Placental pathologic changes of maternal vascular underperfusion in bronchopulmonary dysplasia and pulmonary hypertension.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy, and BPD-associated pulmonary hypertension (PH) is a serious complication that can negatively impact later childhood health. There is growing evidence that lung injury leading to BPD and PH is due to chronic fetal hypoxia-ischemia. The purpose of this study was to investigate whether placental pathologic changes of maternal vascular underperfusion (MVU) are associated with BPD, and further increased with PH. METHODS: We conducted a 5-year retrospective cohort study of premature infants born ≤28 weeks. BPD was defined as persistent oxygen requirement at 36 weeks corrected gestational age. PH was identified using a standardized algorithm of echocardiogram review. Archived placental slides underwent standardized masked histopathologic review. Logistic regression modeling was performed, taking into account important maternal and infant covariates. RESULTS: Among 283 births, 121 had MVU, of which 67 (55%) developed BPD, and 24 (20%) had PH. Among the common neonatal complications of extreme prematurity, BPD was the only outcome that was increased with MVU (P < 0.001). After adjustment for birth weight, fetal growth restriction, preeclampsia and other factors, infants with MVU were more likely to develop BPD (adjusted odds ratio = 2.6; 95% confidence interval = 1.4, 4.8). Certain MVU sublesions (fibrinoid necrosis/acute atherosis and distal villous hypoplasia/small terminal villi) were increased with PH (P < 0.001). DISCUSSION: Placental MVU may identify BPD infants who were exposed to intrauterine hypoxia-ischemia, which increases their risk for development of PH disease. CONCLUSIONS: Our findings have important implications for providing earlier and more effective therapies for BPD.

Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia.

OBJECTIVE: To identify the association between birth weight (BW)-for-gestational age (GA) and pulmonary hypertension (PHTN) at 36 weeks in infants with moderate-severe bronchopulmonary dysplasia (BPD). STUDY DESIGN: In this retrospective cohort study, we followed 138 premature infants (≤ 28 weeks) with moderate and severe BPD (National Institutes of Health consensus definition) born at Prentice Women's Hospital between 2005 and 2009. BW percentiles were calculated using the Fenton growth curve for premature infants. PHTN was determined using a standardized algorithm of echocardiogram review at 36 weeks. Logistic regression was used to evaluate the associations between BW percentile subgroups and PHTN, taking into account antenatal and neonatal factors that were related to PHTN. RESULT: PHTN was associated with small BW-for-GA, ranging from thresholds of <10th to <25th percentile (P<0.001). These associations remained significant when comparing BW <25th percentile to the reference group (50 to 89 th percentile); after adjustment for GA, gender, multiple gestation, race/ethnicity (odds ratio (OR)=4.2; 95% confidence interval (CI)=1.5, 12.1); and after further adjustment for maternal vascular disease, intrauterine infection, oligohydramnios and relevant postnatal factors (OR=5.7; 95% CI=1.5, 21.2). Longitudinal follow-up of this cohort showed a trend toward higher morbidity and death among PHTN infants with BW <25th percentile. CONCLUSION: BW-for-GA is an important predictor of PHTN in premature infants with moderate-severe BPD. Our findings contribute to the growing evidence supporting fetal mechanisms of later onset pulmonary vascular disease.

Cord blood immune biomarkers in small for gestational age births.

Fetal growth restriction is a risk factor for development of adulthood diseases, but the biological mechanism of this association remains unknown. Limited biomarkers have been studied in settings of preterm birth and maternal inflammation, but the relationship between a wide range of immune biomarkers and fetal growth has not been studied. The hypothesis of this study was that fetal growth restriction is associated with altered immune biomarker levels. We examined the relationship between small for gestational age (SGA) status and 27 umbilical cord blood immune biomarkers. This study was part of a large-scale cohort study of preterm birth and low birth weight conducted at Boston Medical Center, an inner city, predominantly minority patient population. Growth status was determined based on birth weight standardized to an internal reference. There were 74 SGA births and 319 appropriate for age (AGA) births with complete clinical and biomarker data. Adjusting for covariates and using AGA as reference, SGA births had lower levels of log IL-1ß (ng/l; ß -0.38, 95% CI -0.57, -0.19, P < 0.01), log BDNF (ß -0.29, 95% CI -0.55, -0.03, P < 0.05) and log NT-3 (ß -0.46, 95% CI -0.77, -0.15, P < 0.01). No associations were found between other biomarkers and SGA. In conclusion, three biomarkers were selectively associated with SGA status. Our results provide information that could be used to guide additional studied aimed at determining mechanisms that contribute to fetal growth.