Abstract
Background
Antenatal corticosteroids, specifically betamethasone, administered to patients at risk for late preterm delivery have been associated with reduced rates of neonatal respiratory complications. However, whether these risks vary by delivery indication among betamethasone-exposed, late-preterm infants is not known.
Objective
This study aimed to evaluate if spontaneous preterm labor or preterm prelabor rupture of membranes, compared with indicated late preterm delivery, is associated with better neonatal respiratory outcomes after accounting for betamethasone administration in the late preterm period.
Study Design
This was a secondary analysis of the Antenatal Late Preterm Steroids trial, a multicenter, placebo-controlled trial in which patients with singleton pregnancies at risk for delivery at 34 0/7 to 36 5/7 weeks of gestation were randomized to a single course of antenatal corticosteroids (betamethasone) or placebo. Patients were eligible if they had spontaneous preterm labor, preterm prelabor rupture of membranes, or if they were undergoing indicated late preterm delivery. The primary outcome was a composite of need for respiratory support, stillbirth, or neonatal death within 72 hours after delivery. Secondary outcomes included individual neonatal morbidities. Bivariate analyses were performed, and multivariable logistic regression models were used to control for potential confounders. Using the indicated preterm delivery group as the reference group, adjusted odds ratios and 95% confidence intervals were calculated for the outcomes by delivery indication. Subgroup analyses separately examined the treatment and placebo groups to determine the odds of the primary outcome by delivery indication.
Results
Of 2827 participants at high risk for late preterm delivery, 1427 (50.5%) received betamethasone. There were 790 (27.9%) infants born after preterm labor, 620 (21.9%) born after preterm prelabor rupture of membranes, and 1417 (50.1%) born after indicated preterm delivery. Compared with indicated preterm delivery, the odds of the primary outcome were lower among those born after preterm labor (7.3% vs 16.4%; adjusted odds ratio, 0.57; 95% confidence interval, 0.40–0.82) and among those born after preterm prelabor rupture of membranes (12.4% vs 16.4%; adjusted odds ratio, 0.49; 95% confidence interval, 0.35–0.69). Preterm labor had lower odds of all neonatal complications except feeding problems, and preterm prelabor rupture of membranes had lower odds of all neonatal complications except newborn intensive care unit admission for ≥3 days when compared with indicated preterm delivery. For the placebo group, the odds of the primary outcome were lower for the preterm labor group (8.2% vs 18.5%; adjusted odds ratio, 0.55; 95% confidence interval, 0.34–0.91) and the preterm prelabor rupture of membranes group (13.2% vs 18.5%; adjusted odds ratio, 0.46; 95% confidence interval, 0.29–0.73) than for the indicated preterm delivery group. For those exposed to betamethasone, the odds of the primary outcome remained lower for the preterm labor group (6.5% vs 14.3%; adjusted odds ratio, 0.58; 95% confidence interval, 0.34–0.99) and the preterm prelabor rupture of membranes group (11.7% vs 14.3%, adjusted odds ratio, 0.56; 95% confidence interval, 0.34–0.91) than for the indicated preterm delivery group.
Conclusion
Compared with indicated preterm delivery, preterm labor and preterm prelabor rupture of membranes were associated with reduced odds of neonatal respiratory complications irrespective of betamethasone exposure in the late preterm period.
Key words: Antenatal Late Preterm Steroids, betamethasone, glucocorticoids, iatrogenic preterm birth, iatrogenic preterm delivery, indicated preterm birth, indicated preterm delivery, planned preterm delivery, preterm labor, preterm prelabor rupture of membranes, steroids
AJOG MFM at a Glance.
Why was this study conducted?
Late preterm infants are at increased risk for respiratory complications when compared with term-born infants. Maternal antenatal corticosteroid (betamethasone) administration during late preterm gestation has been shown to reduce these risks. However, whether these neonatal risks vary by delivery indication among betamethasone-exposed infants is unknown.
Key findings
Compared with indicated preterm delivery (iPTD), late-preterm infants born after spontaneous preterm labor (PTL) or preterm prelabor rupture of membranes (PPROM) had 43% and 51% reduced odds, respectively, of neonatal respiratory complications. These significant differences persisted irrespective of betamethasone exposure.
What does this add to what is known?
Although betamethasone improves respiratory outcomes for late preterm infants overall, the benefit seems to be greater for those delivered following PTL and PPROM than for those delivered for iPTD. This suggests that beyond prematurity, delivery indication influences neonatal outcomes even after receipt of antenatal late preterm corticosteroids.
Introduction
Compared with term infants, late preterm infants (34 0/7–36 6/7 weeks’ gestation) are at increased risk for adverse neonatal outcomes, including respiratory distress syndrome (RDS), intraventricular hemorrhage, necrotizing enterocolitis, and sepsis.1, 2, 3, 4, 5, 6 These neonatal morbidities are primarily attributed to prematurity, although the indications for preterm delivery also likely play a role.7, 8, 9 For example, placental abruption, intrauterine growth restriction (IUGR), and maternal conditions leading to preterm delivery have all been associated with increased neonatal complications when compared with preterm prelabor rupture of membranes (PPROM) and spontaneous preterm labor (PTL)10, 11, 12, 13, 14, 15, 16, 17 and are possibly caused by intrinsic fetal or placental––rather than obstetrical––disorders.
Antenatal corticosteroids are administered to patients anticipated to deliver prematurely to accelerate fetal lung maturation.18,19 This treatment is associated with decreased incidence of RDS in preterm and late preterm neonates as demonstrated by the Antenatal Late Preterm Steroids (ALPS) trial conducted by the Maternal-Fetal Medicine Units (MFMU) Network in 2016.20 In this large randomized trial, betamethasone administration to patients at risk for late preterm delivery improved neonatal respiratory outcomes when compared with a placebo. A subsequent systematic review and meta-analysis of 6 randomized clinical trials (RCTs) including 5698 pregnancies confirmed these findings.21
However, few studies have examined late preterm neonatal outcomes by delivery indication,6,22, 23, 24 and to the best of our knowledge, none have accounted for administration of late antenatal preterm corticosteroids. Greater understanding of these distinct modifiers of neonatal morbidity may facilitate prognostication, patient counseling, and resource allocation when caring for patients at risk for late preterm delivery. Therefore, we used the ALPS trial data to examine outcomes by delivery indication and treatment group, comparing neonates born after PTL or PPROM with those born after indicated preterm delivery (iPTD). We hypothesized that PTL and PPROM, compared with iPTD in the late preterm period, would be associated with reduced odds of neonatal respiratory complications and that these differences would persist irrespective of betamethasone administration to patients at risk for late preterm delivery.
Materials and Methods
We performed a secondary analysis of the ALPS trial, a multicenter RCT of antenatal corticosteroid (betamethasone) or placebo administration to patients with singleton pregnancies at risk for late preterm delivery.20 Patients were eligible if they were in spontaneous PTL with intact membranes, had PPROM, or were undergoing iPTD with expected delivery between 34 0/7 and 36 6/7 weeks’ gestation and if it occurred between 24 hours and 7 days after planned randomization. Exclusion criteria included previous receipt of antenatal glucocorticoids during pregnancy, chorioamnionitis, cervical dilation ≥8 cm, abnormal fetal testing requiring immediate delivery, expected delivery within 12 hours of enrollment, and suboptimal pregnancy dating. Delivery was not delayed for betamethasone administration. The study protocol and eligibility criteria for the ALPS trial have been previously published.20
The primary outcome was a composite of respiratory treatment (including use of continuous positive airway pressure [CPAP] or high flow nasal cannula [HFNC] for ≥2 continuous hours, supplemental oxygen with a fraction of inspired oxygen [FiO2] ≥0.30 for ≥4 hours, extracorporeal membrane oxygenation [ECMO], or mechanical ventilation [MV]) or stillbirth or neonatal death (included in the composite as competing events) within 72 hours of delivery.
Secondary neonatal outcomes included (1) severe respiratory complication (defined as a composite of CPAP or HFNC for ≥12 continuous hours, O2 support with a FiO2 ≥0.30 for ≥24 hours, ECMO, MV, stillbirth, or neonatal death within 72 hours of delivery); (2) CPAP or HFNC for ≥2 hours (designated CPAP/HFNC); (3) a composite of respiratory distress syndrome (RDS) (defined as clinical signs of respiratory distress including tachypnea, retractions, flaring, grunting, or cyanosis), transient tachypnea of the newborn (TTN) (defined as tachypnea with or without chest radiography showing perihilar interstitial markings and symptom resolution within 72 hours), and apnea (AP) (defined as respiratory pauses lasting >20 seconds leading to bradycardia or O2 desaturation below baseline) (designated RDS/TTN/AP); (4) newborn intensive care unit (NICU) admission for ≥3 days (designated NICU admission); and (5) feeding problems, defined as inability to take all feeds orally (ie, requiring gavage feeds or intravenous supplementation at least once). All secondary outcomes were defined in the ALPS trial's Supplementary Appendix.20
Maternal characteristics including age, race or ethnicity, relationship status, employment status, education level, smoking history, and prepregnancy body mass index (BMI) were examined. Race or ethnicity was self-reported and categorized as Black, Hispanic, White, Asian, and Other (including mixed or unknown race). Patients of any race could report Hispanic ethnicity. Relationship status was categorized as married or living with a partner, divorced or widowed or separated, or never married. Employment was categorized as fulltime employed (≥35 h/wk), parttime employed (≥4 and <35 h/wk), and unemployed (<4 h/wk). Education level was categorized as high school or less, some college, or bachelor's degree or greater. Smoking history referred to those who smoked or did not smoke during the current pregnancy. Major congenital malformations were defined in the ALPS trial's Supplementary Appendix.20 We also examined gestational age at delivery, delivery route (vaginal vs cesarean delivery), infant birthweight, and infant sex.
Analyses were performed using the intention-to-treat principle. Bivariate analyses compared baseline characteristics among delivery indication groups (PTL, PPROM, and iPTD) using chi-square or Fisher exact tests for categorical variables and Kruskal-Wallis tests for continuous variables. Unadjusted logistic regression was performed, followed by multivariable logistic regression modeling with adjustment for confounders including gestational age at delivery, birthweight, infant sex, delivery route, major congenital malformations, race or ethnicity, prepregnancy BMI, maternal age, relationship status, employment status, education level, and treatment group (placebo vs betamethasone). Given that patients were randomized to treatment or placebo in the ALPS trial, we expected treatment to be balanced among delivery indication groups. Nevertheless, possible treatment effects were examined by repeating the analysis after removing treatment from the multivariable regression model.
The variables included in our model are known to be associated with neonatal outcomes and those with P<.05 in the bivariate analysis. Acknowledging the influence of racism and social determinants of health on perinatal outcomes, we repeated our analysis with exclusion of race or ethnicity from our model to assess for differences in our findings. Unadjusted and adjusted odds ratios (ORs and aORs) and 95% confidence intervals (CIs) were generated for outcomes by delivery indication, comparing PTL with iPTD and PPROM with iPTD.
Subgroup analyses were performed for the primary outcome by delivery indication, separately examining infants exposed to betamethasone and those exposed to the placebo, using multivariable regression modeling and controlling for the same confounders except for treatment group.
The iPTD group was further examined to identify specific indications for iatrogenic PTD. The ALPS trial included gestational hypertension or preeclampsia, oligohydramnios, IUGR and other in the iPTD group, with the other category comprising >30% of these patients. Therefore, we reclassified patients in the other group to better characterize their delivery indications. We combined all patients delivered for hypertensive disorders of pregnancy (HDP), defined as preeclampsia, gestational hypertension, and hemolysis, elevated liver enzymes, and low platelets or HELLP syndrome into a single category. Patients who delivered for nonreassuring fetal testing were separated into a distinct group. All remaining patients, including those who delivered for previous classical cesarean delivery, previous myomectomy, abnormal placentation, placental abruption, cholestasis, other maternal diseases requiring late PTD, and undefined indications were included in the other group. Given the heterogeneity in delivery indications for iPTD, a subgroup analysis was performed that examined the outcomes for HDP, which was the most common reason for iPTD.
Statistical analysis was performed using SAS, version 9.4 (SAS Institute, Cary, NC). For the original trial, all participants provided written informed consent before randomization at the 17 centers in the National Institute of Child Health and Human Development MFMU Network. This secondary analysis of de-identified data was determined by our institutional review board (protocol #2000026230) not to be human subjects research.
Results
Of 2827 participants, there were 790 (27.9%) with PTL, 620 (21.9%) with PPROM, and 1417 (50.1%) who underwent iPTD. Maternal characteristics differed among delivery indication groups in maternal age, prepregnancy BMI, race or ethnicity, relationship status, employment status, education level, gestational age at delivery, infant birthweight, delivery route, and infant sex (Table 1).
Table 1.
Baseline participant characteristics by delivery indication
| Maternal characteristics | PTL (n=790) | PPROM (n=620) | iPTD (n=1417) | P value |
|---|---|---|---|---|
| Betamethasone exposure, n (%) | 398 (50.4) | 316 (51.0) | 713 (50.3) | .96 |
| Maternal age (y), n (%) | <.01 | |||
| <20 | 89 (11.3) | 50 (8.1) | 75 (5.3) | |
| 20 to <25 | 239 (30.3) | 142 (22.9) | 296 (20.9) | |
| 25 to <30 | 233 (29.5) | 143 (23.1) | 366 (25.8) | |
| 30 to <35 | 154 (19.5) | 171 (27.6) | 370 (26.1) | |
| 35 to <40 | 63 (8.0) | 92 (14.8) | 238 (16.8) | |
| ≥40 | 12 (1.5) | 22 (3.5) | 72 (5.1) | |
| BMI (kg/m2), n (%) | <.01 | |||
| Underweight (<18.5) | 43 (5.4) | 33 (5.3) | 50 (3.5) | |
| Normal weight (18.5 to <25) | 384 (48.6) | 272 (43.9) | 459 (32.4) | |
| Overweight (25 to <30) | 198 (25.1) | 144 (23.2) | 317 (22.4) | |
| Obese (≥30) | 147 (18.6) | 144 (23.2) | 552 (39.0) | |
| Missing BMI information | 18 (2.3) | 27 (4.4) | 39 (2.8) | |
| Race or ethnicity, n (%)a | <.01 | |||
| Black | 200 (25.3) | 149 (24.0) | 378 (26.7) | |
| Hispanic | 302 (38.2) | 161 (26.0) | 390 (27.5) | |
| White | 250 (31.6) | 259 (41.8) | 596 (42.1) | |
| Asian | 24 (3.0) | 38 (6.1) | 31 (2.2) | |
| Other/Mixed/Unknown | 14 (1.8) | 13 (2.1) | 22 (1.6) | |
| Relationship status, n (%) | <.01 | |||
| Married/living with partner | 478 (60.5) | 415 (66.9) | 934 (65.9) | |
| Divorced/widowed/separated | 41 (5.2) | 15 (2.4) | 65 (4.6) | |
| Never married | 271 (34.3) | 190 (30.6) | 418 (29.5) | |
| Employment status, n (%) | <.01 | |||
| Fulltime (≥35 h/wk) | 191 (24.2) | 237 (38.2) | 449 (31.7) | |
| Parttime (<35 h/wk) | 80 (10.1) | 57 (9.2) | 134 (9.5) | |
| Not employed/missingb | 519 (65.7) | 326 (52.6) | 834 (58.9) | |
| Education, n (%) | <.01 | |||
| High school or less | 486 (61.5) | 289 (46.6) | 694 (49.0) | |
| Some college | 156 (19.7) | 114 (18.4) | 302 (21.3) | |
| Bachelor's degree or greater | 129 (16.3) | 209 (33.7) | 388 (27.4) | |
| Missing education information | 19 (2.4) | 8 (1.3) | 33 (2.3) | |
| Smoked during pregnancy | 111 (14.1) | 83 (13.4) | 195 (13.8) | .94 |
| GA (wk), median (IQR) | 36.6 (35.7–37.7) | 35.6 (34.9–36.1) | 36.1 (35.6–36.7) | <.01 |
| IBW (g), median (IQR) | 2830 (2488–3175) | 2550 (2310–2792) | 2552 (2225–2890) | <.01 |
| Cesarean delivery, n (%) | 71 (9.0) | 75 (12.1) | 739 (52.2) | <.01 |
| Major congenital malformations | 6 (0.8) | 11 (1.8) | 15 (1.1) | .19 |
| Infant sex, n (%) | .03 | |||
| Male | 423 (53.5) | 354 (57.1) | 721 (50.9) | |
| Female | 367 (46.5) | 266 (42.9) | 696 (49.1) |
Totals may not equal 2827 because of missing observations and percentages may not equal 100% owing to rounding. Chi-square test of association was performed for categorical variables; Kruskall Wallis test was performed for continuous measures.
BMI, body mass index (prepregnancy); GA, gestational age at delivery; IBW, infant birthweight; IQR, interquartile range; iPTD, indicated preterm delivery (for maternal or fetal indications); PPROM, preterm prelabor rupture of membranes; PTL, spontaneous preterm labor with intact membranes.
Race or ethnicity was self-reported by participants. Patients of any race could report Hispanic background
Data on employment status were missing for 9 patients.
Deshmukh. Late preterm outcomes by delivery indication and antenatal corticosteroid exposure. Am J Obstet Gynecol Glob Rep 2022.
The frequency of the primary outcome varied significantly by delivery indication (Table 2). No stillbirths or neonatal deaths occurred within 72 hours of delivery. The primary outcome occurred in 58 (7.3%) neonates born after PTL, 77 (12.4%) neonates born after PPROM, and 232 (16.4%) neonates born after iPTD. Compared with iPTD, late preterm neonates born after PTL and PPROM had reduced odds of having the primary outcome (OR, 0.41; 95% CI, 0.30–0.55 and OR, 0.72; 95% CI, 0.55–0.96, respectively). These differences persisted after multivariable adjustment; neonates born after PTL had 43% reduced odds (aOR, 0.57; 95% CI, 0.40–0.82) and those born after PPROM had 51% reduced odds (aOR, 0.49; 95% CI, 0.35–0.69) of having the primary outcome when compared with those born after iPTD.
Table 2.
Neonatal outcomes by delivery indication
| Neonatal outcomes | PTL (n=790) | PPROM (n=620) | iPTD (reference) (n=1417) | PTL |
PPROM |
||
|---|---|---|---|---|---|---|---|
| n (%) | OR (95% CI) | aORa (95% CI) | OR (95% CI) | aORa (95% CI) | |||
| Primary outcomeb | 58 (7.3) | 77 (12.4) | 232 (16.4) | 0.41 (0.30–0.55) | 0.57 (0.40–0.82) | 0.72 (0.55–0.96) | 0.49 (0.35–0.69) |
| Severe respiratory complicationsc | 46 (5.8) | 58 (9.4) | 178 (12.6) | 0.43 (0.31–0.60) | 0.57 (0.39–0.85) | 0.72 (0.53–0.98) | 0.47 (0.32–0.68) |
| CPAP/HFNCd | 53 (6.7) | 69 (11.1) | 207 (14.6) | 0.42 (0.31–0.58) | 0.59 (0.41–0.86) | 0.73 (0.55–0.98) | 0.48 (0.34–0.68) |
| RDS/TTN/APe | 67 (8.5) | 107 (17.3) | 273 (19.3) | 0.39 (0.29–0.52) | 0.57 (0.41–0.80) | 0.87 (0.68–1.12) | 0.64 (0.48–0.87) |
| NICU admissionf | 166 (21.0) | 274 (44.2) | 548 (38.7) | 0.42 (0.35–0.52) | 0.75 (0.57–0.99) | 1.26 (1.04–1.52) | 0.84 (0.65–1.09) |
| Feeding problems | 83 (10.5) | 107 (17.3) | 244 (17.2) | 0.56 (0.43–0.74) | 0.93 (0.67–1.28) | 1.00 (0.78–1.29) | 0.73 (0.54–0.99) |
aOR, adjusted odds ratio; AP, apnea; CI, confidence interval; CPAP, continuous positive airway pressure; HFNC, high flow nasal cannula; iPTD, indicated late preterm delivery (for maternal or fetal indications); NICU, newborn intensive care unit; OR, unadjusted odds ratio; PPROM, preterm prelabor rupture of membranes; PTL, spontaneous preterm labor with intact membranes; RDS, respiratory distress syndrome; TTN, transient tachypnea of the newborn.
Odds ratios were adjusted for gestational age at delivery, birthweight, infant sex, delivery route, major congenital malformations, race or ethnicity, prepregnancy BMI, maternal age, relationship status, employment status, education level, and treatment group (placebo vs betamethasone)
The primary outcome was a composite of stillbirth, neonatal death, CPAP/HFNC for ≥2 hours, supplemental O2 with fraction of inspired O2 of ≥0.30 for ≥4 hours, mechanical ventilation, or extracorporeal membrane oxygenation within 72 hours of delivery
Severe respiratory complication was defined as a composite of the following occurrences within 72 hours after birth: CPAP or high flow nasal cannula for ≥12 continuous hours, supplemental O2 with a fraction of inspired oxygen of 30% or more for at least 24 hours, mechanical ventilation, stillbirth or neonatal death, or the need for ECMO
CPAP or HFNC for ≥2 continuous hours in the first 72 hours of life
RDS/TTN/AP was defined as a composite of respiratory distress syndrome, transient tachypnea of the newborn, or apnea
Admission to NICU or intermediate care nursery for ≥3 days.
Deshmukh. Late preterm outcomes by delivery indication and antenatal corticosteroid exposure. Am J Obstet Gynecol Glob Rep 2022.
Neonates born after PTL also had reduced adjusted odds of severe respiratory complications, CPAP/HFNC, RDS/TTN/AP, and NICU admission when compared with those born after iPTD (Table 2, Figure 1). PPROM was associated with reduced adjusted odds of severe respiratory complications, CPAP/HFNC, RDS/TTN/AP, and feeding problems when compared with iPTD (Table 2, Figure 2).
Figure 1.
Odds of neonatal outcomes for PTL vs iPTD
Adjusted ORs with 95% confidence intervals comparing neonatal outcomes among late preterm infants born after PTL vs those born after iPTD. ORs were adjusted for gestational age at delivery, birthweight, infant sex, delivery route, major congenital malformations, race or ethnicity, prepregnancy BMI, maternal age, relationship status, employment status, education level, and treatment group (placebo vs betamethasone).
AP, apnea; CPAP, continuous positive airway pressure; HFNC, high flow nasal cannula; iPTD, indicated late preterm delivery (for maternal or fetal indications); NICU, newborn intensive care unit; OR, odds ratio; PTL, spontaneous preterm labor with intact membranes; RDS, respiratory distress syndrome; TTN, transient tachypnea of the newborn.
Deshmukh. Late preterm outcomes by delivery indication and antenatal corticosteroid exposure. Am J Obstet Gynecol Glob Rep 2022.
Figure 2.
Odds of neonatal outcomes for PPROM vs iPTD
Adjusted ORs with 95% confidence intervals comparing neonatal outcomes among late preterm infants born after PPROM vs those born after iPTD. ORs were adjusted for gestational age at delivery, birthweight, infant sex, delivery route, major congenital malformations, race or ethnicity, prepregnancy BMI, maternal age, relationship status, employment status, education level, and treatment group (placebo vs betamethasone).
AP, apnea; CPAP, continuous positive airway pressure; HFNC, high flow nasal cannula; iPTD, indicated late preterm delivery (for maternal or fetal indications); NICU, newborn intensive care unit; OR, odds ratio; PPROM, preterm prelabor rupture of membranes; PTL, spontaneous preterm labor with intact membranes; RDS, respiratory distress syndrome; TTN, transient tachypnea of the newborn.
Deshmukh. Late preterm outcomes by delivery indication and antenatal corticosteroid exposure. Am J Obstet Gynecol Glob Rep 2022.
Reduced odds of having the primary outcome among neonates born after PTL and PPROM, compared with those born after iPTD, persisted in the subgroup analyses by treatment group. Among the 1400 (49.5%) placebo-exposed neonates, multivariable regression demonstrated reduced odds of having the primary outcome when comparing neonates born after PTL and PPROM with those born after iPTD, respectively. Among the 1427 (50.5%) betamethasone-exposed neonates, the odds of the primary outcome were also reduced for neonates born after PTL and PPROM when compared with those born after iPTD (Table 3).
Table 3.
Subgroup analyses of neonatal outcomes by delivery indication for placebo and betamethasone groups
| Neonatal outcomes | Placebo (n=1400) |
Betamethasone (n=1427) |
||
|---|---|---|---|---|
| PTL vs iPTD | PPROM vs iPTD | PTL vs iPTD | PPROM vs iPTD | |
| aORa (95% CI) | aORa (95% CI) | |||
| Primary outcomeb | 0.55 (0.34–0.91) | 0.46 (0.29–0.73) | 0.58 (0.34–0.99) | 0.56 (0.34–0.91) |
| Severe respiratory complicationsc | 0.50 (0.29–0.85) | 0.47 (0.29–0.77) | 0.68 (0.38–1.24) | 0.52 (0.29–0.93) |
| CPAP/HFNCd | 0.54 (0.33–0.91) | 0.46 (0.28–0.74) | 0.62 (0.36–1.09) | 0.53 (0.31–0.89) |
| RDS/TTN/APe | 0.47 (0.29–0.75) | 0.56 (0.37–0.85) | 0.71 (0.44–1.15) | 0.81 (0.52–1.26) |
| NICU admissionf | 0.64 (0.43–0.94) | 0.68 (0.47–0.98) | 0.87 (0.58–1.30) | 1.06 (0.73–1.55) |
| Feeding problems | 0.76 (0.48–1.20) | 0.43 (0.27–0.67) | 1.19 (0.74–1.91) | 1.22 (0.79–1.88) |
aOR, adjusted odds ratio; AP, apnea; CI, confidence interval; CPAP, continuous positive airway pressure; HFNC, high flow nasal cannula; iPTD, indicated late preterm delivery (for maternal or fetal indications); NICU, newborn intensive care unit; OR, unadjusted odds ratio; PPROM, preterm prelabor rupture of membranes; PTL, spontaneous preterm labor with intact membranes; RDS, respiratory distress syndrome; TTN, transient tachypnea of the newborn.
Odds ratios were adjusted for gestational age at delivery, birthweight, infant sex, delivery route, major congenital malformations, race or ethnicity, prepregnancy BMI, maternal age, relationship status, employment status, education level, and treatment group (placebo vs betamethasone)
The primary outcome was a composite of stillbirth, neonatal death, CPAP/HFNC for ≥2 hours, supplemental O2 with fraction of inspired O2 of ≥0.30 for ≥4 hours, mechanical ventilation, or extracorporeal membrane oxygenation within 72 hours of delivery
Severe respiratory complication was defined as a composite of the following occurrences within 72 hours after birth: CPAP or high flow nasal cannula for ≥12 continuous hours, supplemental O2 with a fraction of inspired oxygen of 30% or more for at least 24 hours, mechanical ventilation, stillbirth or neonatal death, or the need for ECMO
CPAP or HFNC for ≥2 continuous hours in the first 72 hours of life
RDS/TTN/AP was defined as a composite of respiratory distress syndrome, transient tachypnea of the newborn, or apnea
Admission to NICU or intermediate care nursery for ≥3 days.
Deshmukh. Late preterm outcomes by delivery indication and antenatal corticosteroid exposure. Am J Obstet Gynecol Glob Rep 2022.
More than half (56.6%) of all iPTDs were as a consequence of maternal HDP. Other precursors for iPTD were oligohydramnios (7.3%), IUGR (6.9%), nonreassuring fetal testing (4.0%), and other (25.2%), including a previous myomectomy, previous classical cesarean delivery, placental abruption, abnormal placentation, cholestasis, and other maternal disease (Table 4). Because HDP was the most common cause of iPTD, a subgroup analysis was performed restricting iPTD to the 802 infants delivered for HDP alone. Once again, when comparing neonates born after iPTD as a consequence of HDP, neonates born after both PTL (aOR, 0.59; 95% CI, 0.40–0.87) and PPROM (aOR, 0.50; 95% CI, 0.35–0.72) had persistently reduced odds of having the primary outcome.
Table 4.
Indications for late preterm delivery among the indicated late preterm delivery group
| Delivery indication | n (%) |
|---|---|
| Maternal hypertensive disorders of pregnancy | 802 (56.6) |
| Previous surgerya | 126 (8.9) |
| Oligohydramnios | 104 (7.3) |
| Intrauterine growth restriction | 98 (6.9) |
| Placenta previa | 63 (4.5) |
| Nonreassuring fetal status | 57 (4.0) |
| Cholestasis | 38 (2.7) |
| Placenta accreta | 37 (2.6) |
| Other maternal disease | 29 (2.1) |
| Placental abruption | 24 (1.7) |
| Other | 39 (2.8) |
| Total | 1417 (100.0) |
iPTD, indicated late preterm delivery (for maternal or fetal indications).
Previous surgery includes patients with previous classical cesarean delivery or other uterine surgery necessitating late preterm delivery.
Deshmukh. Late preterm outcomes by delivery indication and antenatal corticosteroid exposure. Am J Obstet Gynecol Glob Rep 2022.
Removing race or ethnicity or treatment group from the multivariable regression model did not alter the aORs for the primary or secondary outcomes (data not shown).
Discussion
Principal findings
Our study demonstrated that late preterm infants born after PTL or PPROM have reduced neonatal respiratory complications when compared with those delivered after iPTD, irrespective of exposure to antenatal corticosteroids.
Results
Our findings are consistent with those reported in the literature before the ALPS trial was published, and it became standard practice to administer betamethasone to patients at risk for late preterm delivery.25,26 A study based on a 2001 US birth cohort linked birth and death files of nearly 300,000 late preterm births and found that neonatal outcomes were substantially worse among those with no recorded delivery indication when compared with those delivered for isolated spontaneous PTL.24 Another analysis of >15,000 late preterm deliveries as part of the Consortium on Safe Labor study conducted in 2002 to 2008 found that neonates delivered for PPROM had decreased severe respiratory morbidity when compared with those delivered for all other indications, whereas those born after iPTD had higher incidences of neonatal sepsis, NICU admission, and death.6 As in our study, the most common cause of iPTD was HDP, comprising 47.7% of indicated deliveries.
We are unaware of any previous studies examining the impact of antenatal late preterm steroids on neonatal outcomes by delivery indication. Although our findings confirm the previously recognized increased neonatal risks associated with iPTD, we further demonstrated that the relative increase in respiratory complications with iPTD compared with PTL and PPROM persists irrespective of administration of antenatal late preterm corticosteroids.
Clinical implications
Our findings have significant clinical implications, lending support to the theory that delivery antecedents and indications, rather than prematurity alone, contribute to neonatal morbidity among late preterm infants. These findings suggest that the factors leading to late preterm delivery confer variable neonatal risks, with infants born after PPROM or PTL faring better than those delivered for iPTD, irrespective of administration of antenatal corticosteroids.
Our findings may be explained by the fetal hypothalamic-pituitary-adrenal (HPA) axis’ modulation of the fetal stress response, which plays a major role in labor onset. Evidence suggests that the fetal HPA axis stimulates the release of endogenous steroids that help accelerate fetal lung maturity before birth in the setting of spontaneous labor.27,28 The stress experienced by fetuses after PPROM may also activate the HPA axis and may similarly trigger lung maturation before birth. On the contrary, among fetuses undergoing planned delivery without spontaneous labor or PPROM, this process may be absent. This provides a plausible explanation for the relatively decreased odds of postnatal respiratory complications in infants born after PTL and PPROM when compared with iPTD, which persists irrespective of exogenous late preterm corticosteroid administration.
Another possible explanation is the effect of chorioamnionitis on fetal lung maturation. Although patients with suspected chorioamnionitis were excluded from the ALPS trial, the incidence of subclinical chorioamnionitis may have differed among the indication groups. Indeed, histologic chorioamnionitis has been shown to occur more frequently in PTL and PPROM when compared with iPTD.29 The increased levels of interleukin-1, interleukin-6, and endotoxin seen in histologic chorioamnionitis are believed to stimulate surfactant production and lung maturation, leading to lower incidence of RDS in affected neonates by a mechanism independent of cortisol and the fetal HPA axis.30,31 Thus, the presence of subclinical chorioamnionitis may explain the reduced risk for respiratory complications observed among neonates born after PTL and PPROM when compared with those born after iPTD irrespective of administration of late preterm corticosteroids.
Increasing evidence suggests that fetal lung maturation is a multifactorial process influenced by gestational age, the fetal HPA axis, the actions of endogenous and exogenous cortisol, and the presence of intrauterine inflammation and endotoxins, which may have an additive effect on neonatal pulmonary function.32 Preeclampsia may also be independently associated with pulmonary disease in exposed neonates, although the mechanism by which this occurs remains unknown.33,34 Chronic maternal vasoconstriction associated with preeclampsia may lead to placental hypoperfusion and fetal hypoxia, which can cause neonatal respiratory complications.35 In addition, the increased levels of maternal antiangiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased free circulating levels of vascular endothelial growth factor, observed in preeclampsia36 may alter fetal lung vasculature and impair surfactant production.37 These theories may explain the reduced risk for respiratory complications observed among neonates in the PTL and PPROM groups when compared with those in iPTD group (which mostly included neonates delivered for maternal HDP), irrespective of antenatal corticosteroid exposure.
Our study contributes to the literature on late preterm delivery and the associated neonatal morbidities, building on previous studies that have demonstrated variable neonatal outcomes based on gestational age and delivery indication, by analyzing whether these risks are modulated by the administration of antenatal late preterm corticosteroids. With the increasing use of antenatal corticosteroids in the late preterm period, further research on this topic may aid in delivery planning, risk stratification, and counseling of patients at risk for late preterm delivery. Additional research may enable obstetrical providers to individualize counseling of and shared decision-making with patients when discussing thr risks and benefits of late preterm delivery, taking into account delivery indication, gestational age, and administration of late preterm corticosteroids. Improved understanding of these issues will also help neonatologists to prognosticate and anticipate the risks of postnatal complications associated with late preterm neonates.
Research implications
Follow-up studies for the ALPS trial are ongoing to examine the long-term effects of late preterm corticosteroids on pulmonary and neurocognitive functioning among exposed children.38 Future studies should also examine if long-term outcomes differ by delivery indication in the context of late preterm corticosteroid administration. Additional research is also needed to determine if neonatal outcomes differ based on specific indications for planned preterm delivery.
Strengths and limitations
Strengths of this study include its large sample size with racially and ethnically diverse patients, its prospective and randomized study design, standardized data collection of participant characteristics, delivery indications, and neonatal outcomes, and adjustment for covariates known to impact neonatal outcomes. Furthermore, neonatologists were blinded to exposure status, removing potential bias during postnatal evaluation of the outcomes.
There are limitations to our study. First, neonatal hypoglycemia was not included as an outcome because of limitations in our data set. However, this potential morbidity for neonates exposed to late preterm steroids has been explored in other studies.39,40 Second, we could not control for variables that were not collected in the ALPS trial, such as magnesium sulfate exposure, which may be a confounder given the higher number of patients in the iPTD group who delivered for the indication of maternal HDP. These infants likely had intrapartum magnesium sulfate exposure more often than those born after PTL or PPROM. Magnesium sulfate, when used for eclampsia prophylaxis, may be associated independently with neonatal morbidity.41, 42, 43, 44 In addition, although we controlled for delivery route, we could not control for the presence of labor because of data set limitations. Duration of betamethasone exposure may also have varied across delivery indication groups and was not accounted for in our study. Furthermore, although it would be ideal to stratify by delivery indication and examine the effect of betamethasone exposure in comparison with placebo exposure within each group, the resulting sample sizes would be too small and underpowered to detect differences in outcomes, and this would heighten the risk of multiplicity bias, which is already a limitation of our study. Similarly, this study was not powered for a subgroup analysis stratified by gestational age. In addition, the external validity of our findings beyond the MFMU centers and the strict ALPS trial inclusion criteria is unknown. Lastly, although our study sheds light on outcomes affecting late preterm infants immediately after birth, the impact of delivery indication on long-term morbidities beyond the neonatal period, including pulmonary and neurodevelopmental outcomes, remains uncertain.
Conclusion
Infants born following PTL or PPROM experience less neonatal morbidity than those delivered after iPTD irrespective of exposure to antenatal corticosteroids during the late preterm period. These findings contribute to existing literature examining the impact of delivery indication on neonatal outcomes, adding important findings that are relevant to providers caring for late preterm infants in the era of antenatal late preterm corticosteroids. With further research, these findings may aid in the counseling of patients at risk for late preterm delivery, prognostication of neonatal outcomes based on delivery indication, and allocation of resources in preparation for postnatal care.
Acknowledgments
We wish to acknowledge the Maternal-Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. We also wish to thank the participants of the Antenatal Late Preterm Steroids trial.
Footnotes
The authors report no conflict of interest.
Patient consent was not required because no personal information or details were included.
This study did not receive any funding.
The preliminary findings of this study were presented as a poster at the 40th annual meeting of the Society for Maternal-Fetal Medicine, Grapevine, TX, February 3–8, 2020.
Cite this article as: Deshmukh US, Lundsberg LS, Pettker CM, et al. Neonatal outcomes by delivery indication after administration of antenatal late preterm corticosteroids. Am J Obstet Gynecol Glob Rep 2022;2:100097.
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