Late Preterm Infants: Severe Hyperbilirubinemia and Postnatal Glucose Homeostasis

Home , Bilirubin, Kernicterus

Journal of Perinatology (2009) 29, S12–S17 r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32 www.nature.com/jp REVIEW Late preterm infants: severe hyperbilirubinemia and postnatal glucose homeostasis

DH Adamkin Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA

definitions along a gestational time line from the first day of the The identification of late preterm infants as a high-risk group of infants has last menstrual period through 41 6/7 weeks gestation. been an important public health breakthrough. These infants have suffered The complications of prematurity and risks of these problems a relative ‘silent morbidity and mortality’ before the recognition that they for late preterm infants vs term infants are listed in Table 1. These have unique physiology and risks. These infants represent almost include temperature instability, feeding difficulties, the need for three-fourths of all premature births in the United States. Many of these mechanical ventilation and a number of problems related to infants, because of their birthweight and appearance, have been treated in metabolic immaturity.2–6 Late preterm infants are 3.5 times more Well Baby Nurseries and even discharged by 48 h of birth despite specific likely to suffer from two or more of these problems than are term unidentified or unappreciated risks that have led to their readmission and infants.6 It is not unusual for many of the late preterm infants possible severe morbidities or even death. Two common problems for these to have to spend more than five hospital days in neonatal infants include neonatal hypoglycemia and severe hyperbilirubinemia. The intensive care unit.5 In addition, those ‘larger’ late preterm infants definition of hypoglycemia remains controversial but is nonetheless a who are treated more like term infants and have a short stay after problem of increasing frequency in these infants. delivery are readmitted to the hospital at rates 1.5 to 3.0 times Journal of Perinatology (2009) 29, S12–S17; doi:10.1038/jp.2009.41 greater than term infants.2,7,8 This has led to the description of Keywords: late term; early term; hypoglycemia; hyperbilirubinemia these infants as the ‘great impostors’, as they look like and weigh similarly to term infants, but do not have the physiologic maturity of the term infant (personal communication, Lucky Jain). In 2002, the neonatal mortality rate (deaths among infants 0 to Introduction 27 days chronologic age) for late preterm infants was 4.6 times The recognition and description of late preterm infants as a higher than the rate for term infants (4.1 vs 0.9 per 1000 live high-risk group of patients has been an important public health births, respectively). This difference has actually widened when breakthrough to prevent morbidity and mortality and hopefully, compared to 1995 data where there was a fourfold difference even lead to a decrease in rates of prematurity in the United States. between late preterm and term infants (4.8 vs 1.2 per 1000 live There are approximately 500 000 infants born preterm in the births, respectively). This relationship also carries over into infant United States annually (births before 37 completed weeks of mortality. In 2002, the infant mortality rate for late preterm infants gestation) and these account for 12.5% of live births. Of these was also greater than the infant mortality rate for term infants preterm births, greater than 70% (approximately 350 000 live (7.7 vs 2.5 per l000 live births, respectively).6 births) are late preterm infants. That means they are between As more attention has been paid to these late preterm infants as a 34 0/7 and 36 6/7 weeks gestation. Most recently has come the group of preterm infants, we are learning more about their uniqueness. additional recognition of the early term infant (37 0/7 to Among the most recent developments come revelations about 38 6/7 weeks) as a unique group as well. These infants comprise developmental and the neurobiology of the growth and maturation of 17.5% of live births or 700 000 that have additional risks vs the brain during the final few weeks of gestation. Maturation of term babies beyond 38 weeks gestation.1 Therefore, both of these oligodendroglia, increasing neuronal arborization and connectivity, groups of infants have been identified as at risk for both short- and maturation of neurotransmitters and an increase in brain size of 30% long-term consequences associated with either preterm or early occur in these previously unappreciated last 3 weeks of gestation.9–11 term delivery. Figure 1 depicts these late preterm and early term In December 2007, the Committee on the Fetus and Newborn published a clinical report that defined late preterm and Correspondence: Dr DH Adamkin, Department of Pediatrics, University of Louisville School of Medicine, 571 South Floyd Street, Suite 342, Louisville, KY 40202, USA. recommended a change in terminology from ‘near-term’ to late E-mail: [email protected] preterm. They also proposed guidelines for evaluation and Late preterm infants DH Adamkin S13

“Late Preterm” Infants*

Late Preterm Early Term First day of LMP Day # 1 239 259 260 274 294

Week # 0/7 34 0/7 36 6/7 41 6/7

Preterm Term Post term

* Raju TNK. NIH Consensus Conference on “Optimizing Care and Outcome of the Near-Term Pregnancy and the Near-Term Newborn Infant”, 2005

Figure 1 ‘Late preterm’ and ‘early term’ deﬁnitions.

Table 1 Complications of prematurity in late preterm vs term infant with recommendations for the management of hyperbilirubinemia in infants at 35 weeks of gestation or greater.13 The approach is directed Complication Frequency at reducing the frequency of severe neonatal hyperbilirubinemia (levels Late preterm (%) Term (%) >17 mg per 100 ml) and bilirubin encephalopathy, whereas minimizing the risk of unintended harms such as increased parental Feeding 32 7 anxiety, decreasing breastfeeding and hoping to avoid excessive cost or Hypoglycemia 16 5 waste in our practices. Jaundice 54 38 Temperature instability 10 0 Hyperbilirubinemia is the most common clinical condition Apnea 6 <0.1 requiring evaluation and treatment in the newborn and the Receive intravenous fluids 27 5 most common cause for hospital readmission during the first 14–18 Evaluations for sepsis 37 13 week of postnatal life. Infants must be monitored for Mechanical ventilation 3.4 0.9 potential toxicity of bilirubin. We must have a plan in place to identify those who develop severe hyperbilirubinemia and the rare case that may proceed to acute bilirubin management of these infants.12 In Table 2, I have adapted and encephalopathy, evolving into kernicterus, a devastating, modified the committee document of the salient features of the chronic and disabling condition characterized by the clinical criteria for discharge of these infants. tetrad of: The conference Evidence vs Experience and the articles Choreoathetoid cerebral palsy included in this supplement review many of the cardiovascular High-frequency central neural hearing loss and respiratory issues that are associated with late prematurity. Palsy of vertical gaze The two unique problems of late preterms that I reviewed Dental enamel hypoplasia, the result of bilirubin induced cell included management of jaundice and prevention of severe toxicity19 hyperbilirubinemia and the topic of neonatal glucose homeostasis. There is an approximate eightfold increased risk of developing a total serum bilirubin greater than 20 mg per 100 ml in infants Management of jaundice and prevention of severe born at 36 weeks gestation (5.2%) vs those born at 41 or 42 weeks hyperbilirubinemia in late preterm infants gestation (0.7 and 0.6%, respectively).20 Approximately 1 in 650 to In July 2004, the Subcommittee on Hyperbilirubinemia of the 1000 infants >35 weeks gestation develop total serum bilirubin American Academy of Pediatrics published a clinical practice guideline values greater than or equal to 25 mg per 100 ml and 1 in 10 000

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Table 2 Criteria for discharge: late preterm infants Table 3 Key elements to prevent severe hyperbilirubinemia

Physical exam on admission and discharge (1) Promote and support successful breastfeeding Accurate gestational age determination (2) Establish nursing protocols for identification and evaluation of No discharge before 48 h of age hyperbilirubinemia Normal vital signs for 12 h preceding discharge (3) Measure total serum bilirubin or transcutaneous bilirubin level of infants Respiratory rate p60 breaths per minute jaundiced in the first 24 h Heart rate 100–160 beats per minute (4) Recognize that visual estimation of the degree of jaundice can lend to errors, Axillary temperature 36.5–37.4 1C (97.7–99.31F) in open crib with appropriate particularly in darkly pigmented infants clothing (5) Interpret all bilirubin levels according to infant’s age in hours At least 1 stool passed spontaneously (6) Perform a systematic assessment on all infants before hospital discharge Twenty-four hours of successful feeding (breast or bottle) (7) Provide parents with written and oral information about newborn jaundice Weight loss >7% during birth hospitalization should be assessed for evidence of (8) Provide appropriate follow-up based on postnatal age at discharge and the dehydration and not discharged predischarge risk assessment. Clinical judgment should be used in determining the Formal evaluation of breastfeeding has been undertaken and documented in chart timing of follow-up. Earlier or more frequent follow-up should be provided for those by trained caregivers at least twice daily after birth who have risk factors for subsequent severe hyperbilirubinemia, whereas those Serum glucose screening before discharge discharged with few or no risk factors can be seen after longer intervals Risk assessment for development of severe hyperbilirubinemia and appropriate (9) When indicated, treat newborns with intensive phototherapy or other recognized follow-up arranged therapeutic interventions, including exchange transfusion. Measurement of albumin No evidence of active bleeding at circumcision site for at least 2 h and calculation of the bilirubin/albumin ratio is recommended in addition to Maternal and infant test results available and have been reviewed but not in lieu of total bilirubin level as an additional factor in determining the Initial hepatitis B vaccine has been administered or an appointment scheduled for need for an exchange transfusion administration Metabolic and genetic screenings have been performed in accordance with state requirements Car seat safety test passed Postnatal glucose homeostasis in late preterm infants Hearing assessment performed and results documented Family, environmental and social risk factors have been assessed. If risk factors There is limited evidence and no consensus regarding the identified, discharge should be delayed until they are resolved definition of neonatal hypoglycemia (NH), who is at risk, when screening should be performed, the level and duration of NH that may cause neurologic sequelae and the interaction with other 17,21 have levels greater than 30 mg per 100 ml. Although there are conditions, such as HIE, that frequently occur simultaneously.23 It few population-based studies that provide data on the incidence is clear that no single concentration of plasma glucose is always of acute bilirubin encephalopathy or kernicterus, there is an associated with the appearance of clinical signs that might be overrepresentation of late preterm infants in the US Pilot attributed to NH or the direct causation of cerebral injury.24 Kernicterus Registry, a database of voluntarily reported cases of Treatment should be based, therefore, on a more flexible approach 22 kernicterus. An analysis of the 125 reported cases in the registry guided by clinical assessment and not solely on plasma glucose suggests that this condition should be largely preventable if concentration.25,26 health-care personnel follow the recommendations provided Despite many studies that indicate NH might be a significant 13 by the subcommittee guideline. The key elements of these problem, we are still left without certainty and/or consistency recommendations are listed in Table 3. when analyzing the data in light of the methodologic limitations These guidelines are based on hour-specific phototherapy of the studies themselves.24 To help resolve the clinical (Figure 2) and exchange transfusion (Figure 3) treatment dilemmas that result, Cornblath et al.27 suggested that clinical 13 thresholds for three separate groups of neonates and these are management of NH be based on four basic principles: as follows: Monitoring infants at high risk Infants at lower risk (at least 38 weeks gestation and well) Confirming that the plasma glucose concentration is low Infants at medium risk (at least 38 weeks gestation with risk Demonstrating that the clinical manifestations were because factors, defined as isoimmune hemolytic disease, G6PD of the low plasma glucose by showing that they resolve after deficiency, asphyxia, significant lethargy, temperature restoring plasma glucose to normoglycemic levels instability, acidosis or albumin less than 3.0 g per 100 ml or Observing and carefully documenting all of these events 35 0/7 to 37 6/7 weeks gestation and well) Infants at higher risk (35 0/7 to 37 6/7 weeks gestation with risk The algorithm in Figure 4 attempts to use these Cornblath factors) principles to provide a more consistent approach to diagnosis and

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10 (mg/dL)

5 Total Serum Bilirubin 0 Birth 24h 48h 72h 96h 5 Days 6 Days 7 Days Age

Infants at higher risk (35-37 6/7 wk.+risk factors) Infants at medium risk (≥38 wk+risk factors or 35-37 6/7 wk and well) Infants at lower risk (≥38 wk and well)

Figure 2 Phototherapy guideline from the 2004 practice parameter of the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Use total bilirubin. Do not subtract direct-reacting or conjugated bilirubin. Risk factors include isoimmune hemolytic disease, G6PD deﬁciency, asphyxia, signiﬁcant lethargy, temperature instability, sepsis, acidosis or albumin less than 3/0 g per 100 ml (if measured). For well infants (35 0/7 to 37 6/7 weeks), we can adjust total serum bilirubin (TSB) levels for intervention around the medium risk line. It is an option to intervene at lower TSB levels for infants closer to 35 weeks and at higher TSB levels for those closer to 37 6/7 weeks. (Adapted from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: 304; with permission. Copyright 2004 by the American Academy of Pediatrics.)

Infants at higher risk (35-37 6/7 wk.+risk factors) Infants at medium risk (≥38 wk+risk factors or 35-37 6/7 wk and well) infants at lower risk (≥38 wk and well)

25 20

(mg/dL) 10

5 Total Serum bilirubin bilirubin Serum Total 0 Birth 24h 48h 72h 96h 5 Days 6 Days 7 Days Age Figure 3 Exchange transfusion guideline from the 2004 practice parameter of the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. The first 24 h indicate uncertainty caused by a range of clinical circumstances and a range of responses to phototherapy. Immediate exchange transfusion is recommended if infant shows signs of acute bilirubin encephalopathy (hypertonia, arching, retrocollis, opisthotones, fever, high-pitched cry (functional immaturity of the late preterm neonate may mask these signs of acute bilirubin encephalopathy12) or if total serum bilirubin (TSB) is X5 mg per 100 ml (85 mmol lÀ1 above these lines). Risk factors include isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis and acidosis. Measure serum albumin and calculate B/A ratio (see Table 2). Use total bilirubin. Do not subtract direct-reacting or conjugated bilirubin. If infant is well and 35 0/7 to 37 6/7 weeks (medium risk), we can individualize TSB levels for exchange based on actual gestational age. (Adapted from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of huperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: 305; with permission Copyright 2004 by the American Academy of Pediatrics.)

treatment. Its aims are to alleviate acute symptoms and any It is beyond the scope of this article to go into the justiﬁcation physiologic or neurologic abnormalities related to signiﬁcantly for each of the decisions in the algorithm and it is presented low plasma glucose concentrations while preventing permanent only to stimulate thought and provide a template for practices sequelae. or institutions to frame their own clinical guides.

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ASYMPTOMATIC At Risk SYMPTOMATIC IDM, PT, LGA, SGA Glucose Level <45mg/dl Screen IDM on Admission Minibolus*** Any Screen before<30 Minibolus subsequent feed*<40 IV infusion IV infusion Goal >55mg/dl

Screen after first feed or before any <35 IV infusion**** subsequent feed** >45mg/dlGoal >55mg/dl

rescreen q3 for 12 hours IDM/LGA >35 rescreen q3 for 36 hours PT/SGA

Screen after 24 hours PT/SGA with suspected<40 Minibolus Illness *Subsequent feeds q3 screen before feeds IV infusion **1st feed by 2 hrs/1st screen

Goal >55mg/dl ***Minibolus – D10W (200mg/kg) 2ml/kg ****IV infusion – D10W at 6 – 8mg/kg/min

Figure 4 Screening and management of neonatal hypoglycemia.

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