Umbilical Cord Clamping Among Infants with a Prenatal Diagnosis of Congenital Heart Disease

Clamping and cutting the umbilical cord at birth occurs for each of the 140 million neonates born annually.1 The benefits of delayed cord clamping (DCC; waiting ∼1-2 minutes before clamping and cutting) vs early cord clamping (ECC; clamping and cutting the umbilical cord early, ∼30 seconds following delivery) in healthy, term pregnancies have been well-characterized across multiple randomized clinical trials (RCTs).2

In light of the increasing body of evidence in favor of DCC practices, the American College of Obstetricians and Gynecologists (ACOG), American Academy of Pediatrics (AAP), and American Heart Association (AHA) endorse DCC, as opposed to ECC, in uncomplicated, term (>37 weeks gestation) pregnancies.3,4 However, high risk neonates, specifically those with a prenatal diagnosis of congenital heart disease (CHD), have largely been excluded from RCTs, wherein the best approaches to the timing of umbilical cord clamping and cutting are not well understood.5 In fact, only one small, pilot RCT of cord clamping practices among CHD neonates has been conducted to date, and this study lacked longer-term markers of safety or efficacy.6 Although one might assume the benefits of DCC in low-risk newborn populations would translate simply to CHD neonates, concerns regarding additional blood volumes and viscosities suggest this may not be the case.

Among CHD neonates, a subgroup has critical congenital heart disease (CCHD), defined as the need for cardiac surgery or catheterization in the first 30 postnatal days. CCHD neonates represent a high-risk cohort,7,8 wherein 5-10% do not survive to hospital discharge,9 ∼30% suffer major neonatal morbidities, and >90% receive RBC transfusions that are associated with myocardial injury and multisystem organ dysfunction.6, 10, 11, 12 CCHD survivors have 11-fold higher risks of adverse neuromotor outcomes than do age-matched neonates without heart defects.13 CCHD occurs in 2-3 per 1000 live births and is the second leading cause of neonatal mortality.14,15 Thus, these neonates comprise a vital cohort to determine best umbilical cord clamping practices to optimize outcomes.

Based on the lack of available data to guide evidence-based practice, the ACOG, AAP, and AHA have identified the critical need for data to guide evidence-based umbilical cord clamping practices in high-risk pregnancies with prenatal diagnoses of CCHD.3,16 While DCC may represent a simple, no-cost intervention with the potential to reduce the burden of morbidity in term CCHD neonates, evidence-based medicine, rather than supposition, should guide clinical care. In this review, we will: 1) outline the supporting evidence on potential benefits of DCC in term infants without CCHD; 2) identify the need to study DCC in CCHD neonates, including specific risk/benefit profiles in this subgroup 3) characterize contemporary cord clamping practices among mother-infant dyads following diagnosis of CCHD; and 4) review considerations in the design and execution of a RCT on optimal cord clamping practices among CCHD neonates.

Hematological: When compared to ECC, DCC results in an additional 20-40ml/kg (body weight) of blood for term neonates, representing 30% of the fetal-placental blood volume.17,18 Increased blood volume following DCC increases iron-rich red blood cells and subsequently reduces iron-deficiency anemia.17,18 Andersson et al. found that among 400 term infants enrolled in a randomized controlled trial, infants who received DCC (cord cutting >180 seconds after delivery) as opposed to ECC (cord cutting <10 seconds after delivery) had 45% higher (95% CI, 23%-71%) mean ferritin levels and a lower prevalence of iron deficiency at 4 months of age.19 Furthermore, no significant differences were observed in the rates of adverse events such as polycythemia, postnatal respiratory symptoms, or hyperbilirubinemia following DCC compared to ECC.19 Thus, DCC represents a safe and effective means of reducing iron-deficiency anemia in uncomplicated term neonates.

Neurodevelopmental: Iron deficiency in neonates has previously been associated with poor neurodevelopmental outcomes.20 DCC reduces iron deficiency anemia by providing a source of iron-rich red blood cells, which may subsequently improve neurodevelopmental outcomes among term neonates. To investigate the potential neurodevelopmental benefits of DCC among term neonates, Andersson and colleagues conducted a follow-up of their previous RCT and compared effects of DCC vs ECC on neurodevelopment at 4 years of age.21 The primary outcome of full-scale IQ was measured by masked examiners using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III).21 Secondary outcomes were; 1) development, assessed using the WPPSI-III, Movement Assessment Battery for Children (Movement ABC), and the parental-reported Ages and Stages Questionnaire (ASQ), and 2) behavior, assessed using the strengths and Difficulties Questionnaire.21 For the 263 children followed, full scale IQ did not differ between DCC and ECC randomization groups.21 DCC improved adjusted mean difference (AMD) ASQ scores in personal-social (AMD, 2.8; 95% CI, 0.8-4.7) and fine-motor (AMD, 2.1: 95% CI, 0.2-4.0) domains, as well as Strength and Difficulties Questionnaire prosocial subscale scores (AMD, 0.5; 95% CI>0.0-0.9).21 Data from this follow-up study suggest DCC improves social and fine-motor domains among term neonates at 4 years of age. Similarly, Rana et al. observed that at 12 months of age, children in the DCC group had improved overall neurodevelopment, measured by ASQ scores, compared to children in the ECC group.22 Taken together, the results of these two studies indicate DCC may improve social and fine motor domains and may represent an effective means to improve neurodevelopment among term neonates.

Mercer et al. studied mechanisms by which DCC could improve neurodevelopmental outcomes by quantifying effects on brain myelination.23 Their hypothesis was that adequacy of iron stores supports myelinating oligodendrocytes, essential to white matter genesis and maturation.24,25 In healthy, term pregnancies randomized to either DCC or ECC,23 blood ferritin levels were measured and Mullen Scales of Early Learning was administered at 4 months of age.23 Myelination was measured on MRI using water volume fraction.23 No significant differences in neurodevelopmental testing in the Mullen verbal and nonverbal quotient scores or in overall cognitive ability were observed between DCC and ECC groups.23 Increased iron stores following DCC promoted increased brain myelination.26, 27, 28, 29 DCC increases myelination in the posterior arms of the internal capsule,23 where neural pathways critical to motor function occurs.30 Observed differences in myelin contents on brain MRI among term neonates without CCHD following DCC versus ECC may therefore underlie neuromotor advantages in later childhood.22,23

While DCC represents an appealing approach to reducing morbidity in CCHD neonates, unique anatomic and physiologic differences in CCHD neonates suggest that risks of DCC in this subgroup may differ from risks in neonates without CCHD. DCC increases hematocrit2,31 and blood viscosity.32, 33, 34 Whether these differences are beneficial or detrimental to CCHD neonates is unknown, due to their historic exclusion from RCTs. In terms of potential harms, CCHD infants are prone to complications related to polycythemia31,35 and hyperviscosity,31 including pulmonary hypertension, venous thromboembolism, embolic stroke, and post-operative thrombosis.36,37

The additional blood volumes following DCC may contribute to fluid overload,38,39 which might impair cardiopulmonary adaptation at birth.40 However, in CCHD neonates, postnatal RBC transfusion is often used to increase oxygen delivery, and DCC is arguably more physiologic than a postnatal transfusion.41, 42, 43 Data from neonates without CCHD demonstrate that those receiving DCC have greater cardiac output (increased preload), higher oxygen saturation, and require less oxygen at delivery than do those receiving ECC.44,45 These potential benefits indicate that DCC should be studied in CCHD neonates.

In view of their exclusion from previous RCTs,46, 47, 48 we conducted a survey of health care providers, to examine contemporary umbilical cord clamping practices among infants following prenatal diagnoses of CCHD. Healthcare providers [neonatologists (n=63), cardiologists (n=47), nurses (n=30), midwives (n=21), and surgeons (n=8) were provided a survey to assess their umbilical cord management practices among term infants with and without CCHD, as well as maternal and fetal exclusions for performing DCC.49 A five-point Likert Scale (strongly disagree to strongly agree with a neutral option) was used.49

While DCC was practiced by the vast majority of respondents (86.2%) in term infants without CHD, the reported practice of DCC among infants with CHD was markedly lower (36.0%; p<0.05) (Figure 1A). The primary reason for performing ECC in infants with CCHD was the perceived need for immediate resuscitation/cardiac intervention (39.7%) or concerns that the additional blood volumes would worsen cardiac performance (39.1%). While only 36.0% of respondents indicated they practice DCC in infants with CHD, 38.1% of respondents indicated they were unsure or did not know the optimal time to clamp the umbilical cord among infants with CHD (Figure 1A), highlighting a gap in current knowledge among providers caring for infants with prenatal diagnoses of CHD. When asked about cord clamping guidelines in their divisions, 15.8% indicated their division did not follow specific cord clamping guidelines and another 14.9% were unsure or did not know (Figure 1B). Similarly, 9.9% of respondents indicated their teams did not discuss the timing of cord clamping following prenatal diagnosis of CHD, and 18.3% did not know or were unsure (Figure 1C). Consistent with the observed variation in cord clamping practices among respondents and the absence of evidence on which to base practice decisions, most respondents (80.2%) agreed that a clinical trial of umbilical cord clamping practices among term infants with a fetal diagnosis of CHD was needed (Figure 1D).

Utilize novel and innovative outcome measures: CCHD is a rare, heterogeneous disease; thus, a number of challenges emerge in the design and conduct of RCTs in this subgroup of at-risk pediatric patients.50 Recently, pioneering investigators have used novel study designs and analytic methods to overcome barriers of relatively small patient numbers. For example, in the design of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial, Hill and colleagues described use of the global rank score (GRS) as the primary outcome.51 GRS is composite score composed of specific outcomes ranked from worst to best; a participant's outcome ranking is then determined based on the most severe outcome experienced.52 In contrast to traditional outcomes (mortality, morbidity), GRS includes a broad subset of relevant outcomes by combining binary (mortality, major complications) and continuous (length of stay) outcomes. To that end, GRS improves study power by ensuring that every neonate receives an outcomes rank; thus improving discriminatory potential by allowing neonates to be compared based on the worst outcome measure experienced.

Characterizing caregiver/parental willingness to participate in a RCT among CCHD neonates: Many RCTs among maternal-infant dyads have consent rates less than 50%.53 In view of poor consent rates, many investigators have begun to engage caregivers in the design and conduct of RCTs, to ensure that findings are meaningful and relevant to families. While most providers agree that RCTs of DCC in CCHD term neonates are needed, caregiver perspectives of RCTs in this group have not been characterized and may represent a significant barrier to the conduct and execution of these essential RCTs.54

We sought to engage caregivers of infants/children with CCHD to gain a better understanding of potential barriers and enablers to a RCT of cord clamping practices. Thus, we conducted a survey of caregivers (n=111) of CCHD neonates using semi-structured interviews to explore their attitudes towards theoretical participation in a RCT of cord clamping practices. Caregivers were asked a series of questions regarding the following: delivery treatment preference (ECC vs DCC), feelings towards randomization, willingness to participate in a hypothetical clinical trial, and reasons for their selections.

Most (58%; 95% Confidence Interval: 43-73%) caregivers agreed they would have allowed their neonates to participate and be randomized, if the option had been available.55 Of note, 43.2% of respondents indicated they would prefer DCC (>1 min), and 55.0% had no preference in cord clamping practice. While willingness to participate in a RCT of cord clamping practices was high, caregivers did express concerns that represent potential barriers to participation, most notably that the concept of randomization was unfavorable or neutral (not sure) in most respondents (60%), with 64.9% of caregivers indicating they would not be willing to permit randomization to either ECC or DCC. A qualitative analysis of free-text comments showed over half of caregivers surveyed questioned the reason for random allocation. Among caregivers unwilling to permit randomization, 42% cited a lack of control in decision-making as the primary reason. However, the majority (65%) of caregivers noted that they would be willing to permit randomization if their physician approved study participation. In addition, 67.6% of caregivers responded that the severity of heart disease would influence their decision to participate in a RCT.

The results from our survey study suggest that caregivers have a high willingness to participate in RCT of cord clamping practices. However, concerns among caregivers over the randomization process represent a significant potential barrier to recruitment and participation in RCT for cord clamping. To increase recruitment and improve informed consent for RCTs of cord clamping practices among CHD neonates, strategies to train healthcare providers to improve information delivery to caregivers, specifically including clearer descriptions of the rationale for randomization, are needed. 56, 57, 58

Preliminary evidence supporting DCC among CCHD neonates: We conducted a retrospective, multicenter chart review (IRB # to characterize outcomes (both maternal and infant) following DCC vs ECC in term pregnancies with fetal diagnoses of CCHD from 2015-2019. A fetal diagnosis of CHD was based on a Fetal Cardiovascular Disease Severity Score (FCDSS) (Table 1). The FCDSS is a standardized method to categorize prenatal CCHD severity, with previous studies showing the scores have excellent reliability (Interclass correlation=0.93; 95% CI: 0.88-0.95.65).59 Maternal outcomes included adverse safety events (e.g., severe post-partum hemorrhage and maternal blood loss) and maternal blood loss (change in maternal hemoglobin levels on postpartum day 1 compared with pre-delivery hemoglobin levels). GRS was determined a priori to be the primary outcome. The nonparametric win ratio statistic (number of wins [lower GRS] divided by number of losses in pairs) was used to compare GRS between DCC and ECC recipients

Of the 160 infants in the study with fetal diagnoses of CCHD (FCDSS:4-7), 79 received DCC (clamping >60 seconds) and 81 received ECC (clamping <60 seconds). The median time to cord clamping was 84 seconds (IQR 63-105) in the DCC group and 19 seconds (IQR 5-34) in the ECC group. No differences were observed between DCC and ECC groups in pre-delivery to post-delivery hemoglobin levels (-1.84 versus -1.65, p=0.72) or in risk of maternal adverse events, including no evidence of severe post-partum hemorrhage. Overall, among CCHD neonates (FCDS 3-7), GRS trends appears lower (better health outcomes) following DCC (n=79; 42.5 [IQR:23-97]) than ECC (N=81; 65.2 [IQR:31.8-97]; P=0.09; Figure 2). Consistent with evidence of better neurodevelopmental profiles following DCC,21, 22, 23 we observed neonates receiving DCC had trends towards higher neuromotor scores (Bayley-III) through two years than those receiving ECC (94.0 vs 87.4, p=0.10). However, the small sample size of this initial RCT limits broad generalizability of the data, reinforcing the clear need for large RCTs on cord clamping practices in this population.

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