Objective
Data regarding long-term outcomes of neonates reaching viability following early preterm premature rupture of membranes (PPROM; <25.0 weeks at rupture) are limited. We hypothesized that babies delivered after early PPROM would have increased rates of major childhood morbidity compared with those with later PPROM (≥25.0 weeks at rupture).
Study Design
This was a secondary analysis of a multicenter randomized controlled trial of magnesium sulfate vs placebo for cerebral palsy prevention. Women with singletons and PPROM of 15-32 weeks were included. All women delivered at 24.0 weeks or longer. Those with PPROM less than 25.0 weeks (cases) were compared with women with PPROM at 25.0-31.9 weeks (controls). Composite severe neonatal morbidity (sepsis, severe intraventricular hemorrhage, periventricular leukomalacia, severe necrotizing enterocolitis, bronchopulmonary dysplasia, and/or death) and composite severe childhood morbidity at age 2 years (moderate or severe cerebral palsy and/or Bayley II Infant and Toddler Development scores greater than 2 SD below the mean) were compared.
Results
A total of 1531 women (275 early PPROM cases) were included. Demographics were similar between the groups. Cases delivered earlier (26.6 vs 30.1 weeks, P < .001) and had a longer rupture-to-delivery interval (20.0 vs 10.4 days, P < .001). Case neonates had high rates of severe composite neonatal morbidity (75.6% vs 21.8%, P < .001). Children with early PPROM had higher composite severe childhood morbidity (51.6% vs 22.5%, P < .001). Early PPROM remained associated with composite severe childhood morbidity in multivariable models, even when controlling for delivery gestational age and other confounders.
Conclusion
Early PPROM is associated with high rates of neonatal morbidity. Early childhood outcomes at age 2 years remain poor compared with those delivered after later PPROM.
The rate of preterm birth (delivery prior to 37 weeks’ gestation) in the United States has recently begun to decline slightly but remains unacceptably high at 11.5% of all deliveries. Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth and accounts for approximately one third of cases. The etiology of PPROM is multifactorial and is likely related to factors including overt or subclinical infection/inflammation, abruption, uterine overdistension, smoking, and cervical insufficiency. However, many cases of PPROM occur without a clearly identifiable etiology.
In the United States, women with PPROM prior to 32-34 weeks’ gestation are typically given an antibiotic regimen such as erythromycin and ampicillin; antibiotic administration in this setting has been shown to increase the latency period between membrane rupture and delivery and reduce neonatal morbidity and mortality. The majority of women are also administered antenatal corticosteroids to accelerate fetal lung maturity.
Given the high risk of secondary complications such as placental abruption, cord prolapse, preterm labor, and intraamniotic infection, women with PPROM are typically managed as inpatients until delivery. In the absence of one of these complications, the majority of women are delivered at or by 32-34 weeks’ gestation. The duration of latency between the timing of membrane rupture and delivery appears to be inversely related to the gestational age at PPROM; those women experiencing PPROM earlier in the gestation tend to have the longest latency periods.
Traditionally, when PPROM occurs prior to fetal viability (23-25 weeks’ gestation), neonatal outcomes have been poor. However, contemporary studies have demonstrated that in an era of advanced neonatal care, outcomes for neonates delivered following very early PPROM may be better than previously expected. Despite advances in neonatal care and apparent improved neonatal outcomes, longer-term outcomes of children delivered following early PPROM are largely unknown. One small study examined early childhood outcomes among 13 neonates who were expectantly managed following spontaneous PPROM at less than 24 weeks; 3 (23%) died in the hospital, and only 2 (15%) survived without obvious long-term morbidity at age 4 years. In another small study, Pristauz et al reported that half of 12 infants surviving PPROM between 14.0 and 24.9 weeks had normal neurological and developmental outcomes at age 2 years.
Therefore, we sought to compare initial neonatal (as assessed at initial hospital discharge) and early childhood outcomes (as assessed at age 2 years) between children with early PPROM (prior to 25.0 weeks’ gestation) compared with those with later PPROM (a gestation of 25 weeks 0 days to a gestation of 31 weeks 6 days). We hypothesized that children delivered after early PPROM would have higher rates of neonatal and childhood morbidity and mortality compared with those with later PPROM.
Materials and Methods
This is a secondary analysis of a multicenter randomized controlled trial of magnesium sulfate vs placebo for cerebral palsy prevention conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network (MFMU) Network. Briefly, women with singleton or twin gestations at high risk for imminent preterm birth were recruited and randomized to receive intravenous magnesium sulfate vs placebo. All women and their infants were followed up to hospital discharge and surviving children were reevaluated at or beyond age 2 years for cerebral palsy and neurodevelopmental outcomes. 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 data set, was reviewed by our local institutional review board, was determined to be nonhuman subject research, and was deemed exempt from institutional review board approval.
For the purposes of this secondary analysis, we included women with singleton gestations who had a confirmed diagnosis of PPROM between 15 and 32 weeks’ gestation and subsequently delivered less than 35 weeks’ gestation. Women with free-flowing amniotic fluid from the cervix, a positive indigo carmine dye test, and a positive nitrazine and fluid pooling, positive nitrazine and fluid ferning, or positive fluid pooling and fluid ferning were considered to have PPROM.
Neonates diagnosed with major structural congenital anomalies and/or aneuploidy as well as those who delivered at a gestation of 35.0 weeks or longer were excluded from this analysis. With the exception of the study protocol infusion (magnesium sulfate vs placebo), women were managed per local practices with regard to obstetric management, antibiotic administration, and decision to proceed with delivery.
Trained research nurses obtained standardized 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) as a part of the original study. Specifically, each neonate was assessed for the presence of or history of intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, retinopathy of prematurity, and necrotizing enterocolitis. Additionally, charts were reviewed to determine whether the neonate had 1 or more 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. Additionally, each child was evaluated with the Bayley II Scales of Infant Development Mental Development (MDI) and Psychomotor Development Indices (PDI).
Those with PPROM less than 25.0 weeks (cases) were compared with women with PPROM at 25.0-31.9 weeks’ gestation (controls). Gestational age was determined using the best obstetric estimate, established per standard criteria utilizing menstrual period and ultrasonographic parameters as appropriate. Initially, enrollment in the main trial did not specify a lower gestational age restriction for PPROM. Partway through recruitment, the protocol was amended and only women with PPROM at or beyond 22.0 weeks’ gestation were eligible for enrollment.
The primary outcomes of this analysis were as follows: (1) composite severe neonatal morbidity (defined as a diagnosis of sepsis, grade III or IV intraventricular hemorrhage, periventricular leukomalacia, grade II or III necrotizing enterocolitis, bronchopulmonary dysplasia, and/or death) and (2) composite severe childhood morbidity at age 2 years (moderate or severe cerebral palsy, Bayley MDI or PDI scores greater than 2 SD below the mean, and/or death). Outcomes were compared between those with early vs later PPROM.
Demographics, pregnancy characteristics, neonatal course and outcomes, and early childhood outcomes were also compared using a Student t test, χ 2 , and analysis of the variance as appropriate. Multivariable logistic regression was used to assess factors associated with severe neonatal morbidity and severe childhood morbidity; factors significant in the univariable analysis were included in the initial regression models. Covariates were then removed in a stepwise fashion until all covariates in the final model had a value of P < .20. Data were analyzed using STATA version 12.1 (StataCorp, College Station, TX).
Results
Of 2241 women randomized in the original study, 1531 neonates/children met inclusion criteria for this secondary analysis ( Figure ). Of these, 275 (18%) were delivered following early PPROM at less than 25.0 weeks’ gestation, at a mean gestational age of 23.7 ± 1.2 (range, 15.1–24.9) weeks’ gestation. The remaining 1256 (82%) had later PPROM, at a mean gestational age of 28.7 ± 2.2 (range, 25.0–31.9) weeks’ gestation.
Maternal demographic and pregnancy characteristics are shown in Table 1 . Women with early PPROM were similar to those with later PPROM with regard to demographics. As expected, the gestational age at the time of randomization was earlier for those with early PPROM, 24.7 vs 28.9 weeks ( P < .001). Delivery characteristics and initial neonatal outcomes are shown in Table 2 . Women with early PPROM experienced significantly longer latency-to-delivery intervals yet delivered more than 3 weeks earlier than those with later PPROM.
| Characteristic | Early PPROM (n = 275) | Later PPROM (n = 1256) | P value |
|---|---|---|---|
| Maternal age, y, mean ± SD | 27.0 ± 5.9 | 26.4 ± 6.2 | .127 |
| Maternal prepregnancy body mass index, kg/m 2 , mean ± SD | 26.6 ± 7.3 | 26.1 ± 6.5 | .258 |
| Married | 134 (48.9) | 601 (47.9) | .769 |
| Maternal race or ethnic group a | |||
| Black | 131 (47.6) | 562 (44.8) | |
| White | 104 (37.8) | 467 (37.2) | .332 |
| Hispanic | 34 (12.4) | 198 (15.8) | |
| Other | 6 (2.2) | 29 (2.3) | |
| Maternal education, highest level completed, mean ± SD | 12.2 ± 2.3 | 11.8 ± 2.5 | .016 |
| Prior preterm delivery | 70 (25.5) | 351 (28.0) | .402 |
| Smoked cigarettes during pregnancy | 78 (28.4) | 367 (29.2) | .894 |
| Drank alcohol during pregnancy | 30 (10.9) | 117 (9.3) | .416 |
| Used illicit drugs during pregnancy | 21 (7.6) | 147 (11.7) | .051 |
| Gestational age at randomization, wks, mean ± SD | 24.7 ± 0.9 | 28.9 ± 2.0 | < .001 |
| Randomized to magnesium sulfate | 133 (48.4) | 616 (49.0) | .838 |
| Received antenatal corticosteroids | 272 (98.9) | 1226 (97.6) | .180 |
a Maternal race was analyzed by analysis of the variance. Continuous variables were compared with the use of the Student t test and categorical variables with the χ 2 test.
| Characteristic | Early PPROM (n = 275) | Later PPROM (n = 1256) | P value |
|---|---|---|---|
| Rupture-to-delivery interval, d, mean ± SD | 20.0 ± 20.2 | 10.4 ± 10.7 | < .001 |
| Gestational age at delivery, wks, mean ± SD | 26.6 ± 2.5 | 30.1 ± 2.2 | < .001 |
| Received antenatal corticosteroids | 272 (98.9) | 1226 (97.6) | .180 |
| Placental abruption | 29 (10.6) | 99 (7.9) | .148 |
| Chorioamnionitis | 45 (16.4) | 151 (12.0) | .051 |
| Cesarean delivery | 127 (46.2) | 456 (36.3) | .002 |
| Postpartum endometritis | 24 (8.7) | 74 (5.9) | .082 |
| Maternal length of hospitalization, d, mean ± SD | 19.1 ± 17.1 | 12.5 ± 11.2 | < .001 |
| Male fetus | 153 (55.6) | 667 (53.1) | .446 |
| Birthweight, g, mean ± SD | 930 ± 415 | 1481 ± 444 | < .001 |
| Culture-proven sepsis | 111 (40.4) | 143 (11.4) | < .001 |
| Necrotizing enterocolitis | |||
| Any severity | 40 (14.6) | 91 (7.3) | < .001 |
| Severe (stage 2 or 3) | 22 (8.0) | 43 (3.4) | .001 |
| Retinopathy of prematurity | 138 (50.2) | 190 (15.1) | < .001 |
| Bronchopulmonary dysplasia | 136 (49.5) | 127 (10.1) | < .001 |
| Neonatal seizures | 15 (5.5) | 15 (1.2) | < .001 |
| Intraventricular hemorrhage | |||
| Any severity | 76 (29.5) | 237 (19.4) | < .001 |
| Severe (grade III or IV) | 15 (5.8) | 13 (1.1) | < .001 |
| Periventricular leukomalacia | 10 (3.9) | 16 (1.3) | .004 |
| Death prior to initial hospital discharge | 46 (16.7) | 31 (2.5) | < .001 |
| Composite severe neonatal morbidity a | 208 (75.6) | 274 (21.8) | < .001 |
a Diagnosis of sepsis, bronchopulmonary dysplasia, severe grade III or IV intraventricular hemorrhage, periventricular leukomalacia, severe stage 2 or 3 necrotizing enterocolitis, and/or death.
The vast majority of all women (>98%) received antenatal corticosteroids, regardless of the timing of membrane rupture. A very small number of women received tocolysis (n = 33, 2.2% overall). The majority (n = 1477, 96.5% overall) received antibiotics between randomization and delivery; 1326 (86.6%) received ampicillin, amoxicillin, or penicillin, and 914 (59.7%) received erythromycin. Unfortunately, the data regarding antibiotic use prior to randomization or the reason/intent for antibiotic prescription are not available.
Neonates delivered following early PPROM were more likely to be delivered by cesarean and in general had higher rates of all adverse outcomes, including death ( Table 2 ). Similar trends were seen when examining early childhood outcomes at age 2 years. In univariable analyses, those with early PPROM were more likely to be diagnosed with cerebral palsy and low Bayley II MDI and PDI scores ( Table 3 ).
