Abstract
Background:
Preterm prelabor rupture of membranes (PPROM) before or around the limit of fetal viability is associated with serious maternal and neonatal complications including chorioamnionitis, extremely preterm birth, and pulmonary hypoplasia.
Objectives:
To describe contemporary outcomes of extremely preterm infants born after prolonged periviable PPROM, and to identify perinatal factors associated with survival and survival without severe neurodevelopmental impairment (NDI).
Study Design:
Among actively treated infants born alive at <27 weeks’ gestational age (GA) in centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 2012 to 2018, the outcomes of survival and survival without severe NDI at 22–26 months’ corrected age were compared between infants exposed to prolonged (≥120 hours) periviable (<24 weeks’ GA) PPROM and unexposed infants born after rupture of membranes ≤18 hours before delivery or at delivery, adjusting for birth GA, sex, multiple gestation, antenatal steroids, small for gestational age (SGA), insurance, and center. Regression models were used to identify perinatal factors associated with survival and survival without severe NDI among the infants exposed to prolonged periviable PPROM.
Results:
The analysis included 609 infants exposed to prolonged periviable PPROM and 4,489 unexposed infants. In the prolonged periviable PPROM group, 444/608 (73%) infants survived and 298/533 (56%) infants survived without severe NDI. Odds of survival (OR, 0.84; 95% CI, 0.68–1.05) and survival without severe NDI (OR, 0.91; 95% CI, 0.75–1.12) were not significantly different between prolonged periviable PPROM and unexposed groups. Variables associated with higher odds of survival without severe NDI were later GA at birth (OR, 1.37; 95% CI, 1.13–1.67), later GA at PPROM (OR 1.44; 95% CI, 1.26–1.63), and female sex (OR, 1.57; 95% CI, 1.06–2.34), while SGA infants had lower odds of survival without severe NDI (OR, 0.14; 95% CI, 0.04–0.51).
Conclusions:
Odds of survival and survival without severe NDI among infants exposed to prolonged periviable PPROM were not significantly different from unexposed infants, but decreased with earlier GA at birth and PPROM.
Keywords: extreme prematurity, neonate, preterm prelabour rupture of membranes, periviable, pulmonary hypoplasia, neurodevelopmental outcomes
Tweetable statement:
Among infants born extremely preterm, exposure to prolonged periviable prelabor rupture of membranes was not associated with lower odds of survival without severe neurodevelopmental impairment.
Introduction
Approximately four in 1000 pregnancies are complicated by preterm prelabor rupture of membranes (PPROM) before or around the limit of fetal viability (periviable PPROM; <24 weeks of gestation).1 Periviable PPROM is associated with serious pregnancy complications including chorioamnionitis, sepsis, placental abruption, and extremely preterm birth. Chorioamnionitis complicates approximately 30–40% of periviable PPROM cases, with the peak incidence within five days following PPROM.2–4 While delivery commonly ensues soon after periviable PPROM, around 50–60% of cases are followed by a prolonged latency period.5, 6 In published studies, median latency from the time of periviable PPROM to delivery ranges from 9 to 35 days.7–9 Prolonged periviable PPROM poses unique risks to the fetus and subsequent neonatal outcomes. Exposure to oligohydramnios during early phases of fetal lung maturation can result in pulmonary hypoplasia, characterized by decreased alveolar proliferation and altered pulmonary vascular development.10–12 Exposure to prolonged PPROM also increases the risk for infectious and inflammatory neonatal morbidities such as sepsis and white matter brain injury, which may increase subsequent risk of neurodevelopmental impairment (NDI).13, 14
When PPROM occurs at ≥24 weeks of gestation, clinical management guidelines include expectant management; antenatal corticosteroids; and antibiotics to prolong latency, if not contraindicated.15 Given the significant risks to the mother and uncertain neonatal outcome, management guidelines for periviable PPROM are less well defined.15, 16 It is recommended that obstetric and neonatal care teams provide families an individualized and “realistic appraisal of neonatal outcomes” to guide shared decision making.15 However, data on infant and childhood outcomes following periviable PPROM to base such an appraisal are limited. Most available data come from single-center studies and reported rates of survival and NDI following periviable PPROM vary widely.1, 7, 17–20 A recent systematic review and meta-analysis of studies published since 2000 reported that long-term follow-up was normal in 74.1% (95% CI, 52.9–87.9%) of children born to mothers with PPROM between 14 to 24 weeks’ gestation and assessed at 2 to 4 years of age (n=381 children in 5 studies), but the methods for assessing and defining a normal outcome varied between individual studies.21 The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) outcome model is commonly used for prognostication in the setting of anticipated extremely preterm birth, but does not account for the specific effects of periviable PPROM and latency duration.22 As survival of extremely preterm infants has increased in recent decades, there is a need for contemporary data on neonatal and long-term outcomes to inform management and counseling in the setting of extremely preterm birth after prolonged periviable PPROM.
The objectives of this study were to describe neonatal and early childhood outcomes of extremely preterm infants born to mothers with prolonged periviable PPROM, and to identify perinatal and neonatal characteristics associated with survival and survival without severe NDI at 22–26 months of corrected age.
Materials and Methods
This was a retrospective analysis of prospectively collected data from the Eunice Kennedy Shriver NICHD NRN. The NRN generic database enrolls infants born weighing 401 to 1000 grams and/or born between 22 weeks 0 days’ and 28 weeks 6 days’ gestation. Trained research coordinators prospectively collect maternal and neonatal data from birth until discharge home, transfer, death, or 120 days. Surviving inborn infants born <27 weeks’ gestation are eligible for medical and neurodevelopmental assessment at 22–26 months’ corrected age. A structured neurologic exam to determine level of cerebral palsy (CP) and neurodevelopmental testing (Bayley-III) is performed at follow-up by annually certified examiners. The institutional review board of each participating hospital approved the participation in the registry. Waiver of consent was granted at most hospitals for enrollment in the registry, while 5 hospitals required parental consent (4 written, 1 oral). Five hospitals allowed participation in the follow-up study under waiver of consent and the other participating hospitals required written parental consent.
All infants born <27 weeks’ gestation from July 2012 to December 2018 in the NRN generic database were categorized by duration of rupture of membranes (ROM). Time of rupture of membranes (ROM) prior to delivery was recorded individually for each infant. The exposed group included infants exposed to prolonged (defined as ROM ≥120 hours) periviable PPROM, and the unexposed group included infants born without prolonged ROM (ROM ≤18 hours prior to delivery or at delivery) for any indication. The cut-off of ≥120 hours was used to select infants at risk for complications associated with very early and prolonged latency duration on fetal development. Data on residual amniotic fluid volume after ROM was not collected. To specifically evaluate the association of prolonged periviable PPROM with neonatal outcomes, infants born after exposure to shorter latency duration after periviable PPROM (>18 to <120 hours) and infants born after prolonged PPROM at ≥24 weeks of gestation were excluded. Infants who did not receive active treatment postnatally also were excluded. Active treatment was defined as receipt of any of the following: surfactant, tracheal intubation, ventilatory support including continuous positive airway pressure (CPAP), bag-valve-mask ventilation, or mechanical ventilation, parenteral nutrition, chest compressions, or epinephrine. Other exclusion criteria were infants with missing data related to timing of ROM, infants with major congenital anomalies other than anomalies associated with oligohydramnios (e.g., pulmonary hypoplasia, limb contractures, skeletal compression deformities, Potter sequence), and infants not eligible for follow-up (outborn infants).
The primary study outcomes were survival to hospital discharge and survival without severe NDI at 22–26 months’ corrected age. Survival without severe NDI was defined as survival without severe CP, Gross Motor Function Classification level 4–5,23 Bayley-III cognitive composite <70, bilateral vision <20/200 despite correction, or severe bilateral hearing loss. Secondary neonatal outcomes included survival without severe (grade 3) bronchopulmonary dysplasia (BPD), defined as survival without need for invasive mechanical ventilation at 36 weeks’ postmenstrual age24 and survival without severe neonatal morbidity, defined as survival without severe BPD, surgical necrotizing enterocolitis, grade 3 or 4 intraventricular hemorrhage, cystic periventricular leukomalacia, or retinopathy of prematurity requiring treatment. Secondary outcomes at follow-up included survival without serious respiratory morbidity (defined as any of the following: tracheostomy any time before follow-up; continued hospitalization for respiratory reasons at or beyond 50 weeks’ postmenstrual age; use of supplemental oxygen, respiratory support, or respiratory monitoring, such as pulse oximetry or apnea monitor at follow-up; or two or more rehospitalizations for respiratory indications before follow-up), moderate or severe NDI (defined as moderate or severe CP, GMFCS level 2 or greater, Bayley-III cognitive score <85, bilateral vision <20/200 despite correction, or severe bilateral hearing loss), and individual components of NDI.
Statistical Analysis:
Maternal and neonatal characteristics, treatments, and morbidities were described using median and interquartile range for continuous variables and counts and proportions for categorical variables. Perinatal characteristics and treatments were compared between infants exposed to prolonged periviable PPROM and unexposed infants using the Wilcoxon rank-sum test for continuous variables and the Chi-square test for categorical variables.
Primary and secondary outcomes were compared between prolonged periviable PPROM-exposed and unexposed groups using logistic regression models adjusted for gestational age (GA) at birth, sex, multiple gestation, any receipt of antenatal steroids, mother’s insurance (non-public versus public), and small for gestational age (SGA) as fixed effects, and center as a random effect. A secondary analysis was performed including only singleton infants, adjusting for the same variables except multiple gestation. Additionally, a planned subgroup analysis was conducted to evaluate the primary outcomes of survival and survival without severe NDI among infants born <24 weeks’ gestation.
Additional logistic regression models were used to identify perinatal characteristics associated with the primary outcomes of survival and survival without severe NDI among the prolonged periviable PPROM-exposed infants, adjusting for center. Variables included in the model were GA at birth, GA at ROM, any antenatal steroid exposure, sex, SGA, clinical chorioamnionitis, and delivery mode. Results were reported with adjusted odds ratios and 95% confidence intervals. Two-sided p-values <0.05 were considered statistically significant. Secondary outcomes were considered exploratory, and p-values were not adjusted for multiple comparisons.
Results
A total of 5,098 infants were included in the analysis, including 609 infants exposed to prolonged periviable PPROM and 4,489 unexposed infants born after ROM within 18 hours of delivery (Figure S1). At 22–26 months’ corrected age, complete data for the outcome of survival without severe NDI was available for 4,448 (87%) infants. In the prolonged periviable PPROM group, ROM occurred a median of 13 (interquartile range, 9 to 21) days prior to delivery. Clinical chorioamnionitis was diagnosed in approximately one-third of the prolonged periviable PPROM cases, compared to approximately 10% of cases without prolonged PPROM (Table 1). Hypertensive pregnancy disorder, cesarean delivery, and multiple gestation pregnancies were less common in the prolonged periviable PPROM group than the unexposed group, and a greater percentage of mothers in the PPROM group received antenatal steroids than the unexposed group.
Table 1.
Perinatal characteristics of mothers and infants
| Prolonged PPROM <24 weeks’ gestation (N=609) |
ROM within 18 hours of delivery (N=4489) |
P* | |
|---|---|---|---|
| Birth gestational age, completed weeks, median (IQR) | 24 (24, 25) | 25 (24, 26) | <0.0001 |
| Gestational age at ROM, weeks, median (IQR) | 22 (21, 23) | 25 (24, 26) | <0.0001 |
| <20 weeks, n/N (%) | 74/609 (12.2) | 0/4489 (0.0) | |
| 20 to <22 weeks, n/N (%) | 154/609 (25.3) | 77/4489 (1.7) | |
| 22 to <24 weeks, n/N (%) | 381/609 (62.6) | 1092/4489 (24.3) | |
| 24 to 26 weeks, n/N (%) | 0/609 (0.0) | 3320/4489 (74.0) | |
| Interval between ROM and birth, hours, median (IQR)** | 317.2 (205.3, 504.0) | 0 (0, 0.02) | <0.0001 |
| Maternal race, n/N (%) | 0.50 | ||
| Black | 246/598 (41.1) | 1804/4334 (41.6) | |
| White | 321/598 (53.7) | 2245/4334 (51.8) | |
| Asian | 20/598 (3.3) | 166/4334 (3.8) | |
| Other | 11/598 (1.8) | 119/4334 (2.8) | |
| Maternal Hispanic ethnicity, n/N (%) | 94/608 (15.5) | 704/4439 (15.9) | 0.80 |
| Maternal education high school or greater, n/N (%) | 421/507 (83.0) | 2970/3635 (81.7) | 0.47 |
| Maternal private insurance, n/N (%) | 252/609 (41.4) | 1938/4472 (43.3) | 0.36 |
| Hypertensive pregnancy disorder, n/N (%) | 24/605 (3.97) | 573/4424 (13.0) | <0.0001 |
| Clinical chorioamnionitis, n/N (%) | 210/609 (34.5) | 475/4471 (10.6) | <0.0001 |
| Histologic chorioamnionitis, n/N (%) | 475/574 (82.8) | 1933/4110 (47.0) | <0.0001 |
| Antenatal hemorrhage, n/N (%) | 122/608 (20.1) | 1011/4486 (22.5) | 0.17 |
| Antenatal steroids, any exposure, n/N (%) | 591/608 (97.2) | 3900/4483 (87.0) | <0.0001 |
| Antenatal steroids, complete course, n/N (%) | 555/591 (93.9) | 2611/3892 (67.1) | <0.0001 |
| Cesarean delivery, n/N (%) | 346/608 (56.9) | 2987/4485 (66.6) | <0.0001 |
| Multiple gestation, n/N (%) | 124/609 (20.4) | 1288/4489 (28.7) | <0.0001 |
| Birth weight, grams, median (IQR) | 720 (600, 840) | 705 (590, 835) | 0.21 |
| Small for gestational age, n/N (%) | 20/609 (3.28) | 460/4484 (10.3) | <0.0001 |
| Male sex, n/N (%) | 324/609 (53.2) | 2311/4489 (51.5) | 0.43 |
| Apgar <5 at 5 minutes, n/N (%) | 204/608 (33.6) | 1306/4459 (29.3) | 0.03 |
| Delivery room resuscitation, n/N (%) | |||
| Endotracheal intubation | 534/607 (88.0) | 3527/4489 (78.6) | <0.0001 |
| Chest compressions and/or epinephrine | 76/609 (12.5) | 394/4489 (8.8) | 0.003 |
| Delayed cord clamping or cord milking† | 103/255 (40.4) | 731/2030 (36.0) | 0.17 |
P-values obtained by Chi-square tests for categorical outcomes and Wilcoxon tests for continuous outcomes.
Interval between ROM and birth was recorded as zero when ROM occurred at the time of delivery.
Data only available for infants born 2016 and later.
IQR, interquartile range; PPROM, preterm prelabor rupture of membranes; ROM, rupture of membranes
Infants exposed to prolonged periviable PPROM were born at a lower median GA and less often SGA at birth compared to the unexposed infants (Table 1). In the delivery room, infants in the prolonged periviable PPROM group were more likely to require endotracheal intubation, chest compressions, and/or epinephrine. Multiple neonatal morbidities and treatments differed between infants in the prolonged periviable PPROM-exposed and unexposed groups (Table 2). Pneumothorax, treatment with inhaled nitric oxide, and high-frequency ventilation were more common among infants exposed to prolonged periviable PPROM than unexposed infants, while pulmonary interstitial emphysema, early hypoxemic respiratory failure, BPD, severe (grade 3) BPD, and postnatal steroids for BPD were not significantly different between groups. Early-onset sepsis, but not late-onset sepsis, was more common among infants exposed to prolonged periviable PPROM. Severe intraventricular hemorrhage, spontaneous intestinal perforation, and treatment for a patent ductus arteriosus were less common among infants exposed to prolonged periviable PPROM than unexposed infants.
Table 2.
Neonatal treatments and morbidities
| Prolonged PPROM at <24 weeks’ gestation (N=609) |
ROM within 18 hours of delivery (N=4489) |
Padj* | |
|---|---|---|---|
| Surfactant | 547/609 (89.8) | 4066/4489 (90.6) | 0.21 |
| High-frequency ventilation | 334/561 (59.5) | 2332/4285 (54.4) | 0.01 |
| Early hypoxemic respiratory failure** | 119/609 (19.5) | 997/4489 (22.2) | 0.35 |
| Pulmonary interstitial emphysema | 89/562 (15.8) | 629/4288 (14.7) | 0.32 |
| Pneumothorax | 66/562 (11.7) | 324/4289 (7.6) | 0.001 |
| Inhaled nitric oxide | 131/562 (23.3) | 509/4287 (11.9) | <0.001 |
| BPD┼ | 364/448 (81.3) | 2507/3313 (64.6) | 0.11 |
| Grade 3 BPD┼ | 61/448 (13.6) | 372/3313 (11.2) | 0.29 |
| Postnatal steroids for BPD | 161/528 (30.5) | 1077/4009 (26.9) | 0.19 |
| Patent ductus arteriosus, treated | 148/516 (28.7) | 1547/3847 (40.2) | <0.001 |
| Severe intraventricular hemorrhage | 96/539 (17.8) | 920/4132 (22.3) | 0.03 |
| Periventricular leukomalacia | 34/539 (6.3) | 252/4140 (6.1) | 0.77 |
| Early-onset sepsis | 24/562 (4.3) | 100/4289 (2.3) | 0.03 |
| Late-onset sepsis | 155/531 (29.2) | 1106/4053 (27.3) | 0.98 |
| Necrotizing enterocolitis requiring surgery | 30/561 (5.4) | 236/4286 (5.5) | 0.43 |
| Spontaneous intestinal perforation | 26/561 (4.6) | 305/4289 (7.1) | 0.01 |
| Retinopathy of prematurity, treated | 118/463 (25.5) | 854/3413 (25.0) | 0.44 |
P values adjusted for birth gestational age, sex, multiple gestation, antenatal steroids, small for gestational age, and center.
Defined as maximal FiO2 of ≥0.6 on day 1 or 3.
BPD defined as respiratory support at 36 weeks’ postmenstrual age and severe BPD defined as invasive mechanical ventilation at 36 weeks’ postmenstrual age.
BPD, bronchopulmonary dysplasia; PPROM, preterm prelabor rupture of membranes; ROM, rupture of membranes
In the prolonged periviable PPROM group, 444/608 (73%) infants survived to discharge and 298/533 (56%) infants survived without severe NDI at 22–26 months’ corrected age (Table 3). Adjusted odds of survival and survival without severe NDI were not significantly different between exposed and unexposed groups. Prolonged periviable PPROM was associated with lower adjusted odds of survival without severe BPD, while adjusted odds of survival without serious respiratory morbidity at 22–26 months’ corrected age were not significantly different between groups. Other secondary outcomes, including survival without severe neonatal morbidity, individual components of NDI, oxygen use at follow-up, and ventilator or CPAP at follow-up were not significantly different between groups. Consistent with the comparisons from the whole cohort, adjusted odds of survival and survival without severe NDI were not significantly different between groups in a secondary analysis including only singleton infants (Table S1).
Table 3.
Survival and Neurodevelopmental Outcomes at 22–26 months’ corrected age
| Prolonged PPROM at <24 weeks’ gestation (N=609) |
ROM within 18 hours of delivery (N=4489) |
Adjusted OR* (95% CI) | P | |
|---|---|---|---|---|
| Neonatal outcomes, n/N (%) | ||||
| Survival to discharge | 444/608 (73.0) | 3285/4485 (73.2) | 0.84 (0.68, 1.05) | 0.12 |
| Survival without severe BPD | 382/596 (64.1) | 2916/4386 (66.5) | 0.81 (0.67, 0.99) | 0.04 |
| Survival without severe neonatal morbidity** | 252/596 (42.3) | 1818/4382 (41.5) | 1.07 (0.89, 1.30) | 0.47 |
| Outcomes at 22–26 months’ corrected age, n (%) | ||||
| Survival without severe NDI | 298/533 (55.9) | 2212/3915 (56.5) | 0.91 (0.75, 1.12) | 0.37 |
| Survival without serious respiratory morbidity┼ | 294/546 (53.9) | 2308/4049 (57.0) | 0.83 (0.68,1.01) | 0.06 |
| Outcomes among surviving infants at 22–26 months’ corrected age: | ||||
| Severe NDI | 71/369 (19.2) | 503/2715 (18.5) | 0.99 (0.74, 1.33) | 0.96 |
| Moderate or severe NDI | 171/369 (46.3) | 1176/2715 (43.3) | 1.10 (0.87, 1.39) | 0.43 |
| Moderate or severe cerebral palsy | 35/371 (9.4) | 267/2815 (9.5) | 0.96 (0.65, 1.41) | 0.84 |
| Profound visual impairment┼┼ | 9/373 (2.4) | 42/2818 (1.5) | 1.71 (0.81, 3.63) | 0.16 |
| Profound hearing impairment┼┼ | 14/368 (3.8) | 80/2770 (2.9) | 1.33 (0.73, 2.41) | 0.35 |
| Cognitive composite score <70 | 61/368 (16.6) | 442/2744 (16.1) | 0.97 (0.71, 1.32) | 0.83 |
| Oxygen use | 32/376 (8.5) | 168/2850 (5.9) | 1.44 (0.94, 2.19) | 0.09 |
| Ventilator or CPAP | 11/376 (2.9) | 62/2850 (2.2) | 1.44 (0.73, 2.84) | 0.29 |
Adjusted OR and corresponding P-values obtained using logistic regression. The covariates adjusted for were birth gestational age, sex, multiple gestation, receipt of antenatal steroids, small for gestational age, mother’s insurance and center.
Defined as survival without severe (grade 3) BPD, surgical necrotizing enterocolitis, severe (grade 3 or 4) intraventricular hemorrhage, cystic periventricular leukomalacia, or retinopathy of prematurity requiring treatment.
Defined as survival without tracheostomy placed any time before follow-up; continued hospitalization for respiratory reasons at or beyond 50 weeks’ postmenstrual age; use of supplemental oxygen, respiratory support, or respiratory monitoring (e.g., pulse oximeter or apnea monitor) at follow-up; or two or more re-hospitalizations for respiratory reasons before follow-up.
Models not adjusted for center because of convergence issues.
BPD, bronchopulmonary dysplasia; CPAP, continuous positive airway pressure; NDI, neurodevelopmental impairment; OR, odds ratio; PPROM, preterm prelabor rupture of membranes; ROM, rupture of membranes
In a subgroup analysis of infants born at <24 weeks’ gestation, 73 (59%) of 124 infants exposed to prolonged periviable PPROM survived to discharge and 52/113 (46%) survived without severe NDI at 22–26 months of corrected age. Odds of survival were not significantly different between groups, while odds of survival without severe NDI were higher in the prolonged periviable PPROM-exposed infants than the unexposed group (Table S2).
In the group of infants exposed to prolonged periviable PPROM, survival to discharge and survival without severe NDI at 22–26 months’ corrected age were higher among infants with higher birth gestational age, later gestational age at PPROM, and shorter latency duration (Figure 1). Logistic regression was used to identify perinatal factors associated with survival and survival without severe NDI, adjusting for center. Higher gestational age at birth and at ROM were associated with higher odds of survival to discharge and survival without severe NDI at 22–26 months’ corrected age (Table 4). Antenatal steroid receipt was associated with higher odds of survival, and female sex was associated with higher odds of survival without severe NDI. SGA infants had lower adjusted odds of survival and survival without severe NDI.
Figure 1. Outcomes at 22–26 months’ corrected age.
Percentage of infants with death or survival with or without severe NDI at 22–26 months of corrected age by gestational age (completed weeks) at birth and A) gestational age at rupture of membranes, or B) latency duration between rupture of membranes and birth (among infants born to mothers with prolonged PPROM). GA, gestational age; NDI, neurodevelopmental impairment; ROM, rupture of membranes
Table 4.
Factors associated with survival and survival without severe NDI in extremely preterm infants exposed to prolonged PPROM before 24 weeks of gestation
| Survival | Survival without severe NDI | |||
|---|---|---|---|---|
| Adjusted OR* (95% CI) | p | Adjusted OR* (95% CI) | p | |
| Birth gestational age, completed weeks | 1.60 (1.30, 1.96) | <.0001 | 1.37 (1.13, 1.67) | 0.001 |
| Gestational age at rupture, weeks | 1.57 (1.39, 1.78) | <.0001 | 1.44 (1.26, 1.63) | <.0001 |
| Antenatal steroids | 4.07 (1.13, 14.61) | 0.03 | 2.91 (0.68, 12.40) | 0.15 |
| Female sex | 1.26 (0.82, 1.92) | 0.29 | 1.57 (1.06, 2.34) | 0.03 |
| Clinical chorioamnionitis | 0.98 (0.62, 1.55) | 0.94 | 1.11 (0.73, 1.68) | 0.64 |
| Cesarean delivery | 1.10 (0.71, 1.72) | 0.66 | 0.90 (0.60, 1.34) | 0.59 |
| Small for gestational age | 0.25 (0.08, 0.78) | 0.02 | 0.14 (0.04, 0.51) | 0.003 |
Adjusted OR and corresponding P-values obtained using logistic regression. The model was adjusted for center.
Comment
Principal findings
In this multicenter cohort of extremely preterm infants, 73% of infants exposed to prolonged periviable PPROM survived to discharge and 81% of surviving infants did not have severe NDI at 22–26 months’ corrected age. The odds of survival and the odds of survival without severe NDI were not significantly different from unexposed extremely preterm infants born without prolonged ROM. However, earlier gestational age at PPROM was associated with lower odds of survival and survival without severe NDI. These findings have implications for counseling of families of extremely preterm infants born after prolonged periviable PPROM.
Results in the context of what is known:
Exposure to prolonged PPROM prior to the late canalicular stage of fetal lung development (16–25 weeks’ gestation) is a risk factor for pulmonary hypoplasia.12 Neonatal complications of pulmonary hypoplasia include respiratory failure, pulmonary air leak, and pulmonary hypertension.25 In this study, pneumothorax was more common among infants exposed to PPROM than unexposed infants, but other respiratory complications including pulmonary interstitial emphysema, early hypoxemic respiratory failure, and BPD were not significantly different between groups in comparisons adjusted for baseline differences in birth GA and other factors. Odds of survival without severe BPD were lower among the prolonged periviable PPROM-exposed infants than unexposed infants at hospital discharge. Around 54% of infants in the prolonged, periviable PPROM group survived without serious respiratory morbidity at 22–26 months of corrected age, compared to 57% in the unexposed group. Adjusted odds of survival without serious respiratory morbidity were not significantly different between groups (OR 0.83; 95% CI, 0.68–1.01). These findings may represent an improvement in pulmonary function of the PPROM-exposed infants with ongoing growth and development of the lungs.
A higher percentage of infants in the prolonged periviable PPROM group received endotracheal intubation and cardiopulmonary resuscitation in the delivery room than the unexposed group. During the neonatal course, treatment with high-frequency ventilation and inhaled nitric oxide were more common in PPROM-exposed infants than unexposed infants. These results suggest that skilled cared teams with access to these therapies should be available at delivery and strive to minimize lung injury from birth.26 Inhaled nitric oxide may improve oxygenation and decrease the rate of BPD or death in some preterm infants with pulmonary hypoplasia secondary to prolonged PPROM, but further study is needed.25, 27–29
Infection is a common complication of prolonged PPROM.1, 6 In this study, around one-third of infants in the PPROM group were born to mothers with clinical chorioamnionitis and the majority (83%) had histologic chorioamnionitis. Chorioamnionitis and sepsis are reported risk factors for periventricular leukomalacia, CP, and NDI in preterm infants.30–33 Despite greater prevalence of clinical chorioamnionitis and early-onset sepsis in the PPROM-exposed infants, periventricular leukomalacia, CP and NDI occurred with similar frequency in exposed and unexposed infants.
Some neonatal morbidities were less common in the infants exposed to prolonged PPROM than unexposed infants, including treatment for a patent ductus arteriosus, severe intraventricular hemorrhage, and spontaneous intestinal perforation. It is possible that infants exposed to prolonged periviable PPROM were less likely to develop a symptomatic left-to-right shunt through the patent ductus arteriosus prompting treatment secondary to relatively higher pulmonary vascular resistance than the unexposed infants, supported by the circumstantial evidence of more frequent inhaled nitric oxide use in this group of patients. Additionally, differences in maternal characteristics and morbidities between groups, such as the relatively higher proportion of women without prolonged periviable PPROM with hypertensive pregnancy disorders, may have contributed to the observed differences in neonatal morbidities between groups. While comparisons between groups were adjusted for receipt of antenatal steroids, it is possible that differences in the timing of antenatal steroid exposure prior to delivery between groups also may have contributed to differences in neonatal morbidities between PPROM-exposed and unexposed infants.
Clinical and research implications:
This study provides data on outcomes of extremely preterm infants exposed to prolonged periviable PPROM from a multi-center cohort. The study occurred over a period of increased provision of active treatment at 22 weeks’ gestation and increased survival of extremely preterm infants in U.S. hospitals.34–36 The results of this study should be interpreted in the context of the study design and cohort selection criteria. The results are informative for counseling and prognostication in the setting of extremely preterm birth after prolonged periviable PPROM, but do not reflect the outcomes of all pregnancies affected by periviable PPROM. Data from pregnancy terminations, miscarriages, stillbirths, and livebirths after 26 weeks’ gestation were not included. Further, infants who did not receive active treatment were excluded, as inclusion of infants for whom potentially life-sustaining therapies were withheld would underestimate survival of actively treated infants. As such, the results of this study cannot be applied to predict outcomes at the time of periviable PPROM or during the latency period. Further, it should be noted that the causal effects of periviable PPROM on neonatal outcomes cannot be implied from this analysis. Comparisons of outcomes of extremely preterm infants born after prolonged periviable PPROM to unexposed infants provide contextual information on outcomes of other extremely preterm infants from the same centers and time period. However, prospective studies comparing outcomes of all pregnancies affected by periviable PPROM and unaffected pregnancies are needed to understand how periviable PPROM alters infant and childhood outcomes. A recent population-based study of women with PPROM at 16–22 weeks’ gestation in the United Kingdom estimated the rate of infant survival to discharge in the range of 17–53% with expectant management of singleton pregnancies.6 Ninety-eight of 223 (44%) expectantly managed singleton pregnancies resulted in livebirths. The wide range in estimated infant survival after PPROM reflected uncertainty due to pregnancy terminations in 103/326 (32%) cases as well as unknown infant outcomes for 16/98 (16%) liveborn infants in the United Kingdom cohort.
In the current study, earlier gestational age at PPROM and at delivery were associated with lower odds of survival and survival without severe NDI among infants exposed to prolonged PPROM. Other factors associated with survival and survival without severe NDI were consistent with perinatal factors known to influence prognosis of extremely preterm infants, including antenatal steroids, sex, and SGA status.22, 37 Data related to antenatal factors such as residual amniotic fluid volume or etiology of PPROM (iatrogenic vs. spontaneous ROM) were not available. Further study is needed to better understand how individual factors can be used to support perinatal and neonatal management and prognostication after periviable PPROM.
Strengths and limitations:
Strengths of this study include the rigorous prospective data collection for neonatal and early childhood neurodevelopmental outcomes from a large cohort of infants cared for in multiple tertiary centers. A limitation of the study is that the data represent only a subset of pregnancies affected by prolonged periviable PPROM. Data on fetal deaths, a known complication of periviable PPROM, were not included. Further, data related to maternal morbidities (e.g., sepsis, postpartum hemorrhage) were not available. Counseling and decision-making after periviable PPROM should include consideration of the full spectrum of potential maternal and neonatal outcomes.16 Finally, while early neurodevelopmental assessment is important for the timely identification of children at risk for long-term neurologic impairment or developmental delay, its capacity to predict functioning in later childhood is limited.38 Longer term follow-up studies are needed to fully understand the effects of periviable PPROM on neurodevelopment and pulmonary function.
Conclusions:
Historically, a number of studies have reported poor neonatal outcomes following prolonged periviable PPROM.1 The results of this study demonstrate that, in contemporary practice, many extremely preterm infants exposed to prolonged PPROM survive without severe pulmonary morbidities or NDI in early childhood. Despite increased infectious and pulmonary neonatal morbidities in the prolonged PPROM-exposed infants, the finding that neurodevelopment and pulmonary outcomes at follow-up were not significantly different from unexposed infants suggest that these morbidities are often manageable without severe long-term sequelae. The findings of this study support that individual factors, including GA at PPROM, should continue to be considered for counseling and prognostication for infants born extremely preterm after prolonged PPROM.
Supplementary Material
AJOG at a Glance:
Why was this study conducted?
This study aimed to provide data on contemporary outcomes of extremely preterm infants born after prolonged periviable preterm prelabor rupture of membranes (PPROM).
What are the key findings?
Odds of survival and survival without severe neurodevelopmental impairment were not significantly different between extremely preterm infants born after prolonged periviable PPROM and extremely preterm infants born after rupture of membranes within ≤18 hours of delivery.
What does this study add to what is already known?
In contemporary practice, many extremely preterm infants born after prolonged PPROM survive without severe neurodevelopmental impairment in early childhood. These results may be useful to inform medical decision-making and counseling of families of extremely preterm infants born after prolonged periviable PPROM.
Acknowledgments:
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chair: Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University, (2011–2023).
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (UG1 HD27904) – Abbot R. Laptook, MD; Martin Keszler, MD; Betty R. Vohr, MD; Angelita M. Hensman, PhD RNC-NIC; Elisa Vieira, BSN RN; Lucille St. Pierre, BS; Barbara Alksninis, RNC PNP; Andrea Knoll; Mary L. Keszler, MD; Teresa M. Leach, MEd CAES; Elisabeth C. McGowan, MD; Victoria E. Watson, MS CAS: Jenn Keller, RN.
Case Western Reserve University, Rainbow Babies & Children’s Hospital (UG1 HD21364) – Anna Maria Hibbs, MD MSCE; Nancy S. Newman, RN; Deanne E. Wilson-Costello, MD; Bonnie S. Siner, RN; Elizabeth Roth, MS.
Children’s Mercy Hospital (UG1 HD68284) – William E. Truog, MD; Eugenia K. Pallotto, MD MSCE; Howard W. Kilbride MD; Cheri Gauldin, RN BS CCRC; Anne Holmes RN MSN MBA-HCM CCRC; Kathy Johnson RN, CCRC; Allison Scott, BSN RNC-NIC; Prabhu S. Parimi, MD; Lisa Gaetano, RN MSN.
Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (UG1 HD27853, UL1 TR77) – Stephanie L. Merhar, MD MS; Brenda B. Poindexter, MD MS; Kurt Schibler, MD; Kimberly Yolton, PhD; Tanya E. Cahill, MD; Teresa L. Gratton, PA; Cathy Grisby, BSN CCRC; Devan Hayes, BS; Kristin Kirker, CRC; David Russell, JD; Sara Stacey, BA; Sandra Wuertz, RN BSN CLC.
Duke University School of Medicine, University Hospital, University of North Carolina, Duke Regional Hospital, and WakeMed Health & Hospitals (UG1 HD40492, UL1 TR1117) – Ricki F. Goldstein, MD; Patricia L. Ashley, MD; Deesha Mago-Shah, MD; Joanne Propst, RN JD; Kimberley A. Fisher, PhD FNP-BC IBCLC; Kathryn E. Gustafson, PhD; Matthew M. Laughon, MD MPH; Carl L. Bose, MD; Janice Bernhardt, MS RN; Gennie Bose, RN; Janice Wereszczak, CPNP-AC/PC; Diane Warner, MD MPH; Jennifer Talbert, MS RN; Stephen D. Kicklighter, MD; Alexandra Bentley, MD; Laura Edwards, MD; Ginger Rhodes-Ryan, ARNP MSN, NNP-BC; Donna White, RN-BC BSN.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (UG1 HD27851, UL1 TR454) – Ravi M. Patel, MD MSc; David P. Carlton, MD; Ira Adams-Chapman, MD (deceased); Ellen C. Hale, BS RN CCRC; Yvonne Loggins, RN; Diane Bottcher, RN; Sheena L. Carter, PhD; Salathiel Kendrick-Allwood, MD; Maureen Mulligan LaRossa, RN; Judith Laursen, RN; Colleen Mackie, RRT; Amy Sanders, PsyD; Gloria Smikle, PNP; Lynn Wineski, NNP.
Eunice Kennedy Shriver National Institute of Child Health and Human Development – Andrew A. Bremer, MD PhD; Michele C. Walsh, MD MS; Rosemary D. Higgins, MD; Stephanie Wilson Archer, MA.
Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (UG1 HD27856, UL1 TR6) – Gregory M. Sokol, MD; Brenda B. Poindexter, MD MS; Heidi Harmon, MD MS; Lu Ann Papile, MD; Susan Gunn, NNP CCRC; Abbey C. Hines, PsyD; Jeffery Joyce, CCRC (deceased); Carolyn Lytle, MD MPH; Dianne E. Herron, RN CCRC; Lucy Smiley, CCRC.
McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, and Memorial Hermann Southwest Hospital (U10 HD21373, UG1 HD87229) – Jon E. Tyson, MD MPH; Amir M. Khan, MD; Kathleen A. Kennedy, MD MPH; Barbara J. Stoll, MD; Ricardo A. Mosquera, MD MS; Andrea F. Duncan, MD MS; Patrick Jones, MD MA; Nora Alaniz, BS; Elizabeth Allain, PhD; Julie Arldt-McAlister, MSN APRN; Katrina Burson, RN BSN; Fatima Boricha, MD; Allison G. Dempsey, PhD; Carmen Garcia, RN BSN; Donna J. Hall, RN; Janice John, CPNP; M. Layne Lillie, RN BSN; Karen Martin, RN; Sara Martin, RN; Carrie M. Mason, MA LPA; Georgia E. McDavid, RN; Shannon L. McKee, EdS; Kimberly Rennie, PhD; Tina Reddy, MD; Shawna Rodgers, BSN RNC-NIC; Daniel K. Sperry, RN; Emily Stephens, BSN RNC-NIC; Sharon L. Wright, MT (ASCP); Dinorah Zanger, PhD.
Nationwide Children’s Hospital, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Center for Perinatal Research, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, and Riverside Methodist Hospital (UG1 HD68278) – Pablo J. Sánchez, MD; Leif D. Nelin, MD; Jonathan L. Slaughter, MD MPH; Sudarshan R. Jadcherla, MD; Nathalie L. Maitre, MD PhD; Christopher Timan, MD; Keith O. Yeates, MD PhD; Patricia Luzader, RN; Julie Gutentag, RN BSN; Jennifer L. Grothause, BA RN BSN; Melanie Stein, RRT BBS; Rox Ann Sullivan, RN BSN; Cole D. Hague, BA MS; Helen Carey, PT DHSc PCS; Michelle Chao, BS; Stephanie Burkhardt, BS MPH; Margaret Sullivan, BS; Lina Yossef-Salameh, MD; Mary Ann Nelin, MD; Erna Clark, BA; Julie C. Shadd, BSN RD; Courtney Park, RN BSN; Courtney Cira, BS; Erin Fearns; Kristi Small, BS; Sarah A. Keim, PhD MA MS; Christine A. Fortney, RN PhD; Aubrey Fowler, BS, Jacqueline McCool; Lindsay Pietruszewski, PT DPT; Jessica Purnell, BS CCRC; Kyrstin Warnimont, BS; Laura Marzec, MD; Bethany Miller, RN BSN; Demi R. Beckford, MHS; Hallie Baugher, BS MSN; Julia Newton, MPH; Katelyn Levengood, PT DPT; Nancy Batterson, OT/L; Brittany DeSantis, BS. RTI International (UG1 HD36790) – Carla M. Bann, PhD; Marie G. Gantz, PhD; Dennis Wallace, PhD; Jeanette O’Donnell Auman, BS; Margaret M. Crawford, BS; Jenna Gabrio, BS MPH; Jamie E. Newman, PhD MPH; Lindsay Parlberg, BS; Carolyn M. Petrie Huitema, MS; Kristin M. Zaterka-Baxter, RN BSN.
Stanford University, El Camino Hospital, and Lucile Packard Children’s Hospital (UG1 HD27880, UL1 TR93) – Valerie Chock, MD MS Epi; David K. Stevenson, MD; Susan R. Hintz, MD MS Epi; M. Bethany Ball, BS CCRC; Marian M. Adams, MD; Barbara Bentley, PsychD MSEd; Maria Elena DeAnda, PhD; Anne M. DeBattista, RN PNP PhD; Beth Earhart, PhD; Lynne C. Huffman, MD; Casey E. Krueger, PhD; Ryan E. Lucash, PhD; Melinda S. Proud, RCP; Elizabeth N. Reichert, MA CCRC; Heather Taylor, PhD; Hali E. Weiss, MD; R. Jordan Williams, MD.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (UG1 HD34216) – Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD MPH; Kirstin J. Bailey, PhD; Fred J. Biasini, PhD; Stephanie A. Chopko, PhD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN; Kristy A. Domnanovich, PhD; Chantel J. Jno-Finn, PT DPT; Morissa Ladinsky, MD; Mary Beth Moses, PT MS PCS; Tara E. McNair, RN BSN; Vivien A. Phillips, RN BSN; Julie Preskitt, MSOT MPH; Richard V. Rector, PhD; Kimberlly Stringer, MD MPH; Sally Whitley, MA OTR-L FAOTA; Sheree York Chapman, PT DPT PCS.
University of California – Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (UG1 HD68270) – Uday Devaskar, MD; Meena Garg, MD; Isabell B. Purdy, PhD CPNP; Teresa Chanlaw, MPH; Rachel Geller, RN BSN.
University of Iowa, Mercy Medical Center, and Sanford Health (UG1 HD53109, UL1 TR442) – John A. Widness, MD; Heidi M. Harmon, MD; Karen J. Johnson, RN BSN; Mendi L. Schmelzel, RN MSN; Jacky R. Walker, RN; Claire A. Goeke, DNP ARNP; Sarah E. Faruqui, RN MSN; Diane L. Eastman, RN CPNP MA; Dan L. Ellsbury, MD; Donia B. Bass, RNC-NIC; Tracy L. Tud, RN; Michelle L. Baack, MD; Laurie A. Richards, MD; Megan M. Henning, RN BSN; Chelsey Elenkiwich, NNP APRN CNP; Megan Broadbent, RN BSN; Sarah Van Muyden, RN BSN. University of New Mexico Health Sciences Center (UG1 HD53089, UL1 TR41) – Kristi L. Watterberg, MD; Janell Fuller, MD; Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Carol Hartenberger, BSN MPH; Sandra Sundquist Beauman, MSN RNC; Mary Ruffner Hanson, RN BSN; Jean R. Lowe, PhD; Elizabeth Kuan, RN BSN.
University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, Children’s Hospital of Philadelphia, and Virtua Voorhees Hospital (UG1 HD68244) – Sara B. DeMauro, MD MSCE; Eric C. Eichenwald, MD; Barbara Schmidt, MD MSc; Haresh Kirpalani, MB MSc; Soraya Abbasi, MD; Christine Catts, CRNP; Aasma S. Chaudhary, BS RRT; Toni Mancini, RN BSN CCRC; Dara M. Cucinotta, RN; Judy C. Bernbaum, MD; Noah Cook, MD; Marsha Gerdes, PhD; Sarvin Ghavam, MD; Hallam Hurt, MD; Jonathan Snyder, RN BSN, Kristina Ziolkowski, CMA(AAMA) CCRP.
University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (UG1 HD68263, UL1 TR42) – Carl T. D’Angio, MD; Ronnie Guillet, MD PhD; Gary J. Myers, MD; Satyan Lakshminrusimha, MD; Anne Marie Reynolds, MD; Holly I.M. Wadkins; Michael G. Sacilowski, BS; Rosemary L. Jensen; Deanna Maffett, RN; Joan Merzbach, LMSW; William Zorn, PhD; Osman Farooq, MD; Ashley Williams, MSEd; Julianne Hunn, BS; Stephanie Guilford, BS; Kelley Yost, PhD; Mary Rowan, RN; Diane Prinzing; Melissa Bowman, RN NP; Ann Marie Scorsone, MS CCRC; Michelle Hartley-McAndrew, MD; Caitlin Fallone, MA; Kyle Binion, BS; Constance Orme; Premini Sabaratnam, MPH; Alison Kent, BMBS FRACP MD; Rachel Jones; Elizabeth Boylin, BA; Daisy Rochez, BS MHA; Emily Li, BA; Jennifer Kachelmeyer, BS; Kimberly G. McKee, MPH; Kelly R. Coleman, PsyD.
University of Texas Southwestern Medical Center, Parkland Health & Hospital System, and Children’s Medical Center Dallas (UG1 HD40689) – Luc P. Brion, MD; Roy J. Heyne, MD; Diana M. Vasil, MSN BSN RNC-NIC; Lijun Chen, RN PhD; Sally S. Adams, MS RN CPNP; Maria M. De Leon, RN BSN; Frances Eubanks, RN BSN; E. Rebecca McDougald, MSN APRN CPNP-PC/AC; Lara Pavageau, MD; Pollieanna Sepulveda, RN; Alicia Guzman; Elizabeth Heyne, PsyD PA-C; Lizette E. Lee, RN; Azucena Vera, AS; Jillian Waterbury, DNP RN CPNP-PC; Kristine Tolentino-Plata, MS; Cathy Twell Boatman, MS CIMI.
University of Utah Medical Center, Intermountain Medical Center, McKay-Dee Hospital, Utah Valley Hospital, and Primary Children’s Hospital (UG1 HD87226, UL1 TR105) – Bradley A. Yoder, MD; Mariana Baserga, MD MSCI; Roger G. Faix, MD; Sarah Winter, MD; Stephen D. Minton, MD; Mark J. Sheffield, MD; Erick B. Gerday, MD; Carrie A. Rau, RN BSN CCRC; Shawna Baker, RN; Jill Burnett, RNC BSN; Susan Christensen, RNC BSN; Laura Cole Bledsoe, RN; Sean D. Cunningham, PhD; Brandy Davis, RN BSN; Jennifer O. Elmont, RN BSN; Becky Hall, APRN; Manndi C. Loertscher, BS CCRP; Trisha Marchant, RNC BSN; Earl Maxson, RN CCRN; Kandace M. McGrath, BS; Hena G. Mickelsen, BA; Galina Morshedzadeh, BSN APRN; D. Melody Parry, RN BSN; Brixen A. Reich, MSN RNC CCRC; Susan T. Schaefer, RN BSN RRT; Kelly Stout, PhD; Ashley L. Stuart, PhD; Mike Steffen, PhD; Kimberlee Weaver-Lewis, RN MS; Kathryn D. Woodbury, RN BSN; Jamie Jordan, RN BSN; Katherine Tice, RN BS. Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (UG1 HD21385) – Seetha Shankaran, MD; Girija Natarajan, MD; Beena G. Sood, MD MS; Athina Pappas, MD; Monika Bajaj, MD; Melissa February, MD; Prashant Agarwal, MD; Sanjay Chawla, MD; Rebecca Bara, RN BSN; Kirsten Childs, RN BSN; Eunice Hinz Woldt, RN MSN; Laura Goldston, MA, Bogdan Panaitescu MD PhD; John Barks, MD; Stephanie A. Wiggins, MS; Mary K. Christensen, BA RRT; Martha Carlson, MD; Diane F. White, RRT CCRP.
Sources of Funding:
The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (U10 HD21373, UG1 HD21364, UG1 HD21385, UG1 HD27851, UG1 HD27853, UG1 HD27856, UG1 HD27880,UG1 HD27904, UG1 HD34216, UG1 HD36790, UG1 HD40492, UG1 HD40689, UG1 HD53089, UG1 HD53109, UG1 HD68244, UG1 HD68270, UG1 HD68278, UG1 HD68263, UG1 HD68284; UG1 HD87226, UG1 HD87229) and the National Center for Advancing Translational Sciences (NCATS) (UL1 TR6, UL1 TR41, UL1 TR42, UL1 TR77, UL1 TR93, UL1 TR105, UL1 TR442, UL1 TR454, UL1 TR1117) provided grant support for the Neonatal Research Network, including for the Follow-up Study. NICHD staff provided input into the study design, conduct, analysis, and manuscript drafting; NCATS cooperative agreements provided infrastructure support to the NRN. While NICHD staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government.
Footnotes
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Conflict of Interest: The authors report no conflicts of interest.
ClinicalTrials.gov ID: Generic Database, NCT00063063
Presentation: Preliminary results of this study were presented at the Pediatric Academic Societies Meeting, Denver, Colorado, April 21–25, 2022.
Data Sharing:
Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.
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Data Availability Statement
Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.