Abstract
Objective
To identify whether risk factors for respiratory distress syndrome differ between early-term and full-term births.
Study Design
This is a secondary analysis of a large NIH-funded retrospective cohort study including patients who delivered at a tertiary-care obstetric hospital between January 2002 to March 2013 with comorbid diabetes, hypertensive disorders, and/or fetal growth restriction. Pregnancies complicated by severe preeclampsia and multifetal gestations were excluded. Maternal characteristics, delivery information, and neonatal information were abstracted by trained clinicians blinded to the comorbidity leading to study inclusion. In this secondary analysis of the infant health outcomes of pregnancies with one or more of the qualifying conditions, risk of respiratory distress syndrome (RDS) among neonates born early term (37w0d to 38w6d gestation) was compared to risk of RDS among full-term neonates (39w0d to 40w6d).
Results
Among 10,532 singleton newborns, there were 99 cases of early-term RDS (0.94%) and 95 cases of full-term RDS (0.90%). Maternal demographics were similar between those with and without RDS in both groups. Among early-term infants, lower gestational age, presence of meconium, non-spontaneous labor, and cesarean delivery were positively associated with RDS, whereas hypertensive disorders, diabetes, fetal growth restriction, and many other comorbid delivery conditions were not. The strongest risk factor for RDS among early-term infants was delivery via cesarean (RR 1.98, 95% CI 1.31, 3.01). Among full-term neonates, cesarean delivery was also positively associated with RDS, although presence of meconium, chorioamnionitis, and endometritis were all stronger risk factors with RRs > 2.0.
Conclusion
In this cohort of high-risk deliveries, maternal demographics and comorbidities were found not to be associated with increased risk for RDS, but novel risk factors for RDS after 37 weeks’ gestation—chorioamnionitis and endometritis—were identified. A focus on preventing infectious comorbidities may help reduce incidence of RDS at full-term.
Keywords: Respiratory distress syndrome, early-term pregnancy, full-term pregnancy, maternal infection
Introduction
Respiratory disorders are the most common cause for special care nursery admission1, occurring in up to 7% of newborns across all gestational ages2. Of the respiratory disorders affecting newborns, respiratory distress syndrome (RDS) is among the most prevalent2. RDS is caused by a deficiency of surfactant and, therefore, most often affects preterm infants3,4. However, though the odds of developing RDS decrease with each week of gestation until 38 weeks3, the risk of RDS in early-term births—37w0d to 38w6d—remains two to three-fold greater compared to that of full-term births3,5 (39w0d to 40w6d).
Previous studies have investigated risk factors for the development of RDS6–11. Both cesarean delivery and newborn male sex6–9 have been consistently shown to be independently associated with increased risk of developing RDS6–10. Other risk factors for RDS including low birth weight6,7, maternal age above 32 years6, multiple gestation6,9, and multiparity11 have been suggested, but not demonstrated consistently7. Furthermore, risk factors for RDS can differ in their magnitude of effect at different gestational ages: cesarean delivery is associated with RDS with a higher OR in late preterm and term infants than in early/moderate preterm infants7. However, even though the risk of RDS varies significantly between early-term and full-term births3,5, information on whether risk factors for RDS differ between early-term and full-term births is limited.
In this secondary analysis of a large retrospective cohort study of pregnancies affected by diabetes, hypertensive disorders, or fetal growth restriction, the researchers examined the effect that obstetric and perinatal factors have on the development of RDS separately among early-term and full-term neonates. To that end, the objective of this study was to determine whether risk factors for RDS differ between early-term and full-term births.
Materials and Methods
This is a secondary analysis of a large NIH-funded retrospective study performed at a single-center tertiary care maternity hospital with over 8000 deliveries annually (NICHD grant 1R01HD077592, Primary Investigator: Savitz, Title: Effect of Iatrogenic Delivery at 34–38 weeks’ gestation on pregnancy outcome)12. The original study aimed to assess the effect of clinician-initiated delivery between 34–38 weeks’ gestation on perinatal outcomes among singleton pregnancies affected by fetal growth restriction (FGR), maternal diabetic disorders, or mild hypertensive disorders. Mild hypertensive disorders included chronic hypertension, gestational hypertension, and preeclampsia without severe features, which were defined according to diagnostic criteria established by the American College of Obstetricians and Gynecologists13. Of note, women diagnosed with superimposed preeclampsia or preeclampsia with severe features were excluded from primary analysis because iatrogenic delivery was mandatory at or before 34 weeks’ gestation. ICD9-CM codes from discharge data were used to determine eligibility of patients who delivered between January 1, 2002 and March 31, 2013. Chart abstraction was completed by trained research nurses and quality assurance checks on data abstraction were performed regularly.
In this secondary analysis, the analytic population was restricted to women who delivered at or after 37 weeks’ gestation and stratified into infants born during early-term (37w0d-38w6d) and full-term (39w0d-40w6d). The primary outcome was development of RDS. Potential risk factors for RDS identified in existing literature included maternal sociodemographic factors6,11, maternal medical comorbidities6,7,9 and perinatal outcomes ranging from fetal growth restriction to placental abruption6–9. Risk factors for RDS belonging to all these categories among infants born at early-term versus full-term were assessed. Fischer’s exact and Wilcoxon rank-sum tests were used for categorical and continuous risk factors for RDS, respectively. Linear regression models were utilized to calculate risk ratios for all risk factors for RDS, with beta coefficients used in addition for continuous risk factors like gestational age. All statistical tests were carried out in SAS (Cary-NC) and statistical significance was defined as p value <.05
Results
10,532 singleton newborns born after 37 weeks’ completed gestation were included in the parent study, with 3,996 early-term and 6,536 full-term infants included in this analysis. There were 99 cases of RDS among 3,996 early-term infants (2.5%) and 95 cases of RDS among 6.536 full-term infants (1.5%). Maternal demographics were similar between those with and without RDS, both in early-term and in full-term infants (Table 1). When maternal or obstetric medical conditions were analyzed as potential risk factors for RDS, risks were similar for both early-term and full-term pregnancies with chronic hypertension, preeclampsia, pre-gestational diabetes, and fetal growth restriction (Table 2).
Table 1.
Maternal demographics as risk factors for RDS among early-term (37w0d-38w6d) and full-term (39w0d-40w6d) infants
| Early term (37w0d to 38w6d) | Full term (39w0d to 40w6d) | |||||||
|---|---|---|---|---|---|---|---|---|
| Total Cohort (N=3996) | No RDS (n=3897) | RDS (n=99) | p-value | Total Cohort (N=6536) | No RDS (n=6441) | RDS (n=95) | p-value | |
| Age Mean (SD) |
29.8 (6.4) |
29.8 (6.4) |
28.8 (6.8) |
0.171 |
29.9 (6.4) |
9.9 (6.4) |
30.3 (6.7) |
0.531 |
| Race/ethnicity Black White Hispanic Asian Other |
504 (12.7) 2289 (57.6) 656 (16.5) 222 (5.6) 303 (7.6) |
495 (12.8) 2226 (57.5) 642 (16.6) 217 (5.6) 295 (7.6) |
9 (9.2) 63 (64.3) 13 (13.3) 5 (5.1) 8 (8.2) |
0.692 |
787 (12.1) 3894 (60.1) 992 (15.3) 299 (4.6) 512 (7.9) |
779 (12.2) 3833 (60.0) 979 (15.3) 297 (4.7) 500 (7.8) |
8 (8.5) 59 (62.8) 13 (13.8) 2 (2.1) 12 (12.8) |
0.292 |
| Insurance Uninsured/self-pay Public Private |
53 (1.3) 1799 (45.1) 2139 (53.6) |
50 (1.3) 1756 (45.1) 2085 (53.6) |
3 (3.0) 42 (42.4) 54 (54.6) |
0.242 |
84 (1.3) 2740 (42.0) 3694 (56.7) |
82 (1.3) 2699 (42.0) 3640 (56.7) |
2 (2.1) 40 (42.1) 53 (55.8) |
0.612 |
| Multiparous Yes |
1923 (48.1) |
1875 (48.1) |
48 (48.5) |
0.942 |
2851 (43.6) |
2817 (43.7) |
34 (35.8) |
0.122 |
| BMI at 1st prenatal visit (continuous) Mean (SD) |
29.1 (7.5) |
29.1 (7.5) |
30.2 (8.5) |
0.221 |
29.9 (7.5) |
29.9 (7.5) |
28.9 (7.7) |
0.152 |
| BMI at 1st prenatal visit (categorical) < 30 30–40 > 40 |
2429 (61.9) 1140 (29.1) 354 (9.0) |
2376 (62.1) 1108 (28.9) 345 (9.0) |
53 (56.4) 32 (34.0) 9 (9.6) |
0.512 |
3690 (57.6) 2087 (32.6) 633 (9.9) |
3631 (57.5) 2062 (32.6) 625 (9.9) |
59 (64.1) 25 (27.2) 8 (8.7) |
0.442 |
| Conceived with ART (proxy)3 Yes |
141 (4.1) |
138 (4.1) |
3 (3.6) |
0.832 |
215 (3.7) |
214 (3.8) |
1 (1.2) |
0.382 |
Categorical data are N(%)
Wilcoxon rank-sum
Fisher’s exact test
ART (proxy) includes all assisted reproductive technologies that involve handling of egg, sperm and/or embryos, including vitro fertilization, gamete intrafallopian transfer, pronuclear stage tubal transfer, tubal embryo transfer, and zygote intrafallopian transfer
Table 2:
Medical and obstetric risk factors for respiratory distress syndrome among high-risk early-term and full-term neonates
| Early-term (37w0d to 38w6d) | Full-term (39w0d to 40w6d) | |||||
|---|---|---|---|---|---|---|
| No RDS (n=3897) | RDS (n=99) | RR (95% CI) | No RDS (n=6441) | RDS (n=95) | RR (95% CI) | |
| Chronic hypertension1 | 496 (29) | 15 (38) | 1.28 (0.85, 1.91) | 709 (27) | 13 (29) | 1.06 (0.67, 1.68) |
| Preeclampsia without severe features or gestational hypertension1 | 694 (41) | 16 (41) | 1.01 (0.69, 1.48) | 532 (21) | 11 (25) | 1.19 (0.71, 2.00) |
| Pre-gestational diabetes1 | 1691 (44) | 42 (44) | 1.00 (0.79, 1.26) | 3280 (51) | 39 (41) | 0.80 (0.63, 1.02) |
| Fetal growth restriction1 | 792 (20) | 26 (26) | 1.29 (0.92, 1.81) | 477 (7) | 10 (11) | 1.42 (0.79, 2.57) |
| GA at delivery Median (IQR) |
38.1 (37.6–38.6) |
37.6 (37.1–38.3) |
[β (95% CI)] −0.32 (−0.44, −0.20) |
39.6 (39.1–40.1) |
39.4 (39.1–40.1) |
[β (95% CI)] 0.08 (−0.06, 0.21) |
| Mode of delivery Vaginal Cesarean Operative delivery |
2259 (59) 1418 (37) 134 (3) |
41 (43) 51 (54) 3 (3) |
Referent 1.98 (1.31, 3.01) 1.23 (0.38, 4.04) |
3456 (55) 2585 (41) 283 (5) |
39 (42) 52 (55) 3 (3) |
Referent 1.78 (1.17, 2.71) 0.94 (0.29, 3.06) |
| Labor type Spontaneous Spontaneous/augmented Induction |
789 (20) 535 (14) 1824 (47) |
8 (8) 16 (16) 40 (40) |
0.46 (0.22, 0.99) 1.36 (0.76, 2.45) Referent |
990 (15) 950 (15) 3246 (50.5) |
15 (16) 12 (13) 47 (49.5) |
1.05 (0.58, 1.88) 0.87 (0.46, 1.65) Referent |
| Meconium1 | 300 (8) | 14 (14) | 1.84 (1.12, 3.02) | 1056 (17) | 32 (34) | 2.06 (1.54, 2.74) |
| Chorioamnionitis1 | 105 (11) | 2 (8) | 0.71 (0.19, 2.72) | 271 (16) | 11 (41) | 2.49 (1.56, 3.98) |
| Endometritis1 | 116 (3) | 2 (2) | 0.68 (0.17, 2.70) | 219 (3) | 9 (10) | 2.78 (1.47, 5.25) |
Categorical data are N(%)
Risk ratios, unless otherwise noted, with 95% Confidence Intervals for the occurrence
All patients with the condition compared to all patients without the condition
Some obstetric risk factors were predictive of RDS among early-term infants (Table 2). Delivery via cesarean (RR 1.98, 95% CI 1.31, 3.01) and presence of meconium at delivery (RR 1.84, 95% CI 1.12, 3.02) were independently associated with increased risk of RDS development in this gestational age range. Conversely, spontaneous labor (RR 0.46, 95% CI 0.22, 0.99), and gestational age (β −0.32, 95% CI −0.44, −0.20) were independently associated with a reduction of risk of RDS in this gestational age range. However, no differences in the risk of RDS were identified in relation to chorioamnionitis or endometritis, augmented labor, or operative vaginal delivery.
Among full-term infants, predictors of RDS included the presence of endometritis (RR 2.78, 95% CI 1.47, 5.25), chorioamnionitis (RR 2.49, 95% CI 1.56, 3.98), or meconium (RR 2.06, 95% CI 1.54, 2.74) at delivery, or delivery via cesarean (RR 1.78, 95% CI 1.17, 2.71). However, at full-term, there was no association between gestational age or spontaneous labor and the development of RDS.
Discussion
In this secondary analysis of a large retrospective study, cesarean delivery and presence of meconium at delivery were independently associated with RDS at both early-term and full-term gestation, but many risk factors for RDS differed between early-term and full-term deliveries. Specifically, spontaneous labor and gestational age were independently associated with RDS only at early-term, and endometritis and chorioamnionitis only at full-term. These findings suggest that even after 37 weeks’ gestation, risk factors for RDS evolve during pregnancy, and that a focus on preventing infectious comorbidities may help reduce incidence of RDS at full-term.
Both the evolution of risk factors for RDS with increasing gestational age5,7 and cesarean delivery6–9 as a risk factor are consistent with findings in existing literature. Specifically, cesarean delivery as a risk factor for RDS has been particularly well established6–9 and has been attributed to the greater residual volume of lung fluid, less effective lung fluid excretion, and reduced surfactant secretion among infants born via cesarean compared to vaginal delivery.14 Furthermore, low birth weight and cesarean delivery have also been shown previously to have different associations with RDS when comparing term to late preterm births7. However, biological differences between preterm neonates and term neonates11,15 may explain much of that phenomenon. In this analysis, the study population was limited to neonates born at or after 37 weeks’ gestation, and risk factors were shown to vary between infants born at early-term versus full-term gestation. This suggests that meaningful biological differences between infants born at early-term and full-term exist, especially as relates to risk of developing RDS.
Some of the present findings meaningfully differ from existing literature. There is an established association between intrauterine inflammation and decreased risk of RDS16–18. In fact, with each step-wise increase in intrauterine inflammation—from no inflammation to chorioamnionitis alone, and from chorioamnionitis alone to chorioamnionitis with umbilical vasculitis—across all gestational ages, there is a decrease in risk of RDS16. This effect may be explained by direct dose-dependent fetal pulmonary benefits associated with intrauterine inflammation16–18. Critically, previous studies describing this association included mostly infants born preterm, while this study included only infants born at term. The study data demonstrate an association of chorioamnionitis and endometritis with RDS in the opposite direction of previous findings, but this finding was demonstrated only among full-term infants. Thus, the inflammation caused by chorioamnionitis and endometritis which is protective in early-term and preterm infants appears to be detrimental at full-term. Prospective research is needed to first support this finding and then clarify the pathophysiology behind which maternal infections are associated with an increase of RDS among full-term deliveries.
Many of the strengths of this study stem from the strengths of the large parent database it derives from. The socioeconomically diverse patient population included in this study enhances the generalizability of its results. The systematic abstraction by trained research nurses and regular validation of data adds to the validity of the findings. Finally, the large size of the database accommodates the study of RDS at term, a relatively uncommon outcome.
There are also several limitations to this study. Data were collected from a single tertiary care center, which could limit study generalizability; however, the diverse patient population reduces this limitation. RDS at term is caused by a multitude of etiologies. However, given this study used ICD9-CM codes for RDS diagnosis, specific etiologies of RDS were not analyzed. Complete data was not available for nearly all patients. For this secondary analysis, missing data were excluded from analysis. The parent study also included only women who had pre-gestational diabetes, chronic hypertension, or FGR, and was thus lacking a comparison group free of all those conditions. Specifically, the parent study did not include patients with gestational diabetes, only pre-gestational diabetes, making the present study unable to do so. The present study also did not specifically analyze birth weight beyond diagnoses of fetal growth restriction and macrosomia. These exclusions make generalizability to a low-risk population questionable. Finally, predictors that we identified may or may not be causal, awaiting further study.
Conclusions
This analysis identified novel risk factors for RDS after 37 weeks’ gestation: chorioamnionitis and endometritis. These are especially intriguing findings given previous analyses have identified uterine inflammation as protective against RDS at other gestational ages16–18. These findings suggest not only that the etiology of RDS may differ between term and preterm infants, but also that prospective research is needed to determine whether prevention and early treatment of maternal infectious comorbidities may reduce the burden of RDS.
Key Points.
RDS risk factors vary by gestational age
Novel risk factors for RDS at full-term identified
Intrauterine inflammation associated with RDS at term
Acknowledgements
NICHD grant 1R01HD077592, Primary Investigator: Savitz, Title: Effect of Iatrogenic Delivery at 34–38 weeks’ gestation on pregnancy outcome
Footnotes
Conflict of Interest
Conflict of Interest: none declared
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