Guidelines on Deferred Cord Clamping and Cord Milking: A Systematic Review

We conducted this systematic review (PROSPERO identifier CRD42019143332) according to available methodological guidance on conducting a systematic review of guidelines.^16,17 

We searched the following 10 academic and guideline databases from January 1, 2010, to July 17, 2019 (Supplemental Table 2): Ovid Medline, Ovid Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Web of Science, Clinical Practice Guideline (CPG) Infobase, Guidelines International Network, National Institute for Health and Care Excellence (NICE) Evidence, Royal College of Obstetricians and Gynaecologists Guidance, and Trip Medical Database. We hand searched the Web sites of members of the International Federation of Gynaecology and Obstetrics that had Web sites with recommendation statements (Supplemental Table 3).

With no language restrictions, we included the most recent versions of CPGs and other recommendation statements published after 2010 that provide at least 1 recommendation on DCC or UCM among preterm or term infants. On the basis of the definition provided by the Institute of Medicine, we defined CPGs as statements developed by a dedicated multidisciplinary panel, after a thorough review of the evidence, to optimize patient and practitioner decisions.¹⁸  We also reported on other statements that could not be described as CPGs (position statements and consensus statements) in order to comprehensively summarize all recommendations that inform health providers’ cord management practices.

Two reviewers (S.K.L. and K.N.) independently screened the titles and abstracts and full texts. Data from included full texts regarding guideline authorship, guideline development methodology, DCC and UCM recommendations, and sources of evidence supporting the recommendations were abstracted by using a piloted data extraction form. Discrepancies were discussed between reviewers to reach consensus, and a third reviewer (S.D.M) was consulted, as necessary.

Two reviewers independently appraised the quality of included statements using the modified Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument (Supplemental Table 4).¹⁹  AGREE II was modified to only include 3 of the 6 domains (scope and purpose, clarity of presentation, and editorial independence). The remaining 3 domains (stakeholder involvement, rigor of development, and applicability) were removed for 3 key reasons. First, only 3 domains were scored so that the AGREE II appraisal highlights the quality of cord management recommendations specifically (rather than the quality of recommendations on other topics as well), thus more accurately reflecting our research topic. Second, we wanted to prevent bias toward assessing the few guidelines dedicated to cord management as higher quality than the majority of guidelines, which had a broader or different focus (eg, preterm labor) and, thus, less comprehensive recommendations on cord management. Finally, because the reviewers were not experienced in all topics addressed by the guidelines (eg, neonatal resuscitation), we wanted to avoid arbitrary scoring of areas in which we lacked knowledge.

The clinical credibility and implementability of the relevant recommendations on cord management were appraised by using Appraisal of Guidelines for Research and Evaluation Recommendation Excellence (AGREE-REX) (Supplemental Table 4), which comprises 3 domains (clinical applicability, values and preferences, and implementability).²⁰  We also applied AGREE II and AGREE-REX to position papers and consensus statements. Although it is important to note that these statements will inherently receive lower-quality assessments because they do not follow the rigorous CPG development methodology that Appraisal of Guidelines for Research and Evaluation (AGREE) is designed to assess, we wanted to appraise all statements using a consistent framework.

AGREE advises users to determine their own thresholds to interpret scores according to the context of their study. Hence, in line with a number of other systematic reviews of CPGs,^21,22  we considered domain scores ≥50% to be consistent with higher quality and domain scores <50% to be consistent with lower quality. Because different domains were not equally relevant in our study, we did not pool together domain scores, and instead we reported individual domain scores.

We calculated the proportion of statements that recommended DCC and UCM for preterm or term infants. We reported on the details of the recommendations and their concordance with the highest level of evidence available at the time of publication regarding the mortality benefit of DCC among preterm infants because we hypothesized that physicians would be more likely to employ DCC if it is supported by this type of evidence.

The searches retrieved 4765 records (Fig 1). After excluding 1540 duplicates, we screened 3225 titles and abstracts and selected 311 records for full-text screening. Before resolving discrepancies, the reviewers had 97% agreement for inclusion and exclusion of full texts. We included 44 statements,^23–66  of which 24 met the criteria for a CPG because they were developed by a dedicated national or international panel after a systematic search and synthesis of the evidence to inform practitioner and patient decisions.¹⁸  Twenty statements were described as position papers or consensus statements or could not be confirmed to be a CPG because of a lack of detail on guideline development methodology or lack of a comprehensive evidence search (Supplemental Table 5). The included statements represented the views of 35 national and international professional societies, commonly in the fields of obstetrics, midwifery, neonatology, pediatrics, and resuscitation. Statements addressed a global audience but predominantly high-income countries: 33 of 44 addressed 17 different high-income countries, 4 specifically addressed Europe, 5 addressed 5 different middle-income countries, and 3 had a global focus (Fig 2). The available clinical guidelines on DCC and UCM are summarized in Figure 3 and described in detail below.

Detailed and summarized AGREE II and AGREE-REX scores are listed in Supplemental Table 4 and Figure 2, respectively. On the modified AGREE II instrument to assess methodologic rigor, 18 of the 44 (41%) statements had high quality in all 3 domains (scope and purpose, clarity of presentation, and editorial independence). On the AGREE-REX instrument to assess the quality of recommendations, 11 statements (25%) were high quality in all 3 domains (clinical applicability, values and preferences, and implementability). Eight statements (18%) had high quality in all domains of AGREE II and AGREE-REX, with statements by NICE³²  and the World Health Organization (WHO)⁴¹  having the highest scores overall.

On AGREE-REX, clinical applicability is used to assess the quality of the evidence review and applicability to clinicians and patients: 31 statements scored high quality in this domain. Values and preferences was the weakest domain overall (only 11 statements scoring high quality); it is used to assess efforts taken to make recommendations and outcomes important to clinicians, patients, and policy- and decision-makers.

Forty-four statements contained a total of 70 recommendations on DCC for subpopulations (Supplemental Fig 5); 24 recommendations were specific to preterm infants, with 3 for extremely preterm infants (≤28 weeks),^29,33,62  and 3 addressing extremely preterm and moderately preterm infants.^23,30,55  Thirty-one applied to both preterm and term infants, and 15 applied only to term infants (>37 weeks). Two recommendations were specific for multiple gestations.^23,24  Three statements identified monochorionic twins or multiples as a contraindication to DCC.^23,31,34  Recommendations on DCC provided by CPGs are summarized in Figure 4, whereas those provided by non-CPGs are summarized in Supplemental Fig 6.

Three recommendations did not explicitly endorse DCC in certain instances. First, a committee opinion by the American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice stated that there is insufficient evidence to recommend for or against DCC in multiple gestations.²⁴  Second, a CPG by the Society of Obstetricians and Gynaecologists of Canada stated that in term infants, the benefits of DCC must be balanced with the risks of neonatal jaundice requiring phototherapy.⁴³  Finally, a CPG by the Italian Task Force for the Management of Umbilical Cord Clamping recommended immediate clamping in directed cord blood collection for at-risk families.²³ 

Regarding mode of delivery, 3 recommendations on preterm infants,^23,57  3 on term infants,^23,25,57  and 1 on both preterm or term infants provided recommendations specific to DCC after cesarean delivery (CD).⁵⁷ 

Fifty-one of 67 (76%) recommendations endorsing DCC made a recommendation regarding the optimal duration to defer clamping (Fig 4, Supplemental Fig 5). The shortest evidence-based durations included 30 to 60 seconds in preterm infants, 30 to 60 seconds in term infants, and ≤30 seconds in preterm and term infants. The longest evidence-based durations included 30 to 180 seconds in preterm infants, until cord pulsation ceases in term infants, and ≥60 seconds in preterm and term infants. The most commonly recommended lower limit of optimal duration was at least a minute (20 recommendations), whereas 10 recommendations suggested an upper limit of at most a minute.

Among the 51 recommendations that included an optimal timing, we reviewed the sources of evidence that the authors cited to support the suggested time (Supplemental Fig 5). For 11 timings (22%), a source of evidence was not cited. In 25 (50%), primary studies or systematic reviews were cited. In 6 (12%), the authors cited other guidelines rather than primary research. For the remaining 9 (18%) recommended timings, the authors did cite evidence to support the recommendation; however, there was a mismatch between either the upper or lower limit of the durations recommended in the evidence sources and the durations recommended in the statements. Hence, we could not confidently determine if and how these recommendations were informed by the cited evidence, expert opinion, and authors’ consensus decisions (Supplemental Table 6).

Common maternal and infant contraindications to DCC included significant maternal bleeding and unstable maternal conditions (6 statements), the need for immediate neonatal resuscitation (29 statements), an infant heart rate <60 beats per minute (2 statements), and suspected fetal asphyxia (1 statement). Common uteroplacental contraindications included concerns about the integrity of the cord and placental circulation and placental abruption or previa (7 statements).

The 23 recommendations on UCM in 20 statements were more cautious and less detailed than those on DCC (Supplemental Table 7). Fifteen recommendations suggested that UCM may be considered when DCC is infeasible and when there is significant maternal bleeding, when there is a need for immediate neonatal support, or in emergency situations. Only 4 recommendations provided suggestions on the numbers of times to milk the cord, ranging from 2 to 5 times. Thirteen statements discouraged the routine use of UCM because of insufficient evidence of its benefits and harms.

Given our hypothesis that clinicians would be more likely to change practice on the basis of evidence revealing benefit in compelling outcomes, such as reductions in infant death, we examined the number of statements that used mortality data to justify DCC. Among the 39 statements that provided recommendations relevant to preterm infants (recommendations for preterm or both preterm and term infants), only 3 (8% of statements) reported a mortality benefit of DCC for preterm infants. Guidelines by the Italian Task Force for the Management of Umbilical Cord Clamping²³  and the European Society for Paediatric Research⁵⁶  both reported the findings of the systematic review by Fogarty et al,³  which found that DCC (mainly ≥60 seconds) significantly reduced hospital mortality in preterm infants compared with immediate cord clamping. Additionally, the 2016 guideline by the Confalonieri Ragonese Foundation³¹  cited the results of a systematic review by Backes et al,⁶⁷  which found that DCC and UCM reduced mortality among preterm infants <32 weeks’ gestation (relative risk 0.42; 95% confidence interval 0.19–0.95).

In concordance with meta-analytic evidence, a mortality benefit for preterm infants was reported in none of the statements that provided recommendations on UCM.^7,68,69 

In this systematic review, we included 24 CPGs and 20 other statements, which together contained 70 recommendations on DCC and 23 recommendations on UCM for preterm and term infants. There was significant variation between statements on the specific details of performing DCC and UCM, despite all endorsing placental transfusion. Statements frequently failed to cite the most compelling evidence of reductions in mortality in preterm infants.

Motivated by the clinical goal of improving DCC rates by improving guideline quality,¹⁵  we comprehensively searched in multiple academic and gray literature sources without language or country restrictions. We included CPGs, consensus statements, and position papers; hence, we synthesized all retrieved recommendations that may shape health providers’ practices. In addition, we reviewed the concordance of recommendations with cited evidence regarding the duration of DCC and the availability of high-quality evidence on the mortality benefits of placental transfusion for preterm infants. Finally, we used a modified AGREE II and the AGREE-REX to appraise the methodologic quality and applicability of all recommendations.

Our study also has limitations. First, given that using guidelines as the study type is relatively new in the world of systematic reviews (although increasing^22,70 ), there is a lack of tools to inform study design and execution. To mediate this limitation, we closely followed methodologic guidance for systematic reviews of CPGs by Johnston et al¹⁷  and referred to published systematic reviews of CPGs. Second, we could not ascertain the level of authority possessed by each authoring organization, which would allow us to comment on the degree to which particular recommendations influence practitioners. Third, for feasibility, we used Google Translate to interpret guidelines not written in English, when local translation was not available, for the following languages: Estonian, French, German, Italian, Japanese, Romanian, and Spanish. Finally, because our search strategy was designed to capture guidelines that mention terms describing placental transfusion, we are unable to calculate the proportion of all perinatal guidelines that comment on cord management.

CPGs and other recommendation statements published within the past decade agree that DCC should be offered to stable preterm and term infants. Furthermore, several guidelines on preventing postpartum hemorrhage included DCC as a component of the active management of the third stage of labor, in line with evidence that DCC does not increase the risk of severe postpartum hemorrhage at term.⁷¹ 

There is significant heterogeneity among recommendations about the methods of performing DCC, especially regarding the timing of cord clamping. Indeed, even recent systematic reviews and meta-analyses among preterm infants suggest deferring ≥30 seconds⁷²  or ≥60 seconds³  but do not suggest an upper limit at which time to clamp the cord. One reason for this may be that because most preterm infants require early support, an optimal time to clamp the cord has not yet been established. We identified a few statements recommending clamping the cord at times that are not yet verified by robust evidence (eg, 5 minutes, after delivery of the placenta). To maximize the benefits of DCC and prevent adverse effects, recommended durations should reflect high-quality evidence.

Nearly two-thirds of the statements exclude nonvigorous infants who require immediate neonatal resuscitation from receiving DCC in order to move the infant away from the mother to perform resuscitation. Unfortunately, this means that the sickest infants, who might benefit from DCC the most, are excluded from this intervention. Innovative technological solutions that may address this issue are being studied: prototypes of mobile trolleys that allow neonatal resuscitation to be performed with an intact cord have revealed safety, feasibility, and acceptability among health providers (eg, Bedside Assessment, Stabilization and Initial Cardiorespiratory Support, LifeStart).^73,74  If proven to be beneficial, bringing resuscitation to the mother’s bedside will require changes to hospital policy and ergonomics and collaboration between care providers, including pediatricians, obstetricians, and midwives.⁷⁵ 

Beyond DCC, UCM is a potential simple alternative that can allow placental transfusion to be quickly performed in infants who need immediate resuscitation.^69,75  Statements recommended UCM less frequently compared with DCC. Because milking disrupts the normal fetoplacental circulation to increase blood flow to the infant more rapidly than DCC, there are concerns that UCM may have adverse effects.⁷⁶  Guidelines echoed the need for more research on UCM, some of which has recently emerged. A trial by Katheria et al⁸  was prematurely terminated because of concerns about severe IVH in infants born at 23 to 27⁶ weeks’ gestation who received UCM. In their systematic review, Balasubramanian et al⁶⁹  also found significantly increased risk of severe IVH (grades 3 or higher) among preterm infants <34 weeks who received UCM compared with DCC in 4 RCTs. Importantly, the RCT by Katheria et al,⁸  which was the only included trial that found significantly increased risk, contributed nearly half the sample size of the UCM versus DCC comparison in this systematic review.⁶⁹  Ongoing trials among infants of older gestational ages and follow-up studies on long-term neurodevelopmental outcomes will be important to support future recommendations on UCM.^77,78  Additionally, high-quality evidence on various cord milking techniques (eg, the number of milkings, speed of milking, and position of the infant) and studies on the outcomes of cord milking among infants needing resuscitation are needed.

Increased granularity of recommendations may improve health providers’ ability and confidence in performing DCC. Only 4 statements were dedicated to DCC; all others embedded recommendations about DCC within broader topics. Guidelines focused on cord management would allow for specific recommendations for subpopulations (eg, various preterm gestational ages, modes of delivery). Further guidance is required on the position to hold the infant, the sequence of administration of uterotonic medications, temperature control, and other details. Additionally, DCC’s life-saving benefits to extremely preterm and preterm infants³  should be noted as the basis of recommendations.

The language we use to discuss DCC may also encourage its practice and assist patients in understanding it as being a positive rather than a negative intervention. Among the 33 English-language statements, only 1 used the term “deferred cord clamping”⁵¹ ; all others referred to “delayed” or “late” cord clamping, which connote negativity and that immediate cord clamping is the norm.¹²  Hence, we recommend that future guidelines and studies use the more neutral term, “deferred.”

Although many professional societies advocate DCC for preterm and term infants, improved clarity and granularity can improve the quality of guidance on this issue. In this systematic review, we found that guidelines representing different professions within the same country provided different recommendations. For example, although the ACOG recommended deferring clamping for at least 30 to 60 seconds for term infants,²⁴  the American College of Nurse-Midwives recommended deferring for up to 5 minutes for vaginally delivered term infants positioned skin to skin.²⁵  Before its closure in 2018, the National Guideline Clearinghouse, an initiative of the US Department of Health and Human Services, allowed health providers to succinctly synthesize and compare guidelines on topics of interest to identify recommendations that are most suitable to their clinical setting and population. Our study provides this knowledge synthesis with the methodologic rigor of a systematic review and with quality appraisal of guidelines and recommendations. The abundance and heterogeneity of guidelines on placental transfusion emphasize the need for an updated resource for health providers that compiles and compares the content and quality of relevant statements.

To improve rates of DCC for infants born worldwide, strong guidelines should be amenable to adoption in everyday clinical settings. Among our included CPGs and other recommendation documents, 42% satisfactorily (domain score ≥50%) met the criteria within the AGREE-REX domain of implementability, which is used to assess the suitability of the recommendations for local adoption.²⁰  In their systematic review of 18 studies conducted in high- and middle-income countries, Anton et al⁷⁹  describe barriers to implementing placental transfusion in hospital settings. General challenges included staff unawareness and resistance to change, and pediatrician-specific concerns included uncertainty about the role of placental transfusion when neonatal resuscitation is needed and concerns about potential adverse outcomes, such as jaundice.⁷⁹  Strategies to overcome barriers to implementation included education, creating protocols, auditing, providing constructive feedback, and improving multidisciplinary collaboration.⁷⁹  For example, the CPG by NICE provides a modifiable clinical auditing tool for the third stage of labor.⁵¹  Additionally, joint guidelines by obstetrical and pediatric care providers and establishing of opportunities for multidisciplinary communication, such as a predelivery surgical pause and team debriefing, may facilitate improved rates of DCC. Beyond revealing the evidence-informed nature of DCC, efforts to address resistance to change and make DCC acceptable to policy-makers, health workers, and families will improve the rates of its adoption to practice.²⁶  Although we found no country-specific recommendation statements produced in low-income countries, the WHO promotes the integration of DCC to national childbirth and postnatal care programming worldwide by employing strategies such as culturally appropriate education on DCC, linking of implementation with other interventions (eg, improving women’s health literacy), and robust monitoring and evaluation.²⁶ 

Birth brings together many disciplines; it is thus important that organizations guiding various disciplines are unified in their messages and use the current best evidence to provide detailed, comprehensive, and locally applicable recommendations so that change at the level of the birth can be implemented in a collaborative and sustainable way.¹⁰ 

In our systematic review of 44 CPGs and other recommendation statements, we found that professional maternal and infant health societies endorsed DCC to prevent neonatal morbidity and mortality among stable preterm and term infants. Only half the recommendations on the optional duration of DCC were supported by primary research or systematic review evidence, and in only 8% of statements was a mortality benefit of DCC for preterm infants reported. The current implementation of DCC may be increased with the provision of more unified, detailed, and evidence-based guidance on cord management.

We thank Ms Kaitlin Fuller, liaison and education librarian at Gerstein Science Information Centre, University of Toronto, for her assistance in developing the search strategies. We value the contributions of Ms Rifaa Fatima Ali and Ms Angel Gao in the administrative aspects of the study.

ACOG

American College of Obstetricians and Gynecologists

AGREE

Appraisal of Guidelines for Research and Evaluation

AGREE II

Appraisal of Guidelines for Research and Evaluation II

AGREE-REX

Appraisal of Guidelines for Research and Evaluation Recommendation Excellence

CD

cesarean delivery

CPG

clinical practice guideline

DCC

deferred cord clamping

IVH

intraventricular hemorrhage

NICE

National Institute for Health and Care Excellence

RCT

randomized controlled trial

UCM

umbilical cord milking

WHO

World Health Organization