Roza and associates (2008) found that fetuses with circulatory redistribution-brain sparing-had a higher incidence of later behavioral problems. In another study, evidence of brain sparing was found in half of 62 growth-restricted fetuses with birthweights < 10th percentile and who showed abnormal middle cerebral artery Doppler low studies (Figueras, 2011). Compared with controls, these neonates had significantly lower neurobehavioral scores in multiple areas, suggesting profound brain injury. Zhu and coworkers (2016) prospectively compared late-onset growth restriction in 14 fetuses with that in 26 non-growth-restricted fetuses using magnetic resonance imaging to analyze hemodynamic flow. Despite the concept of brain sparing, growth-restricted infants had significantly smaller brains than controls. he complex efects of such insults-with respect to timing and severity-on brain structure, connectivity, and neurobehavioral outcomes have been recently reviewed by Miller and colleagues (2016).
Fetal-growth restriction is one of the "major obstetrical syndromes" associated with defects in early placentation (Brosens, 2015). Rogers and coworkers (1999) concluded that implantation-site disorders may be both a cause and consequence of hypoperfusion at the placental site. This comports with the association of certain placental angiogenic factors with pregnancy hypertensive disorders (Chap. 40, p. 716). Thus, it may be that placentas from pregnancies complicated by hypertension elaborate these angiogenic factors in response to placental-site hypoperfusion, whereas pregnancies complicated by fetal-growth restriction without hypertension do not Qeyabalan, 2008).
Mechanisms leading to abnormal trophoblastic invasion are likely multifactorial, and both vascular and immunological etiologies have been proposed. For example, atriaL natriuretic peptide converting enzyme, also known as corin, plays a critical role in trophoblastic invasion and remodeling of the uterine spiral arteries (Cui, 2012). hese processes are impaired in corin-deficient mice, which also develop evidence of preeclampsia. Moreover, mutations in the gene for corin have been reported in women with preeclampsia (Chen, 2015a).
Several immunological abnormalities are associated with fetalgrowth restriction. This raises the prospect of maternal rejection of ther" paternal semiallograft." Rudzinski and colleagues (2013) studied C4d, a component of complement that is associated with humoral rejection of transplanted tissues. They found this to be highly associated with chronic villitis-88 percent of cases versus only 5 percent of controls-and with reduced placental weight. In a study of 10,204 placentas, chronic villitis was associated with placental hypoperfusion, fetal acidemia, and fetal-growth restriction and its sequelae (Greer, 2012). im and coworkers (2015) extensively reviewed chronic inflammatory placental lesions and their association with fetal-growth restriction, preeclampsia, and preterm birth.