Objective
Neonatal diagnoses are often used as surrogate endpoints for longer-term outcomes. We sought to characterize the correlation between neonatal diagnoses and early childhood neurodevelopment.
Study Design
We conducted secondary analysis of a multicenter randomized controlled trial of antenatal magnesium sulfate vs placebo administered to women at imminent risk for delivery <32.0 weeks to prevent death and cerebral palsy in their offspring. Singletons and twins delivering 23.0-33.9 weeks who survived to hospital discharge and had 2-year-old outcome data were included. Those surviving to age 2 years were assessed by trained physicians and the Bayley II Scales of Infant Development Mental Development and Psychomotor Development Indices. Neonatal diagnoses at the time of each baby’s initial hospital discharge were examined singly and in combination to determine those most predictive of childhood neurodevelopmental impairment, defined as a childhood diagnosis of moderate/severe cerebral palsy and/or Bayley scores >2 SD below the mean. Data were analyzed by multiple regression models and area under receiver operating characteristic curves.
Results
A total of 1771 children met criteria. Children were delivered at a mean of 29.4 weeks’ gestation. In all, 459 (25.9%) had neurodevelopmental impairment. In models controlling for gestational age at delivery, maternal education, maternal race, tobacco/alcohol/drug use during pregnancy, randomization to magnesium, fetal sex, and chorioamnionitis, individual neonatal morbidities were moderately predictive of childhood neurodevelopmental impairment (best model area under receiver operating characteristic curve, 0.68; 95% confidence interval, 0.65–0.71). Combinations of 2, 3, and 4 morbidities did not improve the prediction of neurodevelopmental impairment.
Conclusion
Approximately 1 in 4 previously preterm children had neurodevelopmental impairment at age 2 years. Prediction of childhood outcomes from neonatal diagnoses remains imperfect.
Preterm delivery <37 weeks’ gestation remains the leading cause of neonatal and childhood morbidity among nonanomalous infants in the United States and the developed world. Recent advances in perinatal and neonatal medicine over the last 2 decades have resulted in substantial increases in survival among premature infants. However, this survival increase may be accompanied by an increase in survival with subsequent major morbidities, resulting in sicker children who require intensive postnatal medical care and costly developmental services. Among the most premature, those children born <1000 g, approximately 10-15% develop moderate to severe cerebral palsy and 30% have deficits in cognitive development.
Frequently, obstetric and pediatric researchers use neonatal morbidity as a surrogate outcome for longer-term, childhood outcomes when studying pregnancy exposures and/or interventions. While risks factors such as extremely low birthweight (<750 g), early gestational age (<28 weeks’ gestation), chorioamnionitis, intracranial hemorrhage, and fetal sex have been identified, the correlation between neonatal and childhood outcomes is imprecisely defined. Additionally, many preterm infants acquire multiple neonatal morbidities, but it remains uncertain if this confers an additive risk for adverse childhood neurodevelopment.
Previous studies have been limited. Schmidt et al recently examined 3 neonatal diagnoses: bronchopulmonary dysplasia (BPD), brain injury (defined as intraventricular hemorrhage, ventriculomegaly, and/or periventricular leukomalacia), and severe retinopathy of prematurity (ROP), diagnosed singly or in combination, with adverse neurodevelopmental outcomes at 18 months among infants delivered very prematurely (birthweight 500-999 g). These researchers found a correlation between the number of neonatal diagnoses and 18-month outcomes. Babies with all 3 of the studied diagnoses had an 88% chance of adverse childhood outcomes compared to an 18% chance if the infant had none of these diagnoses. The impact of other factors, including other major neonatal morbidity such as necrotizing enterocolitis, and pregnancy or antenatal characteristics such as chorioamnionitis, could not be assessed. Furthermore, it is unknown if these results are applicable to a wider range of the preterm population or are limited to the extremely low birthweight neonate.
The purpose of this study was to determine the relationship between neonatal diagnoses prior to initial hospital discharge and neurodevelopmental outcomes at age 2 years among a large, prospectively collected cohort of infants delivered preterm between 23-34 weeks’ gestation.
Materials and Methods
This is a secondary analysis of a multicenter randomized controlled trial conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network of antenatal magnesium sulfate vs placebo administered to women at imminent risk for preterm delivery <32.0 weeks’ gestation. The aim of this study was to investigate the role of magnesium in the prevention of death and cerebral palsy in their offspring. The methods and results from the primary study have been previously published. Briefly, the main trial found that fetal exposure to magnesium sulfate did not reduce the combined risk of moderate or severe cerebral palsy or death, but the rate of cerebral palsy was reduced among survivors. All participants provided written informed consent at the time of enrollment in the original study. This secondary analysis was performed on a deidentified dataset, and was reviewed by our local institutional review board and determined to be nonhuman subjects research and therefore exempt from institutional review board approval.
Singleton and twin infants admitted and randomized between 23.0-31.9 weeks’ gestation and delivered <34.0 weeks’ gestation who survived to hospital discharge postbirth and had childhood outcome data at age 2 years were included in this secondary analysis. Infants delivered with chromosomal abnormalities or major congenital malformations and/or with incomplete outcome data at hospital discharge or 2 years of age were excluded. Gestational age was determined by the best obstetric estimate per previously published criteria. Trained research nurses obtained data on neonatal outcomes during hospitalization and at discharge, and at scheduled follow-up visits at 6, 12, and 24 months of age (corrected for prematurity). Specifically, each neonate was assessed for the presence or history of intraventricular hemorrhage, periventricular leukomalacia, BPD, ROP, and necrotizing enterocolitis. Additionally, charts were reviewed to determine if the neonate had ≥1 documented (culture-proven) episode(s) of sepsis during their hospitalization.
Trained pediatricians or pediatric neurologists also evaluated those children who survived to age 2 years. Each child was assessed for the presence of cerebral palsy. When cerebral palsy was diagnosed, the Gross Motor Function Classification System was used to assess severity. Additionally, each child was evaluated with the Bayley II Scales of Infant Development Mental Development Index (MDI) and Psychomotor Development Index (PDI). We defined childhood neurodevelopmental impairment as a diagnosis of moderate or severe cerebral palsy and/or Bayley MDI and/or PDI scores >2 SD below the mean. Babies who survived to initial hospital discharge but died prior to 2-year follow-up were considered to have met the primary adverse childhood outcome.
Demographics, pregnancy characteristics, and neonatal courses were compared between children with and without neurodevelopmental impairment at age 2 years. These univariate analyses were conducted using Student t test and χ 2 as appropriate. Next, data were analyzed by multiple logistic regression models and area under receiver operating characteristic curves (AUC). Separate regression models were created for each individual neonatal diagnosis and combinations of 2, 3, and 4 neonatal diagnoses and correlated with childhood neurodevelopmental impairment. Other covariables included in each regression model were gestational age at delivery, maternal education, maternal race/ethnicity, maternal use of tobacco, alcohol, and/or drugs during pregnancy, treatment group assignment (magnesium sulfate vs placebo), fetal sex, and chorioamnionitis. For each model, the odds of neurodevelopmental impairment were calculated for infants with neonatal morbidities compared to infants without neonatal morbidities. A limited subgroup analysis was also performed for neonates delivered <28 weeks’ gestation and for twins. Data were analyzed using software (Stata, version 12.1; StataCorp, College Station, TX).
Results
Of 2444 neonates randomized in the original study, 1771 neonates/children met inclusion criteria for this secondary analysis ( Figure ). Of these, 32 (1.8%) died during the follow-up period between initial hospital discharge and 2-year-old evaluation. The last childhood evaluation occurred at a mean 28.6 months of age, corrected for prematurity (range, 22.5–44.5 months). In total, 459 (25.9%) children (including the 32 deceased) met criteria for neurodevelopmental impairment at age 2 years. Demographics and pregnancy characteristics are shown in Table 1 . Delivery characteristics and initial neonatal outcomes are shown in Table 2 . Children with neurodevelopmental impairment were smaller and were enrolled and subsequently delivered, on average, approximately 1 week earlier than those without neurodevelopmental impairment.
| Characteristic | Neurodevelopmental impairment at age 2 y, n = 459 | No neurodevelopmental impairment at age 2 y, n = 1312 | P value |
|---|---|---|---|
| Maternal age, y | 26.3 ± 6.5 a | 26.4 ± 6.1 a | .848 |
| Maternal prepregnancy body mass index, kg/m 2 | 27.2 ± 7.2 a | 26.1 ± 6.4 a | .003 |
| Married | 212 (46.3) | 682 (52.0) | .035 |
| Maternal race or ethnic group | < .001 | ||
| Black | 217 (47.3) | 555 (42.3) | |
| White | 137 (29.9) | 527 (40.2) | |
| Hispanic | 96 (20.9) | 202 (15.4) | |
| Other | 9 (2.0) | 28 (2.1) | |
| Maternal education–highest level completed | 11.5 ± 2.6 a | 12.1 ± 2.6 a | < .001 |
| Prior preterm delivery | 124 (27.0) | 328 (25.0) | .394 |
| No prenatal care | 29 (6.3) | 84 (6.4) | .949 |
| Smoking during pregnancy | 135 (29.4) | 326 (24.9) | .055 |
| Alcohol use during pregnancy | 47 (10.2) | 103 (7.9) | .114 |
| Illicit drug use during pregnancy | 56 (12.2) | 114 (8.7) | .028 |
| Gestational age at randomization, wk | 27.6 ± 2.5 a | 28.6 ± 2.3 a | <.001 |
| Randomized to magnesium sulfate | 213 (46.4) | 641 (48.9) | .366 |
| Preterm premature rupture of membranes | 394 (85.8) | 1152 (87.8) | .276 |
| Product of a twin gestation | 82 (17.9) | 220 (16.8) | .591 |
| Characteristic | Neurodevelopmental impairment at age 2 y, n = 459 | No neurodevelopmental impairment at age 2 y, n = 1312 | P value | Unadjusted OR for neurodevelopmental impairment (95% CI) |
|---|---|---|---|---|
| Gestational age at delivery, wk | 28.6 ± 2.6 a | 29.7 ± 2.3 a | < .001 | – |
| Received antenatal corticosteroids | 445 (97.0) | 1280 (97.6) | .479 | 0.79 (0.42–1.50) |
| Chorioamnionitis | 62 (13.5) | 161 (12.3) | .492 | 1.12 (0.82–1.53) |
| Cesarean delivery | 200 (43.6) | 523 (39.9) | .164 | 1.16 (0.94–1.44) |
| Male fetus | 270 (58.8) | 659 (50.2) | .002 | 1.42 (1.13–1.76) |
| Birthweight, g | 1199 ± 407 a | 1407 ± 438 a | < .001 | – |
| Culture-proven sepsis | 106 (23.1) | 176 (13.4) | < .001 | 1.94 (1.48–2.54) |
| Any necrotizing enterocolitis | 53 (11.6) | 80 (6.10) | < .001 | 2.01 (1.40–2.90) |
| Severe (stage II/III) necrotizing enterocolitis | 24 (5.2) | 33 (2.5) | .005 | 2.14 (1.25–3.66) |
| Retinopathy of prematurity | 178 (38.8) | 275 (21.0) | < .001 | 2.39 (1.90–3.01) |
| Bronchopulmonary dysplasia | 136 (29.6) | 189 (14.4) | < .001 | 2.50 (1.94–3.22) |
| Neonatal seizures | 15 (3.3) | 9 (0.70) | < .001 | 4.89 (2.12–11.25) |
| Any grade intraventricular hemorrhage and/or periventricular leukomalacia | 118 (25.7) | 252 (19.2) | .003 | 1.46 (1.13–1.87) |
| Grade III or IV intraventricular hemorrhage and/or periventricular leukomalacia | 38 (8.3) | 25 (1.9) | < .001 | 4.64 (2.77–7.79) |
In all, 898 infants (50.7%) were discharged from the neonatal intensive care unit (NICU) without any major neonatal morbidities (no diagnoses of necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, seizures, ROP, or BPD). Of these, 174/898 (19.4%) were ultimately diagnosed with neurodevelopmental impairment at age 2 years, compared to 285/873 (32.7%) of those who had ≥1 adverse neonatal outcomes ( P < .001). In univariate analyses, those with neurodevelopmental impairment were more likely to be diagnosed with culture-proven neonatal sepsis, BPD, any ROP, necrotizing enterocolitis and severe (stage II or III) necrotizing enterocolitis, any grade intraventricular hemorrhage and/or periventricular leukomalacia, neonatal seizures, and severe intraventricular hemorrhage and/or periventricular leukomalacia in unadjusted models ( Table 2 ). When adjusting for confounders including gestational age at delivery; maternal education; maternal race; maternal use of tobacco, alcohol, and/or drugs during pregnancy; treatment group assignment (magnesium sulfate vs placebo); fetal sex; and chorioamnionitis, each individual neonatal morbidity with the exception of culture-proven neonatal sepsis, severe necrotizing enterocolitis, and any grade intraventricular hemorrhage remained associated with adverse neurodevelopmental outcomes at age 2 years ( Table 3 ).
| Individual neonatal morbidity | n (%) | Adjusted OR for neurodevelopmental impairment (95% CI) | AUC (95% CI) |
|---|---|---|---|
| Culture-proven sepsis | 282 (15.9) | 1.27 (0.94–1.72) | 0.66 (0.63–0.69) |
| Any necrotizing enterocolitis | 133 (7.5) | 1.61 (1.10–2.35) | 0.66 (0.63–0.69) |
| Severe (stage II/III) necrotizing enterocolitis | 57 (3.2) | 1.55 (0.89–2.69) | 0.66 (0.63–0.69) |
| Retinopathy of prematurity | 453 (25.6) | 1.48 (1.10–2.00) | 0.66 (0.63–0.69) |
| Bronchopulmonary dysplasia | 325 (18.4) | 1.58 (1.14–2.17) | 0.66 (0.63–0.70) |
| Any grade intraventricular hemorrhage and/or periventricular leukomalacia | 370 (20.9) | 1.24 (0.96–1.62) | 0.66 (0.63–0.69) |
| Neurologic injury: diagnosis of grade III or IV intraventricular hemorrhage and/or periventricular leukomalacia and/or neonatal seizures | 81 (4.6) | 3.91 (2.41–6.34) | 0.68 (0.65–0.71) |
Next, we examined the correlation between specific combinations of 2, 3, and 4 neonatal diagnoses and adverse early childhood neurodevelopment ( Table 4 ). The majority of combinations significantly increased the odds of neurodevelopmental impairment, but the predictive value remained fair with AUC values in the range of 0.61–0.68. Overall, the combination of BPD and ROP was the most predictive, with an adjusted odds ratio of 2.89 (95% confidence interval, 1.75–4.79) and AUC of 0.68 (95% confidence interval, 0.64–0.72). However, this was only marginally better than a large number of other combinations.
| Neonatal morbidities | n (%) | Adjusted OR (95% CI) | AUC (95% CI) |
|---|---|---|---|
| 2 diagnoses | |||
| BPD + sepsis | 129 (7.3) | 3.02 (1.71–5.32) | 0.65 (0.61–0.69) |
| BPD + any NEC | 47 (2.7) | 3.34 (1.58–7.06) | 0.63 (0.58–0.67) |
| BPD + severe (stage II/III) NEC | 23 (1.3) | 2.21 (0.83–5.88) | 0.61 (0.56–0.66) |
| BPD + any grade IVH and/or PVL | 111 (6.3) | 3.45 (1.96–6.06) | 0.65 (0.61–0.70) |
| BPD + grade III/IV IVH and/or PVL and/or neonatal seizures | 81 (4.6) | 7.52 (1.26–44.9) | 0.61 (0.57–0.66) |
| BPD + ROP | 235 (13.3) | 2.89 (1.75–4.79) | 0.68 (0.64–0.72) |
| Sepsis + any NEC | 54 (3.1) | 2.79 (1.46–5.35) | 0.63 (0.58–0.67) |
| Sepsis + severe (stage II/III) NEC | 29 (1.6) | 2.41 (1.05–5.53) | 0.62 (0.57–0.66) |
| Sepsis + any grade IVH and/or PVL | 80 (4.5) | 2.76 (1.50–5.06) | 0.63 (0.59–0.68) |
| Sepsis + grade III/IV IVH and/or PVL and/or neonatal seizures | 27 (1.5) | 5.78 (2.33–14.34) | 0.63 (0.58–0.67) |
| Sepsis + ROP | 164 (9.3) | 2.53 (1.48–4.33) | 0.66 (0.61–0.70) |
| Any NEC + any grade IVH and/or PVL | 20 (1.4) | 3.97 (1.76–8.97) | 0.62 (0.58–0.67) |
| Any NEC + grade III/IV IVH and/or PVL and/or neonatal seizures | 13 (0.7) | 14.2 (3.54–56.6) | 0.62 (0.58–0.67) |
| Any NEC + ROP | 53 (3.0) | 3.90 (1.91–7.98) | 0.63 (0.59–0.68) |
| Severe (stage II/III) NEC + any grade IVH and/or PVL | 13 (0.7) | 2.81 (0.88–9.01) | 0.61 (0.56–0.66) |
| Severe (stage II/III) NEC + grade III/IV IVH and/or PVL and/or neonatal seizures | 7 (0.4) | 10.01 (1.76–56.8) | 0.61 (0.56–0.66) |
| ROP + severe (stage II/III) NEC | 26 (1.5) | 2.93 (1.18–7.27) | 0.62 (0.57–0.66) |
| ROP + any grade IVH and/or PVL | 131 (7.4) | 3.68 (2.16–6.27) | 0.66 (0.62–0.70) |
| ROP + grade III/IV IVH and/or PVL and/or neonatal seizures | 47 (2.7) | 8.28 (3.83–17.9) | 0.65 (0.61–0.70) |
| 3 diagnoses a | |||
| BPD + sepsis + any NEC | 24 (1.4) | 2.20 (0.81–5.98) | 0.61 (0.56–0.65) |
| BPD + sepsis + any grade IVH and/or PVL | 49 (2.8) | 3.90 (1.86–8.19) | 0.63 (0.59–0.68) |
| BPD + sepsis + ROP | 100 (5.7) | 3.93 (2.08–7.42) | 0.66 (0.61–0.70) |
| BPD + any NEC + any grade IVH and/or PVL | 11 (0.8) | 7.08 (1.84–27.3) | 0.61 (0.56–0.67) |
| BPD + any NEC + ROP | 37 (2.1) | 5.44 (2.34–12.62) | 0.63 (0.59–0.68) |
| BPD + any grade IVH and/or PVL + ROP | 84 (4.7) | 4.56 (2.38–8.73) | 0.66 (0.61–0.70) |
| Sepsis + any grade IVH and/or PVL + ROP | 61 (3.4) | 3.57 (1.78–7.17) | 0.64 (0.59–0.68) |
| Sepsis + any NEC + any grade IVH and/or PVL | 12 (0.7) | 3.17 (0.95–10.6) | 0.61 (0.57–0.66) |
| Sepsis + any NEC + ROP | 28 (1.6) | 3.18 (1.27–7.94) | 0.61 (0.57–0.66) |
| Any NEC + any grade IVH and/or PVL + ROP | 14 (0.8) | 11.0 (3.05–39.6) | 0.62 (0.58–0.67) |
| 4 diagnoses a | |||
| BPD + sepsis + any NEC + any grade IVH and/or PVL | 7 (0.4) | 2.81 (0.58–13.8) | 0.61 (0.56–0.65) |
| BPD + sepsis + any NEC + ROP | 19 (1.1) | 3.50 (1.18–10.4) | 0.61 (0.56–0.66) |
| BPD + sepsis + any grade IVH and/or PVL + ROP | 42 (2.4) | 5.19 (2.31–11.7) | 0.64 (0.59–0.68) |
| Sepsis + any NEC + any grade IVH and/or PVL + ROP | 7 (0.4) | 4.92 (0.99–24.3) | 0.61 (0.56–0.66) |
| BPD + any NEC + any grade IVH and/or PVL + ROP | 13 (0.7) | 10.2 (2.79–37.7) | 0.62 (0.57–0.67) |
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