Outcome of late preterm newborns in Upper Egypt

The incidence of preterm births is increasing and has become a global health concern. This study aimed to compare the outcome of late preterm (LPT) to full term (FT) neonates at two large hospitals in Upper Egypt. Out of 250 newborns included in the study, 180 (72%) were FT and 70 (28%) were LPT. More than half of the LPT newborns (52.9%) were admitted to the neonatal intensive care unit (NICU), compared with 26.7% of FT newborns. Delivery of LPT was associated with an increased risk of neonatal morbidity, including jaundice requiring phototherapy (34.3% vs. 7.8%), respiratory morbidities (32.9% vs. 13.9%), hypoglycemia (8.6% vs. 1.7 %), and convulsions (4.3% vs. 0.6%). LPT neonates were more susceptible to suffer from jaundice and respiratory distress among other morbidities. They also had a higher rate of NICU admission, longer duration of NICU stay, as well as a higher mortality rate. The best treatment of late prematurity is to prevent it. Public and professional awareness of the problems associated with late prematurity should be highlighted. Follow-up programs for early detection and intervention for long term complications are recommended.


Background
Gestational age has a major impact upon the clinical outcome of neonates. Therefore, it is necessary to standardize medical terminology related to neonatal maturation by gestational age rather than birth weight so that gestational age-appropriate care can be administered, and data from different studies can be compared. Term infants are defined as those with a gestational age 37 to 41 weeks [1]. According to the World Health Organization (WHO), the American Academy of Pediatrics (AAP), and the American College of Obstetricians and Gynecologists (ACOG), preterm birth is defined as the delivery of an infant before the completion of 37 weeks of gestation [2,3].
The incidence of preterm births is increasing in many countries around the world and has become a global health concern [4]. The National Center for Health Statistics of the Centers for Disease Control and Prevention generally reports data on three categories of preterm birth: overall preterm (< 37 weeks' gestation), moderately preterm (between 32 and 36 weeks' gestation), and very preterm births (< 32 weeks' gestation) [5]. Late preterm infants are born at a gestational age between 34 weeks and 0 day and 36 weeks and 6 days.
The LPT infants are recognized as the fastest increasing and largest proportion of singleton preterm births [6]. Data from the year 2010 have shown that LPT births accounted for 3.0 to 6.0% of live singleton births and constituted about 65 to 75% of preterm births [7]. The prevalence of LPT is affected by the rate of multiple births. While multiples constitute about 3% of all births, they accounted for about 20% of late preterm births and 5% of early term births [7][8][9].
They have higher morbidity and mortality rates than term infants due to their relative physiologic and metabolic immaturity, even though they are often the size and weight of some term infants [10,11].
The period between 34 and 40 weeks of gestation is considered a critical growth period for the development of many neural structures and connections. Dramatic changes occur in brainstem development in terms of neuronal origin and proliferation, migration pathways, morphological and neurochemical differentiation, neurotransmitter receptors, neurotransmitters and enzymes, dendritic arborization, spinal formation, synaptogenesis, axonal growth, and myelination. In addition, cortical volume increases by 50% during this time. Therefore, the occurrence of brain injury during this critical period of neural development might affect late cerebral development [12].
Moreover, the development of other body systems and chemical pathways is affected by prematurity. The development of the terminal respiratory sacs and alveoli continues through gestational weeks 34 and 36 and the surfactant surge takes place at 34 weeks. Therefore, preterm infants suffer from delayed pulmonary maturation and are at an increased risk of respiratory distress syndrome (RDS), particularly when mothers have not administered antenatal steroids [13,14]. In addition, late preterm infants suffer from a delay in the development of hepatic bilirubin conjugation pathways [15],have less brown adipose tissue to generate heat and less white adipose tissue for insulation [13], and are immunologically immature [16].
Many obstetric decisions during the final weeks of a pregnancy involve weighing the risks and benefits of delivering the infant prematurely against the risks and benefits of extending the pregnancy. For fully informed decision-making, an accurate understanding of the risks related to either choice is necessary. The studies of complications during birth showed substantial increases in the risks of morbidity and death for LPT infants, compared with term infants [17]. However, short-and longterm outcomes of LPT infants have not been adequately studied as the outcomes of extremely preterm newborns [6]. Meanwhile, the public health impact of LPT births is probably as great as or greater than that of early or moderate preterm births because of the increasingly larger rates of LPT births [17]. Therefore, the aim of the present study was to identify the outcome and clinical complications associated with LPT newborns as compared with FT newborns.

Study population and settings
This study included a cohort of 250 neonates born in Fayoum University Hospital and Beni Suef General Hospital during 6 consecutive months (May 2018 to November 2018).
The study subjects were divided into two groups: group I, including late preterm neonates (full 34 to 36 weeks and 6 days) and group II, including full term neonates (from 37 to 40 weeks and 6 days).

Inclusion criteria
All singleton, live birth, and neonates of both sexes who were born in Fayoum University Hospital or Beni Suef General Hospital during the study period were included, whether born as late preterm or at full term.

Exclusion criteria
Neonates were excluded from the study if they were twins or multiple pregnancies, had major congenital and/or chromosomal anomalies, were suspected to have inborn error of metabolism, were born before 34 weeks or after 41 weeks of gestation or were still birth.

Data collection
Data for each subject were collected from hospitals' files and included the following: History including maternal and gestational variables such as maternal age at the infant's birth, parity and gravidity, prior history of abortions, still births or premature deliveries, type of delivery, current clinical status observed during gestation including medical conditions (e.g., diabetes mellitus, hypertension, urinary tract infection), premature rupture of membrane (PROM) > 18 h before delivery, placental abruption, umbilical cord pathologies (e.g., cord coiling, true knot, cord prolapse), fever or rash, drug intake during pregnancy, heart disease, and other diseases. Also, we included data regarding neonatal variables such as sex, birth weight, gestational age (calculated from date of last menstruation and early obstetric ultrasonography), and resuscitation in delivery room.
Physical examination including 1 and 5-min Apgar scores, gestational age assessment by Ballard score, anthropometric measurements (circumference of head and length), general examination (integument, head and neck, eye, chest, heart, abdomen examination), and examination of neonatal reflexes.
Investigations including complete blood count, C-reactive protein, random blood glucose, serum calcium (total/ionized), electrolytes, bilirubin, arterial blood gases, chest X-Ray, echocardiography, and CT scan of the brain.

Outcome measures
The studied outcome measures included the pattern of feeding, admission to NICU, as well as the duration of hospitalization and readmission within neonatal period, neonatal morbidity, and neonatal mortality. Neonatal morbidities comprised the following: (a) respiratory morbidity (transient tachypnea of the newborn, hyaline membrane disease, pneumonia, pulmonary hypertension, apnea of prematurity, need for mechanical ventilation), (b) hyperbilirubinemia requiring phototherapy or blood exchange, (c) hypoglycemia (glucose below 40 mg/dL), (d) hypothermia (body temperature below 36°C) or hyperthermia, (e) sepsis or necrotizing enterocolitis, and (f) neurological manifestations (e.g., convulsions, intraventricular hemorrhage).

Statistical analysis
The collected data were statistically analyzed using the Statistical Package for the Social Science software, version 18 (SPSS Inc, USA). For quantitative data, Kolmogorov-Smirnov (KS) test was performed to evaluate the distribution of data. Variables that followed normal distribution were summarized as mean and standard deviation; independent samples t test was used to compare between two groups and one-way analysis of variance (ANOVA) to compare between more than two. Variables that were not normally distributed were summarized as the median and range; Mann-Whitney-U test was used to compare between two groups. Qualitative data were presented as number and percentages; chi square or Fisher's exact test were used to study the association between categorical variables. Statistical significance was considered at p < 0.05.

Results
This cohort study included 250 newborns; out of them, 70 were LPT neonates, while 180 were FT neonates born at Fayoum University Hospital and Beni Suef General Hospital. Table 1 shows the characteristics of the studied neonates and their mothers. The mean gestational age of the studied neonates was 35.7 ± 0.8 in the LPT and 39.1 ± 1.0 in the FT neonates. There were no statistically significant differences of gender distribution among groups. The LPT neonates were born with significantly lower mean birth weight, length, and head circumference than the FT group (p < 0.001). Compared with the FT group, a significantly higher percentage of LPT was small for GA (11.4% vs. 2.2%, respectively; p = 0.002) and had microcephaly (4.3% vs. 0.6%; p = 0.038).
Also, that the mean age of mothers of LPT neonates was 27.3 ± 6.9 years compared with 26.3 ± 6.7 of FT ones. The percentage of mothers in extremes of age (≤ 17 years and ≥ 35 years) were significantly higher in the LPT group (5.7% vs. 0.56% and 21.4% vs. 8.34%; p = 0.001). Mothers of LPT neonates had history of more previous preterm delivery compared with mothers of FT ones (14.3% vs. 6.1%; p = 0.036). History of repeated abortion was higher among mothers of LPT neonates (p = 0.025) where 8.6% of them reported abortion for two times. Regarding maternal morbidities during pregnancy, hypertension was found in 27.1% of mothers of LPT compared with 14.4% of those of FT ones with a statistically significant difference (p = 0.012). Hypertensive mothers had an increased risk of LPT delivery than those with normal blood pressure by about two folds {OR (95% CI) = 2.21 (1.13-4.32)}. There were no statistically significant differences between both groups regarding history of other diseases or parity. Table 2 demonstrates the history of delivery. Vaginal delivery was significantly higher among FT neonates (60.6%) compared with the LPT group, where cesarean section (CS) was predominant (64.3%; p < 0.0001). Vaginal delivery was indicated in full term mothers mainly due to onset of labor (53.9%), while it was mainly either due to onset of labor (28.6%), PROM (27.1%) or fetal distress (21.4%) in LPT group, with a statistically significant difference between both groups (p value < 0.001). Compared with FT group, significantly (p < 0.001) higher percentage of LPT cases were delivered by CS mainly due to breech presentation (35.7% vs. 8.3%) or previous CS (21.4% vs. 13.9%). Increased risk of LPT delivery was associated with placental abruption, fetal distress, and history of PROM > 18 h by about 11, 4, and 2 folds, respectively. Table 3 compared the clinical condition and outcome between the studied LPT and FT neonates. The Apgar score after 1 and 5 min showed significantly lower means among LPT neonates (5.2 ± 1.7 after 1 min and 7.7 ± 1.5 after 5 min) with p = 0.015 and 0.033, respectively. There was an increased risk of low Apgar score (< 7) in LPT neonates than FT group by more than four times {OR (95% CI) = 4.93 (2.17-11.18)}. Formula feeding rate was significantly higher in the LPT group (61.4% vs. 10.6%; p < 0.001).
A significantly higher percentage of LPT neonates was admitted to NICU (52.9% vs. 26.7%; p < 0.001) with a statistically significant longer duration of admission (6.9 ± 2.4 vs. 4.25 ± 1.9 days; p < 0.001). The LPT neonates had an increased risk of NICU admission by about three folds than FT neonates {OR (95% CI = 3.08 (1.74-5.47)}. There was no statistically significant difference between the two groups regarding readmission. As regards the indications of NICU admission, significantly higher percentage of LPT neonates were admitted due to respiratory diseases (32.9% vs. 13.9%; p < 0.001), jaundice (34.3% vs. 7.8%; p < 0.001), hypoglycemia (8.6% vs. 1.7%; p = 0.009), and convulsions (4.3% vs. 0.6%; p = 0.038). The LPT neonates had 6 times higher risk of neonatal jaundice {OR (95% CI = 6.19 (2.96-12.91)} and more than 5 times higher risk of hypoglycemia {OR (95% CI = 5.53 (1.342-2.77)} as compared with FT. A significantly higher mortality rate was observed in LPT group (3 cases, 4.3%) compared with FT group (1 case, 0.6%; p = 0.035). The causes of death were necrotizing enterocolitis in two cases and apnea of prematurity in the third. Figures 1 and 2 show the respiratory diseases that were found in the studied neonates and the type of oxygen support that was used. Respiratory distress syndrome (RDS, 72% of cases with respiratory disease) and pneumonia (8.7%) were more frequent in LPT neonates, while in FT neonates, transient tachypnea of the newborn was the commonest cause for respiratory distress (84% of cases with respiratory diseases). The need for  Table 4 summarizes the results of laboratory investigations in the studied neonates. The mean values of WBCs and platelet count were significantly lower in LPT neonates compared with FT group (p = 0.031 and 0.002, respectively). The mean value of CRP was higher in LPT 7.4 ± 20.6 compared with 1.6 ± 9.2 for FT ones (p value < 0.026). The mean values of calcium (total, ionized) and random blood sugar were significantly lower in LPT neonates compared with FT group (p < 0.001). Total and direct bilirubin were analyzed in 150 neonates (50 LPT and 100 FT); 40.0% of LPT infant and 11.0% of FT had elevated bilirubin from their second day of life and required phototherapy. Also 8% of LPT infant (6% due to ABO incompatibility and 2% due to RH incompatibility) and 3.0% of FT (2% due to ABO incompatibility and1% due to RH incompatibility) had jaundice from their first day of life and needed NICU admission.
The LPT neonates were then subdivided into three subgroups: those born between 34 weeks of gestation and before the 35th week; those born between the 35th week of gestation and the 36th week; and neonates born between 36 weeks of gestation and before the 37th week. Table 5 displays the comparison between the three subgroups. There was no significant difference among the three subgroups as regards Apgar scores at 1 and 5 min (p = 0.0141 and 0.220, respectively), percentage of NICU admission (p = 0.060), as well as incidence of jaundice (p 0.347), hypothermia (p = 0.279), sepsis (p = 0.874 and 0.842 for early and late, respectively), hypoglycemia (p = 0.758), hypocalcemia (p 0.836), convulsions (p = 0.748), bleeding disorders (p = 0.651), and mortality (p = 0.289). A significantly higher number of LPT neonates born between 36th and 37th weeks had lower incidence of respiratory diseases, compared with the other two subgroups (p < 0.001). The duration of NICU stay was significantly lower in neonates born between the 36th and 37th weeks compared with those in the other two subgroups that were born earlier.

Discussion
The growing interest about late preterm newborns in the medical literature encouraged us to conduct this study to evaluate the outcome and clinical complications that could be associated with LPT compared with FT newborns. Our study was conducted on 250 neonates born in Fayoum University Hospital and Beni-Suef General Hospital. Out of them, 70 were LPT and 180 were FT neonates.
We found no statistically significant association between the gender of neonates and LPT delivery. This was in agreement with Teoh et al. [18] However, several earlier studies [19][20][21][22] reported an increased risk of preterm delivery associated with male fetus. Wilms et al. [21] suggested an effect of maternal race on the association between gender and preterm delivery. The postulated explanations for this association included that placental or chorionic trophoblastic cells of the male fetus produce more pro-inflammatory TNFα and lesser anti-inflammatory IL-10 and granulocyte colony stimulating factor than cells from pregnancies with a female fetus, resulting in the generation of a more proinflammatory intrauterine environment. Also, differences in gene expressions between placentae of male and female fetuses have been proposed as an explanation for male gender predominance in preterm labor [20].
In the present study, mothers at the extremes of reproductive age have a higher risk of preterm labor. The incidence of late preterm labor was significantly the highest among mothers who were less than 17 years of age, where 80% of them gave birth before 37 weeks of gestation, and the prevalence was also high (50%) when the maternal age was more than 35 years old. In agreement to our results, Carter et al. [23] found that maternal age ≤ 17 and ≥ 35 was associated with increased risk of LPT birth. Kozuki et al. [24] conducted a metaanalysis to study the association of maternal age with preterm delivery and neonatal outcome, and they found that the nulliparous women with age < 18 had the highest risk of preterm birth followed by multiparous women aged ≥ 35 years.
In our study, we did not find any significant association of LPT birth with parity, which is in line with the data reported by a case-control study in 5 Italian Centers [25]. However, in a study conducted over 10 years to estimate outcomes of LPT deliveries, a significantly increased prevalence of late preterm birth in multiparous patient was reported [26].
Comparison between LPT births and FT births in the present study indicated that mothers of LPT neonates were more likely to have had a previous preterm birth, which agrees with results reported by McDonald and his colleagues [27].
Till today, there is a controversy regarding the association between previous abortions and the risk of LPT birth. A systematic review [28] defined that, out of 24 considered papers, 12 reported an increased risk of preterm birth among women with previous abortions. In the present study, there was a significant association  between LPT birth and having more than 1 previous abortion. Several maternal medical conditions, including hypertensive disorders of pregnancy, diabetes, and asthma, have been associated with an increased risk for indicated or spontaneous preterm birth. In the present study, we found an increased incidence of LPT birth with hypertension, while it was not statistically different for gestational diabetes, urinary tract infection, cardiac, or respiratory diseases. In partial agreement to our results, Carter et al. [23] found that comorbidities, particularly hypertension and gestational diabetes, have been associated with the risk of LPT birth.
The mode of delivery has been linked to the risk of LPT births. We found that LPT neonates were more likely to be delivered by cesarean section than FT neonates. The most frequent indications for cesarean sections in LPT neonates were breech presentation and previous cesarean section. None of the CS was elective or indicated for maternal comorbidities. Cesarean sections in preterm deliveries are known to pose increased risks of neonatal morbidity and mortality [29,30].
We found that Apgar scores after 1 min and 5 min were significantly lower among LPT neonates. These findings were comparable to those reported by in an Indian tertiary care teaching hospital [31]. Also, LPT neonates had significantly lower birth weight and head circumference, which agrees with some earlier reports [12,32]. Accordingly, the incidence of 11.4% of SGA was significantly higher in LPT neonates compared with the FT group; this was comparable to the results of Araújo et al. [33] as about one quarter of the LPT neonates in their study were SGA.
The outcome of the studied neonates has been evaluated in terms of the feeding pattern, the incidence of NICU admission, as well as neonatal and mortality. In the present study, the LPT neonates had a higher incidence of formula feeding compared with the FT group, which agrees with previous reports [34][35][36]. Some of the reasons postulated for poor breastfeeding included decreased alertness, poor latching on skills, decreased oromotor tone, disorganized sucking patterns, and poor suck/swallow coordination. The immature suction pressures produced may reduce lactogenesis [34,35]. All these factors may result in difficulty in establishing maternal-infant bonding and the initiation/maintenance of successful breastfeeding. Feeding issues are of paramount importance in such cases; poor feeding can lead to decreased caloric intake and dehydration, which further exacerbate neonatal complications such as hypoglycemia, hyperbilirubinemia, respiratory distress, and temperature instability [37].
Our results showed that LPT neonates were more frequently admitted to NICU compared with FT neonates; however, no significant difference was observed in NICU readmissions. Moreover, we found that the lower the gestational age, the rate of NICU admission is increased, as there were 43.3%, 50%, and 83.3% for infants born at 36, 35, and 34 weeks of gestation, respectively. Similar results were reported by Tsai and his colleagues [2], where 21%, 43%, and 74% of their cases were to in NICU or special care nursery when born at 36, 35, and 34 weeks of gestation, respectively. Also, they found that hospital readmission rate was not different between LPT and FT neonates.
The duration of NICU stay in LPT neonates in our study was significantly longer than in FT neonates; the mean length of stay in NICU was significantly higher in neonates born at 34 weeks and 35 weeks than in those born at 36 weeks of gestation. Similarly, Hibbard and his colleagues [38] reported a statistically significant increase in both the incidence of NICU admission and duration of stay with decreased gestational age.
From our study, the mortality rate among LPT neonates was significantly higher than among the FT group; stratification of neonates by their GA revealed that the highest rates were among those born at 34th week of gestation, though statistical significance was not reached. In accordance with our findings, Hibbard and his colleagues [38] and Steure et al. [39] reported a significantly increasing mortality rate with the lowering of the gestation age. The lack of statistical significance in comparisons of the preterm subcategories may be attributed to the relatively small size of each subgroup. Moreover, a large population-based cohort study [40] from the USA and Canada showed that preterm infants are at high relative risks for infant death. In our study, neonatal complications were more frequent in LPT compared with FT infants. The most common complications in the LPT group were neonatal jaundice (34.3%) and respiratory diseases (32.9%). In this study, the frequency of neonatal jaundice was significantly higher in LPT neonates compared with the FTs (34.3% vs. 7.8%). Similarly, Darcy [41] and Premji et al. [42] found that hyperbilirubinemia is the most common reason for admission in the LPT population (41.4% vs. 12.9% and 38.4% vs. 7.2%, respectively).
The most common cause of respiratory distress in LPTs was RDS (72%). Our study results were analogous to those reported by Tsai and his colleagues [2], who reported more neonatal respiratory complication in the LPT than in FT neonates (33.4% vs. 14.2%). Also a study from Pakistan found that LPT newborns had an increased risk of RDS (16.5-18.2% in LPTs vs. 0.3-2% in FTs) [43]. The higher incidence of respiratory distress in LPT neonates could result from immaturity of their lungs [44].
Our results showed a higher need for ventilation in LPT compared with FT infants (56.5% vs. 20%), with significantly higher percentage requiring CPAP and head box in the LPT group. In a similar study, Hibbard and his colleagues [38] found that LPT neonates, particularly those delivered at 34 weeks, required more oxygen supplementation (8.3%), intubation (2.9%), and mechanical ventilation (0.2%) in the delivery room than neonates born at each successive week gestational age.
We compared the incidence of neonatal jaundice and RD among different gestational ages, and it showed that the rate of jaundice increased with lowering of gestational age (50% in the 34th, 35.7% in the 35th, and 26.7% in the 36th weeks of gestation). Also, RD showed a similar trend (75% in the 34th, 42.9% in the 35th, and 6.7% in the 36th weeks of gestation). Our results were comparable with those of Hibbard et al. [38] who found the rates of jaundice were 55%, 45.7%, and 16.1% and