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Contents: Labor: Original Research

Association of a Delayed Cord-Clamping Protocol With Hyperbilirubinemia in Term Neonates

Yang, Sophia MD, MS; Duffy, Jennifer Y. MD, MHS; Johnston, Robert MD; Fall, Carolyn MD; Fitzmaurice, Laura E. MD

Author Information
doi: 10.1097/AOG.0000000000003172
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Delayed cord clamping is associated with short-term benefits in preterm neonates, including reduced incidence of intraventricular hemorrhage, enterocolitis, sepsis, and mortality.1–4 Additional short-term benefits include an increased birth hematocrit and decreased need for blood transfusions, without an increased risk of hyperbilirubinemia, need for phototherapy or neonatal intensive care unit (NICU) stay.2,4–7 This has led to the development and implementation of universal delayed cord-clamping protocols in preterm neonates.8–11

The association of delayed cord clamping with neonatal outcomes in term neonates is less clear. Several large trials have demonstrated improved hematologic parameters, decreased short-term anemia, and decreased need for transfusion; all of which have been associated with long-term neuro-cognitive benefit.12,13 A Cochrane review demonstrated an increased risk of jaundice requiring phototherapy among term neonates who received delayed cord clamping.14 Other studies, however, have suggested that, although delayed cord clamping in term neonates leads to increased iron stores, higher hematocrit, and polycythemia, it is not associated with increased peak transcutaneous bilirubin, jaundice, symptomatic polycythemia, or need for phototherapy.15–17

The American College of Obstetricians and Gynecologists recommends performing delayed cord clamping for all neonates regardless of gestational age.3 However, there have been no studies examining the implementation, maternal or neonatal outcomes, or associated costs of a universal delayed cord-clamping protocol in term neonates. Our objective was to evaluate the hypothesis that implementation of such a protocol would lead to increased neonatal hyperbilirubinemia, which could have implications for hospitalization costs and maternal-neonatal lengths of stay.

METHODS

This was a retrospective cohort study of women delivering a term neonate at an academic medical center before and after implementation of a universal delayed cord-clamping protocol. The University of California, Irvine, Medical Center approved and released their delayed cord-clamping protocol in May 2016, before which there was no specific protocol with regards to timing of umbilical cord clamping, and delayed cord clamping was rarely performed in term neonates. This protocol was initially developed by a multi-disciplinary team of neonatologists, obstetric hospitalists, perinatologists, and Labor and Delivery and NICU nurses. After approval, it was disseminated to all obstetric care providers and nurses via in-person trainings and presentations, such as Grand Rounds and skills labs. The protocol was displayed in the physician workroom on Labor and Delivery and in all delivery rooms, and the intention to perform delayed compared with immediate cord clamping was added to the standard precesarean time-out script. A required field indicating whether delayed cord clamping was performed, and, if not, the reason for immediate cord clamping, was added to the nursing delivery summary template in the electronic medical record. The protocol specified a 60-second delay between the time of birth and the clamping of the umbilical cord in all neonates, irrespective of gestational age, unless specified exclusion criteria were met. Protocol exclusion criteria included both neonates at increased risk for polycythemia (monochorionic multiple gestations and neonates of mothers with diabetes at 37 weeks of gestation or more) and neonates in whom delayed resuscitation is inadvisable (interrupted placental circulation, known fetal hydrops, severely depressed newborns requiring immediate resuscitation, and mothers undergoing general anesthesia).

A preprotocol and postprotocol cohort were selected based on the date of protocol release. As the protocol was implemented in May 2016, the postprotocol study period of October 1, 2016 through December 31, 2016 was selected to maximize implementation of the new protocol. The control period was selected to be the same 3-month period in the previous year, October 1, 2015 through December 31, 2015, to control for any temporal differences in delivery volume or characteristics. This study was approved by the Institutional Review Board of University of California, Irvine.

Eligible women included those aged 18 years or older who delivered a term neonate during one of the study periods. A list of all term deliveries (37–42 weeks of gestation) within the study periods was obtained using International Classification of Diseases, 10th Revision codes for term pregnancy (Z3A.37-42), ordered by date of encounter. Charts were reviewed from this pool and included in the analysis if inclusion criteria were met. The initial review was completed via each investigator taking a portion of the master list, assigned at grossly approximated regular intervals, and performing data entry from their list in sequential order until the number needed in each cohort was attained. Once it was recognized that the number of included charts in each group met the sample size required by our a priori power calculations, no further charts were reviewed. Demographics and delivery information was obtained for all maternal-neonatal dyads in the two cohorts. In the preprotocol group, immediate cord clamping was assumed to have been performed unless it was explicitly documented otherwise in the physician's delivery note. This assumption is supported by an internal survey of all obstetric providers conducted as part of the delayed cord-clamping protocol project just before protocol roll out in May 2016, where 89.3% of respondents reported that they never or rarely performed delayed cord clamping in term neonates. In the postprotocol group, timing of cord clamping was determined based on the timing documented by the patient's primary nurse in their delivery summary in the electronic medical record, according to their specified role in the protocol.

The primary outcome was the difference in peak mean neonatal transcutaneous bilirubin levels between groups. This was selected as the primary outcome because a minimum of one transcutaneous bilirubin level is obtained routinely on every neonate, with the peak level obtained best correlating with the need for further evaluation and treatment of hyperbilirubinemia, and the ability to detect a clinically significant difference with a feasible sample size. Secondary outcome variables included initial mean neonatal transcutaneous bilirubin levels, neonatal serum bilirubin levels, number of serum bilirubin lab draws, incidence of clinical jaundice (yellow discoloration of the newborn's skin or sclera detected on physical examination) and phototherapy, total costs of maternal and neonatal hospitalizations, maternal and neonatal lengths of stay, rate of discordance in discharge date between mother and neonate, postpartum maternal hemorrhage, and postpartum mean maternal hemoglobin levels.

Neonatal screening practices for hyperbilirubinemia did not vary between the groups. All neonates were screened with a transcutaneous bilirubin measurement either on the day of planned discharge (typically postpartum day 2 for vaginal deliveries and postoperative day 3 for cesarean deliveries), or sooner at the discretion of either the nurse or pediatrician based on clinical jaundice, ABO blood-type incompatibility or history of a sibling requiring phototherapy. Total bilirubin levels in the term newborn normally increase significantly from the time of birth (upper limit of low risk range approximately 4 mg/dL) until a plateau at approximately 5 days of life (upper limit of low risk range approximately 13 mg/dL), so results must be interpreted in the context of an neonate's age in hours, as well as risk factors and physical exam findings. A nomogram based on hours of life and presence of risk factors was used to determine kernicterus risk level from the transcutaneous bilirubin reading, and any neonates in or above the high-intermediate risk range had a serum bilirubin drawn. Need for phototherapy was then determined according to the hour-specific nomogram and associated American Academy of Pediatrics guidelines.18

A priori power analysis revealed that to achieve 80% power to detect a 0.3 mg/dL difference in transcutaneous bilirubin levels between groups using a P-value of 0.05, 211 patients would be needed in each group. Given our institution's average volume of 200 deliveries per month, a 3-month period was estimated to be sufficient to provide the number of term deliveries to attain statistical power.

Maternal and fetal outcomes were compared in the preprotocol and postprotocol periods. Initial analyses were performed on all neonates, regardless of adherence to the delayed cord-clamping protocol. A separate subanalysis was then performed to compare neonates in the preprotocol period who would have been eligible for the delayed cord-clamping protocol (but did not receive delayed cord clamping because it was before protocol implementation), with those in the postprotocol period who actually received delayed cord clamping, thereby evaluating the actual association of the delayed cord clamping with these outcomes. In all comparisons, categorical variables were compared using Chi-squared tests, and continuous variables were compared using an independent sample student's t test and Wilcoxon-Mann-Whitney tests. Logistic and linear regression analyses were performed for confounders.

RESULTS

There were 395 preprotocol and 399 postprotocol patients who may have met inclusion criteria into the study. To obtain the prespecified sample size, 490 charts were reviewed (245 in each group). After exclusion for predefined indications, a total of 211 patients were included in the preprotocol group, and 213 in the postprotocol group (Fig. 1). Although the groups did not differ based on age, race, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), or gestational age, feeding method significantly differed between the two groups (Table 1). There was a significant difference in feeding method between the two groups (P=.015) with greater rates of combination breast and formula feeding in the preprotocol group (30.3% vs 18.4%) and more exclusive breastfeeding in the postprotocol group (71.2% vs 62.1%).

Fig. 1.
Fig. 1.:
Charts coded as term pregnancy delivering during preprotocol (October 2015–December 2015) and postprotocol (October 2016–December 2016) periods and reviewed for inclusion in the final study sample. UCI, University of California, Irvine Medical Center.Yang. Delayed Cord Clamping in Term Neonates. Obstet Gynecol 2019.
Table 1.
Table 1.:
Cohort Demographic and Clinical Characteristics Before and After Delayed Cord-Clamping Protocol Implementation

The initial comparison of neonatal outcomes included all individuals in the preprotocol and postprotocol groups, regardless of protocol adherence. In this comparison, the mean peak neonatal transcutaneous bilirubin levels were significantly higher among neonates in the postprotocol group (10.0±3.4 mg/dL vs 8.4±2.7 mg/dL, P<.01). Clinically, this translated into more neonates in the postprotocol group being diagnosed with jaundice on physical exam (27.2% vs 16.6%, P=.01 odds ratio [OR] 1.88; 95% CI 1.17–3.01), compared with those in the preprotocol group (Table 2). Individuals in the postprotocol group were also more likely to require a serum bilirubin measurement (43.7% vs 29.4%, P<.01; OR 1.86; 95% CI 1.25–2.78), and more likely to undergo multiple serum bilirubin measurements (Fig. 2). However, there was no difference in mean peak serum bilirubin levels between groups (9.7±3.0 mg/dL vs 9.1±3.1 mg/dL, P=.17). No significant differences existed between groups in terms of neonatal hemoglobin levels or percent of neonates requiring phototherapy (5.2% vs 6.6%, OR 1.28; 95% CI 0.57–2.89). Because exclusive breastfeeding is a potential confounder with neonatal bilirubin levels and differed between the study groups, regression analyses were performed on the clinical and laboratory neonatal outcomes. All statistically significant relationships remained significant when controlling for feeding method (Table 2).

Table 2.
Table 2.:
Neonatal and Maternal Outcomes Compared Before and After Protocol Implementation
Fig. 2.
Fig. 2.:
Number of serum bilirubin blood draws in the preprotocol compared with the postprotocol group. P<.001.Yang. Delayed Cord Clamping in Term Neonates. Obstet Gynecol 2019.

In terms of protocol adherence, all 211 individuals in the preprotocol group underwent immediate cord clamping. Of the 213 neonates in the postprotocol group, 184 (86.4%) underwent delayed cord clamping and the remaining 29 underwent immediate cord clamping, 21 for valid reasons outlined in the protocol and eight in violation of the protocol. In addition, 18 individuals in the postprotocol group inappropriately underwent delayed cord clamping despite the presence of maternal diabetes, which is a protocol exclusion (Fig. 3). Overall, adherence with the protocol, defined as appropriate timing of umbilical cord clamping as documented in the nursing delivery summary, was 87.8%.

Fig. 3.
Fig. 3.:
Subanalysis of patients.Yang. Delayed Cord Clamping in Term Neonates. Obstet Gynecol 2019.

A post hoc subanalysis was then completed to compare the outcomes associated with delayed cord clamping between the two groups. Because certain maternal and fetal conditions, particularly maternal diabetes, increases the risk of neonatal hyperbilirubinemia, individuals with these conditions were removed from both the preprotocol and postprotocol groups to isolate the association of the length of umbilical cord clamping with the outcome variables (Fig. 3). In this subanalysis, which directly compares immediate with delayed cord clamping, rather than preprotocol and postprotocol, clinical jaundice, number of serum bilirubin draws, initial transcutaneous bilirubin level, and peak transcutaneous bilirubin level were significantly higher in the delayed cord clamping group. These relationships remained significant when controlling for feeding method in regression analyses.

In terms of delivery and hospitalization demographics, there was no difference in cesarean or vacuum-assisted delivery rates between groups. Of those with a vaginal delivery, estimated median blood loss was higher in the preprotocol group (200 [interquartile range 200] vs 200 [interquartile range 100], P=.02), however there was no statistically significant difference in maternal postpartum hemoglobin levels (Table 2). A statistically significant increase of one half-day was noted in the maternal length of stay, regardless of route of delivery (2.89±0.56 days vs 2.38±0.70 days, P<.01 for vaginal deliveries, 4.10±0.58 days vs 3.63±0.77 days, P<.01 for cesarean deliveries) (Table 3). There was no significant difference in neonatal lengths of stay, hospital costs, or discharge discordance (mother and neonate pairs being discharged on different days) between groups (Table 3).

Table 3.
Table 3.:
Length of Stay and Hospitalization Costs for Study Sample*

DISCUSSION

Prior studies of delayed cord clamping in term neonates report mixed results. A trial of 73 term neonates demonstrated increased neonatal hemoglobin levels, but not transcutaneous bilirubin.16 Similarly, a trial of 720 term neonates reported increased neonatal hematocrit, but not jaundice or phototherapy.17 A 2014 Cochrane review, including data from 3,911 term neonates, demonstrated increased need for phototherapy, but no difference in rates of clinically-diagnosed jaundice.14 Conversely, we demonstrated increased positive screening for hyperbilirubinemia and jaundice, and more diagnostic testing in the form of serum bilirubin lab draws, but no increase in neonatal hemoglobin levels or need for phototherapy. As hemoglobin levels are not drawn routinely on all neonates and the rate of phototherapy is low, our study was underpowered to detect differences in either of these latter outcomes, and it should not be concluded from our data that no differences exist.

Protocol adherence in our study was 87.8%. Prior studies of delayed cord-clamping protocols have reported adherence rates from 40 to 80%.8,9,11 Our protocol includes all gestational ages and has few exclusions, making delayed cord clamping appropriate for most deliveries. This, and the consistent involvement of obstetrics hospitalist faculty, obstetrics resident physicians, and neonatologists likely contributed to our high adherence rate. Within private hospitals with greater heterogeneity among delivering providers, physician and nursing champions and individualized feedback on protocol adherence may be required to achieve similar results.

Our institution participated in the Baby-Friendly Hospital Initiative concurrently with the implementation of our delayed cord-clamping protocol, which likely increased exclusive breastfeeding in the postprotocol group. Because exclusive breastfeeding increases the risk of neonatal jaundice, this may have influenced our findings. However, our results remained significant after controlling for feeding method, suggesting an independent relationship between jaundice and delayed cord clamping. An early intervention considered in an exclusively breastfed neonate with jaundice is the introduction of formula, suggesting that a delayed cord-clamping protocol could negatively affect exclusive breastfeeding rates. Our data suggest that this concern may be mitigated successfully with aggressive support of breastfeeding best-practices, but further, prospective research is needed investigating the association of delayed cord clamping with hyperbilirubinemia in exclusively-breastfed neonates, specifically, and on the rates of exclusive breastfeeding continuation.

Previous recommendations for universal delayed cord clamping assume that hyperbilirubinemia, short of kernicterus, is of limited neonatal consequence. However, there may be costs associated with the implementation of delayed cord clamping in term neonates. Our study found no difference in neonatal length of stay or hospitalization costs between groups, likely due to the similar rates of phototherapy and NICU stay between groups. However, longer surveillance of jaundiced neonates may have contributed to the half-day increase in maternal length of stay after protocol implementation, which may have financial significance at institutions focused on discharge-by-noon initiatives. This study did not assess outpatient costs associated with evaluation of persistent jaundice, or the intangible costs a diagnosis of jaundice creates, such as parental anxiety or patient satisfaction.

Limitations of our study include limited generalizability having been performed at a single academic medical center. Additionally, the retrospective nature of the study makes it difficult to control for confounders. Although the two groups studied were similar in terms of age, race, BMI, and gestational age, there was more exclusive breastfeeding in the postprotocol group, which may have affected our results as described above. We also acknowledge only limited support for our assumption that delayed cord clamping was not performed in any of the preprotocol deliveries, and that undocumented early adoption of the practice by some physicians may have affected our results, most likely by underestimating the actual differences in outcomes between the two groups. Lastly, although our study evaluated cost outcomes, it was underpowered to detect subtle differences in cost. Strengths of the study include comprehensive evaluation of confounding conditions, and the fact that it was powered to detect the difference of a clinically meaningful outcome: peak transcutaneous bilirubin.

The data regarding the benefits of delayed cord clamping in term neonates, including improved hematologic status and neurocognitive benefit, remain ambiguous. Its routine practice has not been fully evaluated, neither in terms of health care costs nor psycho-emotional costs to patients. Our findings support the potential existence of significant costs. Further prospective, multi-center research, including evaluation of longer-term, outpatient costs and clinical outcomes, is needed to better evaluate the association of delayed cord clamping with these outcomes in term neonates, as well as families and health care systems, before any definitive recommendations of delayed cord clamping as a best-practice in this population.

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