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Introduction
According to the World Health Organization, a preterm newborn (PNB) is born before 37 weeks of gestation1,2. Three categories are described that classify PNB based on their gestational age:
- Extreme preterm or extremely low birth weight preterm (< 1000 g): born before 28 weeks.
- Very preterm or very low birth weight preterm (< 1500 g): born between 28 and 32 weeks.
- Moderate and late preterm: born between 32 and 37 weeks.
Worldwide, an estimated 15 million neonates are born prematurely each year. Of those who survive, a significant number face lifelong cognitive, motor, or sensory disabilities2.
PNBs have pathologies inherent to their immaturity and require careful and specific management in the neonatal intensive care unit (NICU), as described in books and systematic reviews2-8. Medical advances continue to be made, some modified previous concepts, and others confirmed classical theories and approaches. Table 1 shows the established recommendations in 2011 and 2021, indicating the practices followed in those years9-29.
Table 1 Comparison of PNB management and diagnoses in 2011 and 2021
| Variable | 2011 (n = 10) | 2021 (n = 16) | p-value |
|---|---|---|---|
| Respiratory | |||
| CPAP assistance at admission n (%) | 5 (50%) | 10 (62.5%) | 0.420* |
| Surfactant administration n (%) | 8 (80%) | 8 (50%) | 0.218* |
| LISA s n (%) | 0% | 2 (12.5%) | 0.467† |
| Surfactant timing (hours of life) Mean ± SD | 0.66 ± 0.73 h | 1.8 ± 1.1 h | 0.032‡ |
| Duration of non-invasive ventilation (days) Mean ± SD | 5.9 ± 6.11 days | 7.46 ± 9.82 days | 0.728‡ |
| Median (p25-p75) | 4 (0.5-8.75) | 4 (0.62-9) | 0.787§ |
| Duration of any type of mechanical ventilation (days) Mean ± SD | 5.9 ± 6.1 days | 16.4 ± 25.2 days | 0.452‡ |
| Median (p25-p75) | 6 (4-11) | 4.1 (3-28) | 0.783§ |
| Hemodynamic | |||
| PDA n (%) | 1 (10%) | 3 (20%) | 0.626† |
| Medical or surgical treatment of PDA n (%) | 0 | 1 (7.1%) | 1† |
| Nutrition | |||
| Intravenous feeding n (%) | 1 (10%) | 15 (93.7%) | 0.001† |
| Start of IV feeding | 24 h | 9.86 ± 7 h | 0.073‡ |
| Start of enteral feeding (hours of life) | 1.1 ± 0.56 | 2 ± 0.94 | p = 0.02‡ |
| Breastfeeding/mixed at discharge n (%) | 6 (75%) | 10 (64.3%) | 0.394† |
| Neurological | |||
| Altered cerebral ultrasound at admission n (%) | 4 (40%) | 3 (18.7%) | 0.369† |
| Kangaroo care n (%) | 0 | 15 (100%) | 0† |
| Infectious | |||
| Antibiotics at admission n (%) | 9 (90%) | 3 (18.7%) | 0.001† |
| Nosocomial sepsis n (%) | 6 (60%) | 4 (28%) | 0.211† |
| Hematological | |||
| EPO n (%) | 8 (80%) | 5 (33%) | 0.041† |
| Transfusions n (%) | 5 (50%) | 6 (40%) | 0.622† |
| Ophthalmological | |||
| ROP n (%) | 0 | 1 (7.1%) | 1† |
| Others | |||
| Umbilical vein cannulation at admission n (%) | 5 (50%) | 14 (87.5%) | 0.048† |
| Mortality n (%) | 2 (20%) | 2 (12.5%) | 0.625† |
*χ2.
†Fisher's exact test.
‡Student's t-test.
§Mann-Whitney's U-test. p25-p75: 25th and 75th percentile. CPAP: continuous positive airway pressure; EPO: erythropoietin; IV: intravenous; LISA: less invasive surfactant administration; N: number; PDA: patent ductus arteriosus; PNB: premature newborn; ROP: retinopathy of prematurity; SD: standard deviation.
The changes in management, improvements in the training of neonatal staff, and state-of-the-art medical equipment have led to a significant increase in the survival of preterm infants and a decrease in the prevalence of severe neurological disability30,31. However, other types of less severe neurological problems have increased, such as neuropsychological (autism spectrum disorder, attention deficit hyperactivity disorder, and conduct disorder), motor, and learning disorders. Nutritional support assessment is also relevant, as postnatal malnutrition correlates with future neurological, weight/height alterations. Mid- to long-term follow-up of preterm infants should be coordinated by a multidisciplinary team of pediatricians, rehabilitation specialists, physiotherapists, occupational therapists, and psychologists31,32.
Therefore, the present study aimed to compare the differences in the management of PNBs born in a tertiary level hospital in 2011 and 2021 and to check whether the changes made have an impact on the neurological development and the weight/height of the children in the medium term.
Methods
We conducted a retrospective, observational, and analytical study to examine clinical and NICU management variables of all infants born before 32 weeks of gestation in a Level III-A hospital in 2011 and 2021. Data were obtained from medical record reviews and recorded in an anonymized database designed for the study. Families were contacted at hospital visits and provided verbal consent for review of their children's records. Those who were not followed up at the hospital were contacted by telephone.
Variables were described as mean and standard deviation, median and interquartile range or percentage according to their characteristics. Statistical tests were used according to the type of variable and according to whether the variables fit the normal (Student's t-test) or non-normal (Mann-Whitney's U) distribution. The χ2 test was used for percentage analysis. The statistical analysis program SPSS v.22 was used. Significance was considered at p < 0.05.
The diagnosis of patent ductus arteriosus (PDA) and retinopathy of prematurity (ROP) required the involvement of pediatric cardiologists and ophthalmologists, respectively, using 201133,34 and 202135,36 guidelines. The diagnosis of bronchopulmonary dysplasia was based on dependence on oxygen or mechanical ventilation at 36 weeks of age corrected, according to the 201137 and 202138 definitions.
The percentiles of the somatometric data were obtained from http://www.webpediatrica.com39 and adjusted for gestational age and sex. Data on post-discharge development were obtained from examinations at the hospital outpatient clinic and the health center. The diagnosis of behavioral disorders was based on DSM-5 criteria40.
Results
All patients born in our hospital with gestational age < 32 weeks were included in the study: 10 born in 2011 and 16 born in 2021. The mean gestational age was 29.05 ± 2.4 weeks, varying between 24 and 32 weeks. The surviving lowest gestational-age infants were born in 2021 (their gestational ages were 24 and 25 weeks).
Table 2 shows the epidemiologic data and prenatal management of PNBs in our hospital in 2011 and 2021. We found significant differences between both groups only in the administration of magnesium sulfate.
Table 2 Epidemiological data and prenatal management among premature newborns (PNBs) in 2011 and 2021
| Variable | 2011 (n = 10) | 2021 (n = 16) | p-value |
|---|---|---|---|
| Gestational age Mean ± SD (min-max) | 25 ± 2.4 weeks (25-32) | 29.3 ± 2.5 weeks (24-32) | 0.505‡ |
| Birth weight Mean ± SD (min-max) | 1206.5 ± 257.8 g (680-1490) | 1246 ± 477 g (610-2320) | 0.783‡ |
| Height at birth Mean ± SD (min-max) | 38.5 ± 4.4 cm (29-45) | 37.8 ± 4.7 cm (29.5-44) | 0.932‡ |
| Cranial perimeter at birth Mean ± SD (min-max) | 28 ± 4.7 cm (23-40) | 28 ± 4.6 cm (22-41) | 0.988‡ |
| Gender (males) | 90% | 37.5% | 0.014* |
| Lung maturity | 80% | 87.5% | 0.625* |
| Magnesium sulfate | 0% | 75% | < 0.005† |
| Cesarean section | 50% | 56.2% | 1 |
| Intensive resuscitation at birth (orotracheal intubation, compressions and/or adrenaline) | 50% | 37% | 0.689* |
| Apgar score at 1 min Mean ± SD | 5.5 ± 2.4 | 5.5 ± 2.3 | 0.918‡ |
| Apgar score at 5 min Mean ± SD | 8.1 ± 1.45 | 7.5 ± 1.9 | 0.385‡ |
*χ2.
†Fisher's exact test.
‡Student's t-test. PNB: premature newborn; SD: standard deviation.
Regarding respiratory management, we observed fewer infants treated with surfactant and a delay in its administration in 2021 (Fig. 1). Notably, two patients received surfactant in the delivery room in 2011 but none in 2021. Five of the seven infants with conventional mechanical ventilation in 2021 (84% of infants) were ventilated with volume control strategies, but none in 2011 (p < 0.05).
Since the breast milk bank of our Autonomous Community was inaugurated in 2017, no child born in 2011 received donated breast milk; instead, all children born in 2021, except for one patient at the expressed wish of the family, received donated breast milk during the first days of life. The analysis of weight development during admission showed no significant differences in the percentage of weight lost (14 ± 5.5% vs. 13 ± 8.2%, p = 0.72). However, we observed a higher mean percentile of weight (20.7 ± 27 vs. 6.3 ± 7.2, p = 0.081) (Fig. 2) and height (13 ± 20 vs. 5 ± 4.5, p = 0.206) at discharge in 2021 compared to 2011.
Table 1 shows the percentage of children who required specific treatments and had specific diagnoses each year. Two patients died in each group, representing 20% of children in 2011 and 12.5% in 2021 (p = 0.625).
Regarding the evolution after discharge, we did not observe significant differences in weight development or a significant relationship between somatometric data at discharge from neonatology and subsequent evolution. Only six patients (27.3%) had alterations in psychomotor development (Table 3). No significant relationship was found between weight development at discharge and alterations in psychomotor development. However, it was observed that all children with altered psychomotor development had alterations in the central nervous system (CNS) ultrasound performed at admission.
Table 3 Relationship between results of neonatal cerebral ultrasound performed during admission and neurological disorders developed by the children subsequently and age at diagnosis
| Year | Neonatal cerebral ultrasound | Diagnosis | Age at diagnosis |
|---|---|---|---|
| 2011 | Germinal matrix hemorrhage. | Autism spectrum disorder Grade 2 | 18 m |
| 2011 | Right periventricular cystic leukomalacia | Spastic triplegic cerebral palsy | 12-15 m |
| 2011 | Intraventricular hydrocephalus secondary to Grade III intraventricular hemorrhage and Grade II cystic leukomalacia. | Mild left hemiparesis | 15 m |
| 2021 | Grade II periventricular leukomalacia+ex vacuo hydrocephalus | Spastic diplegic cerebral palsy | 19 m |
| 2021 | Germinal matrix hemorrhage. | Mild global developmental delay | 18 m |
| 2021 | Grade II intraventricular hemorrhage | Mild global developmental delay | 18 m |
Diagnoses according to DSM-5 criteria39. m: months.
Discussion
The medical records of 26 neonates born at a gestational age of < 32 weeks and admitted to the NICU of our hospital (level III-A) between 2011 and 2021 were analyzed. Although the sample size is small, the analysis of the records showed the changes that have occurred in the care of preterm infants over a decade.
Although we did not find significant differences between the two groups in gestational age and somatometric data, we observed that infants of lower gestational age (24 and 25 weeks) who survived were born in 2021. These patients had a high number of complications, longer mechanical ventilation duration, and longer hospital stays. It is noteworthy the high rate of males born in 2011, when, according to data from the Spanish National Statistics Institute (Instituto Nacional de Estadística español), the percentage of males born that year in our Autonomous Community was similar to that of females (51.9% males vs. 48.1% females)41. The analysis of prenatal management showed only differences in the administration of magnesium sulfate, which was expected since it was not until the mid-2010s that its use became widespread in Spain following the publication of its role as a neuroprotectant42.
There are three fundamental points in which we have observed changes in the management of these patients in our NICU that have allowed greater harmonization with international guidelines. First, we observed differences in several aspects of respiratory management, particularly in the reduced use of surfactant, a significant delay in administering the first dose, and the generalization of less invasive administration techniques such as surfactant administration16. Similarly, we observed a trend toward greater use of noninvasive ventilation, especially continuous positive airway pressure, at admission and during hospitalization, and modalities with tidal volume control in the case of invasive mechanical ventilation, both strategies in line with the latest published evidence16,43. It is noteworthy that the duration of mechanical ventilation was longer in neonates born in 2021. This is secondary to the fact that this year, there were two patients of extreme gestational age (24 and 25 weeks) who required respiratory support for 85 and 61 days, respectively.
Second, we noted the early and widespread initiation of optimized parenteral nutrition in 2021, as indicated by national and international recommendations20,22,23, in addition to the significantly earlier initiation of enteral nutrition based on breastfeeding from the milk bank. Both factors have allowed these neonates' weight and height percentiles at discharge to be higher than in 2011. However, we could not demonstrate a relationship between weight development and neurological development as has been published44.
Third, thanks to the internationally recommended rational use of antibiotics26,27, rates of empiric antibiotic therapy decreased significantly in 2021 without an increase in early mortality due to sepsis of vertical transmission or an increase in the rate of nosocomial sepsis. In this context, the reduced use of erythropoietin, as recommended27,29, was also confirmed, being used only in selected patients without an increase in transfusion rates.
In contrast, we did not observe significant differences in the rates of PDA, ROP, and brain lesions, problems that are very common in the first weeks of life of extremely preterm infants6-8. As for PDA and ROP, there were more cases of both in 2021 because the youngest gestational-age infants in the study were born in that year, although their incidence was lower than that published in the literature32. The rate of brain lesions observed at each stage was also lower than other reports30,31,45-47, but has a subsequent neurological impact. Based on our results and large international series30-47, we can correlate the alteration of the neonatal cerebral ultrasound with alterations in psychomotor development during early childhood. In this sense, although the differences are not significant, the most severe pictures correspond to children born in 2011 and are characterized by severe motor problems secondary to intraventricular hemorrhage.
Finally, although not statistically significant, the mortality rate is much lower in 2021, which is consistent with review articles relating improved care to increased survival of patients, especially those with extreme gestational age45-47.
As limitations, we consider that despite including all preterm infants born in our hospital in 2011 and 2021, the total sample size was small. This fact has limited the achievement of statistical significance in some comparisons but gives more value to those comparisons that have achieved it. Although there is a decade between both years studied, the changes may need more time to be evaluated. Therefore, in subsequent studies, we will consider analyzing years that are further apart in time.
There are differences in the management of preterm infants over 10 years, with greater adherence to current national and international guidelines.
Lower mortality and fewer CNS ultrasound changes, and significantly less growth retardation were observed in neonates born in 2021; however, no improvement in long-term somatometrics or neurological prognosis were demonstrated so far.
