Objective
The purpose of this study was to identify ante- and intrapartum risk factors for serious morbidity in term nonanomalous neonates.
Study Design
We analyzed the first 5000 subjects within an ongoing prospective cohort study of consecutive term births from 2010-2012. The primary outcome was a composite of serious neonatal morbidity defined as ≥1 cases of hypoxic ischemic encephalopathy, meconium aspiration with pulmonary hypertension, requirement of hypothermia therapy, respiratory distress syndrome, seizures, sepsis or suspected sepsis, or death. We calculated odds ratios for the composite morbidity that is associated with ante- and intrapartum factors. Multivariable logistic regression was used to estimate adjusted odds ratios.
Results
Of 5000 term nonanomalous births, 393 had the composite morbidity. Significant risk factors for morbidity were nulliparity, presence of meconium, first stage of labor >95th percentile, second stage of labor >95th percentile, pregestational diabetes mellitus, chronic hypertension, obesity, maternal intrapartum fever, and cesarean delivery. In contrast, induction of labor and gestational age ≥41 weeks were not associated with significant morbidity.
Conclusion
We identified several significant risk factors for serious morbidity in term nonanomalous neonates. Clinicians may use these risk factors to help anticipate the potential need for additional neonatal support at delivery.
Approximately 5-18% of term gestational age (≥37 weeks) infants are admitted to the neonatal intensive care unit (NICU), which accounts for up to 40% of admissions to higher-level nurseries. In addition to the use of limited resources and the financial burden on the health care system, these admissions frequently are unanticipated.
Previous studies have identified the most common diagnoses for NICU admission in term infants, which include congenital anomalies, followed by respiratory conditions, jaundice, hypoglycemia, and infection. However, the vast majority of infants who are born at term are anatomically normal, and few studies have sought to identify ante- and intrapartum risk factors for these serious morbidities in term nonanomalous infants.
The aim of our study was to identify risk factors for serious morbidity in term nonanomalous neonates. We hypothesized that there are specific identifiable ante- and intrapartum risk factors for serious morbidity in anatomically normal term infants. Identification of these factors will assist physicians to anticipate the need for additional neonatal support at delivery.
Materials and Methods
We analyzed the first 5000 subjects within an ongoing prospective cohort study from 2010-2012. This study included all births at term (≥37 weeks’ gestational age) without major congenital anomalies. The parent database included all consecutive births at a single tertiary care hospital. Research assistants extracted the data from the medical records after delivery. The study was approved by the Washington University Human Research Protection Office.
The primary outcome was a composite neonatal morbidity defined by ≥1 of the following occurrences: hypoxic ischemic encephalopathy, meconium aspiration with pulmonary hypertension, requirement of hypothermia therapy, respiratory distress syndrome, seizures, sepsis or suspected sepsis, or neonatal death. Those infants with composite morbidity were compared with term neonates who did not have one of the composite neonatal outcomes or any other neonatal morbidity that required a higher level of nursery care.
Hypoxic-ischemic encephalopathy was defined by ≥1 of the following occurrences: (1) umbilical arterial pH <7.0, (2) base deficit −16, (3) need for respiratory support at 10 minutes of life, (4) 5-minute Apgar score <5 and (1) moderate-severe neonatal encephalopathy by National Institute of Child Health and Human Development criteria or (2) seizure activity. Meconium aspiration with pulmonary hypertension was defined as respiratory distress (nasal flaring, subcostal and intercostal retractions, and need for supplemental oxygen to maintain oxygen saturations >95%) and transthoracic echocardiographic findings of elevated main pulmonary artery pressures (right-to-left shunting across the patent ductus arteriosus and atria, a flattened septum, and a tricuspid regurgitation jet). Respiratory distress syndrome included all neonates who required oxygen support after 6 hours of life or any need for mechanical ventilation. Suspected sepsis was diagnosed as a symptomatic neonate defined as ≥1 of the following occurrences: respiratory distress, temperature instability, apnea, lethargy, with or without abnormal complete blood count 6-12 hours after birth with leukopenia or leukocytosis with a ratio of immature cells of the neutrophilic series to total cells of the neutrophilic series >0.2, and/or positive blood culture. Suspected sepsis was included given that antibiotics are initiated empirically if there is a high clinical concern for neonatal infection because of associated risk for encephalopathy, seizures, cerebral palsy, and death. Further, the sensitivity and specificity of blood cultures are poor for neonatal sepsis; thus, the inclusion of both suspected and confirmed sepsis cases includes those who required treatment for sepsis by either laboratory or clinical criteria and is most clinically relevant. The attending neonatologist confirmed all diagnoses.
Data were extracted from the maternal and neonatal medical records to obtain sociodemographic information, medical and antenatal history, and neonatal outcomes. The labor and delivery record was used to collect data on all intrapartum events and duration of each stage of labor. Obesity was defined as an admission body mass index (BMI) ≥30 kg/m 2 . A maternal fever included maternal temperature ≥38.0°C during labor. The duration of the first stage of labor was started at the time at which a woman presented in labor or an induction of labor was begun and concluded when the woman reached 10 cm of cervical dilation. The second stage of labor was begun at 10 cm of cervical dilation and concluded with delivery of the infant. Prolonged first or second stages of labor were defined with the use of labor duration data from the patients in this cohort. Duration of >95th percentile was considered prolonged. Prolonged first stage of labor was defined as >13.75 hours for nulliparous women and >11 hours for multiparous women. Prolonged second stage of labor was defined as >3 hours for nulliparous women and >2 hours for multiparous women.
Baseline characteristics were compared between those with and without composite neonatal morbidity. Categoric variables were compared with the use of the χ 2 or Fisher exact test, as appropriate. Continuous variables were assessed for normality with the Kolmogorov-Smirnov test. Variables that were not normally distributed were compared with the Mann-Whitney U test, and normally distributed variables were compared with the Student t test.
Odds ratios were calculated for composite morbidity based on the presence or absence of each risk factor. Logistic regression was used to identify the independent risk factors. Candidate variables for the logistic regression models were selected on the basis of biologic plausibility and significant baseline factors from our univariable analysis. A probability value of < .1 identified factors to be considered in the models. Backwards elimination was used to reduce the number of variables in each model. Differences between hierarchic explanatory models were assessed using the likelihood ratio test. Model fit for the final model was assessed with the Hosmer-Lemeshow goodness-of-fit test. The analyses were then repeated for sepsis or suspected sepsis and respiratory distress alone, which are the 2 most common morbidities in the composite. The analysis was also repeated for a separate composite of the more rare, and often more severe, morbidities in our composite, which included all morbidities except sepsis or suspected sepsis and respiratory distress. All subjects meeting inclusion criteria were included; no a priori sample size estimation was performed. Analyses were performed using Stata statistical software (Special Edition 10; StataCorp LP, College Station, TX) and SAS software (version 9.2; SAS Institute, Inc, Cary, NC).
Results
Of 5000 term nonanomalous births, 3 infants were diagnosed postnatally with congenital anomalies that were not known previously; 5 infants had unknown admit nursery level status, and 38 infants had other neonatal morbidities that were not part of our morbidity composite, which left 4954 for this analysis. Of these, 393 infants (7.9%) had the composite neonatal morbidity. Several neonates were diagnosed with multiple morbidities: 331 (84.2%) had sepsis or suspected sepsis; 170 (43.3%) had respiratory distress syndrome; 26 (6.6%) required hypothermia therapy; 22 (5.6%) were diagnosed with hypoxic-ischemic encephalopathy; 12 (3.1%) had meconium aspiration with pulmonary hypertension; 11 (2.8%) had seizures, and 3 (0.8%) resulted in neonatal death.
Comparison of baseline characteristics found that patients with neonatal morbidity were significantly more likely to be nulliparous and younger maternal age, to have a higher BMI and pregestational diabetes mellitus, to use regional anesthesia, to undergo induction or augmentation of labor, or to have a maternal fever during labor as compared with those without composite morbidity. Patients with morbidity composite were also more likely to be delivered by operative vaginal delivery or cesarean delivery. In contrast, there was no significant difference between the groups in gestational age at delivery, maternal black race, advanced maternal age, preeclampsia, gestational diabetes mellitus, or birthweight >4000 g ( Table 1 ). Of those patients who underwent an induction of labor or cesarean delivery, there was no significant difference between those with and without composite morbidity by indication for induction or cesarean delivery ( Table 2 ).
| Variable | Morbidity composite | No morbidity composite | P value |
|---|---|---|---|
| n | 393 | 4561 | |
| Maternal age, y a | 24.6 ± 6.2 | 25.6 ± 5.9 | < .01 |
| Advanced maternal age ≥35 y, n (%) | 29 (7.4) | 388 (8.5) | .51 |
| Gestational age at delivery, wk a | 39.0 ± 1.3 | 38.9 ± 1.2 | .32 |
| Maternal black race, n (%) | 259 (65.9) | 2965 (65.0) | .71 |
| Body mass index, kg/m 2 a | 33.1 ± 7.1 | 31.9 ± 7.3 | < .01 |
| Preeclampsia, n (%) | 47 (12.0) | 429 (9.4) | .10 |
| Gestational diabetes mellitus, n (%) | 16 (4.1) | 123 (2.7) | .15 |
| Pregestational diabetes mellitus, n (%) | 10 (2.5) | 41 (0.9) | < .01 |
| Nulliparous women, n (%) | 257 (65.4) | 1834 (40.2) | < .01 |
| Previous cesarean, n (%) | 45 (11.5) | 383 (8.4) | .04 |
| Labor type, n (%) | < .01 | ||
| Spontaneous | 76 (19.4) | 1368 (30.0) | |
| Augmented | 122 (31.0) | 1223 (26.8) | |
| Induced | 195 (49.6) | 1970 (43.2) | |
| Prostaglandin use, n (%) | 99 (25.2) | 784 (17.2) | < .01 |
| Foley bulb use, n (%) | 60 (15.3) | 415 (9.1) | < .01 |
| Oxytocin use, n (%) | 296 (75.3) | 3006 (65.9) | < .01 |
| Regional anesthesia, n (%) | 371 (94.4) | 4082 (89.5) | < .01 |
| Birthweight, g a | 3289 ± 531 | 3238 ± 453 | .04 |
| Birthweight >4000 g, n (%) | 27 (6.9) | 228 (5.0) | .12 |
| Delivery, n (%) | |||
| Vaginal | 195 (49.6) | 3653 (80.1) | < .01 |
| Operative vaginal | 31 (7.9) | 242 (5.3) | .03 |
| Cesarean | 167 (42.5) | 666 (14.6) | < .01 |
| Maternal fever ≥38.0°C, n (%) | 141 (36.0) | 59 (1.3) | < .01 |
| Indication | Morbidity composite, n (%) | No morbidity composite, n (%) | P value |
|---|---|---|---|
| Induction | 195 | 1968 | |
| Oligohydramnios | 9 (4.6) | 77 (3.9) | .57 |
| Premature rupture of membranes | 19 (9.7) | 240 (12.2) | .36 |
| Preeclampsia/eclampsia | 28 (14.4) | 216 (11.0) | .16 |
| Medical comorbidity | 16 (8.2) | 122 (6.2) | .28 |
| Elective | 66 (33.9) | 703 (35.7) | .61 |
| Nonreassuring antenatal testing | 23 (11.8) | 167 (8.5) | .14 |
| Other | 44 (22.6) | 527 (26.8) | .20 |
| Cesarean | 167 | 667 | |
| Nonreassuring fetal status | 94 (56.3) | 364 (54.6) | .69 |
| Arrest of labor | 78 (46.7) | 332 (49.8) | .48 |
| Maternal exhaustion | 0 | 3 (0.5) | .99 |
| Inadequate expulsive efforts | 2 (1.2) | 3 (0.5) | .26 |
| Failed vaginal delivery | 6 (3.6) | 14 (2.1) | .26 |
| Other | 35 (21.0) | 105 (15.7) | .11 |
Antepartum risk factors that were associated with morbidity included nulliparity (adjusted odds ratio [aOR], 2.1; 95% confidence interval [CI], 1.6–2.6), obesity (aOR, 1.4; 95% CI, 1.1–1.8), pregestational diabetes mellitus (aOR, 3.9; 95% CI, 1.9–8.1), and chronic hypertension (aOR, 1.8; 95% CI, 1.1–3.0). Gestational age of ≥41 weeks was not associated with composite morbidity (aOR, 1.1; 95% CI, 0.8–1.6; Table 3 ). An analysis of BMI identified a 2% increase in the odds of composite morbidity for each unit increase in BMI ( Table 3 ).
| Factors | Morbidity composite (n = 393) | No morbidity composite (n = 4561) | Odds ratio (95% confidence interval) | |
|---|---|---|---|---|
| Unadjusted | Adjusted a | |||
| Antepartum | ||||
| Gestational age ≥41 wk, n (%) | 42 (10.7) | 383 (8.4) | 1.3 (0.9–1.8) | 1.1 (0.8–1.6) |
| Nulliparity, n (%) | 257 (65.3) | 1834 (40.2) | 2.8 (2.3–3.5) | 2.1 (1.6–2.6) |
| Obesity (body mass index, ≥30 kg/m 2 ), n (%) | 243 (61.8) | 2490 (54.6) | 1.4 (1.1–1.7) | 1.4 (1.1–1.8) |
| Body mass index (continuous), kg/m 2 b | 33.1 ± 7.1 | 31.9 ± 7.3 | 1.02 (1.01–1.03) | 1.02 (1.01–1.04) |
| Pregestational diabetes mellitus, n (%) | 10 (2.5) | 41 (0.9) | 2.8 (1.4–5.6) | 3.9 (1.9–8.1) |
| Chronic hypertension, n (%) | 22 (5.6) | 178 (3.9) | 1.5 (0.9–2.3) | 1.8 (1.1–3.0) |
| Severe preeclampsia, n (%) | 32 (8.1) | 278 (6.1) | 1.4 (0.9–2.0) | 1.2 (0.8–1.9) |
| Intrapartum | ||||
| Induction of labor, n (%) | 195 (49.6) | 1970 (43.2) | 1.3 (1.1–1.6) | 1.1 (0.9–1.4) |
| Oxytocin exposure, n (%) | 296 (75.3) | 3006 (65.9) | 1.6 (1.3–2.0) | 1.0 (0.8–1.4) |
| Maternal intrapartum fever, n (%) | 141 (35.9) | 59 (1.3) | 42.0 (30.3–58.3) | 34.7 (24.8–48.4) |
| Meconium present, n (%) | 151 (38.4) | 908 (19.9) | 2.5 (2.0–3.1) | 2.5 (2.0–3.3) |
| Prolonged 1st stage of labor, n (%) | 152 (38.8) | 775 (17.0) | 2.4 (1.6–3.7) | 2.1 (1.3–3.5) |
| Prolonged 2nd stage of labor, n (%) | 41 (15.0) | 250 (6.3) | 2.6 (1.8–3.8) | 1.8 (1.1–2.7) |
| Cesarean delivery, n (%) | 167 (42.5) | 666 (14.6) | 4.3 (3.5–5.4) | 3.1 (2.4–4.0) |
| Regional anesthesia, n (%) | 371 (94.4) | 4082 (89.5) | 2.0 (1.3–3.1) | 1.1 (0.7–1.8) |
a Adjusted for nulliparity, fever, induction of labor, body mass index, and mode of delivery
Intrapartum risk factors that were associated with morbidity included the presence of meconium (aOR, 2.5; 95% CI, 2.0–3.3), first stage of labor >95th percentile (aOR, 2.1; 95% CI, 1.3–3.5), second stage of labor >95th percentile (aOR, 1.8; 95% CI, 1.1–2.7), maternal intrapartum fever (aOR, 34.7; 95% CI, 24.8–48.4), and cesarean delivery (aOR, 3.1; 95% CI, 2.4–4.0). In contrast, induction of labor (aOR, 1.1; 95% CI, 0.9–1.4), severe preeclampsia (aOR, 1.2; 95% CI, 0.83–1.9), oxytocin exposure (aOR 1.0; 95% CI, 0.8–1.4), and the use of regional anesthesia (aOR, 1.1; 95% CI, 0.7–1.8) were not associated with composite morbidity ( Table 3 ).
Sepsis or suspected sepsis and respiratory distress syndrome were the 2 most common components of the composite. Sepsis or suspected sepsis was diagnosed in 331 infants (84.2%) with composite morbidity. Ante- and intrapartum risk factors that were associated with sepsis or suspected sepsis were unchanged from those for composite morbidity ( Table 4 ). Respiratory distress syndrome was the second most prevalent morbidity in the composite, occurring in 170 infants (43.3%). Nulliparity and pregestational diabetes mellitus were antepartum risk factors that were associated with respiratory distress syndrome. However, in contrast to the composite morbidity, obesity and chronic hypertension were not significant (aOR, 1.3 [95% CI, 0.9–1.8] and 1.7 [95% CI, 0.9–3.4], respectively). Also in contrast to the composite morbidity, severe preeclampsia was found to be associated with respiratory distress syndrome (aOR, 1.9; 95% CI, 1.1–3.1). Intrapartum risk factors for respiratory distress were consistent with those for the composite morbidity, with the exception of a prolonged first and second stage of labor, which were no longer significant risk factors (aOR, 1.2 [95% CI, 0.5–2.7] and 1.1 [95% CI, 0.6–2.3], respectively; Table 4 ).
| Factor | Sepsis (n = 331), n (%) | No sepsis (n = 4561), n (%) | Adjusted odds ratio a (95% confidence interval) | Respiratory distress syndrome (n = 170), n (%) | No respiratory distress syndrome (n = 4561), n (%) | Adjusted odds ratio a (95% confidence interval) |
|---|---|---|---|---|---|---|
| Antepartum | ||||||
| Gestational age ≥41 wk | 37 (11.2) | 388 (8.4) | 1.2 (0.8–1.7) | 17 (10.0) | 402 (8.4) | 1.1 (0.7–1.8) |
| Nulliparity | 225 (68.0) | 1858 (40.2) | 2.3 (1.7–2.9) | 97 (57.1) | 1923 (40.2) | 1.7 (1.2–2.3) |
| Obesity (body mass index, ≥30 kg/m 2 ) | 204 (61.6) | 2524 (54.6) | 1.4 (1.0–1.8) | 102 (60.0) | 2612 (54.6) | 1.3 (0.9–1.8) |
| Body mass index (continuous), kg/m 2 b | 33.0 ± 7.2 | 31.9 ± 7.3 | 1.02 (1.00–1.04) | 32.9 ± 7.1 | 31.9 ± 7.3 | 1.02 (0.99–1.04) |
| Pregestational diabetes mellitus | 6 (1.8) | 42 (0.9) | 3.0 (1.2–7.5) | 7 (4.1) | 43 (0.9) | 5.7 (2.5–12.9) |
| Chronic hypertension | 19 (5.7) | 180 (3.9) | 2.0 (1.1–3.4) | 9 (5.3) | 187 (3.9) | 1.7 (0.9–3.4) |
| Severe preeclampsia | 27 (8.2) | 282 (6.1) | 1.2 (0.8–2.0) | 20 (11.8) | 292 (6.1) | 1.9 (1.1–3.1) |
| Intrapartum factors | ||||||
| Induction of labor | 157 (47.4) | 1997 (43.2) | 1.0 (0.7–1.2) | 86 (50.6) | 2067 (43.2) | 1.3 (0.9–1.7) |
| Oxytocin exposure | 255 (77.0) | 3047 (65.9) | 1.1 (0.8–1.4) | 114 (67.1) | 3153 (65.9) | 0.7 (0.5–1.1) |
| Maternal intrapartum fever | 137 (41.4) | 60 (1.3) | 42.3 (30.0–59.5) | 29 (17.1) | 62 (1.3) | 13.0 (8.0–21.1) |
| Meconium present | 122 (36.9) | 920 (19.9) | 2.2 (1.7–2.9) | 78 (45.9) | 952 (19.9) | 3.3 (2.4–4.6) |
| Prolonged 1st stage of labor | 38 (11.5) | 213 (4.6) | 2.4 (1.4–4.1) | 9 (5.5) | 220 (4.6) | 1.2 (0.5–2.7) |
| Prolonged 2nd stage of labor | 41 (17.8) | 250 (6.3) | 2.3 (1.4–3.6) | 10 (8.8) | 250 (6.3) | 1.1 (0.6–2.3) |
| Cesarean delivery | 140 (42.3) | 675 (14.6) | 2.9 (2.2–3.8) | 75 (44.1) | 698 (14.6) | 4.2 (3.0–5.9) |
| Regional anesthesia | 320 (96.7) | 4082 (89.5) | 1.9 (0.9–3.5) | 153 (90.0) | 4082 (89.5) | 0.7 (0.4–1.3) |
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