This single-center cross-sectional study was conducted from January 2018 through December 2022 at the Maternal-Fetal Medicine and Neonatology Divisions of the Instituto Nacional de Perinatologia in Mexico City, a tertiary-level national maternal and neonatal care referral center. The study population consisted of all consecutive extremely preterm newborns (i.e., gestational age 22.0–27.6 weeks) born from a singleton pregnancy. Gestational age was primarily determined using the best obstetric estimation, defined as a reliable last menstrual period confirmed by a first-trimester crown-rump length measurement or early second-trimester biometry (i.e., biparietal diameter) (13). In cases where this information was unavailable, gestational age was estimated using standardized neonatal assessment tools (14). Births with unknown gestational age were excluded from the analysis. Stillbirths occurring outside the hospital, neonates with major structural anomalies (i.e., those expected to cause mortality or severe morbidity identifiable at birth) or genetic syndromes, cases with incomplete medical records, and neonates receiving perinatal palliative care were excluded from the study.

For the present analysis, fetal death was defined as the delivery of a neonate without signs of life (i.e., absence of breathing, heartbeat, umbilical cord pulsation, or voluntary muscle movement) after complete expulsion or extraction from the mother, occurring either before labor (i.e., antepartum mortality) or during labor and delivery (i.e., intrapartum mortality) (15). Live birth was defined as the delivery of a neonate exhibiting any sign of life following complete expulsion or extraction (15). Obstetric and neonatal management were at the discretion of the attending obstetrician and neonatologist. Notably, all live-born neonates included in this analysis received active neonatal care at birth, including cardiopulmonary resuscitation, intubation, and invasive or non-invasive mechanical ventilation (16). The Neonatal Intensive Care Unit (NICU) level at our institution is classified as level III, according to the American Academy of Pediatrics (17).

Data regarding the pregnancy, neonatal period, and infant outcomes were retrieved from electronic medical records. Definitions for neonatal morbidities are presented in Supplementary Table S1. According to institutional regulations, retrospective analyses of anonymized data are exempt from formal ethics committee review and approval. Additionally, all women provided written consent at the time of prenatal care enrollment to use their routinely collected hospital data in retrospective studies, ensuring no patient identifiers were included.

Baseline characteristics and morbidity are reported using n (%) for categorical variables, mean (standard deviation) for normally distributed continuous variables, and median (interquartile range) for non-normally distributed variables. For this descriptive analysis, the neonatal survival rate was estimated using three different denominators and expressed as percentages: (1) the total number of extremely preterm births, including intrapartum fetal deaths; (2) the total number of all live births, including neonatal deaths in the delivery room, and (3) the total number of extremely preterm neonates admitted to the NICU. A 95% confidence interval (CI) for proportions using the method proposed by Clopper-Pearson was calculated for the outcomes of interest. Statistical analyses were performed in Stata (Version 18.0, StataCorp LLC, Texas, USA).

Table 3 presents survival rates to NICU discharge calculated using three different denominators: (1) all births (including antepartum and intrapartum fetal deaths), (2) all live births, and (3) neonates admitted to the NICU. Additionally, Figure 2 provides a visual representation of survival estimates across gestational ages for each denominator.

The overall survival rate to NICU discharge among extremely preterm infants was 49% (65/132) when considering all births, 67% (65/97) when considering all live births, and 69% (65/93) when considering NICU admissions. No neonates born before 24.6 weeks of gestation survived to discharge. At all gestational ages, the survival rate calculated based on all births was lower than the estimated when only live births or NICU admissions were considered. However, the difference in survival rates between denominators diminished with increasing gestational age, as shown in Table 3.

Among neonates who survived NICU discharge, 96.9% (63/65) developed at least one major morbidity, defined as the presence of one or more of the following: septic shock, neonatal seizures, necrotizing enterocolitis, grade 3–4 intraventricular hemorrhage, periventricular leukomalacia, moderate-to-severe bronchopulmonary dysplasia, and retinopathy of prematurity. The most common morbidity was moderate-to-severe bronchopulmonary dysplasia, occurring in 90.8% of cases, followed by retinopathy of prematurity (75.4%) and necrotizing enterocolitis (24.6%), as shown in Table 4. Therapeutic interventions administered in the NICU are detailed in Supplementary Table S2.

Our analysis highlights the impact of denominator selection when reporting neonatal survival. The choice of the denominator (i.e., all births, live births, NICU admissions) considerably affects reported survival rates, particularly at lower gestational ages. At 25 weeks, survival rates varied from 13 to 33%, depending on the denominator used. However, this variation diminished with increasing gestational age, and differences became clinically irrelevant from 26 weeks onwards. A decreasing fetal mortality rate may explain this trend as gestational age increases, as well as our institution's active neonatal care policy (i.e., ≥26.0 weeks of gestation or birth weight ≥700 g). Similar findings have been reported in previous studies (1, 26, 29, 30).

The denominator used in survival analysis can significantly influence the interpretation of neonatal outcomes. Estimations based on NICU admissions may exclude neonates who did not receive resuscitation. In contrast, reports based solely on live births may overestimate survival by ignoring pregnancies at the limits of viability, where active obstetric or neonatal care is not provided (1, 29). The WHO recommends considering fetal and delivery room mortality in survival analysis, yet many studies that estimate neonatal survival fail to include this critical information (31).

Neonatal morbidity at discharge was high in our study population. Moderate-to-severe bronchopulmonary dysplasia (90.8%), retinopathy of prematurity (75.4%), and necrotizing enterocolitis (24.6%) were the most frequently observed complications. This pattern has been previously described in the literature (6); however, our observed morbidity rates were significantly higher than those reported in high-income countries (24, 32). While survival rates are critical in extremely preterm neonates, long-term morbidity remains a significant concern, posing challenges for healthcare systems and families. Our findings highlight the need for improved access to high-quality neonatal care and the potential optimization of existing management strategies.

Our study has some strengths. It provides updated data on a topic with limited research in middle-income settings, addressing a critical knowledge gap. We also included an unselected population with reliable gestational age assessment and all neonatal care was overseen by experienced neonatologists. Moreover, the study performed a comprehensive survival analysis using different denominators, emphasizing their impact on reported outcomes and their importance when counseling families. Furthermore, we provide precision estimates of the reported results via 95% confidence intervals.

However, some limitations should be acknowledged. First, the retrospective design may introduce biases inherent to observational studies. Second, obstetric and neonatal management were at the discretion of the attending clinicians, potentially influencing neonatal outcomes. Third, the lack of active management at periviable gestational ages may have affected survival estimates. Additionally, long-term follow-up data (e.g., neurodevelopment outcomes) were unavailable, limiting a comprehensive assessment of health trajectories beyond NICU discharge.

Finally, as this was a single-center study conducted in a national tertiary-level referral hospital, the findings reflect local clinical practices and may not be generalizable to other institutions or healthcare systems. Further studies addressing causal relationships between outcomes and exposures are warranted beyond a detailed description. Moreover, the relatively small sample size, particularly at the lowest gestational ages, hampered the possibility of additional analyses. Future studies involving larger and diverse samples are needed to validate the reported results and to account for heterogeneity in care practices across regions and countries.