narrative review was performed to evaluate the correct timing of umbilical cord clamping for term infants. It was intended to determine any advantages or disadvantages from early or delayed cord clamping for newborns, infants or mothers. Methods A systematic search on two databases was conducted using the PICO pattern to define a wide search. Out of 43 trials, 12 were included in this review. Three of the included studies are meta-analyses, nine are randomized controlled trials. Results Early or delayed cord clamping was defined differently in all the included trials. However, there are many advantages from delayed cord clamping of at least > 60 s for newborns and infants up to 12 months of age. The trials showed no disadvantages for newborns or mothers from delayed cord clamping, except for a lightly increased risk of jaundice or the need for phototherapy. Conclusion Delayed umbilical cord clamping for term infants should be performed. Further research is needed to improve knowledge on physiological timing of umbilical cord clamping in term infants, which also leads to the same advantages as delayed cord clamping.


Umbilical cord clamping-overview
The correct timing of umbilical cord clamping for term newborns has long been debated in obstetrics [1][2][3].This is a usual intervention during the active or passive management of the third stage of labour, and, the question arises as to whether the neonatal outcome after different timings of cord clamping should be investigated.Active management includes the prophylactic administration of uterotonic medication, cord clamping and controlled traction of the umbilical cord to deliver the placenta.Passive management is described as waiting for physiological signs of placental detachment before it is spontaneously delivered.Since 2014, the WHO recommends a waiting period of 1-3 min before cord clamping after the birth of term infants [4].
The maternal outcome of active management has already been thoroughly documented: it decreases the risk of postpartum haemorrhage [5].Studies have been conducted with regard to the handling of the third stage of labour, in which obstetricians and midwives took part.These studies indicate that 73% of the midwives in the UK prefer active management and 41% usually clamp the umbilical cord within 20 s after the birth of term infants [6].
There is ample evidence showing the advantages for term infants when the cord was clamped at a later point in time, e.g. 60 s after birth [7].The advantages for term infants include higher haemoglobin levels, a decreased risk of anaemia and lower rates of chronic lung disease [7].There is also evidence proving the longer term advantages for term infants whose cord was clamped more than 60 s after birth, ranging up to 12 months of life [8].
The actual guideline for obstetrics in Germany recommends waiting at least 1 min and up to 5 min, or when it stops pulsating, before cord clamping [9].The guideline from paediatrics also recommends delayed cord clamping between 1 to 3 min after birth [10].

Aims
This narrative review aims to evaluate the timing of umbilical cord clamping for term infants.Furthermore, the review was conducted to expound any advantages and disadvantages from early or delayed cord clamping for mothers, newborn and infants.To improve the evidence-based work of midwives in Germany, the handling of the third stage of labour should be critically evaluated.

Study design
This study design (narrative review) was chosen to detect the actual meta-analyses, systematic reviews and RCTs covering the research question of this review.Furthermore, the study design offers an opportunity to summarize all study results achieved since 2011 and to survey the current state of research.The search strategy adheres to the standards of a systematic search to decrease the risk of selection bias [11].

Search strategy
The PICO pattern was used to differentiate the search strategy.Patients were pregnant women who gave birth at > 37 weeks of gestational age and their newborns.The intervention was declared as the time of umbilical cord clamping.Therefore, the comparison refers to the type of intervention to compare the outcome of early or delayed cord clamping management.The outcome was defined as measurable short-and long-term effects for the baby.To determine if there were any disadvantages in connection with the cord clamping methods for the mother, whether active or passive management of the third stage of labour was performed was not specified.This led to the central research question: Which timing of umbilical cord clamping on term infants provides advantages for the newborn and produces no disadvantages for mother or newborn?
An electronic search in the Cochrane library and Pub-Med within a time range from 3 rd October to 1 st November 2022 was performed.The language for both databases was restricted to German and English.The searched article types were predetermined as meta-analyses, systematic reviews, randomized controlled trials and clinical trials from the last 10 years.A search string for an advanced search was created to extract data to follow the guidelines for systematic search and to improve the reproducibility.The first sequence chosen was "effects umbilical cord clamping" which should be mentioned in the title or abstract.The second sequence was supposed to exclude the literature concerning preterm birth.Search string: (effects umbilical cord clamping) [Title/Abstract]) NOT (preterm [Title])).A filter was added to search for meta-analyses, systematic reviews and randomized controlled trials for the time range between 2011 and 2022.This search method produced 43 results, the exclusion and inclusion criteria are described in the following section.

Inclusion/exclusion criteria and data synthesis
The included studies were selected using the following criteria.The search was directed towards studies investigating short-term and long-term effects for newborns whose cord was clamped early or delayed after birth, differentiated in two points of time.Only trials with mothers and newborns with > 37 weeks of gestational age were included.There were no restrictions regarding different birth modes.Studies were also included which investigated the impact of umbilical cord clamping on maternal factors to evaluate a potential disadvantage from cord clamping for the mother.
Trials examining other central interventions than umbilical cord clamping were excluded.The studies which showed effects for extremely low birthweight newborns or other preterm births before 37 weeks of gestation were also excluded.Two studies were excluded because of a protocol-based study design and a comment, which did not contain relevant information.The PRISMA flowchart (Fig. 1) shows the search procedure; the exact data from included and excluded studies are presented in the table for study characteristics.

Quality of evidence
The quality of the systematic reviews and meta-analyses was evaluated by the AMSTAR 2 tool [12].The conduct of RCTs is transparently presented using the CONSORT checklist to assess the risk of bias of the summary of results in this review [13].

Study characteristics
The 12 included studies investigated the effects of different timing of umbilical cord clamping for newborns and mothers and the long-term effects for infants from 2 months to 3 years.The timing of umbilical cord clamping extended from immediately to 5 min or no pulsation of the umbilical cord, the literature review showed a high heterogeneity of management of cord clamping.Out of 12 articles, 3 were meta-analyses and 9 RCTs and no RCTs were included which were already included in one of the meta-analyses [14][15][16][17][18][19][20][21][22][23][24][25].The study population in the different RCTs ranged from 56 to 720 participants [14,15,17,[19][20][21][22][23][24].The details of included studies can be found in Table 1.

Neonatal outcomes
The results of 12 included studies show significant advantages in delayed cord clamping (different timings) for newborns and infants up to 12 months of age, as shown in Table 2.The advantages concern haemoglobin, haematocrit, iron and ferritin levels and mean corpuscular volumes for newborns and infants up to 12 months of age [16,18,19,[22][23][24][25].In addition, delayed cord clamping seems to reduce the incidence of anaemia and iron deficiency anaemia in infants up to 12 months of age [16,18,22,25].Furthermore, the results show that delayed cord clamping seems to affect early neuronal development advantageously, measured by the Ages and Stages Questionnaire [26].One meta-analysis showed jaundice requiring phototherapy for the delayed cord clamping group, another meta-analysis showed an increase in serum bilirubin for infants at 3-5 months of age [18,25].One result shows low haematocrit levels in the first hours after birth, but the confidence interval was large [18].In summary, there are many advantages of delayed cord clamping and one possible disadvantage regarding the incidence of jaundice or need for phototherapy.

Quality of evidence
Overall, the quality of all included studies, RCTs and metaanalyses seems to be moderate or high.Table 4 shows the results of the evidence evaluation of the meta-analyses via AMSTAR-2 score and Table 5 shows the results of the evidence evaluation of the RCTs via CONSORT.

Results' overview
The aim of this review was to evaluate the timing of umbilical cord clamping for term infants from 37 + 0 weeks gestational age, to describe the effects of the timing of cord clamping for newborns and mothers and to improve the evidence-based work of midwives in Germany.The results of this review regarding the timing of umbilical cord clamping arose from low-risk populations in most of the trials [14,15,[18][19][20][22][23][24][25].The majority of infants were born vaginally, three of the included trials also included primary caesarean sections [18,21,24].Furthermore, most of the included mother-newborn pairs had singleton pregnancies [15-17, 20, 21, 24].The results may not apply to vaginaloperative deliveries or other birth risks; however, overall, there were no birth risks such as asphyxia, placental anomalies, intrauterine growth restrictions, differences in APGAR scores between groups or differences in neonatal mortality and morbidity [17,18,[21][22][23][24][25].
The evaluation about the exact timing of umbilical cord clamping in term infants cannot be concluded, the included trials report about many advantages for newborn and infants up to 12 months of age from delayed cord clamping, but all the included trials reached this outcome for different timings of cord clamping.The timing of early cord clamping ranged from immediately to < 60 s, the timing of delayed cord clamping ranged from 60 s after birth up to cessation of umbilical cord pulsation, which is a broad description because of the individual, physiological differences depending on the time of onset of respiration.However, delayed cord clamping > 60 s seems to be advantageous for newborns in terms of iron stores and its short and long-term effect up to 12 months of age [16,[18][19][20][21][23][24][25].Timing of cord clamping in term infants could have an impact on neuronal development [14,18,22].Some trials reported an increase in bilirubin levels or clinical jaundice which increases the need for phototherapy, but other risk factors were not strictly considered [18,25].Delayed cord clamping for different timings seems to have no disadvantages for mothers; one trial described pain reduction while suturing perineal tears, but this result can also be correlated with psychological satisfaction with the birth [17].
There is need for further research to evaluate if there are different results in terms of advantageous effects for newborns when the mother's haemoglobin is low at the start of labour.One trial measured the effects of change of mother's haemoglobin from early or delayed cord clamping which was not significant, but did not measure the correlation between the strength of effects for newborns and their mother's haemoglobin [21].There is also heterogeneity in the definition of delayed cord clamping.Maybe the measurement of effects of placental blood perfusion after birth should include the physiological process of adaptation.What the duration of umbilical cord pulsation depends on should also be evaluated, and whether a physiological time of cord clamping can be determined.

Limitations and risk of bias
The inclusion criteria were strictly observed and evaluated if the trial was appropriate (Table 1).A risk of selection bias could be present, as only one person assessed the inclusion process.However, the inclusion process took place using the PICO pattern to make sure the research questions and aims are matching.Despite the orientation on systematic search by creating a search string, there is a risk of not accessing all relevant articles, especially because of language restrictions (German and English).The data extraction and synthesis were also made by one person, but reviewed by an independent researcher; however, this could have led to an observer bias.The data collected from all included studies are shown in Tables 2 and 3.The structure for data extraction was to collect all relevant data, primary and secondary outcomes independent of the significance, to eliminate reporting bias.The data synthesis consciously produced a sort of performance bias because the aim was to evaluate the timing of umbilical cord clamping, and nearly every included study had a different timing of cord clamping.It is unavoidable that there is a risk of bias for the search strategy because the search was not conducted in many databases and maybe could not include every trial concerning the effects of umbilical cord clamping.Tables 4 and 5 show the methodological quality of each included trial or meta-analysis.Nevertheless, all the biases created in the included trials lead to an increased risk of bias in this review.Some of the included RCTs did not perform a structured randomization, and the blinding of patients or research staff was not completely described in every RCT.The determination of cord clamping by stopwatch was performed in many trials, and some did not describe in detail how the timing was measured.As mentioned, the placement of the newborn above or below the placenta and the impact of gravity were not considered in this review, some studies mentioned placement and others did not, and this could have an impact on the effects from cord clamping.
In summary, there is a risk of different biases and a limitation in informative value; however, the results of this review correspond to the actual recommendations for practitioners in Germany, and the review gives an important impulse for further research to evaluate the exact timing of umbilical cord clamping, the effects of waiting until pulsation has stopped and also to explore the boundaries of waiting 1 min before cord clamping.

Authors' conclusion
This narrative review shows that delayed cord clamping on term infants > 37 weeks of gestational age, with no or low birth risks, born vaginally or by primary caesarean section, has advantageous effects for newborns and infants up to 12 months of age.This management of umbilical cord clamping could reduce the incidence of anaemia and seems to correlate with a better neurodevelopment during the early life of infants.In addition, it shows that there are no adverse effects for the mothers, so the management of delayed cord clamping seems to be safe concerning postpartum haemorrhage and high blood loss.Unfortunately, the second part of this central research question about the exact timing of umbilical cord clamping leading to the aforementioned advantages cannot be answered.The critical value for both early and delayed cord clamping has to be determined in further research to produce exact results for their implementation into practice.Rana et al. showed a cut-off point of 61 s for early cord clamping, other authors describe advantageous effects from 60 to 120 s, while the effects could be stronger when the umbilical cord was cut later because of the perfusion of placental blood [22].In contrast, Chen et al. showed no significant increase in haematocrit levels in newborns after 90 s [15].Further research should address the question of if there are any signs to improve the knowledge about physiological umbilical cord clamping to achieve the advantages of longer placental perfusion for each individual term infant.

Table 2
Neonatal outcomes

Table 3
Maternal outcomes