Phenotypic overlap in neonatal respiratory morbidity following preterm premature rupture of membranes versus spontaneous preterm labor

Background: Bronchopulmonary dysplasia (BPD), a major source of morbidity in premature neonates, has been associated with intrauterine infection and preterm birth. Both preterm premature rupture of membranes (PPROM) and spontaneous preterm labor (sPTL) are linked with intrauterine inflammation. Whether PPROM and sPTL, as two phenotypic categories of preterm birth, are associated with exposure to different degrees and durations of inflammation that might impact fetal lung development is unknown. PPROM may be associated with longer latency until delivery, which is beneficial for neonatal mortality, but may impart greater injury risk to the developing fetal lungs. It is unknown if PPROM is associated with a greater risk of adverse neonatal respiratory outcomes than sPTL.

Objective: The objective of this study was to determine if PPROM imparts a differentially greater risk for neonatal BPD than sPTL. A secondary objective was to determine if PPROM was associated with a greater risk of adverse neonatal respiratory outcomes other than BPD and whether gestational latency following PPROM or sPTL diagnosis constitutes a risk factor for fetal lung injury.

Study design: We conducted a retrospective secondary analysis of a large cohort of women at risk for spontaneous preterm birth, who were originally enrolled in a randomized controlled trial of magnesium sulfate versus placebo examining neuroprotection. For our study, we included women with a singleton pregnancy complicated by PPROM or sPTL and delivery between 24 and 34 weeks gestational age. Cases with multiple gestation, congenital anomalies, maternal seropositivity for human immunodeficiency virus, or hypertensive diseases of pregnancy (including preeclampsia) were excluded. The primary outcome was BPD. Secondary outcomes were respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), requirement for mechanical ventilation, pneumonia, neonatal sepsis, fetal or neonatal death, and a composite of adverse neonatal respiratory outcomes including (BPD, pneumonia, RDS, and TTN). Statistical analyses included chi-square, Student's t-test and logistic and multiple regression.

Results: A total of 1729 women were included in this analysis including 1554 with PPROM and 175 with sPTL. Women in the PPROM group were more likely to be older, not of Hispanic race, married, more educated, have smoked during pregnancy and have a greater body mass index. The BPD rate was not significantly different following PPROM versus sPTL. Neonates in the PPROM group experienced a lower rate of pneumonia (p = .001), neonatal sepsis (p = .009) and patent ductus arterious (PDA) requiring either medical or surgical therapy (p < .001) than neonates in the sPTL group. Chorioamnionitis was more common in the PPROM group (p = .008) than the sPTL group. After multivariable logistic regression with BPD or composite of adverse neonatal respiratory outcomes as the dependent outcomes, and controlling for gestational age at delivery, maternal smoking history, duration of mechanical ventilation and RDS, there was no significant difference between PPROM and sPTL.

Conclusions: BPD rates were not significantly different in neonates born to women following PPROM versus sPTL. However, PPROM was associated with lower rates of pneumonia, neonatal sepsis, and PDA requiring therapy in the univariate analysis, but not the multivariate analysis. Neonatal respiratory outcomes may have a similar phenotypic overlap regardless of whether preterm birth follows PPROM or sPTL.