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The effect of placental cord drainage in the third stage of labour on feto-maternal transfusion: a systematic review

13 January, 2009

The effect of placental cord drainage in the third stage of labour on feto-maternal transfusion: a systematic review

To understand the transfer of fetal cells into maternal circulation and subsequent effect of placental cord drainage.

EBM: Dec 2005



Hora Soltani1 PhD, MMedSci, BSc, RM. Fiona Dickinson2 BSc, RM. TN Leung3 MD, MRCOG.
1 Lead Research Midwife, Maternity Unit, Derby Hospitals NHS Foundation Trust, Derby City General Hospital, Uttoxeter Road, Derby DE22 3NE England. Email:
hora.soltani@nhs.net
2 Research Assistant, Maternity Unit, Derby Hospitals NHS Foundation Trust, Derby City General Hospital, Uttoxeter Road, Derby DE22 3NE England. Email:
fiona.dickinson@derbyhospitals.nhs.uk
3 Senior Lecturer, Division of Obstetrics and Gynaecology, School of Human Development, The University of Nottingham, Derby City General Hospital, Uttoxeter Road, Derby DE22 3NE England. Email: dannytnleung@cuhk.edu.hk 



Abstract

Aim. To understand the transfer of fetal cells into maternal circulation and subsequent effect of placental cord drainage.
Objectives. The objective of this review is to examine the evidence relating to the effectiveness of placental cord drainage in reducing feto-maternal transfusion.
Method.A number of databases were searched including MEDLINE, Embase and CINAHL for randomised controlled trials investigating placental cord drainage in the third stage of labour in relation to feto-maternal transfusion. This was widened to include non-randomised controlled trials. Trial quality was assessed and data extracted by two of the reviewers independently and agreed by all following discussion.
Findings/results. Four randomised studies were identified, of which two were included in the review. The other two were excluded on the grounds of inadequate reporting. In addition, two non-randomised studies were identified, the results of which are presented and discussed. The combined effect of the two randomised trials did not show a statistically significant effect of cord drainage on feto-maternal transfusion.
Implications. Heterogeneity between the studies, varying methodologies and the different styles of cord management indicated a need for assessment of the individual aspects of the third stage of labour. Closer examination of the randomised trials, as well as the two non-randomised studies, with special attention to the timing of cord clamping, suggests that there may be potential benefits from cord drainage or delayed cord clamping (in practice this allows drainage into the baby). The occurrence and the extent to which cord drainage, as a simple practical technique, may have an impact on feto-maternal transfusion needs further investigation using well-designed studies.

Key words: Feto-maternal transfusion, placental cord drainage, third stage labour


Background

Feto-maternal transfusion involves the passage of fetal blood cells into the maternal circulation and happens to varying degrees (Devi et al, 1968; Hofmeister et al, 1972; Percival, 2003). It occurs through microscopic tears in the placental barrier and although it can happen at any time during pregnancy, it most commonly occurs during labour and birth (Woodrow et al, 1965). For most women this is not an issue, however, where the mother is rhesus negative and the fetus is rhesus positive, it can cause problems.

Although there are a number of rhesus factors, rhesus D (RhD) is the most common antigen with this concern (Spong et al, 2001). Fetal RhD-positive cells in the circulation of a RhD-negative mother, if left untreated, trigger the mother’s immune system to produce anti-D antibodies. This does not normally cause complications in the first pregnancy, but in subsequent pregnancies maternal RhD iso-immunisation presents a major risk of haemolytic disease of the newborn (HDN). This condition is the result of agglutination of the baby’s red blood cells and the breakdown of haemoglobin and can lead to a number of complications for the baby including jaundice, hyperbilirubinaemia, deposition of bilirubin in the brain and neurological damage and hypoxia (Beischer et al, 1997).

According to the National Institute for Health and Clinical Excellence, there are approximately 62000 RhD- positive babies born to RhD-negative mothers each year inEngland and Wales, representing about 10% of all births (National Institute for Health and Clinical Excellence, 2002). Of these, approximately 500 develop HND of which about 45 either have major, permanent developmental problems or die as a result. It is recommended that all women should be offered anti-D prophylaxis at 28 and 34 weeks, after any sensitising event such as antepartum haemorrhage and postnatally if the baby is found to be RhD-positive (RCOG, 2002).

There are however, theoretical questions about the use of anti-D prophylaxis as it is developed from blood products (National Institute for Health and Clinical Excellence, 2002).  Anti-D prophylaxis in RhD-negative women has largely reduced sensitisation, although it does sometimes occur where either the bleed or the pregnancy are undiagnosed and no prophylaxis is given (Stables, 2005).

There have been suggestions (Terry, 1970) that umbilical cord blood drainage in the third stage of labour may help to reduce feto-maternal transfusion. This is based on the theory that the volume and pressure of fetal blood within the placenta will be reduced if the maternal side of the divided umbilical cord is allowed to bleed freely. This in turn will lead to a diminution in the passage of fetal blood into the maternal circulation (Doolittle, 1963). As this practice has not been systematically evaluated, the purpose of this review is to examine whether the relatively simple action of draining the cord in the third stage of labour will affect the incidence of fetomaternal transfusion.

Objectives

The objectives of this study are to determine whether cutting and draining the placental end of the umbilical cord immediately after birth reduces the risk of fetal cells being transfused, via the placenta, into the maternal circulation.


Search strategy

A number of databases were searched including MEDLINE (1951 to 2005) (see Box 1), Embase (1974 to 2005) and CINAHL (1982 to 2005). The search strategy
used for MEDLINE was adapted for the other two databases. The strategies used varied due to the differing construction of each database, but included combining the
exploded terms ‘human’, ‘female’ and ‘pregnancy’ with ‘labour-obstetric’, ‘delivery-obstetric’ and ‘umbilical-cord’, in addition to ‘feto-maternal transfusion’. Help was sought from a specialist librarian with the construction of the search strategies and it was found to be necessary to explode the subject headings due to the wide variety of terms and phrases used to describe the phenomenon of feto-maternal transfusion. A manual search of the reference lists from the obtained articles was also carried out to identify additional relevant articles.


Box 1. Search strategy with MEDLINE via Dialog Datastar


1   Feto-maternal transfusion DE
2   (1) and human=yes and female=yes
3   Pregnancy w. DE
4   Labour-obstetric DE
5   Delivery-obstetric DE
6   Umbilical-cord DE
7   2 and 3
8   4 or 5 or 6
9   7 and 8


Selection criteria

Types of studies

Initially, all randomised controlled trials (RCTs) investigating the use of placental cord drainage in the management of third stage of labour in relation to feto-maternal transfusion were considered. The results of other types of studies
are categorised as non-RCTs and are presented separately. 


Types of interventions


The intervention was cord drainage that involves unclamping the previously clamped and separated umbilical cord and allowing the blood from the placenta to drain freely. Participants included all women who had had spontaneous vaginal deliveries.

 
Types of outcome measures

This was identified as feto-maternal haemorrhage, defined as transfusion of fetal cells into the maternal circulation.


Methods of the review

All trials identified by the search were evaluated independently by two reviewers (and agreed by all) for methodological quality and suitability for inclusion in the
review, irrespective of their results. As a criterion to assess validity of the RCTs, each trial was graded on the basis of allocation concealment – A = adequate, B = unclear, C = inadequate and D = not used (Clarke and Oxman, 2003). Trials graded as A, B or C were considered for inclusion in the meta-analysis.

Statistical analysis was performed using Review Manager software (Review Manager, 2003). The results have been presented as odd’s ratio (OR) for binary outcomes, with 95% confidence intervals for the synthesis of the results of RCTs. The I squared
statistical test, described as ‘a measure of consistency between trials’ (Higgins et al, 2003), was used to explore the heterogeneity (dissimilarity) of the trials. Values of more than 50% may indicate substantial heterogeneity (Higgins et al, 2003). In this study, I squared statistic was 68% meaning that the differences between studies were likely to be due to clinical or statistical inconsistencies rather than chance. Therefore, the causes of heterogeneity were investigated and a random effects meta-analysis was used due to the large variation between the included studies.

The non-RCT studies were reported separately, as due to their lack of compatibility it was not possible to aggregate their results with the RCT studies.


Description of the studies

RCTs

Four RCTs (Terry, 1970; Johansen et al, 1971; Moncrieff et al, 1986; Thomas et al, 1990) were identified, of which Terry (1970) and Johansen et al (1971) met the inclusion criteria for this review.

Terry (1970) looked at 125 women who had a normal delivery in the study hospital over a three-month period. Cases were alternately allocated to one of two groups. In the control group, the third stage was managed using syntometrine and controlled cord traction. The experimental group was also given syntometrine, but the umbilical cords were immediately divided and the placental end allowed to bleed freely, controlled cord traction being applied once the cord had stopped bleeding. Maternal blood was taken 30 minutes after placental delivery in both groups and when the sample was examined microscopically the number of fetal cells in the maternal blood were counted. Cases were reported as having feto-maternal transfusion if any fetal cells were identified in the maternal sample.

In Johansen et al’s study (1971), 200 women were allocated on alternate days to either the control or experimental group. The third stage was managed using ergometrine with the anterior shoulder and the cord being cut on cessation of pulsation in both groups. In the experimental group the cord was then allowed to drain freely. Placental delivery was spontaneous in both groups.  The study by Moncrieff et al (1986) was excluded due to inadequate reporting of methodology and results. The only published information is a short letter to the editor of The Lancet giving results in terms of the range of volume of fetal cells in the maternal circulation. Although efforts were made to contact the authors to obtain further data, no reply was forthcoming.

The most recent study by Thomas et al (1990), as part of a larger study into the effect of placental cord drainage on the management of third stage of labour, carried out a sub-group analysis on the Kleihauer results of 40 subjects (20 in each arm). No detailed information on the subgroup characteristics or the timing of cord drainage of the participants was reported in this study, and therefore it was excluded on the basis of inadequate reporting.


Non-RCTs

Two non-RCTs were identified. Ladipo’s (1972) study compared the size of feto-maternal transfusion across three groups. Method one (M1) had immediate cord clamping with no cord drainage (n=100), method two (M2) had immediate cord clamping followed by immediate cord drainage (n=62) and method three (M3) had delayed clamping (after cessation of cord pulsation) (n=38). No information was given as to how the women were allocated to each of the groups.

Hofmeister et al (1972) carried out Kleihauer tests on 531 women who had had various different methods of managing their deliveries. This study does not provide a clear description of how and when the cord was clamped or drained in relation to cessation
of pulsation.


Methodological quality

In terms of allocation concealment, both included RCTs were category C, no attrition was reported and there was no indication as to the blinding of investigators, women or analysts. There was no limitation in terms of the parity of women included, encompassing both nulliparous and parous women.

While it was not possible for the professionals participating in the research to be unaware of the type of management allocated, the studies were assessed in terms of whether the researchers who carried out the analysis were blind to the intervention allocations. Due to the risk of attrition bias, to be included in the review outcome data had to be available for at least 80% of participants randomised in each study.




Figure 1. Comparison of the effect of placental cord drainage in the third stage of labour on feto-maternal transfusion



Results


RCTs

There was substantial heterogeneity in the results of included studies (see Figure 1). Terry (1970) showed a statistically significant difference between the experimental group and the control group in the mean fetal cell count in the maternal circulation. 

Within Johansen et al’s (1971) study there was no statistical difference between the two groups. 

The overall effect for both studies is not significant (OR=0.67 (95% confidence interval 0.29, 1.56)).


Non-RCTs

Ladipo (1972) showed a statistically significant difference between the non-cord drainage (M1) and cord drainage groups (M2 and M3) in terms of the proportion of cases where five or more cells were transfused (see Table 1). Where the cord wasleft intact until pulsation had ceased (M3), the results were similar to those in the cord drainage group (M2) and significantly different to the non-cord drainage group (M1). As a side observation, another finding of this study was the significantly reduced number of infants with Apgar scores below seven where the cord was left intact (M1 versus M3).

Hofmeister et al (1972) report a small difference between the proportion of cases of feto-maternal blood transfusion in two groups of cord drainage and non-cord drainage. This is not statistically significant (10/106 (10%) versus 11/94 (12%) respectively).



Table 1. Comparison of three methods of cord management in the third stage of labour from Ladipo's (1972) study

Discussion

The management of the umbilical cord in the third stage of labour may appear to be a small part of the whole intrapartum period, however, in practice any effect on
feto-maternal transfusion could be of great significance. The age and limited number of available studies indicate an apparent lack of interest in this area of research. One reason for this could be the non-profit-making nature of the intervention and lack of enthusiasm from investors and funding organisations.
 
The combined results of the two RCT studies included in this review do not show a significant result, but there is a possibility that the difference in timing of cord clamping influenced the findings. The study by Terry (1970) described a methodology where the cord was clamped and cut immediately in the intervention and control groups, and it was drained in the intervention group. However, in Johansen et al’s study (1971), the cord was left intact until umbilical artery pulsation had ceased and it was then clamped, cut and drained. In effect, the control group in Johansen et al’s study also received some degree of cord drainage, the only difference being that it was into the baby rather than into a kidney dish.

It has been suggested that an average of 80ml of placental blood would be transfused to the neonate if the umbilical cord is only clamped after the cessation of cord pulsation at delivery (Yao and Lind, 1974). The reduced pressure in the placenta caused by cord drainage into the baby may have effectively negated any difference between the control and experimental groups. This is further supported by the findings of Ladipo (1972) who had very similar results between the two groups where cord drainage was allowed (either into a container or into the baby) (see Table 1 – M2 and M3), but a significant difference between these two groups and the control group, where the cord was clamped immediately and no cord drainage took place (see Table 1 – M2 and M3 versus M1).

The age and limited number of available studies restricted the scope of this review to some extent. Heterogeneity between the studies, various methodologies and different styles of cord management in the third stage of labour employed indicate a need for individual assessment. In general, this review suggests that if the cord is clamped after cessation of pulsation or drained after immediate clamping, there are some potential benefits in terms of reducing feto-maternal transfusion. 

The side observation of the increased number of babies with lower Apgar scores in the delayed cord clamping group (Ladipo, 1972) is of considerable importance. It may well be that the delay in clamping the cord allowed a small extra transfusion of oxygenated blood to reach the baby, increasing the baby’s haemoglobin levels. This finding had been seen in other studies that look specifically at placental transfusion to the baby (Saigal et al, 1972). This is beyond the remit of this review and needs to be evaluated robustly with a focus on the timing of cord clamping.

The subject of timing of cord clamping in general is under review by McDonald and Abbott (2003). However, feto-maternal transfusion is not listed in their proposed
protocol as an outcome measure. Another Cochrane review on the timing of cord drainage in preterm infants similarly does not give any information on feto-maternal
transfusion (Rabe et al, 2004). A further systematic review that focuses on the effect of cord drainage on the management of third stage of labour (Soltani et al, 2004) has not addressed this issue, due to the diversity of the objectives and the fact that the relevant studies did not meet the strict inclusion criteria.

The quality of the RCTs included in this review, based on allocation concealment, is category C. They are not highly ranked in terms of quality, but they are the only
available evidence. In terms of attrition rate, there was a 100% follow-up for both studies. This could be due to the nature of these studies and the timing of recruitment. Understandably, the clinicians were not blinded to the results, but the researchers and subjects also were not blinded. However, the impact this has on the results is not expected to be considerable.


Conclusion

The limited number of studies and the differences in methodologies and timing of cord clamping in this review do not allow a generalisable conclusion in relation to feto-maternal transfusion. They do, however, suggest that cord drainage, either into a container or a baby, may potentially have an effect of reducing the degree of feto-maternal transfusion. Further, high-quality research with a robust methodology is required to investigate the impact of cord drainage on feto-maternal transfusion.


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