Introduction

The timing of delivery is widely acknowledged as a crucial factor influencing neonatal outcomes1,2. Although term pregnancy is commonly defined as delivery occurring between 37+ 0 and 41+ 6weeks of gestation, and neonates born during this period have commonly been considered a homogeneous low-risk group, however, considerable evidence indicates that the rates of neonatal morbidity and mortality can vary significantly within this time frame3,4,5. Among the various outcomes, neonatal respiratory failure (NRF) - which includes conditions such as transient tachypnea of the newborn, respiratory distress syndrome, and persistent pulmonary hypertension - stands out as a major contributor to neonatal morbidity6,7. Infants with NRF often require intensive respiratory support and extended hospitalization, with potential short- and long-term consequences on their health8,9,10. Therefore, it is essential to prioritize the identification of risk factors and the implementation of preventive strategies in the realm of perinatal care.

Previous studies have shown that infants born at 37 and 38 weeks, have a higher probability of experiencing respiratory issues compared to those born at 39 or 40 weeks in elective repeat cesarean deliveries11. As a result, infants born at 37–38 weeks have been designated as “early-term” to emphasize the need for increased medical attention12,13,14. However, while infants born post-term, with a gestational age of more than 42 weeks, are recognized as being at risk for adverse outcomes, term infants born at 41 weeks have not been as thoroughly studied. These infants are often categorized alongside those born at 39–40 weeks as full-term infants or separately named as “late-term”15,16. The precise relationship between gestational age throughout the entire term period and the occurrence of NRF remains not fully understood. This research endeavor seeks to present compelling evidence on the association between gestational age and NRF, identify term infants at higher risk, and explore the potential implications for the timing of non-medically indicated elective cesarean sections in reducing NRF occurrences and improving neonatal outcomes.

Methods

Study design and population

This retrospective cohort investigation utilized a vast, population-centered dataset compiled by 50 states and the District of Columbia for the National Vital Statistics System in the United States. The study focused on singleton term infants born within the gestational age range of 37 to 41weeks. Infants with significant congenital anomalies such as congenital heart defects or chromosomal disorders, those with unclear respiratory support status post-birth, or lacking essential data on delivery method, crucial maternal, or infant clinical features were excluded.

Exposure

The primary focus of this study was on gestational age, which was divided into distinct categories of completed weeks: 37, 38, 39, 40, and 41 weeks. Gestational age was determined through obstetric assessment at birth and sourced from the database.

Outcome

The main outcome measured was neonatal respiratory failure (NRF), defined as the need for assisted ventilation exceeding six hours record in the database. The assisted ventilation includes conventional ventilation, high-frequency ventilation, or continuous positive airway pressure (CPAP). However, it excludes free-flow oxygen only, laryngoscopy for aspiration of meconium, and the use of a nasal cannula.

Covariates

Various covariates were considered to account for potential confounding variables. These covariates included maternal aspects: age, race/ethnicity, educational background, marital status, parity, pre-pregnancy body mass index (BMI), and pre-existing medical conditions (diabetes and hypertension). Additionally, factors related to pregnancy were included: gestational diabetes, gestational hypertension, infertility treatments, antenatal corticosteroid use, and chorioamnionitis. Delivery-related variables, including the method of delivery (vaginal or cesarean section), induction of labor and infant characters of sex and birth weight were among the covariates analyzed in the study.

Maternal age was categorized based on age at delivery into the following groups: 15–19 years, 20–24 years, 25–29 years, 30–34 years, 35–39 years, 40–44 years, and 45–54 years. Maternal race and ethnicity were self-reported and categorized as Hispanic, non-Hispanic Black, non-Hispanic White, or Other. Maternal educational levels were recorded as less than high school, high school diploma, or more than high school. Marital status was classified as married or unmarried. Parity, defined as the total number of live births excluding the current delivery, was categorized as 1, 2, 3, or more than 3. The timing of prenatal care initiation was grouped by trimester: no prenatal care, 1st to 3rd month, 4th to 6th month, and 7th to 9th month. Maternal pre-pregnancy BMI was calculated using pre-pregnancy weight in kilograms divided by height in meters squared and classified into the following categories: less than 18.5, 18.5–24.9, 25.0-29.9, 30.0-34.9, 35.0-39.9, or 40 or higher. Gestational diabetes, pre-pregnancy diabetes, gestational hypertension, pre-pregnancy hypertension, and infertility treatment were each categorized as yes or no. Information on these maternal variables was directly obtained from the database. Neonatal sex was categorized as male or female. Birth weight, converted from pounds and ounces to grams by the National Center for Health Statistics. Method of delivery, induction of labor, antenatal corticosteroid use, and chorioamnionitis were also included.

Statistical analysis

Statistical analyses were conducted using Stata, version 15.0 (StataCorp LLC) and R Studio, version 2023.03.0 + 386 (Posit Software, PBC). All P values were two-sided, with P < 0.05 considered statistically significant. For continuous variables, means and standard deviations (SDs) were reported, while frequencies and percentages were provided for categorical variables. Differences between groups were assessed using the χ² test for categorical variables.

The occurrence of NRF was determined for each gestational age group, and odds ratios (ORs) with 95% confidence intervals (CIs) were computed to assess NRF risk across these groups, using the gestational age with the lowest NRF risk as the reference category.

Multivariable logistic regression models were utilized to adjust for identified covariates and estimate adjusted ORs(aORs) for NRF associated with each gestational age group. These models were developed to account for potential confounding factors, including maternal age, race, education level, marital status, parity, maternal BMI, maternal diabetes, hypertension, infertility treatment, antenatal corticosteroid use, chorioamnionitis, delivery mode, infant sex, and birth weight to ensure the validity of the results.

Subgroup analyses were conducted to investigate potential interactions by infant sex or delivery mode. The analysis employed Restricted Cubic Splines (RCS) with three knots to model the nonlinear relationship between gestational age and NRF risk. Gestational age was considered a continuous variable, and the model was adjusted for the aforementioned potential confounding factors. aORs with 95% CIs were calculated using 39 weeks as the reference point. Notably, infants delivered via elective C-section were a key focus population. Elective C-section infants were defined as infants born via C-section without labor induction, no trial of labor, and no maternal diabetes, hypertension, or chorioamnionitis. However, the database does not specify whether these cesarean sections were performed for medical or non-medical indications. Thus, the term “elective” in this study reflects the absence of labor-related factors but does not preclude the possibility of underlying medical indications.

Ethical considerations

The study protocol was reviewed and approved by the Children’s Hospital of Fudan University Institutional Review Board (IRB). The study was conducted in compliance with the Declaration of Helsinki and the Children’s Hospital of Fudan University IRB waived the requirement for informed consent due to the retrospective nature of the study and the use of de-identified data. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies17.

Results

Study population

Following the exclusion process, the study cohort comprised 4,978,703 term newborns delivered between 37 and 41+ 6weeks of gestation (Fig. 1). The breakdown of infants based on gestational age was as follows: 628,553 (12.6%) born at 37 weeks, 996,691 (20.0%) at 38 weeks, 1,876,502 (37.7%) at 39 weeks, 1,053,911 (21.2%) at 40 weeks, 423,046 (8.5%) at 41 weeks and the incidence of NRF was found to be highest among infants born at 37 weeks (1.7%), gradually decreasing as gestational age advanced, reaching a low point at 39 weeks (0.6%). Subsequently, there was a slight increase for deliveries at 40weeks (0.7%) and 41 weeks (0.8%). (Fig. 2).

Fig. 1
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Participant flowchart.

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Fig. 2
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Proportion of deliveries at different gestational age and incidence of primary outcome.

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Maternal and neonatal characteristics

Maternal and neonatal attributes displayed notable differences among various gestational age categories. Specifically, mothers of babies born at 37 weeks typically exhibited advanced maternal age, along with a higher occurrence of pre-existing diabetes, gestational diabetes, and hypertension. The rate of cesarean deliveries was notably elevated in cases of early-term births. Moreover, as gestational age progressed, birth weights showed a gradual increase, with infants delivered at 37 weeks weighing an average of 3071 g in contrast to 3505 g at 41 weeks. (Table 1).

Table 1 Population characteristics by gestational age.
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Risk of neonatal respiratory failure in term infants

Upon adjusting for potential variables, compared to 39 weeks, the risk of NRF was higher at 37 weeks (aOR 2.08; 95% CI, 2.02–2.14), 38 weeks (aOR 1.27; 95% CI, 1.23–1.30), 40 weeks (aOR 1.18; 95% CI, 1.15–1.22), and 41 weeks (aOR 1.30; 95% CI, 1.25–1.35). (Table 2).

Table 2 Gestational age and odds ratios of the primary outcome.
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Subgroup analyses

Subgroup analyses indicated a consistent relationship between gestational age and NRF across various infant sex and delivery mode categories as illustrated in Table 3; Fig. 3. Compared to 39 weeks, the risk of NRF was higher in female infant at 37 weeks (aOR 2.00; 95% CI, 1.92–2.09), 38 weeks (aOR 1.34; 95% CI, 1.32–1.37), 40 weeks (aOR 1.12; 95% CI, 1.10–1.15), and 41 weeks (aOR 1.40; 95% CI, 1.33–1.48). Compared to 39 weeks, the risk of NRF was higher in male infant at 37 weeks (aOR 2.07; 95% CI, 2.00-2.15), 38 weeks (aOR 1.37; 95% CI, 1.34–1.39), 40 weeks (aOR 1.12; 95% CI, 1.10–1.14), and 41 weeks (aOR 1.39; 95% CI, 1.33–1.46). Compared to 39 weeks, the risk of NRF was higher in infant by vaginal delivery at 37 weeks (aOR 1.96; 95% CI, 1.87–2.04), 38 weeks (aOR 1.33; 95% CI, 1.31–1.36), 40 weeks (aOR 1.10; 95% CI, 1.08–1.13), and 41 weeks (aOR 1.34; 95% CI, 1.28–1.41). Compared to 39 weeks, the risk of NRF was higher in infant by cesarean section at 37 weeks (aOR 2.10; 95% CI, 2.03–2.18), 38 weeks (aOR 1.37; 95% CI, 1.35–1.39), 40 weeks (aOR 1.15; 95% CI, 1.12–1.17), and 41 weeks (aOR 1.48; 95% CI, 1.40–1.55). The risk for NRF in infants delivered by elective C-section at 37, 38, 40, and 41 weeks were found to be significantly higher compared to those delivered at 39 weeks with aORs of 2.51 (2.37, 2.66), 1.37(1.29, 1.46), 1.09 (1.01, 1.18), and 1.35 (1.22, 1.51) respectively. (Table 4).

Table 3 Adjusted odds ratios [95% CI] of the primary outcome in infants with different gestational age by infant sex or delivery mode.
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Fig. 3
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Subgroup analyses of odds ratios based on infant sex or birth route with 39 weeks as reference.

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Table 4 Gestational age and odds ratios of the primary outcome in infants born by elective c-section.
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Discussion

The findings of this research emphasize the significant association between gestational age and neonatal respiratory outcomes, particularly concerning the incidence of NRF among full-term infants. Our study reveals that NRF risk decreases from 37 to 39 weeks and then increases from 39 to 41 weeks, with early-term infants (37 and 38 weeks) and 40 to 41 weeks exhibiting a notably higher NRF rate compared to those born at 39 weeks. These results hold important implications for clinical decision-making and perinatal policies, especially in the context of elective cesarean deliveries.

The heightened NRF risk in early-term infants, as evidenced in our study, was consistent with previous research on the susceptibility of infants born prior to 39 weeks to respiratory challenges and contributed to the mounting evidence indicating that the maturation of fetal lungs, which progresses significantly between 37 and 39 weeks, plays a critical role in mitigating NRF risk18,19,20. During this period, the lungs undergo crucial developments, such as increased surfactant production and enhanced lung compliance, which are vital for effective postnatal breathing21.

The observed decline in NRF incidence at 39 weeks, followed by a slight rise at 40 and 41 weeks, likely signifies a delicate balance between optimal lung development and potential complications associated with prolonged gestation, like meconium aspiration syndrome and placental insufficiency22,23,24. These results imply that while 39 weeks seems to be the best gestational age for reducing NRF risk, pregnancies exceeding 40 weeks may pose elevated respiratory risks due to different physiological factors.

The implications of this study hold particular importance in making decisions about elective deliveries. The heightened NRF risk observed at 37 and 38 weeks underscores the importance of further research into the potential risks associated with early-term deliveries. These findings may inform discussions among healthcare providers regarding the timing of non-medically necessary deliveries25,26. Existing guidelines from organizations such as the American College of Obstetricians and Gynecologists (ACOG) advise against elective delivery before 39 weeks, a stance strongly supported by this study’s findings27. Adherence to these recommendations and conducting quality improvement to decrease elective deliveries before 39 weeks of gestation can contribute not only to lowering NRF incidences but also to reducing mortality and enhancing neonatal outcomes28,29,30. Additionally, based on our finding, to limit NRF risk, careful consideration should also be given to elective C-sections beyond 39 weeks, as they may also carry increased risks.

Strengths and limitations

This study had strengths, including a sizable population-based cohort that bolsters the applicability of the results. The implementation of rigorous statistical approaches to account for a diverse range of confounding variables further fortifies the credibility of the outcomes. Through meticulous adjustments for factors like maternal age, race, education, pre-pregnancy BMI, and comorbidities, the research offers a more precise understanding of how gestational age independently impacts NRF risk.

However, there are certain limitations that warrant consideration. It is important to note that our study design, being retrospective and observational, can only establish associations between gestational age and NRF risk but fail to reflect causality. While we have adjusted for a wide range of potential confounders, unmeasured factors such as socioeconomic factors, environmental influences, whether labor had initiated, the reason for cesarean section and specific neonatal comorbidities (e.g. neonatal depression or hypoxic ischemic encephalopathy)—might still affect the results. The study’s failure to distinguish between different causes of NRF may have limited its ability to provide more deep insights into the specific respiratory conditions associated with varying gestational ages. Additionally, our analysis of elective C-sections was limited by the inability to distinguish between non-medically indicated elective C-sections and those performed for other reasons not captured in the dataset. While we excluded cases with known medical indications (e.g. maternal diabetes or hypertension), other factors such as maternal request or non-urgent indications may have influenced the timing of delivery. Future studies with more detailed data on the reasons for elective C-sections are needed to better understand the relationship between delivery timing and neonatal outcomes.

Given the findings of this study, future research should focus on prospective studies that can more precisely measure the impact of gestational age on specific types of neonatal respiratory complications. Additionally, research exploring the long-term outcomes of infants who experience NRF at different gestational ages would be valuable in understanding the broader implications of early-term delivery. Studies that investigate interventions to reduce NRF risk in early-term infants, such as antenatal corticosteroid administration in early term infants, could also provide important insights for clinical practice, however, the long-term neurodevelopmental impairments need to be cautiously monitored31.

Conclusion

This study highlights significant associations between gestational age and the risk of NRF in term infants. While our findings suggest that 39 weeks may be the optimal gestational age for minimizing respiratory complications, further research is needed to establish causality and inform clinical guidelines to optimize neonatal outcomes.