The purpose of our study was to investigate relationships between antenatal factors and CLD risk. We found that among infants born before the completion of the 28th week of gestation, the presence of growth restriction during fetal life is prominently associated with an increased risk of CLD. Because FGR may result from a variety of maternal conditions, most notably preeclampsia, a critical aspect of our investigation was to explore the inter-relationships among these conditions and CLD risk. The association between FGR and CLD risk persists after adjustment for a variety of antenatal and neonatal characteristics also associated with CLD risk. In fact, FGR was the only maternal or antenatal characteristic that was highly predictive of CLD after these adjustments.
In contrast to some previous studies, we found no association between markers of placental or fetal infection and inflammation and CLD risk. Two of these studies report a relationship between elevated concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6) in cord blood, and CLD risk.(19
) One possible explanation for the difference between our observations and these reports is that we used funisitis, rather than cord blood IL-6, as a marker of fetal inflammation. However, this explanation is uncertain because funisitis has been associated with higher cord blood IL-6 levels.(21
) An additional study reported an association between histologic chorioamnionitis, but not funisitis or elevated cord blood IL-6 levels, and CLD risk.(22
) That study enrolled more mature infants compared to our cohort. It is possible that the antecedents of lung injury may vary with gestational age, with inflammation more likely to influence risk among infants born after the 27th
week of gestation. Finally, two additional studies identified increased CLD risk following chorioaminionitis, but only among infants also exposed to prolonged mechanical ventilation during the early neonatal period.(23
) These studies used varying techniques for accounting for the effect of confounders. After extensive adjustment of our data for critical antenatal confounders, particularly FGR, we conclude that, among infants at the earliest gestations, intrauterine infection and inflammation does not increase the risk of CLD.
Several large, contemporary studies have previously identified an association between FGR and CLD risk. In one study of a geographically-defined population in the United Kingdom, which did not adjust for potential confounders, the risk of CLD was increased among small for gestational age (SGA) infants and decreased among large for gestational age infants.(25
) A study of infants from a regional population in Germany found that SGA infants were at increased risk of CLD defined as treatment with oxygen at 28 days of age (26
), an endpoint with less relevance in extremely immature infants. A third study found that infants considered growth restricted at birth, based on an obstetrical diagnosis of intrauterine growth restriction or by identifying infants who were SGA, were more likely than their normal weight peers to need respiratory support of any kind at 28 days of age.(27
) Several other small studies report associations between restricted fetal growth and CLD risk.(28
) Despite methodologic differences between these studies and ours, collectively they support the strong relationship between impaired fetal growth and CLD risk.
Our findings suggest that processes that limit fetal growth may also limit fetal lung growth and maturation, thereby making the lung more vulnerable to adversities after birth. Lung development is highly programmed and regulated by a variety of growth factors and hormones. For example, a critical phase in lung development is angiogenesis under the influence of vascular endothelial growth factors and their receptors. Abnormal angiogenesis appears to be a feature in the pathogenesis of CLD.(31
) An imbalance between angiogeneic and anti-angiogeneic factors also appears to be a critical feature in the pathogenesis of preeclampsia(33
) and among preeclamptic mothers who deliver an infant with growth restriction.(34
) In the presence of preeclampsia, this imbalance might result in a cascade of events, including disruption of normal placental angiogenesis, a cardinal feature of preeclampsia, and abnormal fetal angiogenesis, including the vasculature of the fetal lung. Our observed association between increased syncytial knots in the placenta, a histologic correlate of preeclampsia(35
), and CLD supports this hypothesized scheme of events. Although we did not observe an increase in CLD risk among infants of preeclamptic mothers who were not growth restricted, it is possible that abnormal angiogenesis in the fetal lung occurs only when preeclampsia reaches a sufficient severity to cause FGR.
Fetal growth restriction has also been attributed to the failure of the placenta to meet the fetus's needs for oxygen and substrate(36
), and hypoxia may have secondary effects on the fetal lung. In neonatal mice, chronic hypoxia during the first two weeks of life, a period of lung development that corresponds to human fetal lung development during the third trimester, interferes with alveolar and pulmonary artery development and up-regulates transforming growth factor beta (TGFβ).(37
) Therefore, it is possible that chronic fetal hypoxia in humans causes both growth restriction and impairment of lung development, the latter perhaps mediated by TGFβ.
FGR may also cause ineffective or abnormal lung growth after birth as a result of abnormal programming of growth. This possibility is suggested by two observational studies. In one study, lung function was measured at approximately 10 months of age in SGA infants and compared to measurements in appropriately grown premature infants.(38
) Increased airway resistance was associated with FGR after adjustment for confounders, including CLD. This observation suggests that FGR may impact subsequent growth and development of small airways. Another study confirmed a relationship between FGR and small airway pathology by identifying an association between FGR and the risk of childhood asthma.(39
Rather than influencing lung growth and morphology, factors that result in FGR may alter the biochemical milieu of the immature lung. Growth restricted mice have reduced expression of mRNA for surfactant proteins.(40
) Perhaps significant alterations in the surfactant system predispose growth restricted infants to pulmonary abnormalities, resulting either from a direct effect on the role of surfactant in lung mechanics or in its modulating role in lung inflammation.
One potential limitation of our study might follow from our defining FGR on the basis of the relationship between an infant's birth weight and a birth weight distribution for each gestational age in a similar population. This method may misclassify infants who have genetically determined growth percentiles that are peculiarly high or low. As an alternative, when accurate measurements of birth length are available, ponderal index can be used as an indicator of growth restriction, which for some outcomes may be a more discriminating predictor compared to BW Z-score.(39
) Finally, BW Z-scores can be calculated using weight distributions derived from sonographically determined estimates of fetal weights in a healthy obstetrical population.(41
) Compared to this approach, the use of BW Z-scores calculated from birth weight distributions appears to underestimate fetal growth prior to term and therefore the frequency of impaired fetal growth.(42
Because of the observational design of our study, we cannot be certain that FGR is critical in the causal pathway of CLD. It is possible that FGR is merely a surrogate for other characteristics of the uterine environment that cause the fetal or neonatal lung to grow or function poorly. However, it seems likely that factors that control fetal somatic growth in general have a significant impact on lung growth and development, and in this way increase CLD risk. Therefore, the ability to modify neonatal pulmonary outcomes among ELGANs may be dependent on a more precise understanding of the modulators of fetal growth in the context of problems that result in FGR. Future investigation should focus on these factors.