Predictors of adverse short-term outcomes in late preterm infants

Globally, the increase in the incidence of premature birth is almost entirely due to infants born late preterm [39].

The increase in late-preterm births may be attributed to the increasing use of ART. ART is associated with adverse maternal and newborn outcomes [40, 41]. The progress in obstetric practices and early recognition of foetal endangerment, more frequently result in the completion of pregnancies with infants born late preterm [42].

Of the 8544 infants born in the three-year period, there were 842 (9.85%) preterm infants, including 504 (5.89%) LPIs. Of these, 154 LPIs required intensive care and therapy in the ICU, i.e., 1.8% of all infants, 18.2% of preterm infants or 30.5% of all LPIs born in the studied period.

It is important to note that within the UKC Clinic for Gynecology and Obstetrics, there is a department for newborns where LPIs who do not require an intensive level of care are treated. In the USA, the preterm delivery rate is 12–13%; in Europe and other developed countries, the reported rates generally range from 5 to 9% [33, 43]. Increases in the singleton preterm birth rate are almost entirely due to infants born late preterm [39].

The results of our study showed that preterm infants were predominantly treated in the ICU, including 430 (63.8%) preterm and 244 (36.2%) term infants. Out of the 430 preterm infants treated in the ICU, one-third were late preterm (154; 35.2%), and the majority of them were male, similar to other studies [19, 35, 44].

Of the 154 preterm infants included in our study, 104 (68.18%) were born by CS. A higher CS rate was also reported by Tsai et al. and Ma et al. [9, 37]. On the other hand, Champion et al. [45], Aliaga et al. [35] and Liqun Lu et al. found that vaginal delivery, especially with the induction of labour, was the main mode of delivery of late preterm infants (59.6%) [46].

When making decisions regarding obstetric interventions, such as induced labour, vaginal delivery or CS, the risks of continuing the pregnancy in a suboptimal uterine environment must be compared with the risks of early delivery [47].

Neonatal morbidity is significantly higher in combination with maternal medical conditions, with the independent effect of late preterm birth on early neonatal morbidity being nearly seven times greater than the independent effect of maternal risk factors [48].

Rate od LPIs was highest among women of < 20 and > 35 years of age and lowest among women of 20–34 years of age. Due to an increased prevalence of diabetes and hypertension, as well as higher use of ART, older women may be in increased risk of having preterm birth [41]. Increased preterm risk among teens may be due to biologic immaturity, socioeconomic status, and different life habits [22, 49]. 3.9% and 6.5% of mothers who delivered late preterm infants were aged < 20 years and ≥ 35 years, respectively, compared to the study in China where 4.5% and 8.4%. There is also a difference in the method of delivery. In their study vaginal was dominant, while in ours it was an emergency caesarean section. The mentioned difference may be due to the inclusion of all late preterm infants in their study, not only those treated in the ICU [46]. Differences in the incidence of hypertension, preeclampsia and PROM can be interpreted in the same way.

It is known that birth weight in relation to gestational age affects the morbidity and outcomes of late-preterm infants [50]. The average birth weight in our study was 2518 g and was between the 3rd and 97th percentiles of birth weight for gestational age.

Preterm birth is not a single entity but a common final outcome of underlying maternal and foetal factors. Parity (i.e., the number of offspring a female has delivered) was also found to be associated with adverse birth outcomes [51, 52]. For nulliparous mothers, late-preterm birth was significantly and independently associated with an increased risk for adverse neonatal outcomes, similar to a recent study with 837,226 singleton births conducted in the Netherlands. The mentioned study showed that the risks of PTB were significantly higher in nulliparous mothers than in mothers who had given birth at least once (RR: 1.95, 95% CI: 1.89–2.00 for PTB) [53]. In the results presented by Torres-Munoz, 41.04% of the group of cases with LPIs were primiparous women, and 54.72% were multiparous women (2–5 births), compared to the control group in which primiparous women were represented in a smaller percentage, i.e., 37.26% [54]. However, a systematic review consisting of 41 studies did not reach the same conclusion [55]. Additionally, significant heterogeneity was found among the included studies, indicating the need for more studies.

A study by De Luca et al. [27] revealed a strong age-related trend in respiratory morbidity independent of delivery mode and a > 10-fold increase in respiratory morbidity in infants born at 34 weeks GA compared with those born at term. A retrospective study in Canada by Kitsommart et al. [28] revealed significantly worse respiratory outcomes (including the prevalence of NP and the rates of positive pressure therapy, and mechanical ventilation assistance; all P < 0.001) in 1481 infants born at 34 to 36 weeks GA compared with 9332 infants born at ≥ 37 weeks GA.

The risk of adverse short-term outcomes changes with each week of gestation [19, 45, 56, 57]. Our results were fairly consistent, and the rate of almost all complications in the late-preterm group decreased as gestational age increased from 34 to 36 weeks.

Adverse short-term respiratory outcomes were the most common complications at all gestational ages. Infants born at 34 weeks had 40-fold increased odds of developing RDS versus infants born at 39 weeks [58]. In our study, the rates of RDS were 74,7%, 70,8% and 7.,6% for infants born at 34 weeks GA, 35 weeks GA and 36 weeks GA, which was similar to the rates of 70.3%, 79.5% and 70.65% in the study by McIntire et al. [11] but significantly higher than those of 22.3%, 31.5% and 32.5% in the study by Jones et al. [59]. Respiratory support was needed for up to 58,1% of infants admitted to the NICU according to Aliaga et al. [35]. The need for mechanical ventilation followed the rate of RDS in our study and was the highest in the 36th gestational week. We had more LPIs on MV at 36 weeks GA because 3 LPIs had sepsis, 1 had severe asphyxia, and 2 had a severe form of RDS with pneumothorax.

The studies by Tutdibi et al. and Derbent et al. indicate that TTN is strongly related to elective CS delivery and low GA [15, 16]. The rates of TTN and NP in our study were similar at 34 and 36 weeks GA and were present exclusively in neonates born by CS. In a study performed in 2017–2019 in the same clinic as our study, a lower gestational week and CS delivery were shown to be risk factors for NP in neonates on mechanical ventilation [60]. For PPHT, the vast majority of infants with PPHN were born at term or near term, although approximately 2% of cases were born prematurely [61]. Our study supports the claim that the highest incidence of PPH occurs at the highest GA, i.e., 25.6%.

In LPIs, treatment for suspected systemic infection is far more common than for term infants, and the diagnosis is made on the basis of clinical symptoms, laboratory findings and/or positive blood cultures [44]. Sepsis was diagnosed in 22.7% of the late-preterm infants in our study, and the literature mentions infection frequency percentages of 4,9–20,6%[11, 62]. The pattern of pathogen distribution differs from region to region as well as between developed and less developed countries due to patient demographic characteristics, the colonization of the microflora of the hospital environment and antibiotic use policies.

[38], which may explain the higher rate of sepsis in our study. Pneumonia was present in 18.8% of the LPIs, while according to Loftin et al., the frequency was 1.2% in newborns at 34 weeks GA; an overall rate of 0.7% was described in the study by Melamed et al. [7, 40], in which 2.6% of the LPIs had meningitis.

Regarding the short-term CNS morbidity outcomes, neonatal convulsions accounted for 3.9% of the LPIs in our study. Although the incidence of severe intraventricular haemorrhage is low in LPIs when compared to other preterm infants, LPIs are still at higher risk when compared to term neonates. The large variation in the reported rates of IVH is due to the lack of standard guidelines for screening neuroimaging in LPIs, so we can elucidate the reason for the high number of LPIs with IVH grade 1 and 2 in our study. McIntire et al. reported rates of IVH grade 1 and 2 in LPIs of 0.5% at 34 weeks GA, 0.2% at 35 weeks GA and 0.06% at 36 weeks GA, but when we analyse only at the data on LPIs admitted to the NICU, the percentage increases to 10.9% at 34 weeks GA. Teune et al. reviewed 22 studies and found that intracranial haemorrhage occurred more frequently in LPIs. The rate of either IVH grade 3 or 4 was extremely low in LPIs [11]; however, it remained higher than that in term neonates (0.01% vs. 0.004%) [63]. Our rate of IVH grade 3 or 4 was higher, at 2.6%, and occurred only in the 34th week of gestation. This percentage was expectedly higher, considering that Teune et al. reviewed the data of all LPIs, not only those admitted to the NICU.

The most common additional short-term outcome in our study was hyperbilirubinemia, defined as jaundice that required phototherapy, as in multiple studies in which it occurred during initial hospitalization [11, 64, 65]. Very high rates of jaundice were reported by Wang et al., and more than half of the LPIs in a large-based practice report developed hyperbilirubinemia requiring phototherapy [12, 66]. Aliaga et al. reported that 33.2% of late-preterm newborns in the study group received phototherapy. More late-preterm newborns admitted to the NICU (58.3%) received phototherapy than those admitted to the newborn nursery (19.9%). Phototherapy was more common in infants born at 34 weeks GA than at 35 and 36 weeks GA (63.5 vs. 34.7 vs. 21.2%). LPIs who were treated for hyperbilirubinemia in the same way as term infants developed kernicterus and had more sequelae from hazardous hyperbilirubinemia [67]. Existing guidelines are helpful for treating hyperbilirubinemia in infants who are born at 35 weeks GA or later.

As a result of metabolic immaturity, hypoglycaemia is common among LPIs, with an overall incidence of up to 50% [7, 37, 64, 66, 67]. Our study, with a total of 26% of infants with hypoglycaemia, confirms the metabolic immaturity of preterm infants and is consistent with the results of the aforementioned studies. A meta-analysis further confirmed the increased risk of hypoglycaemia in LPIs compared with term infants [63].

In our study, 11,0% of LPIs had anaemia requiring blood transfusion, which was expected considering the morbidities of preterm infants requiring admission to the NICU. The rate of anaemia decreased as gestational age increased from 34 to 36 gestational weeks.

LPIs not requiring intensive treatment are treated at the Neonatal Department of the Clinic for Gynecology and Obstetrics. Neonates born at 35 weeks GA and 36 weeks GA who required intensive care and therapy were included in this study, which provides an explanation for the greater number of respiratory and infectious diseases in infants with older gestational age.