Gestational age–dependent effects of intrauterine inflammation, delivery mode, and fetal growth on respiratory morbidity in preterm neonates

Abstract

Introduction:

Respiratory morbidity in preterm neonates is influenced by both lung immaturity and antenatal environmental exposures. Because lung maturation continue throughout late gestation, the effects of these factors may vary according to gestational age. As most preterm neonates are born after 28 weeks, a better understanding of respiratory morbidty in this population is clinically important. We aimed to evaluate the gestational age–specific effects between intrauterine inflammation, other perinatal factors, and respiratory morbidity in neonates born between 28 and 36 weeks of gestation.

Methods:

We retrospectively analyzed the data of 912 neonates born between 28 and 36 weeks of gestation from March 2013 to December 2018 at Nagoya City University West Medical Center. Respiratory morbidity was defined as the need for invasive ventilation or continuous positive airway pressure for ≥24 h. Logistic regression analyses, including interaction terms with gestational age, were used to assess gestational age–specific associations.

Results:

Respiratory morbidity occurred in 275 neonates (30.2%) and was associated with lower gestational age, cesarean delivery, chorioamnionitis, funisitis, and low umbilical cord pH. At earlier gestational ages (33.4 weeks; 1 SD below the mean), intrauterine inflammation and higher birth-weight Z-score increased the risk of respiratory moribidity, whereas the adverse role of cesarean delivery was significant only at later gestational ages (36.5 weeks; 1 SD above the mean).

Conclusion:

The effects of intrauterine inflammation, fetal growth, and cesarean delivery on respiratory morbidity differed according to gestational age. These findings suggest that gestational age–specific assessment of perinatal factors may improve the prediction and management of respiratory morbidity in preterm neonates. However, because only gestational age was adjusted for, residual confounding by other factors cannot be excluded, and these findings should be interpreted with caution.

Introduction

Approximately one-third to one-half of preterm infants experience cognitive or learning difficulties requiring support during school age or beyond (1), highlighting the gap between improved survival and suboptimal long-term outcomes. Inflammation, along with immaturity and hypoxia-ischemia, influences outcomes in preterm neonates through its association with morbidities such as periventricular leukomalacia, necrotizing enterocolitis, and chronic lung disease (2). The impact of inflammation on neonatal lungs has been extensively studied in extremely preterm neonates born before 28 weeks of gestation and in extremely low birth-weight neonates (3, 4). Preclinical studies have shown that the saccular stage of lung development is particularly vulnerable to inflammation (5). Neonates born between 28 and 36 weeks of gestation are predominantly in this developmental stage, during which alveolar and microvascular maturation remain ongoing (6). Experimental studies suggest that inflammatory exposure can disrupt ongoing alveolar and microvascular maturation, potentially affecting pulmonary function and respiratory adaptation after birth (7, 8). Consistent with these findings, intrauterine inflammation has been associated with an increased risk of bronchopulmonary dysplasia. However, its association with respiratory distress syndrome remains controversial, with previous studies reporting both higher and lower incidences of respiratory distress syndrome among exposed neonates (9–13). These inconsistent findings may reflect difference in clinical context, therapeutic interventions, and timing of exposure (12).

While substantial evidence is available regarding respiratory outcomes in extremely preterm neonates, relatively few studies have focused on more mature preterm neonates, likely due to their favorable survival outcomes. Both restricted and excessive fetal growth may influence lung maturation through alterations in the intrauterine hormonal environment (14), whereas cesarean delivery may affect postnatal respiratory adaptation by modifying the timing and physiological processes of birth (15). However, because 95% of preterm neonates are born after 28 weeks of gestation (16), improved prediction, diagnosis, and management of respiratory morbidity in very, moderate, and late preterm infants may substantially reduce healthcare burden. Because lung maturation continues throughout this period, the effects of various perinatal factors, including inflammation, on respiratory morbidity may vary according to gestational age. Accordingly, we aimed to evaluate the gestational age–specific effects of inflammation and other perinatal factors on respiratory morbidity in preterm neonates born after 28 weeks of gestation.

Methods

This retrospective observational study was approved by the Ethics Committee of Nagoya City University West Medical Center, Nagoya, Japan (21-04-393-45). The review board waived the requirement for informed parental consent because anonymized data collected during routine clinical practice were used. All procedures complied with relevant guidelines and regulations.

Study population

Between March 2013 and December 2018, 1,092 preterm neonates (<37 weeks of gestation) were born at the birth center of Nagoya City University West Medical Center, a single tertiary center. We reviewed the data of 912 preterm neonates born between 28 and 36 weeks of gestation after excluding those born before 28 weeks (n = 60). At this center, histopathological placental examination is routinely performed for all preterm births. The following neonates were excluded: 101 without placental samples, 15 with major congenital anomalies, four who died before discharge, one with anencephaly, one with intrauterine Listeria infection, one with fetomaternal transfusion, and one with hyperkalemia (Figure 1).

Figure 1

Clinical variables

Clinical records were reviewed for background characteristics, treatments, and clinical findings. Maternal variables included multiple births, antenatal steroid use, parity, premature rupture of the membranes, placenta previa, hypertensive disorders of pregnancy, gestational diabetes mellitus, gestational age at delivery, chorioamnionitis, and funisitis. Neonatal variables included birth weight and Z-score, sex, Apgar scores, need for respiratory support at birth, and laboratory results from cord and venous blood obtained at admission. Meconium-stained amniotic fluid, defined as the presence of meconium in the amniotic fluid, was visually assessed either at the time of membrane rupture or during labor (17). All placentas and umbilical cords were examined by an experienced pathologist. Chorioamnionitis was defined as Blanc's classification stage II or greater, indicating neutrophil infiltration of the chorionic plate (18), and funisitis as neutrophil infiltration within the walls of umbilical vessels or Wharton's jelly (19).

Laboratory studies

At this center, serum C-reactive protein (CRP), α₁-acid glycoprotein (α₁‐AG), and haptoglobin are routinely measured using venous blood obtained at admission; cord blood is used for neonates not admitted to the Neonatal Intensive Care Unit (NICU). All assays were performed using a turbidimetric immunoassay (Quick Turbo, Shino-Test, Tokyo, Japan). Positivity was defined as CRP ≥0.3 mg/dL, α₁-AG ≥20 mg/dL, and haptoglobin ≥13 mg/dL. An Acute-Phase Inflammatory Reaction Score was assigned: 0 (no positive biomarker), 1 (one positive), 2 (two positive), and 3 (all three biomarkers positive) (Online Supplementary Table) (20–22).

Statistical analysis

Values are presented as mean ± standard deviation (SD), number (%), or median (interquartile range) unless otherwise specified. The primary outcome was short-term respiratory morbidity requiring invasive mechanical ventilation or continuous positive airway pressure for ≥24 h, thereby excluding respiratory support provided solely for immediate postnatal resuscitation or stabilization. Univariable logistic regression was used to assess crude associations between clinical variables and respiratory morbidity. Results from the logistic regression analysis are presented as odds ratios (ORs) with 95% confidence intervals (CIs). No adjustments were made for multiple comparisons in univariable analysis because of its exploratory nature. To assess the influence of gestational age, clinical variables, and their interactions on the incidence of respiratory morbidity, generalized linear models were applied. Interaction terms were tested for variables that showed significant associations in the univariable analysis, inflammation-related variables, and those previously reported to influence respiratory outcomes. Gestational age was mean-centered before analysis. Post-hoc simple slope analyses were performed for predetermined independent variables (chorioamnionitis and funisitis) and for those demonstrating significant interactions with gestational age in the univariable analysis. The simple slope analysis estimated the slope of regression lines for the relationships between the independent variables and respiratory morbidity at two representative gestational ages: “low” (1 SD below the mean) and “high” (1 SD above the mean). Statistical analyses were conducted using SPSS Statistics version 28 (IBM Corp, Armonk, NY, USA). A p-value <0.05 was considered statistically significant.

Results

The final study cohort comprised 912 neonates with a mean gestational age of 34.9 ± 1.6 weeks and mean birth weight of 2,158 ± 405 g. Multiple births occurred in 279 cases (30.6%), and hypertensive disorders of pregnancy in 125 (13.7%). Antenatal steroids were administered in 149 cases (16.3%). Premature rupture of membranes lasting >24 h occurred in 119 cases (13.1%). Cesarean delivery was performed in 575 neonates (63.0%). Overall, 275 neonates (30.2%) required respiratory support. Chorioamnionitis and funisitis were diagnosed in 106 (11.6%) and 127 (13.9%) neonates, respectively.

Influence of clinical variables on respiratory morbidity

Among maternal variables, cesarean delivery (p = .029), multiple birth (p = .027), chorioamnionitis (p < .001), funisitis (p = .045), and antenatal steroid use (p < .001) were associated with increased incidence of respiratory morbidity. Among postnatal clinical variables, lower gestational age (p < .001), lower birth weight (p < .001), male sex (p = .045), lower 1-minute and 5-minute Apgar scores (both p < .001), lower cord blood pH (p < .001), elevated CRP (p = .001), elevated α₁-AG (p = .037), elevated haptoglobin (p = .010), and an acute-phase inflammatory reaction score of 3 (p = .023, compared with score 0) were associated with the incidence of respiratory morbidity (Table 1).

Gestational age–specific influence of clinical variables on respiratory morbidity

Interactions with gestational age were identified for birth-weight Z-score (OR 0.9, 95% CI 0.8–1.0, p = .002), cesarean delivery (OR 1.6, 95% CI 1.2–2.1, p = .001), and funisitis (OR 0.6, 95% CI 0.4–0.9, p = .019) but not for chorioamnionitis (OR 0.7, 95% CI 0.5–1.0, p = .055) (Table 2).

Simple slope analysis was performed to estimate the slope of regression between independent variables and the incidence of respiratory morbidity at low (33.4 weeks) and high (36.5 weeks) gestational ages. A higher birth-weight Z-score (OR 1.4, 95% CI 1.1–1.7, p = .002), chorioamnionitis (OR 2.5, 95% CI 1.1–5.9, p = .034), and funisitis (OR 2.4, 95% CI 1.0–5.5, p = .039) were associated with increased incidence of respiratory morbidity at low gestational ages only. In contrast, cesarean delivery was associated with increased incidence of respiratory morbidity at high gestational ages (OR 3.5, 95% CI 1.7–7.1, p < .001), but not at low gestational ages (Table 3).

Discussion

In this study, we demonstrated that antenatal inflammation, represented by chorioamnionitis and funisitis, was associated with adverse short-term respiratory outcomes only at low gestational ages. A higher birth-weight Z-score showed a similar interaction pattern, being associated with respiratory morbidity only at low gestational ages. Meanwhile, caesarean delivery was associated with respiratory morbidity only in high gestational ages. These findings suggest that intrauterine inflammation and excessive fetal growth disproportionately affect more immature neonates, whereas cesarean delivery poses a greater risk among more mature preterm neonates. Gestational age should be carefully considered when determining the optimal mode and timing of delivery.

Intrauterine inflammation and gestational age

The impact of infection and inflammation on the lungs has been extensively investigated in extremely preterm neonates because of their high incidence of long-term respiratory morbidity, most notably bronchopulmonary dysplasia, and its lifelong consequences (3, 4). Intrauterine inflammation appears to exert both beneficial and deleterious effects on the developing lung. On one hand, inflammatory exposure may induce pulmonary injury, alter vascular permeability, and impair respiratory adaptation after birth. Recent studies have also reported reduced breathing effort at birth among premature infants exposed to chorioamnionitis or funisitis (23). On the other hand, intrauterine inflammation may accelerate pulmonary maturation and surfactant synthesis, leading to a reduced incidence of acute respiratory disorders in some observational studies (9, 10, 12).

The clinical implications of inflammation may extend beyond extremely preterm neonates. Meconium aspiration syndrome, traditionally regarded as a consequence of airway obstruction and lung inflammation triggered by fetal hypoxia-ischemia and subsequent meconium passage, is now thought to involve systemic inflammation. Lung injury may precede aspiration of contaminated amniotic fluid, with fetal exposure to pro-inflammatory cytokines possibly inducing lung injury and stimulating bowel peristalsis, leading to meconium passage (17, 20, 21). Our group previously reported that inflammation-related respiratory morbidities are common among neonates born at 32–34 weeks of gestation (22). Nevertheless, data on the impact of inflammation on lung development and respiratory outcomes among preterm neonates born after 28 weeks remains limited.

In the present study, we found that intrauterine inflammation adversely affected short-term respiratory outcomes only among those with relatively lower gestational ages. Compared to many previous studies reporting a beneficial impact of intrauterine inflammation on short-term neonatal respiratory function (9, 10, 12), our study included relatively more mature neonates. Previous studies suggested that background variables such as antenatal glucocorticoid administration influence the impact of inflammation on the incidence of short-term respiratory morbidities. Since the 2000s, antenatal steroid administration has become widely adopted, particularly in Western countries, with reported administration rates of 80%–90% among neonates born before 34 weeks of gestation (24). Although intrauterine inflammation reportedly improves short-term respiratory outcomes in preterm neonates, such benefits may reflect the effects of antenatal steroid use rather than the inflammation itself. Because extremely preterm neonates are both more likely to receive antenatal steroids and more frequently born due to intrauterine inflammation, separating the independent effects of inflammation remains challenging. Given the complex interplay among these various factors, future studies with larger sample sizes may be necessary to clarify the independent effect of inflammation on respiratory morbidity.

Large birth-weight Z-score and gestational age

Intrauterine growth restriction is a known risk factor for chronic lung disease. However, its effects on short-term respiratory outcomes may differ, as accumulating evidence suggests an inverse relationship between organ maturation and fetal growth (25). Antenatal stress, such as that resulting from prolonged placental dysfunction, may stimulate endogenous cortisol production (14), accelerating lung maturation and potentially reducing the incidence of acute respiratory complications (26). Conversely, large-for-gestational-age fetuses, who experience less intrauterine stress and greater nutrient supply, exhibit delayed lung development in preclinical models (27). Furthermore, even in the absence of maternal diabetes, large-for-gestational-age neonates have been reported to exhibit higher cord blood insulin and C-peptide concentrations than appropriate-for-gestational-age neonates (28, 29), suggesting relative fetal hyperinsulinemia, which may inhibit surfactant production and delay lung maturation. In addition, delayed cardiopulmonary adaptation after birth has been reported in large-for-gestational-age neonates born to both diabetic and nondiabetic mothers (25), which may increase susceptibility to respiratory morbidity during the early neonatal period. Consistent with our previous findings in neonates born at 32–34 weeks (22), the present study demonstrated that greater fetal growth was associated with an increased risk of short-term respiratory morbidity, particularly among less mature preterm neonates. Although “greater fetal growth” is often perceived as reassuring and favorable, our findings indicate that excessive fetal growth may delay lung maturation and contribute to short-term respiratory morbidity.

Mode of delivery and gestational age

Cesarean sections performed for indications other than emergencies‒such as breech presentation, multiple gestation, or prior cesarean delivery‒are becoming increasingly common (30). The World Health Organization has cautioned that the rising use of labor induction and cesarean delivery has contributed to the global increase in moderate-to-late preterm births (31). Among near-term and term neonates, cesarean delivery without labor is associated with a higher risk of respiratory disorders, potentially owing to reduced catecholamine release, absence of thoracic compression, and delayed clearance of lung fluid (32). Consequently, cesarean deliveries performed for non-medical reasons may impose significant health burdens and increase healthcare resource use. Despite the importance of weighing its benefit against potential adverse outcomes, little is known about the gestational age–specific effects of cesarean delivery on neonatal respiratory transition.

We found that cesarean delivery was associated with an increased incidence of short-term respiratory morbidity only in neonates with relatively higher gestational ages. Performing cesarean delivery in relatively more preterm neonates up to 34 weeks of gestation may not confer additional risk of short-term respiratory morbidity. Conversely, cesarean delivery increased the odds of developing short-term respiratory morbidity by 3.5-fold in neonates born at approximately 35‒36 weeks of gestation. Considering that the effect of cesarean delivery on short-term respiratory morbidity was among the most prominent effects observed in this study, further dissemination of these findings may be warranted to minimize non-medical cesarean deliveries during the late-preterm period.

Strengths and limitations

Using a relatively large study population, we could assess the gestational age–specific roles of inflammation and other important variables in the development of short-term respiratory morbidities. The effect of inflammation was evaluated using histological examination of the placenta. Because the study population included neonates across a wide range of gestational ages, we could examine gestational age–dependent associations between antenatal inflammation, additional clinical factors, and respiratory outcomes. Nevertheless, some limitations must be noted. Neonates born before 28 weeks of gestation were not included because their short-term respiratory morbidity is primarily determined by lung immaturity; indeed, most extremely preterm neonates require invasive respiratory support. We evaluated only short-term respiratory morbidities; therefore, the relationship among antenatal inflammation, other clinical background variables, long-term respiratory outcomes, neurodevelopmental outcomes, and economic impact remains unknown. Furthermore, although we assessed acute-phase reactants such as CRP, α₁-acid glycoprotein, and haptoglobin to capture antenatal inflammation across different pathways, we were unable to evaluate pro-inflammatory cytokine responses. Future studies may explore cytokine profiles in amniotic fluid and other biological samples to better characterize gestational age–specific inflammatory responses and subsequent incidence of respiratory morbidities. Finally, although major clinical confounders were included in the multivariable models, residual confounding resulting from the coexistence of multiple perinatal conditions may still be present. Therefore, the observed associations should be interpreted with caution. More detailed obstetric and perinatal information may help further clarify these findings.

Conclusion

Intrauterine inflammation was associated with adverse short-term respiratory morbidities only in neonates born at relatively low gestational ages, a pattern that is consistent with observations in the current perinatal care environment, where antenatal glucocorticoids are widely used. This finding also aligns with earlier reports suggesting that intrauterine inflammation exerts greater deleterious impact on relatively immature lungs. The birth-weight Z-score was inversely associated with respiratory morbidity among neonates with relatively lower gestational ages, indicating that large-for-gestational-age may not necessarily confer a favorable respiratory transition shortly after birth. Our study also confirmed that the risk of respiratory morbidity associated with cesarean delivery was evident only among neonates of relatively higher gestational age, supporting strategies aimed at avoiding non-medically indicated cesarean deliveries while not hesitating to use this delivery mode for medical indications in more premature neonates. Further research is needed to confirm the gestational age–specific roles of inflammation and other independent variables in the development of short- and long-term respiratory morbidities among neonates with diverse gestational stages and clinical backgrounds. Nevertheless, because only gestational age was adjusted for, residual confounding by other factors cannot be excluded, and these findings should be interpreted with caution.

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