Abstract
Purpose.:
To validate a hypothesis of restricted postnatal ocular growth associated with advanced retinopathy of prematurity (ROP), with a view also to preceding intrauterine growth retardation.
Methods.:
A clinically uniform sample of 28 preterm neonates was examined under general anesthesia from 1997 to 2002 for threshold retinopathy of prematurity (T-ROP), axial ultrasound oculometry being part of the evaluation (valid data in 53 eyes). Median values for gestational age at delivery (GA) and birth weight (BW) 27 weeks and 855 g, respectively, ranges 24.7–30.9 weeks and 480–1594 g. Median postconceptional age (PCA) at exam was 36.2 weeks (32.2–41.4 weeks) and median postnatal age was 9 weeks (5.8–14 weeks). “Small for gestational age” (SGA) at delivery was given by an individual birth weight standard deviation score.
Results.:
Compared with a previous Danish preterm series with less ROP, age-adjusted axial lengths (AL) in the T-ROP eyes were roughly 1 mm shorter and anterior chambers shallower. A higher GA was found to coincide with lower AL values; this appeared due to a subpopulation of infants loaded by SGA. The literature has no other uniform oculometry series of preterms of a similar advanced ROP degree. The present Danish results add to the composite picture drawn by neonatal reports from other investigators.
Conclusions.:
There is evidence of postnatal ocular growth restriction in preterms associated with severe ROP. Some kind of latency is probable, from the immediate delivery-related biological effects until the appearance of macroscopic evidence. Statistics further suggested SGA as an apparently independent prenatal predictor of subsequent ocular growth restriction.
The 28 ROP infants under study in a cross-sectional setup (20 males, 8 females) during 1997–2002 were either in-patients in Rigshospitalet's tertiary level neonatal intensive care unit, or referrals from other neonatology services throughout the country. Progression to classical T-ROP
23 released the factual evaluation under general anesthesia, and 26 had retinal cryotherapy, usually in both eyes. The remaining subgroup of 6 untreated eyes was considered too small for separate analysis.
At delivery gestational age (GA) and birth weight (BW) values had ranged from 24.7 to 30.9 weeks and from 480 to 1594 g, respectively, and median values were 27 weeks and 855 g. Age of the infants was given in weeks, as postnatal age (PNA), and as postconceptional age (PCA = GA + PNA).
The issue of intrauterine growth retardation, here used synonymously with SGA, was approached by calculating a standard deviation score (SDS) for the BW of each subject, as relative to expected weight according to normative intrauterine ultrasonic parameters expressing infant size during pregnancy.
24
Axial A-scan ultrasound biometry was performed when “allowed by conditions”; otherwise, the series was considered random. An ultrasound scanner (Sonometrics DBR 400; Sonometrics Corp., London, Ontario, Canada) was used and a handheld solid-tip 12.5-MHz transducer, with a concavity to match the corneal curvature (to minimize shortening by contact and flattening). Axial echograms with acceptable lens and fundus peaks were frozen and calibrated from the screen according to Jansson,
25 usually with at least three readings in fair agreement per eye. Satisfactory axial length data were obtained from 39 male and 14 female eyes, although with anterior chamber depth (ACD) and lens thickness (LT) missing in 18 eyes presenting poor lens surface echoes. Due to the clinical intrapair differences often observed in advanced ROP, measuring data were included from both eyes when technically valid.
Axial lengths were given as measured value (AL), and as ALw36 = value adjusted to week 36, the median PCA when examined. For this purpose regression slopes of averaged growth were used, with 0.18 mm elongation per week added when examined at a PCA earlier than week 36, and by weekly steps of 0.16 mm subtracted when older than 36 weeks.
11,17,18
An infant lid speculum was used; otherwise, a handheld applanation tonometer (Perkins Mk2 Tonometer; Veatch Instruments, Tempe, AZ; to exclude buphthalmic states and blowing up eye size) was the only contact procedure carried out prior to the ultrasonography.
Three funduscopy techniques were used, in a team including at least two senior specialists: indirect ophthalmoscopy, direct ophthalmoscopy (the Richardson contact lens method; Richardson Contact Lenses, Houston, TX), and by wide-field digital retinal photography (RetCam 120 fundus camera; Clarity Medical Systems, Pleasanton, CA). Scleral depressors were used only for the final full clock-hour staging of the ROP.
Data were treated by a commercial program (GraphPad Prism4 program; GraphPad Software, San Diego, CA), using parametric statistics (Student's t-test, regression and correlation) when suited. Comparing groups, however, we also used Mann–Whitney and Bonferroni tests.
The study setup was in accord with the tenets of the Declaration of Helsinki.
With progression to T-ROP confirmed, our main oculometry finding was a smaller eye, given by a shorter axial length and a more shallow anterior chamber, when compared with data from a previous, less immaturity-loaded Danish PT sample. It is interpreted as early evidence of reduced general eye growth for the present group of highly selected PT neonates.
For comparison, relevant reports from the literature are collected in
Table 1.
3–18 The table first shows eye size at term from various series of mainly population-based newborns. Some had a natural small share of surviving PT infants; others were selected as full terms. Added to this are PT series, with “any ROP” excluded in some, and others that include only part of the full disease spectrum.
Allocation to a “surveillance only” T-ROP subgroup being unethical, we have no suitable control group for the present sample of T-ROP eyes. As primary reference, we use Danish preterm findings from approximately one decade earlier that were achieved by the same experienced ultrasound expert and identical equipment.
17,18 The consecutive sample was from a regional center, and demographically it was less premature (GA mean value 31.1 weeks [SD 2.43]) and ocularly less affected (ROP in “only” 25/101; reversible, and maximum stage 1 and stage 2) than the present sample. The mean axial length around term was 17.06 mm. Boys presented larger ocular dimensions than girls, but with an equal boy:girl ratio the two sexes were pooled, as applied also to the various ultrasonic measuring data selected for
Table 1.
By contrast, the present T-ROP sample is a clinically homogeneous highly selected national sample of even smaller preterm infants, in whom advanced ROP after a postnatal latency was documented as rapidly progressing over weeks, eventually to include vascular incompensation of retina and usually also iris. Adjusted to the actual median age of 36.2 weeks at exam (see Materials and Methods), the mean AL measure in the full recent T-ROP series came out as 15.53 mm (SD 0.72), with a 16.2-mm value when further adjusted to week 40. This is significantly lower than that in the regional preterm reference group, with which it shared the oculometry setting, although differing by chronology.
The trend among the T-ROP infants was slight eye elongation by increasing BW (although statistically only close to significance;
Table 4). Those heavier at delivery had marginally longer axial lengths when eventually measured.
Here gestational age certainly differs from its main covariable, the BW. Regression calculations with GA on the x-axis thus present the opposite trend, whatever considering actually measured AL or the value adjusted for age to PCA week 36. Both had negative slopes significantly different from zero. The lower the initial GA values, the higher thus the eventual AL value, if on the regression line. Paradoxically, those of lowest GA appeared least growth restricted.
In the UK in a large-scale study of neonates, eyes were generally shorter, the more advanced the ROP; further, treated stage 3 ROP had a lower AL score than untreated stage 3, a trend that could be noted also prior to the advanced ROP.
11 The few observations of serious ROP in the UK sample suggested that linear growth might apply also for stage 3 ROP cases, although at a weekly AL growth rate a little lower than valid for low-grade and no ROP.
In our series, collective slope values for age-adjusting the AL measurement were used, ignoring individual or hypothetical systematic deviations. Mathematical up and down adjustments of the chosen factors, however, would not affect the main trends.
To conclude, our main result is that premature eyes when progressing to advanced retinopathy of prematurity (T-ROP) are generally small(er) eyes, apparently restrained in growth.
In accord with previous studies we further suggested that at a given low GA a very low BW (SGA) might be a (prenatal) marker of added risk regarding ophthalmic sequels, and that the role of BW as an immaturity parameter is not merely parallel or subordinate to GA.
27,44 A more substantial support is given by the SGA analyses that were added in the present study. The lower the birth weight for gestational age at delivery, the shorter also the eye near term.
An early biological delay or latency soon after the untimely delivery is cautiously hypothesized, of significance not only for the observed manifestations of ROP, but also for the intricate patterns pertaining to the growth of the eye. Here, the present data support a preexisting intrauterine growth retardation as a significant prenatal cofactor.
Clearly our data call for further investigations with similar aims.