N e u ro l o g i c an d M e t a b o l i c I s s u e s in Moderately Preterm, Late P re t e r m , a n d E a r l y Ter m I n f a n t s Abbot R. Laptook,


KEYWORDS  Neurologic morbidities  Intracranial hemorrhage  Periventricular leukomalacia  Apnea  Feeding ability  Suck-swallow-breathing coordination KEY POINTS  The frequency of germinal matrix hemorrhage–intraventricular hemorrhage and white matter injury are low in moderately preterm and late preterm infants.  Apnea of prematurity decreases in frequency as gestational age increases among moderately and late preterm infants.  Coordination of suck, swallow, and breathing is the major neurologic problem for moderately and late preterm infants.  Central nervous system integration is essential for coordination of breathing with sucking and swallowing to facilitate safe oral feeding.  Successful feeding is one of the most important determinants of the duration of hospitalization for moderately preterm and late preterm infants.

Moderately preterm and late preterm infants are generally considered to be low-risk groups of premature infants because they are compared with very preterm or extremely preterm infants. Major morbidities of prematurity reflect both organsystem immaturity and trigger events (infection, inflammation, nutritional state, and so forth), and are the basis of multiple medical problems that very preterm and extremely preterm infants encounter and need to navigate for survival. Fortunately there are prominent gradients in preterm births characterized by marked decreases in the number of infants as gestational age approaches viability. Similarly these same gradients of preterm births have an underappreciated impact on more mature gestational age strata, given the large number of moderately and late preterm births. Late preterm infants are notable for their lower rates of neonatal morbidities compared with more premature infants. However, late preterm infants cannot be considered

A.R. Laptook has nothing to disclose. Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA E-mail address: [email protected] Clin Perinatol 40 (2013) 723–738 http://dx.doi.org/10.1016/j.clp.2013.07.005 perinatology.theclinics.com 0095-5108/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.



equivalent to term infants because multiple morbidities of prematurity and neonatal mortality are more frequent than in term infants.1 Moderately preterm infants also have a distinction of low risk when compared with very preterm and extreme preterm infants; however, the morbidity and mortality of moderately preterm infants lies between those of late preterm and very preterm infants.2 The overall impact of moderately and late preterm infants is the potential for a large effect on public health problems, as noted in the emerging data on the long-term consequences of preterm birth.3 Specifically there was a stepwise increase in disability among young adults with increasing degrees of preterm birth; however, 74% of the total disability was accounted for by infants born between 33 and 38 weeks. This article focuses primarily on clinical neurologic problems of moderately and late preterm infants, and provides information on early term infants where available. The interface between central control of ventilation, metabolic rate, and temperature regulation is also discussed. This review seeks to identify knowledge gaps in our present state of understanding of moderately preterm and late preterm cohorts. INTRACRANIAL HEMORRHAGE

For very preterm and extremely preterm infants a common serious neurologic morbidity is intracranial hemorrhage; specifically, germinal matrix hemorrhage–intraventricular hemorrhage (GMH-IVH). Rates of IVH increase with decreasing gestational age4 and are of a frequency that merit performance of scheduled screening cranial ultrasonography for surveillance of this morbidity.5 For the late preterm infant, data on the occurrence of GMH-IVH are sparse. Meta-analysis indicates that the frequency of GMH-IVH is very low in late preterm infants.6 Multiple reports have documented the clinical morbidities manifested by late preterm infants in single centers,7,8 multicenter consortiums,9 and population-based cohorts,10 and do not list GMH-IVH as an assessed morbidity. McIntire and Leveno1 performed a retrospective cohort study of births at Parkland Hospital, the sole county hospital in Dallas, Texas, over an 18-year period from 1988 to 2005. The study included all live born singleton infants without anomalies born to mothers with prenatal care between 34 and 40 weeks (N 5 213,277) and used deliveries at 39 weeks as a reference point. There were 21,771 infants included between 340 and 366 weeks. Similar to other studies of late preterm infants, multiple morbidities (respiratory distress, transient tachypnea, culture proven sepsis) and mortality decreased progressively from 34 to 39 weeks. GMH-IVH grades 1 and 2 (Papile classification11) also decreased with advancing gestational age from 0.5% at 34 weeks to 0.2% at 35 weeks, 0.06% at 36 weeks, and 0.01% at 39 weeks. Severe GMH-IVH (grade 3 and 4) was documented in only 6 infants between 34 and 39 weeks. There were no differences in the frequency of GMH-IVH for early term infants (37 weeks) relative to 39 weeks. Because cranial ultrasonography is not routinely performed in late preterm and term infants, these estimates of GMH-IVH are subject to selection bias and may underestimate the true incidence of GMH-IVH in late preterm and early term infants. By contrast, the incidence of GMH-IVH has been examined in 2675 full-term newborns (gestational age 39.1  1.2 weeks) between 2003 and 2005 in Poland.12 Surprisingly, 14.6% of infants had GMH-IVH, and grades 1 and 2 represented 72% and 27%, respectively, of the infants with GMH-IVH. These observations are difficult to reconcile with the reduction in germinal matrix across the third trimester, which presumably is a critical variable in the low rates of GMH-IVH with advancing gestational age. For the moderately preterm infant there is less systematic assessment of clinical morbidities in comparison with the late preterm infant, which may reflect attention

Neurologic and Metabolic Issues

to late preterm infants following the 2005 National Institute of Child Health and Human Development (NICHD) workshop. The latter effort delineated consistent terminology and gestational age of late preterm infants (340–366 weeks)13 and identified knowledge gaps that have triggered multiple studies in this area. A similar effort for moderately preterm infants has not occurred. However, there is increasing literature on moderately preterm infants as recognition of the scope of this cohort is appreciated. The most comprehensive data are derived from a population-based analysis of neonatal morbidity in moderately preterm infants (30–34 weeks, N 5 6674 infants) using the Swedish Perinatal Quality Registrar for births between 2001 and 2008.14 Infants born at 30, 31, and 32 weeks were actively screened for GMH-IVH, but not at 33 or 34 weeks. The percentage of infants with any GMH-IVH was 8.3%, 6.2%, and 3.5% for 30, 31, and 32 weeks, respectively, and the rates at 30 and 31 weeks differed from those at 32 weeks. The percentage of infants with grade 3 or 4 IVH was 1.6%, 1.1%, and 1.1% for 30, 31, and 32 weeks, respectively, and the rates at 30 and 31 weeks did not differ from those at 32 weeks. Rates of any GMH-IVH at 33 and 34 weeks were 0.2% and less than 0.1%, and there was less than 0.1% of infants at 34 weeks with grades 3 or 4 IVH. Similar low rates of severe GMH-IVH have been reported in a prospective cohort study using 10 birth hospitals in California and Massachusetts, which examined morbidities among moderately preterm infants of 30 to 34 weeks’ gestation admitted to a Neonatal Intensive Care Unit (NICU) between 2001 and 2003.2 The sample size was 1250 infants and the percentage of infants with grade 3 or 4 GMH-IVH was 1.2% among infants at 30 to 326 weeks compared with no severe GMH-IVH among infants at 33 to 346 weeks. It is not clear whether routine surveillance using cranial ultrasonography was in place for GMH-IVH and whether there were site differences. Clinical outcomes of 4932 moderately preterm infants (between 32 and 34 weeks) born between 2001 and 2004 have been reported for infants cared for by Paradigm Health, a care management company (453 NICUs in the United States).15 Grades 3 and 4 GMH-IVH occurred in less than 0.5% of infants at 32 and 33 weeks, and did not occur at 34 weeks. No information was provided on cranial ultrasonography surveillance practices. Similar retrospective data have been reported for a single institution for infants born at 30 to 34 weeks’ gestation, but only 38% of infants in this gestational age window underwent cranial ultrasonographys.16 Analysis of neonatal morbidities of twin pregnancies delivered moderately and late preterm suggest similar low rates of cranial ultrasonographic abnormalities, although no information is provided on ultrasonography screening practices.17 Based on the available literature, any GMH-IVH or severe GMH-IVH occurs infrequently in moderately preterm and late preterm infants. Most published reports of the incidence of GMH-IVH in these gestational age strata are subject to selection bias because screening was typically not performed. Given the latter, it could be questioned whether screening should be done for this morbidity. In 2002, a report from the American Academy of Neurology and the Child Neurology Society issued a practice parameter on neuroimaging of the neonate.5 Routine screening cranial ultrasonography was recommended for all infants of less than 30 weeks’ gestation once between 7 and 14 days, optimally to be repeated between 36 and 40 weeks postmenstrual age. The target group for screening cranial ultrasonography is based on a higher incidence of severe GMH-IVH, which could affect clinical management (eg, post-hemorrhagic hydrocephalus). Studies that used gestational age as an inclusion criterion and contributed to this practice guideline reported that severe GMH-IVH (Papile grades 3 or 4) occurred in 1% to 2% of infants with a gestational age greater than 30 weeks.18,19 A more recent retrospective review of 486 infants with a gestational age of 30 to 33 weeks and born between 1999 and 2004




determined the number of infants with clinically important abnormal screening cranial ultrasonograms at 7 to 10 days.20 GMH-IVH occurred in 4.3% of infants, and grades 3 or 4 GMH-IVH occurred in 0.8% of infants (all 30–31 weeks). In addition to supporting the 2002 practice guideline, the investigators noted that infants with grades 3 or 4 GMH-IVH had symptoms or a clinical history that would have prompted neuroimaging. PERIVENTRICULAR LEUKOMALACIA

Relative to GMH-IVH there are even fewer data on periventricular leukomalacia (PVL) in late preterm infants from single-center reports,1,7,8 multicenter consortiums,9 or meta-analysis.6 There are limited data on moderately preterm infants. In the population-based Swedish study,14 cystic PVL occurred in 1.6%, 1.1%, and 1.0% of infants at 30, 31, and 32 weeks’ gestation, respectively. The incidence did not differ across these 3 weeks of gestation. At 33 weeks (n 5 1564) and 34 weeks (n 5 2620), cystic PVL was reported in 0.3% and 0.1% of infants, but systematic cranial ultrasonography screening was not used. The practice parameter on neuroimaging5 also noted that cystic PVL was detected in 5% to 26% of infants with a birth weight less than 1 kg, compared with 1% to 5% of infants with a birth weight greater than 1 kg. Screening guidelines for cystic PVL are similar to those for GMH-IVH.5 In view of the prognostic importance of white matter injury, clinicians need to maintain an index of suspicion to guide the use of neuroimaging for infants at or beyond 30 weeks’ gestation. In an analysis of 486 infants born between 30 and 33 weeks and undergoing cranial ultrasonography at 7 to 10 days and at 40 weeks postmenstrual age, abnormalities were found in 9%.20 The latter included GMH-IVH, cystic PVL, intraparenchymal hemorrhage, lissencephaly, agenesis of the corpus callosum, colpocephaly, and choroid plexus cyst. Of the 7 infants with cystic PVL, 5 had a birth weight greater than 1500 g. Townsend and colleagues21 also reported the occurrence of cystic PVL in infants between 30 and 32 weeks, and noted that clinical characteristics were not helpful in guiding who to image. The importance of the diagnosis of cystic PVL is based on analysis of neurodevelopmental outcomes of extremely low birth weight infants; the odds ratio for neurodevelopmental impairment (any one of Bayley Scales of Infant Development

Neurologic and metabolic issues in moderately preterm, late preterm, and early term infants.

Common neurologic morbidities encountered in very preterm and extremely preterm infants (intracranial hemorrhage, white matter injury and periventricu...
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