In obstetric and pediatric practice, late preterm infants (34 0/7 to 36 6/7 weeks of gestation1) are often considered functionally and developmentally mature and are often managed by protocols developed for full-term infants. Thus, limited efforts are usually taken to prolong pregnancy in cases of preterm labor beyond 34 weeks, and the threshold for labor induction becomes much lower in the late preterm period.2 These practices are based on previous studies reporting neonatal morbidity and mortality in the late preterm period to be only slightly higher in comparison with term infants.3,4
As the rate of late preterm deliveries has increased during the last two decades,5 attention has refocused on the outcome of late preterm infants.6–12 Several studies during the past decade have found that when compared with term infants, late prematurity is associated with increased neonatal mortality7 and morbidity, including respiratory morbidity,13–15 feeding problems,16,17 hypoglycemia,18 hypothermia,18 and hyperbilirubinemia.19–21 Nevertheless, some of these studies are limited by a relatively small sample size,6,10 lack of a control group,6,11 and the inclusion of pregnancies complicated by maternal or fetal complications, such as hypertensive disorders, diabetes, fetal growth restriction, oligohydramnios, chorioamnionitis, and placental abruption.6,10,12 Because these complications may adversely affect neonatal outcome independently of late prematurity, the inclusion of such pregnancies may result in overestimation of the mortality and morbidity associated with late prematurity. Indeed, it has been suggested that the excess neonatal morbidity in the late preterm period is mostly related to pregnancy complications leading to either spontaneous or indicated premature delivery.4
Thus, the aim of the current study was to estimate the independent contribution of gestational age to neonatal morbidity in cases of spontaneous, low-risk singleton late preterm deliveries as well as to identify predictors of adverse neonatal outcome in this group of late-preterm infants.
MATERIALS AND METHODS
A retrospective study of all late preterm deliveries (34 0/7 to 36 6/7 weeks of gestation) at a university-affiliated tertiary hospital between January 1997 and December 2006 was conducted. The study group was compared with a control group consisting of full-term deliveries (37 0/7 to 40 0/7 weeks of gestation) selected by the consecutive full-term deliveries after each of the index late-preterm deliveries in the delivery-room logbook, in a 3:1 ratio. The study protocol was approved by the Rabin Medical Center Institutional Review Board.
To isolate the effect of late prematurity on neonatal outcome, only low-risk singleton pregnancies resulting in spontaneous delivery were included in the study and control groups. Pregnancies complicated by any of the following conditions were excluded from both the study and control groups: chronic or gestational hypertension, preeclampsia, pregestational or gestational diabetes, major congenital anomalies, fetal growth restriction (defined as birth weight below 10th percentile according to local birth weight curves22), oligohydramnios (defined as amniotic fluid index less than 50 mm), umbilical artery pH less than 7.2, 5-minute Apgar score less than 7, operative vaginal delivery or cesarean delivery performed due to nonreassuring fetal heart rate, placental abruption, placenta previa, suspected chorioamnionitis or antepartum or intrapartum fever, preterm premature rupture of membranes (PROM), induced labors, and cesarean deliveries performed for indications other than dystocia, breech presentation, or one or more previous cesarean deliveries.
Cases were identified by searching our institutional computerized discharge-records database for all spontaneous low-risk singleton deliveries at gestational age 34 0/7 to 36 6/7 weeks. Abstracted data included maternal age, gravidity, parity, maternal or fetal pregnancy-related complications, gestational age at delivery based on last menstrual period, and whenever available, confirmation by first-trimester ultrasonography, cause for preterm delivery (for the study group), mode of delivery, and intrapartum complications. Neonatal information included sex, Apgar score, umbilical artery pH, and birth weight. Outcome measures included admission to the neonatal intensive care unit (NICU), respiratory morbidity, need for assisted mechanical ventilation, duration of hospitalization, need for phototherapy, hypoglycemia, hypothermia, sepsis work-up, culture-proven infectious morbidity, necrotizing enterocolitis, intraventricular hemorrhage, any neurologic abnormalities, and neonatal death in undischarged infants.
Respiratory morbidity was defined as any of the following: the presence either respiratory distress syndrome, transient tachypnea of the newborn, pulmonary hypertension, or need for ventilatory support. Infectious morbidity was defined as the presence of culture-proven sepsis, meningitis or pneumonia. Central nervous system (CNS) morbidity included seizures or intraventricular hemorrhage (any grade). Composite neonatal outcome was defined as the presence any of the following: respiratory, infectious or CNS morbidity (as defined above), neonatal death, necrotizing enterocolitis, need for phototherapy, hypoglycemia (blood glucose level of less than 40 mg/dL in capillary or venous blood sample),23 or hypothermia (newborn core body temperature of less than 36.0°C).24
According to our departmental protocols, neither tocolytic therapy nor corticosteroids for fetal lung maturation are administrated at gestational age 34 0/7 weeks or more. Group-B streptococcal prophylaxis (intravenous ampicillin, 2g every 6 hours) is routinely administrated to all women who present in spontaneous active labor at gestational age less than 37 0/7 weeks.
Admission criteria to the NICU include any of the following: birth weight less than 1,800 g, gestational age less than 34 weeks, respiratory or cardiac disease, hypoglycemia (2 or more episodes), suspected sepsis, or significant hematologic abnormality (ie, anemia, polycythemia, or thrombocytopenia), or requirement for close observation as assessed by a neonatologist. Head ultrasonography for the detection of intraventricular hemorrhage is performed routinely for all infants delivered at gestational age less than 34 weeks, or when intraventricular hemorrhage is clinically suspected for infants born after 34 weeks of gestation.
Data analysis was performed with the SPSS 15.0 software (SPSS Inc., Chicago, IL). The Student t test and one-way analysis of variance were used to compare continuous variables between the groups, and χ2 and Mann-Whitney U tests were used for categorical variables. For the purpose of subgroup analysis in the late-preterm group, the gestational-week group was determined as the number of completed weeks of gestation. Thus, an infant born at gestational age of 35 6/7 was included in the 35-weeks group. Multivariable logistic regression analysis was used to identify risk factors for adverse outcome among late-preterm infants. Differences were considered significant when P<.05.
Of a total of 81,694 deliveries during the study period, 5,843 (7.2%) occurred in the late-preterm period, of which 42.4% (n=2,478) were eligible for the study group. The demographic and obstetric characteristics of the late-preterm and full-term groups (n=7,434) are summarized in Table 1. Women delivering at late preterm were more likely to be nulliparous, to deliver by cesarean delivery, and to carry a male fetus in comparison with low risk full-term pregnancies.
Table 2 presents the neonatal outcome for women in the late-preterm and full-term groups. All complications assessed were significantly more common among infants delivered in the late-preterm period compared with full-term infants except for low Apgar score. Moreover, the rate of most of the complications in the late-preterm group decreased as gestational age increased from 34 to 36 weeks (Table 2). To estimate the absolute increase in the risk for adverse neonatal outcome attributed to late preterm deliveries we calculated the number needed to harm, which indicates how many late preterm deliveries (compared with full-term deliveries) would result in one additional adverse neonatal event. The number needed to harm was 2.9 for composite neonatal outcome, 5.9 for admission to NICU, 6.5 for jaundice requiring phototherapy, 7.9 for respiratory morbidity, and 250 for CNS morbidity.
Because certain demographic, obstetric, and fetal characteristics may be independently associated with adverse neonatal outcome, we further calculated the risk of neonatal morbidity by gestational week (using full-term infants as reference), while adjusting for potential confounders, including maternal age, parity, mode of delivery, birth weight, and infant sex (Fig. 1). The risk of certain neonatal morbidities (ie, respiratory, hypoglycemia, and hypothermia) was found to be increased by approximately 30-fold at a gestational age of 34 weeks compared with full-term infants. There was a gradual and consistent decrease in the risk of neonatal morbidity as gestational age increased from 34 to 36 weeks (Fig. 1).
Because not all late-preterm infants experience significant morbidity, we sought to identify risk factors for neonatal morbidity among the late prematurity group. Using multivariable logistic regression analysis, gestational age at delivery (34 through 36 weeks) and male sex were significantly and independently associated with increased risk for composite neonatal morbidity (Table 3). Additionally, parity, delivery by cesarean delivery, and male sex were significantly and independently associated with increased risk for respiratory morbidity. After controlling for gestational age, there was no significant correlation between birth weight and neonatal morbidity in this group of late-preterm infants.
To determine whether the relationship between neonatal morbidity and gestational age has a threshold or a continuous nature, we analyzed the rate of several neonatal morbidities by gestational age (Fig. 2). The rate of neonatal morbidity decreased gradually as gestational age increased from 34 weeks, reaching a nadir at about 39 weeks of gestation (Fig. 2).
In the current study we aimed to estimate the independent contribution of gestational age to neonatal morbidity in cases of spontaneous, low-risk singleton late preterm deliveries and to identify predictors of adverse neonatal outcome. Our main findings are 1) Late prematurity is an independent risk factor for neonatal morbidity as compared with full-term infants; 2) Among late-preterm infants, cesarean delivery, male sex, and parity are independent risk factors for adverse neonatal outcome; and 3) The relationship between gestational age and neonatal morbidity represents a continuity, with a nadir at about 39 weeks rather than a term–preterm threshold phenomenon.
Data regarding the effect of late prematurity on neonatal outcome is limited by the fact that most previous studies included pregnancies complicated by either maternal or fetal pregnancy-related complications such as preterm PROM, amnionitis, abruption, and intrapartum fetal distress6,10,12,25 and did not control for other potential confounders, such as maternal age, mode of delivery, fetal sex, and parity. Indeed, it has been suggested the most of the excess neonatal morbidity in the late preterm period is related to pregnancy complications leading to premature delivery rather than to late prematurity by itself.4 To overcome this limitation, we included only low-risk pregnancies with spontaneous onset of delivery, and adjusted the risk of neonatal morbidity for possible confounders. Thus, our results reflect the net effect of late prematurity on neonatal outcome in a single center with consistent management protocol.
We have found that most of the prematurity-related adverse neonatal outcomes were significantly more common in the late preterm group than at full-term. These observations are in concordance with previous studies, although there is considerable variation among different reports. In a recent study, McIntire et al12 compared neonatal outcome of late preterm infants with that of infants born at 39 weeks of gestation. Overall, the rate of neonatal morbidity in their report seems to be lower than in our study, especially with regard to admission to NICU, respiratory complications, clinical jaundice, and necrotizing enterocolitis. It should be noted, however, that the background rates of admission to NICU and necrotizing enterocolitis are also significantly lower than in our population. In the study of Wang et al,10 the rate of respiratory distress syndrome, jaundice, and hypothermia were significantly higher than in our study, although the rate of these complications among full-term infants was also considerably higher than in the current study. Bastek et al25 reported similar findings, although the rate of hypoglycemia was significantly higher than in our study, for both the late-preterm and full-term groups. The reason for this variation is not clear. Possible explanations include 1) Differences in local pediatric practice, especially with regard to outcomes such as admission to NICU, sepsis workup, and investigation for intraventricular hemorrhage; 2) Different definitions for adverse outcomes, including hypothermia, hypoglycemia, jaundice, and necrotizing enterocolitis; 3) Differences in study design, ie, database compared with chart-review studies; 4) Differences in the inclusion and exclusion criteria for the study and control group; and 5) A relatively small sample size of the late preterm groups.6,10,25
The ability to identify late-preterm infants who are prone to neonatal complications would be of great importance for counseling purposes, especially in cases where conservative management of pregnancy is an option. Currently, however, data regarding such risk factors are scarce, and available information is based in most part on studies of relatively small sample size, thus limiting the ability to identify such factors. Shapiro-Mendoza et al11 studied a large number of “healthy” late-preterm infants. They found breast-feeding, being firstborn, maternal race, and labor and delivery complications to be significant predictors of neonatal morbidity. Male sex was a significant risk factor only in the subgroup of non–breast-fed infants, and in contrast to our study, cesarean delivery was not associated with increased risk of neonatal morbidity. In the study of Bastek et al25 described above, chorioamnionitis, maternal race, and cesarean delivery were significant risk factors for neonatal morbidity, whereas maternal age and infant sex were not. Our observation regarding the association of male sex with increased risk of neonatal morbidity is in agreement with previous reports, in which male infants were noted to be at increased risk for respiratory morbidity,14,26 hyperbilirubinemia,19,20,27 NICU admission26, and rehospitalization.13,27 The reason for this association is not clear; however, greater weight and the different hormonal profile of male infants have been suggested as possible explanations.28 The association of parity with respiratory complications was not reported in previous studies, and the reason for this observation cannot be explained by the current study.
A crucial as well as practical question is whether there is a threshold of gestational age or birth weight above which the neonatal mortality and morbidity reaches a plateau. In a large study of uncomplicated spontaneous preterm deliveries, DePalma et al3 found that the birth weight thresholds for neonatal mortality and morbidity were 1,600 g and 1,900 g, respectively. In the current study, however, we failed to detect such a threshold, and neonatal morbidity decreased gradually as gestational age increased from 34 to 39 weeks, even when birth weight exceeded 2,500 g. In fact, we found that at gestational age of more than 34 weeks, birth weight is poorly correlated with neonatal outcome as compared with gestational age.
There are several limitations to our study, which are mainly related to its retrospective design. Because the medical staff was aware of the infant's gestational age, it is possible that late-preterm infants were more likely to be diagnosed with more subjective diagnoses (ie, transient tachypnea of the newborn, sepsis workup) as compared with full-term infants. However, since blinding of the medical staff to the infant's gestational age is not possible under any study design, we believe that this kind of bias is inherent to all studies on this subject and is difficult to overcome. Another limitation is that we did not have data on long-term adverse neonatal outcome. Nevertheless, several of the short-term neonatal morbidities reported in the current study have been shown to be associated with increased risk for adverse long-term neurodevelopmental outcome. These include high-grade intraventricular hemorrhage, neonatal seizures, necrotizing enterocolitis, hyperbilirubinemia requiring phototherapy, and need for blood transfusion.29
The rate of late prematurity has increased significantly during the past two decades, accounting for approximately 8% of overall deliveries and approximately 75% of all preterm deliveries in the United States.5,30 Thus, although the rate and severity of neonatal morbidity associated with late prematurity is lower than in cases of more severe prematurity, the overall consequences of late prematurity in terms of short- and long-term neonatal morbidity, hospitalization days, and costs is of major significance. In the current study about one half of late preterm deliveries were spontaneous, whereas the other half was indicated because of preterm PROM or maternal or fetal complications. Thus, efforts to reduce the rate of late prematurity should address both spontaneous deliveries, in the form of tocolysis and corticosteroids for fetal lung maturation, as well as re-evaluation of current obstetric practices regarding timing of indicated delivery in cases of preterm PROM and other obstetric complications.25 Currently, however, there are no data available to suggest that any of these measures is associated with improved neonatal outcome,4,31–33 and large randomized controlled trials are necessary to evaluate the effect of these interventions. In addition to stimulating efforts to reduce the rate of late prematurity, better understanding of the short- and long-term morbidity associated with late prematurity is important for appropriate counseling regarding expected outcome in cases of late preterm deliveries.
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