Uteroplacental insufficiency present in pregnant women with pre-eclampsia, eclampsia, or HELLP syndrome may lead to vascular compromise in the developing fetus.4,20
Few studies have been performed to determine the associations of these conditions with ROP severity, and the reports are conflicting. Shah et al.11
reported that maternal pre-eclampsia was predictive of ROP in very-low-birth weight infants, whereas Seiberth and Linderkamp12
reported maternal pre-eclampsia was associated with reduced incidence rates of ROP. Therefore, it remains unclear if conditions of new-onset maternal hypertension affect the fetus' developing retinal vasculature and lead to ROP. To explore this, we reviewed all infants at our institution who were born prematurely at <37 weeks of gestation over the course of 11 years. Among them, we found a rare patient cohort of 76 infants, revealing an incidence rate of approximately 7 infants per year.
In pre-eclampsia, maternal antiangiogenic factors have been reported to be elevated and proangiogenic growth factors to be reduced.4,21,22
One antiangiogenic factor that has been studied is s-flt-1, a soluble splice variant of vascular endothelial growth factor receptor 1 (VEGFR1). s-flt-1 can bind VEGF and prevent it from signaling through its receptors.22
Some of the symptoms associated with pre-eclampsia are similar to the side effects reported from systemic inhibition of VEGF—namely, hypertension, proteinuria, and vascular events.23
Angiogenesis is necessary for fetal vasculogenesis, angiogenesis, and development. Elevated maternal s-flt-1 could interfere with infant development, including retinal vascular development, if s-flt-1 were to cross into the fetal circulation at an effective concentration. In the retina, this may manifest as larger areas of peripheral avascular retina (i.e., lower zones) on initial examinations and higher stages and more severe ROP at later examinations when ROP develops. It remains unclear to what extent elevated maternal levels of antiangiogenic factors, including s-flt-1, can cross through the placenta and into the fetal circulation. Pregnant rodents treated with s-flt-1 as a means to model manifestations of preeclampsia yielded mixed results.24–26
Offspring demonstrated mild growth retardation, but these effects were limited to male mice, and treatment did not affect vascular patterning and development in neonatal mice.25
However, lower concentrations of s-flt-1 may also have more profound effects on retinal vessels, which are small and support a complex, developing retinal structure, particularly in preterm infants.
Postgestational age has been closely correlated with severity of ROP27
regardless of infant gestational age or birth weight. Infants born at 27 weeks' gestation or younger usually have their first examinations performed at 31 weeks' postgestational age, whereas those born at or older than 28 weeks gestation are examined at older ages, based on guidelines.2
Infants born to mothers with conditions of new-onset gestational hypertension were more likely to have lower zones on initial examinations than infants born to mothers without new-onset gestational hypertension. After adjustment for gestational age but not birth weight, a significant association was still found between greater infant severity score and maternal diagnosis of new-onset gestational hypertension at the initial examination. These results support the hypothesis that maternal conditions leading to pre-eclampsia are associated with a greater potential for infants to develop ROP. Still, it does not show an association independent of low birth weight. However, at the worst examination, no significant associations were found between severity of ROP and maternal condition in unadjusted analyses or analyses adjusted for birth weight or gestational age.
Recombinant erythropoietin has been used to treat anemia of prematurity13,14
and has been associated with increased risk of severe ROP.15,16
However, erythropoietin has also been shown to reduce avascular retina if given before a hyperoxic insult in a mouse model of oxygen-induced retinopathy.17
Therefore, we sought to determine whether there is an association between erythropoietin use and the severity of ROP in infants born to mothers with new-onset gestational hypertension. However, we found no associations between the use of erythropoietin and ROP severity, even after accounting for maternal condition.
Other investigators have suggested that in response to a hypoxic intrauterine environment from reduced levels of circulating proangiogenic growth factors in pre-eclampsia, the development of the fetal retinal vasculature may actually be accelerated. Hadi and Hobbs28
demonstrated that when infants are under chronic intrauterine stress, either from maternal hypertension or pre-eclampsia, there is accelerated maturation of the tunica vasculosa of the lens in the anterior compartment. It was hypothesized that hypoxia-mediated stabilization of transcription factors, such as hypoxia-inducible factor (HIF)-1α, led to increased fetal expression of molecules, such as VEGF, erythropoietin, and glucose transporter-1.29
These and other factors were then postulated to accelerate the maturation of the retinal vasculature, thus reducing the potential for ROP to develop. Our results at the time points of retinal examination did not provide support for accelerated vascularization.
This was a retrospective study of a rare patient cohort of infants with ROP born to mothers with new-onset gestational hypertension. The low numbers of infants with ROP born to mothers with new-onset gestational hypertension may have limited the power of the analysis. Not all initial examination records were accessible through existing databases and patient hospital charts; however, care was taken to consider the analyses of initial and worst examinations separately. ROP was classified based on stages and zones abstracted from retinal drawings without the benefit of wide-angle fundus imaging. The study may also have had unrecognized confounding variables because of the long duration of the study period from 1996 to 2007, during which significant advances were made in the screening and treatment algorithms for both maternal gestational hypertension and infant ROP. One change was in infant oxygen saturation. The number of infants born to mothers with new-onset maternal hypertension in these subgroups, defined by oxygen protocol, was too small for meaningful analyses. The effect of oxygen should be addressed in larger studies. All study participants were from a single tertiary center, and therefore treatments of both new-onset maternal hypertension and preterm infants were initiated at the time of diagnosis, and little variability within the individual neonatologists' practices was anticipated. Finally, our study grouped maternal pre-eclampsia, eclampsia, and HELLP syndrome under the same disease category to obtain a large enough study sample for analysis. A more precise analysis would stratify infants to each of these conditions; however, this would have further limited the sample size and decreased the power.
In conclusion, the results of this study indicate that conditions of new-onset maternal gestational hypertension, such as pre-eclampsia, were associated with lower zone at initial examinations for ROP but were not associated with an increased severity of ROP at the worst examination. Furthermore, the use of erythropoietin did not have an effect on ROP severity, even when maternal condition was considered. Future studies of larger databases are needed and may provide greater insight into the relationships of these maternal conditions and severity of infant ROP.