Hyperbilirubinemia screening and treatment in neonates born prior to 35 weeks of gestation

Abstract

BACKGROUND:

Guidelines on when to screen for neonatal hyperbilirubinemia apply to infants born at 35 weeks or later of gestation. It is unknown whether infants born earlier would benefit from similar guidelines. Our objective was to examine hyperbilirubinemia screening and phototherapy prescription among early preterm infants during the first 6 days of life.

METHODS:

We reviewed the charts of 193 infants born prior to 35 weeks of gestation who were admitted to a tertiary care NICU in Southeastern Ontario in 2018–2019. Information on total serum bilirubin (TSB) measurements over each 12-hour interval during the first six days of life and the treatment decision (no treatment, initiate, continue, or stop phototherapy) was extracted. We also examined what proportion of infants were prescribed phototherapy during each 12-hour interval.

RESULTS:

Of 1006 TSB measurements performed over the first 6 days of life, 605 were done to determine whether phototherapy should be initiated. Treatment was prescribed in 275 instances (45%). A higher proportion of infants born prior to 28 weeks of gestation required phototherapy in the first 12 hours of life (37%) compared to those born at 28–32 weeks (20%) and 33–34 weeks (5.7%).

CONCLUSIONS:

Our results suggest that TSB measurements are often poorly timed to detect treatment need in infants born prior to 35 weeks of gestation. This unnecessarily increases the risk of complications from phlebotomy and is an ineffective use of health care resources. There is a need to develop guidelines to optimize hyperbilirubinemia screening among early preterm infants.

Keywords

Hyperbilirubinemia neonate phototherapy preterm quality improvement screening

List of abbreviations

IVH:

Intraventricular hemorrhage

NICU:

Neonatal intensive care unit

TSB:

Total serum bilirubin

1 Introduction

Preterm infants are more likely than term infants to experience elevated levels of total serum bilirubin (TSB), also known as hyperbilirubinemia. This is due to an immature hepatic binding and clearing mechanism in premature neonates, along with a short half-life of red blood cells [1]. Those born at earlier gestational ages are particularly vulnerable: increased prematurity is associated with decreased maturation of the liver and gastrointestinal tract, which in turn increases the risk of hyperbilirubinemia due to decreased bilirubin metabolism and excretion [2].

If left untreated, hyperbilirubinemia can cause kernicterus, a form of permanent neurological damage in neonates [2]. Acute bilirubin-induced neurological dysfunction, caused by elevated levels of serum bilirubin and kernicterus, is associated with seizures, intellectual disability, cerebral palsy, sensorineural hearing loss, and death [3]. Thus, it is critical to minimize delays in detecting and treating neonatal hyperbilirubinemia.

Notwithstanding the seriousness of untreated hyperbilirubinemia, overly frequent screening may be problematic. (The focus of this paper is on screening using TSB rather than non-invasive transcutaneous bilirubin measurements. The latter method has not been routinely implemented in Canadian neonatal intensive care units (NICUs) and there are cautions regarding its use in infants born prior to 33 weeks of gestation [4].) Preterm infants are at increased risk of phlebotomy-associated complications, including pain, infection, and blood loss resulting in anemia [5–8]. Screening may also lead to overtreatment: in one study, phototherapy was initiated in 61% of very low birth weight newborns at TSB levels below the recommended threshold [9].

Phototherapy itself has potential side effects. In the short term, it may lead to dehydration, electrolyte imbalance, cardiac arrythmias — seen with conventional phototherapy devices [10–12] — and Bronze Baby Syndrome, a rare complication involving the buildup of bilirubin metabolic by-products [13]. The long-term consequences may include an increased risk of allergies, autoimmune disorders, asthma, cancer, and retinal damage [10, 14–16]. There is a need, therefore, to balance the benefits of serum-based screening with the risks of unnecessary procedures and potential overtreatment of hyperbilirubinemia in the preterm population.

The Canadian Pediatric Society and the American Academy of Pediatrics have published hyperbilirubinemia management guidelines for infants born at 35 weeks or later [17, 18]. There are no recommendations on screening for hyperbilirubinemia in early preterm infants. We reviewed current practices in hyperbilirubinemia management among infants born prior to 35 weeks of gestation who were admitted to a tertiary care NICU in Kingston, Ontario (Canada). Our objectives were to examine a) the proportion of TSB measurements performed in the first six days of life that led to a phototherapy prescription, and b) the proportion of infants born at <28, 28–32 and 33–34 weeks of gestation who were prescribed phototherapy during each 12-hour interval over the first six days of life.

2 Methods

The study protocol was approved by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (# 6028724).

2.1 Setting, sample and data collection

The Kingston Health Sciences Centre is an acute care academic hospital in Southeastern Ontario. At the time this study was initiated, the same locally developed protocol for initiating phototherapy had been in use in the Kingston Health Sciences Centre’s NICU for 10 years. That protocol specified gestational age-based treatment thresholds; for example, the thresholds at 24 hours of life were 70, 90 and 120μmol/L for infants born at <28, 29 and 33 weeks of gestation, respectively. Hyperbilirubinemia risk factors were not considered in treatment decisions.

The timing of TSB measurements is at the discretion of the medical team. Decisions are generally based on visual assessment of the infant. Opportunistic screening (i.e., when other blood work is required) also plays a role in deciding when to measure TSB.

We retrospectively reviewed the charts of infants born at <35 weeks of gestation who were admitted to the Kingston Health Sciences Centre’s tertiary care NICU between February 1, 2018, and December 31, 2019, inclusive. Infants admitted after 24 hours of life, as well as those who died or were transferred out within the first six days of life, were excluded from the study. The following information was extracted: gestational age, sex, method of delivery, birth weight, 5-minute Apgar score, reason for prematurity, risk factors for hyperbilirubinemia or hyperbilirubinemia neurotoxicity (intraventricular hemorrhage (IVH), bruising, low pH (<7.15), positive direct Coombs test, hypoalbuminemia (<25 g/L), positive blood culture), the date and time TSB levels were sampled over the first 6 days of life, and the associated management decision (no treatment, initiate, continue, or stop phototherapy).

Table 1
Characteristics of infants born prior to 35 weeks of gestation who were admitted to neonatal intensive care at Kingston Health Sciences Centre in Ontario, Canada between February 2018 and December 2019 (n = 193)

Overall Gestational age (weeks)

<28 (n = 16) 28–32 (n = 71) 33–34 (n = 106)

Male 97 (50) 10 (62) 40 (56) 47 (44)

C-section 96 (50) 10 (62) 42 (59) 44 (42)

Birth weight in grams, mean (SD) 1897 (578) 931 (249) 1626 (452) 2224 (408)

5-minute Apgar score ≤7^a 60 (32) 13 (81) 27 (39) 20 (20)

Reason for prematurity

Threatened preterm labour 67 (35) 6 (37) 23 (32) 38 (36)

Premature rupture of membranes 69 (36) 5 (31) 22 (31) 42 (40)

Maternal/placental factors 23 (12) 2 (12) 11 (15) 10 (9.4)

Other 34 (18) 3 (19) 15 (21) 16 (15)

Risk factors for hyperbilirubinemia or hyperbilirubinemia neurotoxicity

Intraventricular hemorrhage 29 (15) 9 (56) 19 (27) 1 (0.94)

Bruising 22 (11) 3 (19) 10 (14) 9 (8.5)

Low pH (<7.15) 18 (9.3) 7 (44) 8 (11) 3 (2.8)

Positive direct Coombs test^b 8 (4.6) 0 2 (3.2) 6 (6.2)

Hypoalbuminemia (<25 g/L) 8 (4.1) 3 (19) 3 (4.2) 2 (1.9)

Positive blood culture 1 (0.52) 1 (6.2) 0 0

Number of times screened for hyperbilirubinemia during first 6 days of life, mean (SD) 4.9 (1.6) 5.2 (1.7) 5.2 (1.6) 4.6 (1.6)

Number of phototherapy sessions during first 6 days of life

0 8 (4.1) 1 (6.2) 0 7 (6.6)

1 102 (53) 7 (44) 34 (48) 61 (58)

2–3 83 (43) 8 (50) 37 (52) 38 (36)

Overall	Gestational age (weeks)
Male	97 (50)	10 (62)	40 (56)	47 (44)
C-section	96 (50)	10 (62)	42 (59)	44 (42)
Birth weight in grams, mean (SD)	1897 (578)	931 (249)	1626 (452)	2224 (408)
5-minute Apgar score ≤7^a	60 (32)	13 (81)	27 (39)	20 (20)
Reason for prematurity
Threatened preterm labour	67 (35)	6 (37)	23 (32)	38 (36)
Premature rupture of membranes	69 (36)	5 (31)	22 (31)	42 (40)
Maternal/placental factors	23 (12)	2 (12)	11 (15)	10 (9.4)
Other	34 (18)	3 (19)	15 (21)	16 (15)
Risk factors for hyperbilirubinemia or hyperbilirubinemia neurotoxicity
Intraventricular hemorrhage	29 (15)	9 (56)	19 (27)	1 (0.94)
Bruising	22 (11)	3 (19)	10 (14)	9 (8.5)
Low pH (<7.15)	18 (9.3)	7 (44)	8 (11)	3 (2.8)
Positive direct Coombs test^b	8 (4.6)	0	2 (3.2)	6 (6.2)
Hypoalbuminemia (<25 g/L)	8 (4.1)	3 (19)	3 (4.2)	2 (1.9)
Positive blood culture	1 (0.52)	1 (6.2)	0	0
Number of times screened for hyperbilirubinemia during first 6 days of life, mean (SD)	4.9 (1.6)	5.2 (1.7)	5.2 (1.6)	4.6 (1.6)
Number of phototherapy sessions during first 6 days of life
0	8 (4.1)	1 (6.2)	0	7 (6.6)
1	102 (53)	7 (44)	34 (48)	61 (58)
2–3	83 (43)	8 (50)	37 (52)	38 (36)

Values are n (%) unless otherwise indicated. SD: standard deviation. ^a7 missing values; percentages were calculated after excluding those records. ^b18 missing values; percentages were calculated after excluding those records.

2.2 Analysis

We performed all analyses using IBM SPSS Statistics, v.28 (IBM Corp., Armonk, NY). Eligible infants were grouped into three gestational age categories: <28, 28–32 and 33–34 weeks. Descriptive statistics (frequency distributions for categorical variables, means and standard deviations (SDs) for continuous variables) were run for the overall sample and the three gestational age groups.

We examined TSB measurements for each 12-hour interval during the first six days of life to determine whether those measurements resulted in no treatment or initiation of phototherapy, or, for those being treated, whether phototherapy was continued or stopped. We also calculated the proportion of infants within the gestational age groups who were prescribed phototherapy in each 12-hour interval. The figures were produced using Microsoft Office Excel V16.54 for macOS.

3 Results

A total of 235 infants were admitted to the NICU during the study period. One hundred and ninety-three infants met the eligibility criteria. Their characteristics are presented in Table 1. The primary reasons for prematurity were premature rupture of membranes (36%) and threatened preterm labor (35%). Several risk factors for hyperbilirubinemia or hyperbilirubinemia neurotoxicity (IVH [19], bruising [18], low pH [18], hypoalbuminemia [18]) occurred more frequently in infants born prior to 28 weeks of gestation (Table 1). Only one infant in the sample had a positive blood culture (that infant was born prior to 28 weeks of gestation).

Infants underwent an average of 4.9 TSB measurements (SD: 1.6) during the first 6 days of life (Table 1). Overall, 53% required a single session of phototherapy while 43% required two to three sessions (Table 1). Among the 185 patients who were prescribed phototherapy at least once, 32 (17%) were treated after their first TSB measurement. The majority (n = 127 [69%]) were initially prescribed phototherapy after their second screen, while the remaining 26 infants (14%) were initially prescribed phototherapy after their third (n = 21), fourth (n = 2), or fifth (n = 3) TSB measurement.

Figure 1 shows the number of TSB measurements performed within each 12-hour interval and the associated treatment decision. A total of 1006 TSB measurements were performed over the first 6 days of life, 605 of which were to determine whether phototherapy should be initiated. The decision was made to do so following 275 of these measurements (45%).

Fig. 1

Total serum bilirubin measurements and associated treatment decisions over the first 6 days of life among infants born prior to 35 weeks of gestation.

Overall, 59% of patients were prescribed phototherapy in the first 24 hours of life. A little over one-third of infants (37%) in the < 28 weeks’ gestational age group required phototherapy in the first 12 hours of life, compared to 20% and 5.7% of infants aged 28–32 and 33–34 weeks, respectively. Phototherapy need declined for all gestational age groups after 24 hours of life (Fig. 2).

Fig. 2

Phototherapy prescriptions during the first 6 days of life among infants born at <28, 28–32, and 33–34 weeks of gestation. Summed percentages within gestational age groups exceed 100% because infants may have received more than one phototherapy prescription.

4 Discussion

In our sample of infants born prior to 35 weeks of gestation, over half of the phlebotomies performed for the purpose of deciding whether to prescribe phototherapy resulted in no treatment. A similar imbalance in screening versus treatment was reported by Matsumoto & Kuo [20]: 96% of their sample were screened for hyperbilirubinemia but only 55% were subsequently treated. It is important to note, however, that 96% of the infants in our sample were prescribed phototherapy at least once during the first six days of life, suggesting that the imbalance we observed was due to suboptimal timing of TSB measurements.

While the need for phototherapy in our sample was much higher than that observed by Matsumoto and Kuo [20], it is challenging to directly compare rates among studies. Observed variations could be attributable to differences in recommended treatment levels in published guidelines or local protocols, or to differences in the gestational age range of the cohorts. For example, in a sampling of studies, phototherapy was prescribed for 67% of infants born prior to 33 weeks of gestation [19], 82% of those born prior to 35 weeks [21], and 88% of those born prior to 32 weeks [22].

Raba et al., who used transcutaneous bilirubin screening to determine phototherapy need, reported that 98% of infants born earlier than 32 weeks of gestation were prescribed phototherapy in the first 24 hours of life [23]. While this is a higher figure than the 59% of our sample, at least part of the discrepancy could be because we included infants born up to 34 weeks of gestation. We observed a peak in phototherapy prescriptions between 13 and 24 hours of life, although a substantial proportion (37%) of infants born prior to 28 weeks of gestation required treatment in the first 12 hours (Fig. 2).

Pillai et al. developed a standardized approach to hyperbilirubinemia management in the preterm population by adapting existing consensus-based guidelines [24]. They recommend that in preterm infants considered at low risk due to the absence of risk factors for neurotoxicity (e.g., low serum albumin, acidosis), gestational age or birthweight should be considered in determining when to conduct an initial TSB measurement. Low-risk infants born prior to 30 weeks of gestation or weighing less than 1500 grams should be screened at 12 to 18 hours after birth, while infants born at 33 to 35 weeks or with a birthweight greater than 1500 grams should be screened at 18 to 24 hours of age. Our findings regarding an earlier need for phototherapy in those born prior to 28 weeks are consistent with this approach. Support for basing the timing of the initial TSB measurement on gestational age is bolstered by the fact that as prematurity increases, the prevalence of several risk factors for hyperbilirubinemia or hyperbilirubinemia neurotoxicity, including IVH [25], low pH [26], bruising [27], and sepsis [28], also increases.

Our study was not designed to test hypotheses and the sample size was relatively small, particularly for the group born prior to 28 weeks of gestation. Despite these limitations, our NICU uses a locally developed protocol for initiating phototherapy. Accordingly, we do not expect that overtreatment, as defined by the prescription of phototherapy below the recommended threshold, was an issue in our sample. Our phototherapy data therefore reflect a true treatment need and our comparison of TSB measurements versus phototherapy prescription demonstrates the magnitude of poorly timed screening for hyperbilirubinemia in our NICU.

The current Canadian Pediatric Society [17] and American Academy of Pediatrics guidelines [18] recommend measuring TSB levels at 24 hours of life for infants born at 35 weeks or later of gestation. These guidelines do not contain recommendations for when to initially screen for hyperbilirubinemia in infants born prior to 35 weeks. Thus, while our study was limited by collecting data from a single site, it is unlikely that the poorly timed screenings we observed in our sample are confined to our centre.

The creation of hyperbilirubinemia screening guidelines for infants born prior to 35 weeks of gestation would improve quality of care in the NICU by reducing the number of unnecessary and potentially painful and risky phlebotomy procedures. Any such guidelines should provide gestational age– specific recommendations on when to conduct an initial screen, given that more than one-third of infants born prior to 28 weeks of gestation required phototherapy in the first 12 hours of life compared to only 6% of those born at 33 or 34 weeks of gestation.

Per Jegathesan et al., non-invasive transcutaneous bilirubin screening prior to the initiation of phototherapy may be considered for infants born at 33 to 35 weeks of gestation [4]. Thus, screening guidelines should also incorporate recommendations around the use of transcutaneous bilirubin measurements to eliminate the risks associated with phlebotomy.

Footnotes

Acknowledgments

We would like to thank Yang Ran Cheng for her assistance in preparing this manuscript.

This study was supported through the Queen’s University Summer Studentship Program (2020).

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Overall	Gestational age (weeks)
<28 (n = 16)	28–32 (n = 71)	33–34 (n = 106)
Male	97 (50)	10 (62)	40 (56)	47 (44)
C-section	96 (50)	10 (62)	42 (59)	44 (42)
Birth weight in grams, mean (SD)	1897 (578)	931 (249)	1626 (452)	2224 (408)
5-minute Apgar score ≤7^a	60 (32)	13 (81)	27 (39)	20 (20)
Reason for prematurity
Threatened preterm labour	67 (35)	6 (37)	23 (32)	38 (36)
Premature rupture of membranes	69 (36)	5 (31)	22 (31)	42 (40)
Maternal/placental factors	23 (12)	2 (12)	11 (15)	10 (9.4)
Other	34 (18)	3 (19)	15 (21)	16 (15)
Risk factors for hyperbilirubinemia or hyperbilirubinemia neurotoxicity
Intraventricular hemorrhage	29 (15)	9 (56)	19 (27)	1 (0.94)
Bruising	22 (11)	3 (19)	10 (14)	9 (8.5)
Low pH (<7.15)	18 (9.3)	7 (44)	8 (11)	3 (2.8)
Positive direct Coombs test^b	8 (4.6)	0	2 (3.2)	6 (6.2)
Hypoalbuminemia (<25 g/L)	8 (4.1)	3 (19)	3 (4.2)	2 (1.9)
Positive blood culture	1 (0.52)	1 (6.2)	0	0
Number of times screened for hyperbilirubinemia during first 6 days of life, mean (SD)	4.9 (1.6)	5.2 (1.7)	5.2 (1.6)	4.6 (1.6)
Number of phototherapy sessions during first 6 days of life
0	8 (4.1)	1 (6.2)	0	7 (6.6)
1	102 (53)	7 (44)	34 (48)	61 (58)
2–3	83 (43)	8 (50)	37 (52)	38 (36)