Free
Clinical and Epidemiologic Research  |   June 2012
Eye Size in Threshold Retinopathy of Prematurity, Based on a Danish Preterm Infant Series: Early Axial Eye Growth, Pre- and Postnatal Aspects
Author Affiliations & Notes
  • Hans Callø Fledelius
    The Copenhagen University Eye Department of Rigshospitalet, Capital Region of Denmark, Copenhagen, Denmark; and
  • Christian Fledelius
    Novo Nordisk, Måløv, Denmark.
  • Corresponding author: Hans C. Fledelius, Eye Clinic E 2061, Rigshospitalet, 9 Blegdamsvej, DK 2100 Copenhagen Ø, Denmark; rh03217@rh.dk
Investigative Ophthalmology & Visual Science June 2012, Vol.53, 4177-4184. doi:10.1167/iovs.12-9516
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Hans Callø Fledelius, Christian Fledelius; Eye Size in Threshold Retinopathy of Prematurity, Based on a Danish Preterm Infant Series: Early Axial Eye Growth, Pre- and Postnatal Aspects. Invest. Ophthalmol. Vis. Sci. 2012;53(7):4177-4184. doi: 10.1167/iovs.12-9516.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
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.

Introduction
In a cross-sectional study 40 years ago children born prematurely (PT) had shorter eyes than full-term (FT) children when examined around the age of 10 years. 1,2 Mean keratometry values further indicated a more peaked contour of the cornea, the anterior chamber depth was shallower, and lenses were thicker. Body height and cranial circumference completed the picture of a general deficit in growth for this group of natural history ex-prematures born 1959 to 1961, then part of a large-scale pediatric Copenhagen University prospective study. 
Ultrasonic biometry studies worldwide (Table 1) eventually generated data about the early growth pattern of the eye, full-term or preterm. 318 In a Danish study of eye size around term (week 40) we found no significant difference between PT and FT groups, but within the PT group there was a trend of shorter axial length (AL) for those of a very low gestational age (GA) at delivery. 17,18  
Table 1. 
 
Ultrasound Oculometry at Term, or Specified Age, Pooled for Sex, Citing Data from the Literature 1964–2007
Table 1. 
 
Ultrasound Oculometry at Term, or Specified Age, Pooled for Sex, Citing Data from the Literature 1964–2007
ACD (mm) LT (mm) AL (mm) K Value Crad (mm) Remarks
Gernet3 n = 80 term 2.9 3.4 17.2
Luyckx4 n = 52 term 2.55 3.65 17.6
Grignolo5 n = 19 FT/PT 17.5 FT, 16.7 PT PT not specified
Larsen6 n = 80 term 2.38 3.96 16.6
Blomdahl7 n = 28 term 2.6 3.6 16.6 7.0
Gordon8,9 n = 23 PT + FT 16.8 6.58 Weekly elong. 0.23 mm; PT not specified
Fledelius18
n = 25 FT 2.65 3.76 17.29
n = 101 PT 2.38 3.99 17.0 PT weekly elong. 0.19 mm and 0.13 mm before and, after w40, respectively; ROP 1-2 included
  if GA < 30w 2.33 4.04 16.95
  GA > = 33w 2.44 3.95 17.16
Tucker10 n = 70 PT
 25w 12.6 Weekly elong. 0.30 mm; ROP and sick PT excluded
 37w 16.2
Laws11 n = 171
 PCA 32w 15.4 Cross-sectional/longitudinal, no ROP eyes
 PCA 40w 16.6
O'Brien12 n = 100 PT
 w33 15.38 Longitudinal data, weekly elong. 0.20 mm up to w40, 0.14 mm after; no ROP included
 37w 15.98
 w40 16.73
 w52 18.23
Isenberg13 2.2 16.6 Extrapolated, weekly elong. 0.15 mm
 Mix PT/ FT
Cook14 n = 68 PT
 w32.9 1.98 15.44 6.10 Longitudinal data
 w36.1 2.11 16.09 6.43 Weekly elong. 0.16 mm over full PCA range, no ROP
 w40 2.25 3.98 16.84 6.94
 w44.7 2.43 17.43 7.21
 w52.9 2.80 18.58 7.55
Axer-Siegel15 n = 133 PT Treated ROP excluded
 PCA w31 2.15 15.6 71 in vitro fertil., 62 no IVF; Weekly elong. 0.13 mm
 w35 2.17 16.0
 w39–43 2.25 3.89 16.8
Azad16 n = 25 Weekly elong. 0.14 mm; past w40
 No or low ROP 2.49 17.0
 Cryo-treated 16.20 Pre T-ROP, when treated
With the introduction of the retinopathy of prematurity (ROP) classification in 1984, 19 subsequent clinical and biometric studies subdivided PT findings according to the presence and severity of the retinal disorder (Table 1). Changes in the ROP profile over time have been marked by the immense progress of care and therapy within neonatology, and also by the expanding ophthalmic experience gained from the routine surveillance for ROP in infants at risk. With many ROP cases included in their series of neonates, Laws and colleagues 11 reported “the higher the maximum stage of ROP reached, the shorter the axial length.” Otherwise, the trend is that visual parameters and biometry findings in mild regressed ROP (up to stages 1–2) generally compare with what is found in preterms without ROP. 2022  
For the present study we analyzed eye size based on ultrasonic measurement data from 53 eyes of 28 infants with threshold ROP (T-ROP), as defined by the Cryo-ROP study of 1988. 23 They were all referred (1997–2002) to the vitreoretinal service of the Copenhagen University eye department of Rigshospitalet, where retinal ablation therapy for threshold ROP (T-ROP) has been centralized on a national basis. 
Prompted by axial length trends according to low GA at delivery, the issue of small for gestational age (SGA) was further analyzed. 
Materials and Methods
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. 
Results
Median and Range, Mean Values, and Standard Deviation
Table 2 presents the demography and the oculometry findings in the T-ROP study group. The median PCA was 36.2 weeks (range 32.2–41.4 weeks), and postnatal age averaged 9 weeks (PNA range 5.8–14 weeks) (cf. the scattergrams of Fig. 1). 
Table 2. 
 
Median Values and Ranges Shown for All 53 Preterm Eyes with Threshold ROP, and Mean Values (and SD), after Subdivision by Sex
Table 2. 
 
Median Values and Ranges Shown for All 53 Preterm Eyes with Threshold ROP, and Mean Values (and SD), after Subdivision by Sex
All Preterms
(n = 53)
Boys
(n = 39)
Girls
(n = 14)
P
Value
Median, Range Mean (SD) Mean (SD), Range Mean (SD), Range
Gest. age (w) 27 27.2 (1.96) 27.1 (1.86) 27.4 (2.29)
24.7–30.9 25–30.9 24.7–30.6
Birth weight (g) 855 899 (262) 926 (225) 822 (342) 0.019
480–1594 480–1393 490–1594
PCA at exam (w) 36.2 36.4 (2.31) 35.9 (1.99) 37.7 (2.71) 0.057†
32.2–41.4 32.2–39.9 34.0–41.4
PNA at exam (w) 9.0 8.90 (2.00) 8.79 (1.95) 9.42 (2.20)
5.8–14.0 5.8–14.0 6.7–13.0
ACD (mm)* 2.1 2.09 (0.27) 2.12 (0.22) 2.0 (0.40)
1.3–2.6 1.8–2.6 1.3–2.5
LT (mm)* 4.0 3.92 (0.40) 3.92 (0.45) 3.93 (0.12)
3.8–4.5 3.8–4.5 3.7–4.1
AL actual measure 15.6 15.55 (0.61) 15.63 (0.58) 15.34 (0.65) 0.12
 (mm) 13.9–16.6 13.9–16.6 14.1–16.6
AL adjusted to 15.6 15.53 (0.72) 15.68 (0.66) 15.09 (0.73) 0.015
 GA week 36 (mm) 13.4–16.8 13.9–16.8 13.4–16.2
Figure 1. 
 
Scatterplots of gestational age at delivery versus birth weight (A), postconceptional age at exam (B), and postnatal age at exam (C). (D) PCA versus PNA at exam. All four associations statistically significant (cf. Table 4).
Figure 1. 
 
Scatterplots of gestational age at delivery versus birth weight (A), postconceptional age at exam (B), and postnatal age at exam (C). (D) PCA versus PNA at exam. All four associations statistically significant (cf. Table 4).
Table 3 shows mean axial length measurements and BW standard deviation scores, an individual measure of “weight for GA”; with focus on the role of intrauterine growth retardation this was labeled SGA SDS. The series was subdivided by GA values at delivery, of 26 and 28 weeks, respectively. Findings indicated that the least SGA load was found when GA was low, the median SD score here coming out as zero, compared with more than two negative SDS steps for the higher GA subgroups. 
Table 3. 
 
Birthweight, Axial Length, Age Parameters, and Birth Weight Small for Gestational Age (SGA) Standard Deviation Score
Table 3. 
 
Birthweight, Axial Length, Age Parameters, and Birth Weight Small for Gestational Age (SGA) Standard Deviation Score
BW
(g)
PCA at Exam (wk) PNA at Exam (wk) AL Measured (mm) ALw36 (mm) SGA
(SD Score)
GA ≤26 w (n = 19) 784 (1.45) 36.1 (2.82) 10.2 (2.48) 15.79 (0.47) 15.79 (0.65) −0.63 (1.36)
26.1–28 w (n = 20) 852 (246) 35.3 (1.18) 8.3 (1.44) 15.53 (0.50) 15.69 (0.53) −2.04 (1.63)
>28 w (n = 14) 1121 (285) 38.3 (1.51) 8.3 (1.25) 15.24 (0.78) 14.93 (0.76) −2.48 (1.54)
Table 4. 
 
Linear Regression Statistics, with Gestational Age at Delivery (weeks), Birth Weight (g), Age When Examined (PCA, weeks), and SGA Standard Deviation Score as Independent Variable, against the Parameters under Study
Table 4. 
 
Linear Regression Statistics, with Gestational Age at Delivery (weeks), Birth Weight (g), Age When Examined (PCA, weeks), and SGA Standard Deviation Score as Independent Variable, against the Parameters under Study
On x-Axis Cf. Figure Dependent Variable r = Calculated Regression Line P Value for Slope
GA (w) 1B PCA at exam (w) 0.34 y = 25.44 + 0.402 X 0.013
GA (w) 2A AL (mm) −0.25* y = 17.65 − 0.0775 X 0.07*
GA (w) 2B ALw36 (mm) 0.37 y = 19.20 − 0.135 X 0.007
GA (w) 1A BW (g) 0.51 y = −934 + 67.45 X 0.0001
GA (w) 1C PNA (w) 0.42 y = 20.71 − 0.433 X 0.0021
GA (w) 3A SGA (SDscore) 0.50 y = 0.104 − 0.424 X 0.0002
BW (g) PCA at exam (w) 0.10 y = 35.54 + 0.00091 X 0.46
BW (g) AL (mm) 0.24* y = 15.06 + 0.00055 X 0.089*
BW (g) ALw36 (mm) 0.14 y = 15.17 + 0.00039 X 0.31
PCA (w) 1D PNA (w) 0.56 y = −10.13 + 0.526 X <0.0001
PCA (w) 2C AL (mm) −0.09 y = 16.39 − 0.023 X 0.61
PCA (w) 2D ALw36 (mm) −0.09 y = 16.57 − 0.0286 X 0.52
PCA (w) ACD (mm) 0.38 y = 0.216 + 0.0513 X 0.026
PCA (w) LT (mm) −0.06 y = 4.14 − 0.0045 X 0.73
PCA (w) 3B SGA (SDscore) −0.18 y = −2.97 − 0.127 X 0.21
SGA SDscore 3C AL (mm) 0.49 y = 15.84 + 0.178 X 0.0002
SGA SDscore 3D AL36w (mm) 0.48 y = 15.87 + 0.208 X 0.0003
Distribution of SGA scores showed no influence by sex. Here only two significant differences occurred: boys qualified for examination earlier (PCA 35.9 vs. 37.7 weeks, P < 0.05 by Student's t-test, 0.057 by Mann–Whitney), and AL adjusted to week 36 was longer in boys (15.68 vs. 15.09 mm, P < 0.02, Student's and Mann–Whitney). In both sexes anterior chamber depths and lens thicknesses were approximately 2.1 and 3.9 mm, respectively (Table 4). 
With no evidence of increased intraocular pressure, this parameter was omitted from the table. 
Scatterplots and Regression Statistics
Selected results are shown in Figures 13, and the regression statistics specified in Table 4. Omitted are differences possibly associated with chronology, referring to the current progress in neonatal intensive care unit handling over the 6 years of sampling. Here only the BW parameter came close to significance. A P value for the negative slope was 0.08, with an on-regression line value of 999 g for birth year 1997 and of 788 g for endpoint year 2002. Compared with the stable GA findings this suggests an increasing share of infants (relatively) small for gestational age (SGA) over time. 
With gestational age at delivery on x-axis significant associations were first achieved with the following parameters: 
  1.  
    BW (r = 0.51; slope value 67.45, different from zero, P = 0.0001), that is, higher GA generally = higher BW (Fig. 1A).
  2.  
    Age at examination (r = 0.34, slope 0.40; different from zero, P = 0.012), that is, higher GA at delivery also means later appearance of T-ROP, given by the PCA when examined (Fig. 1B).
  3.  
    With a negative slope, and a correlation coefficient of r = −0.42, the postnatal age at examination also had a significant correlation. The regression line is given by y = 20.71 − 0.43 X (P = 0.002 for slope, different from zero). The lower the GA at delivery, the longer thus the latency to observed T-ROP, and the subsequent examination under general anesthesia (Fig. 1C).
  4.  
    It appeared that adjusted ALw36 had a negative slope of −0.135 (significantly differing from zero, P = 0.007). Mathematically this implies that eyes of the most immature infants, usually considered at highest risk for pathology, had grown more as judged from adjusted ALw36 value (Fig. 2B). A less steep regression line for the actually measured AL at the given age of the infant emerged as y = 17.65 − 0.0775 X, r = −0.25; the P value for the slightly negative slope was 0.07 (Fig. 2A).
  5.  
    Given the results under (4), the SGA standard deviation score was further included, as y-value. A negative slope of −0.424 (P = 0.0002) indicated that intrauterine growth retardation, here expressed by the relative indication of SGA, increased in prevalence the higher the GA at delivery (Fig. 3A).
  6.  
    With BW (g) on the x-axis, the association to both axial length parameters (adjusted ALw36, r = 0.14, and real AL, r = 0.24) showed a positive slope for the regression line. This also held for age at examination (PCA), but only the association with AL came close to significance (P = 0.089). The trend suggested, accordingly: the higher the BW (possibly as a marker of good health, in contrast to SGA), the longer the AL when measured during the T-ROP initiated examination, which, however, would also be (a little) later on the PCA time axis.
  7.  
    Age at examination (PCA) further correlated with postnatal age (Fig. 1D) and with anterior chamber depth.
  8.  
    Finally, with the SGA standard deviation score on x-axis significant P values for slopes different from zero indicated that shorter axial lengths were associated with higher degrees of intrauterine growth retardation (Figs. 3C, 3D).
Figure 2. 
 
Scatterplots of gestational age at delivery (A, B) and of postconceptional age (C, D) versus axial length as actually measured (A, C) and adjusted to week 36 (B, D). Associations (A) and (B) are close to significance and significant, respectively, whereas (C) and (D) are both n.s. (cf. Table 4).
Figure 2. 
 
Scatterplots of gestational age at delivery (A, B) and of postconceptional age (C, D) versus axial length as actually measured (A, C) and adjusted to week 36 (B, D). Associations (A) and (B) are close to significance and significant, respectively, whereas (C) and (D) are both n.s. (cf. Table 4).
Figure 3. 
 
Scatterplots of small for gestational age (SGA) in SD score values, on y-axis in (A) and (B), against GA (highly significant) and PCA at exam (n.s.). SGA further on x-axis in (C) and (D), against the two AL measures under study, both with highly significant positive slopes (cf. Table 4).
Figure 3. 
 
Scatterplots of small for gestational age (SGA) in SD score values, on y-axis in (A) and (B), against GA (highly significant) and PCA at exam (n.s.). SGA further on x-axis in (C) and (D), against the two AL measures under study, both with highly significant positive slopes (cf. Table 4).
Discussion
Axial Eye Dimensions in Preterms
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. 318 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. 
Birth Weight versus Gestational Age
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. 
On the Time Sequence
ROP is not observed until weeks 31–32, a PCA apparently to be attained before the retinal physiology can manifest as the observed abnormal vessel morphology of ROP. 17,18,2630 For those of lowest GA at delivery this implies an interval of at least up to 6–8 weeks until ROP is first recorded. 
Evidently, the ultrasonographic indication of “lowest GA, least growth arrest” does not immediately fit with the theoretical model of a general restraining effect of immaturity, in particular if active from PT day one. By analogy with the delayed retinal findings, tentatively we could hypothesize that the balance between the early effects on eye growth might include a hardly affected postnatal axial elongation initially, and a latency until restrained growth is manifest. 31,32 Our present SGA analysis further supports prenatal growth retardation as a much stronger factor than hitherto perceived, a finding not reported in ROP literature so far. 
In accordance with the literature, it was further confirmed that the smallest GA infants (<26 weeks at delivery, Table 2; regression line Table 4, also cf. Fig. 1) required more time until manifest T-ROP. 2830 Their T-ROP–related examinations were performed on average in week 10.2 (PNA, in weeks, SD 2.48) versus a PNA mean age of 8.3 weeks (SD 1.38; P < 0.01) for those above week 26. The trend is similar with a binary cutoff at GA week 28. The smallest infants thus take longer before (1) they show first evidence of ROP, if any, and (2) before established ROP progresses to T-ROP. 
As for the course after successful cryotherapy, we can hypothesize that the retinal ablation therapy not only saves retinal anatomy and function, but also brings the globe as a whole into a state from which reduced growth can be restarted and go on in a more natural gear, although from a new starting point. This would explain the so-called more fetal anterior and posterior eye segment proportions as met for instance in children and adolescents with myopia of prematurity (eyes shorter for myopia degree, lenses thicker, and located more anteriorly). 1,2,9,20,22,3342  
Small for Gestational Age (SGA)
The issue of retarded intrauterine growth, here manifesting as less retardation the more immature the infant, was addressed by way of an SD score that indicated how much an individual BW deviated from expectedly normal for gestational age. 24 A larger share of those with higher GA values at delivery presented evidence of intrauterine growth retardation, as a prenatal marker that, as generally valid for preterm series, also affected our PT group as a whole. Weighting the two parameters, with AL as yardstick, the effects of SGA could at least match that of gestational age. 
Summing Up the Various Studies on Eye Growth in Preterms
There is fair agreement between most results presented in Table 1, a harmony that is impressive, considering the complicated measuring situation in a tiny infant, the methodological error of the various A-scan techniques used, and also the variation in clinical profile of the included preterm samples. The mean axial length in an FT infant at term (week 40) is approximately 16.6–17 mm, and anterior chamber depth and AL values increase over time, in contrast to the more constant early childhood figures reported for lens thickness. 
Regarding weekly axial elongation prior to term, linear values from the oculometry studies of prematures range from 0.13 to 0.23 mm per week, with an outlier value of 0.30 mm given in a single study. 10 We regard exponential growth as likely also during this early phase of life, 18,43 but the various scattergrams in the literature support that linear regression mathematics can be applied when only narrow age spans are under study, as actually done in the reports quoted in the table. Linear regression has even been reported as best fit, also when tested against quadratic models. 11  
Conclusions
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. 
References
Fledelius HC . Prematurity and the eye. Ophthalmic 10-year follow-up of children of low and normal birth weight. Acta Ophthalmol Suppl . 1976;128:3–245. [PubMed]
Fledelius HC . Inhibited growth and development as permanent features of low birth weight. Acta Paediatr Scand . 1981;71:645–650. [CrossRef]
Gernet H . Achsenlänge und Refraktion lebender Augen bei Neugeborenen [in German]. Graefes Arch Clin Exp Ophthalmol . 1964;166:530–546. [CrossRef]
Luyckx J . Mesure des composantes optiques de l'oeil du nouveau-né par échographie ultrasonique [in French]. Arch Ophthalmol (Paris) . 1966;26:159–170.
Grignolo A Rivara A . Observations biométriques sur l'œil des enfants nés a terme et des prématurés au cours de la première année [in French]. Ann Oculist . 1968;201:817–826.
Larsen J . The sagittal growth of the eye. Ultrasonic measurements of the posterior segment (axial length of the vitreous) from birth to puberty. Acta Ophthalmol . 1971;49:441–453. [CrossRef]
Blomdahl S . Ultrasonic measurements of the eye in the newborn infant. Acta Ophthalmol . 1979;57:1048–1056. [CrossRef]
Gordon A Donzis PB . Refractive development of the human eye. Arch Ophthalmol . 1985;103:785–789. [CrossRef] [PubMed]
Gordon RA Donzis PB . Myopia associated with retinopathy of prematurity. Ophthalmology . 1986;93:1593–1598. [CrossRef] [PubMed]
Tucker SM Enzenauer RW Levin AV Morin JD Hellmann J . Corneal diameter, axial length and intraocular pressure in premature infants. Ophthalmology . 1992;99:1296–1300. [CrossRef] [PubMed]
Laws DE Haslett R Ashby D O'Brien C Clark D . Axial length biometry in infants with retinopathy of prematurity. Eye . 1994;8:427–430. [CrossRef] [PubMed]
O'Brien C Clark D . Ocular biometry in pre-term infants without retinopathy of prematurity. Eye . 1994;8:662–665. [CrossRef] [PubMed]
Isenberg SJ Neumann D Cheong PYY Ling YLF McCall LC Ziffer AJ . Growth of the internal and external eye in term and preterm infants. Ophthalmology . 1994;102:827–830. [CrossRef]
Cook A White S Batterbury M Clark D . Ocular growth and refractive error development in premature infants without retinopathy of prematurity. Invest Ophthalmol Vis Sci . 2003;44:953–960. [CrossRef] [PubMed]
Axer-Siegel R Bourla D Sirota L Weinberger D Snir M . Ocular growth in premature infants conceived by in vitro fertilization versus natural conception. Invest Ophthalmol Vis Sci . 2005;46:1163–1169. [CrossRef] [PubMed]
Azad RV Lakshminarayana P Kumar H Talwar D Pal N Chandra P . Ocular growth pattern in cryotherapy- and laser-treated infants with prethreshold retinopathy of prematurity. J Pediatr Ophthalmol Strabismus . 2005;42:149–154. [PubMed]
Fledelius HC . Eye size of the premature infant around presumed term. Doc Ophthalmol Proc Series . 1990;53:165–172.
Fledelius HC . Pre-term delivery and the growth of the eye. An oculometric study of eye size around term-time. Acta Ophthalmol Suppl . 1992;204;10–15. [PubMed]
Committee for the classification of retinopathy of prematurity, ICROP (1984): an international classification of retinopathy of prematurity. Arch Ophthalmol . 1984;102:1130–1133. [CrossRef] [PubMed]
Kent D Pennie F Laws D White S Clark D . The influence of retinopathy of prematurity on ocular growth. Eye . 2000;14:23–29. [CrossRef] [PubMed]
O'Connor AR Stephenson TJ Johnson A Tobin MJ Ratb S Fielder A . Change of refractive state and eye size in children of birth weight less than 1701 g. Br J Ophthalmol . 2006;90:456–460. [CrossRef] [PubMed]
McLoone EM O'Keefe M McLoone SF Lanigan BM . Long-term refractive and biometric outcomes following diode laser therapy for retinopathy of prematurity. J AAPOS . 2006;10:454–459. [CrossRef] [PubMed]
Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Arch Ophthalmol . 1988;106:471–479. [CrossRef] [PubMed]
Marsal K Persson PH Larsen T Lilja H Selbing A Sultan B . Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr Scand . 1996;85:843–848.
Jansson F . Measurements of introcular distances by ultrasound. Acta Ophthalmol Suppl . 1963;74:11–48.
Schulenburg WE Prendiville A Ohri R . Natural history of retinopathy of prematurity. Br J Ophthalmol . 1987;71:837–843. [CrossRef] [PubMed]
Slidsborg C Olesen HB Jensen PK Treatment for retinopathy of prematurity in Denmark in a 10-year period (1996–2005). Is the incidence increasing? Pediatrics . 2008;121:97–105.
Quinn GE Johnson L Abbasi S . Onset of retinopathy of prematurity as related to postnatal and postconceptional age. Br J Ophthalmol . 1992;76:284–288. [CrossRef] [PubMed]
Fielder AR Shaw DE Robinson J Ng YK . Natural history of retinopathy of prematurity. Eye . 1992;6:233–242. [CrossRef] [PubMed]
Austeng D Kallen KBM Hellström A Tornquist K Holmström GE . Natural history of ROP in infants born before 27 weeks gestation in Sweden. Arch Ophthalmol . 2010;128:1289–1294. [CrossRef] [PubMed]
Hellström A Engström E Hard A-L Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics . 2003;112:1016–1020. [CrossRef] [PubMed]
Romagnoli C . Risk factors and growth factors in ROP. Early Hum Dev . 2009;85 (suppl 10):S79–S82. [CrossRef] [PubMed]
Fledelius HC . Myopia of prematurity. Changes during adolescence. A longitudinal study including ultrasound. Doc Ophthalmol Proc Series . 1981;29:217–223.
Fledelius HC . Retinopathy of prematurity. Clinical findings in a Danish county 1982-87. Acta Ophthalmol . 1990;68:209–213. [CrossRef]
Fledelius HC . Myopia of prematurity oculometric features. Acta Ophthalmol . 1995;73:397–401. [CrossRef]
Fledelius HC . Myopia of prematurity, clinical patterns. A follow-up of Danish children now aged 3-9 years. Acta Ophthalmol . 1995;73:402–406. [CrossRef]
Fledelius HC . Preterm delivery and subsequent ocular development. A 7-10 year follow-up of children screened 1982-84 for ROP. 3) Refraction, 4) Oculometry. Acta Ophthalmol . 1996;74:295–297, 298–301.
Tane S Ito S Kushiro H Kohno J . Echographic biometry in myopia of prematurity in Japan. In: Gernet H , ed. Diagnostica Ultrasonica in Ophthalmologia (SIDUO VII) . Münster, Germany: Remy-Verlag; 1979:190–194.
Gallo JE Fagerholm P . Low-grade myopia in children with regressed retinopathy of prematurity. Acta Ophthalmol . 1993;71:519–523. [CrossRef]
Fielder AR Quinn GE . Myopia of prematurity: nature, nurture, or disease. Br J Ophthalmol . 1997;81:2–3. [CrossRef] [PubMed]
Conolly BP Ng EYJ McNamara JA Regillo CD Vander JF Tasman W . A comparison of laser photocoagulation with cryotherapy for threshold retinopathy of prematurity at 10 years. Part 2: refractive outcome. Ophthalmology . 2002;109:936–941. [CrossRef] [PubMed]
Saw S-M Tong L Chia K-S Lee Y-S Katz J Tan DTH . The relation between birth size and the results of refractive error and biometry measurements in children. Br J Ophthalmol . 2004;88:538–542. [CrossRef] [PubMed]
Fledelius HC Christensen AC . Reappraisal of the human ocular growth curve in fetal life, infancy, and early childhood. Br J Ophthalmol . 1996;80:918–921. [CrossRef] [PubMed]
Fledelius HC Göte H Greisen G Jensen H . Surveillance for retinopathy of prematurity in a Copenhagen high-risk sample 1991-2001: has progress reached a plateau? Acta Ophthalmol . 2004;82:32–37. [CrossRef]
Footnotes
 Disclosure: H.C. Fledelius, None; C. Fledelius, Novo Nordisk (E)
Figure 1. 
 
Scatterplots of gestational age at delivery versus birth weight (A), postconceptional age at exam (B), and postnatal age at exam (C). (D) PCA versus PNA at exam. All four associations statistically significant (cf. Table 4).
Figure 1. 
 
Scatterplots of gestational age at delivery versus birth weight (A), postconceptional age at exam (B), and postnatal age at exam (C). (D) PCA versus PNA at exam. All four associations statistically significant (cf. Table 4).
Figure 2. 
 
Scatterplots of gestational age at delivery (A, B) and of postconceptional age (C, D) versus axial length as actually measured (A, C) and adjusted to week 36 (B, D). Associations (A) and (B) are close to significance and significant, respectively, whereas (C) and (D) are both n.s. (cf. Table 4).
Figure 2. 
 
Scatterplots of gestational age at delivery (A, B) and of postconceptional age (C, D) versus axial length as actually measured (A, C) and adjusted to week 36 (B, D). Associations (A) and (B) are close to significance and significant, respectively, whereas (C) and (D) are both n.s. (cf. Table 4).
Figure 3. 
 
Scatterplots of small for gestational age (SGA) in SD score values, on y-axis in (A) and (B), against GA (highly significant) and PCA at exam (n.s.). SGA further on x-axis in (C) and (D), against the two AL measures under study, both with highly significant positive slopes (cf. Table 4).
Figure 3. 
 
Scatterplots of small for gestational age (SGA) in SD score values, on y-axis in (A) and (B), against GA (highly significant) and PCA at exam (n.s.). SGA further on x-axis in (C) and (D), against the two AL measures under study, both with highly significant positive slopes (cf. Table 4).
Table 1. 
 
Ultrasound Oculometry at Term, or Specified Age, Pooled for Sex, Citing Data from the Literature 1964–2007
Table 1. 
 
Ultrasound Oculometry at Term, or Specified Age, Pooled for Sex, Citing Data from the Literature 1964–2007
ACD (mm) LT (mm) AL (mm) K Value Crad (mm) Remarks
Gernet3 n = 80 term 2.9 3.4 17.2
Luyckx4 n = 52 term 2.55 3.65 17.6
Grignolo5 n = 19 FT/PT 17.5 FT, 16.7 PT PT not specified
Larsen6 n = 80 term 2.38 3.96 16.6
Blomdahl7 n = 28 term 2.6 3.6 16.6 7.0
Gordon8,9 n = 23 PT + FT 16.8 6.58 Weekly elong. 0.23 mm; PT not specified
Fledelius18
n = 25 FT 2.65 3.76 17.29
n = 101 PT 2.38 3.99 17.0 PT weekly elong. 0.19 mm and 0.13 mm before and, after w40, respectively; ROP 1-2 included
  if GA < 30w 2.33 4.04 16.95
  GA > = 33w 2.44 3.95 17.16
Tucker10 n = 70 PT
 25w 12.6 Weekly elong. 0.30 mm; ROP and sick PT excluded
 37w 16.2
Laws11 n = 171
 PCA 32w 15.4 Cross-sectional/longitudinal, no ROP eyes
 PCA 40w 16.6
O'Brien12 n = 100 PT
 w33 15.38 Longitudinal data, weekly elong. 0.20 mm up to w40, 0.14 mm after; no ROP included
 37w 15.98
 w40 16.73
 w52 18.23
Isenberg13 2.2 16.6 Extrapolated, weekly elong. 0.15 mm
 Mix PT/ FT
Cook14 n = 68 PT
 w32.9 1.98 15.44 6.10 Longitudinal data
 w36.1 2.11 16.09 6.43 Weekly elong. 0.16 mm over full PCA range, no ROP
 w40 2.25 3.98 16.84 6.94
 w44.7 2.43 17.43 7.21
 w52.9 2.80 18.58 7.55
Axer-Siegel15 n = 133 PT Treated ROP excluded
 PCA w31 2.15 15.6 71 in vitro fertil., 62 no IVF; Weekly elong. 0.13 mm
 w35 2.17 16.0
 w39–43 2.25 3.89 16.8
Azad16 n = 25 Weekly elong. 0.14 mm; past w40
 No or low ROP 2.49 17.0
 Cryo-treated 16.20 Pre T-ROP, when treated
Table 2. 
 
Median Values and Ranges Shown for All 53 Preterm Eyes with Threshold ROP, and Mean Values (and SD), after Subdivision by Sex
Table 2. 
 
Median Values and Ranges Shown for All 53 Preterm Eyes with Threshold ROP, and Mean Values (and SD), after Subdivision by Sex
All Preterms
(n = 53)
Boys
(n = 39)
Girls
(n = 14)
P
Value
Median, Range Mean (SD) Mean (SD), Range Mean (SD), Range
Gest. age (w) 27 27.2 (1.96) 27.1 (1.86) 27.4 (2.29)
24.7–30.9 25–30.9 24.7–30.6
Birth weight (g) 855 899 (262) 926 (225) 822 (342) 0.019
480–1594 480–1393 490–1594
PCA at exam (w) 36.2 36.4 (2.31) 35.9 (1.99) 37.7 (2.71) 0.057†
32.2–41.4 32.2–39.9 34.0–41.4
PNA at exam (w) 9.0 8.90 (2.00) 8.79 (1.95) 9.42 (2.20)
5.8–14.0 5.8–14.0 6.7–13.0
ACD (mm)* 2.1 2.09 (0.27) 2.12 (0.22) 2.0 (0.40)
1.3–2.6 1.8–2.6 1.3–2.5
LT (mm)* 4.0 3.92 (0.40) 3.92 (0.45) 3.93 (0.12)
3.8–4.5 3.8–4.5 3.7–4.1
AL actual measure 15.6 15.55 (0.61) 15.63 (0.58) 15.34 (0.65) 0.12
 (mm) 13.9–16.6 13.9–16.6 14.1–16.6
AL adjusted to 15.6 15.53 (0.72) 15.68 (0.66) 15.09 (0.73) 0.015
 GA week 36 (mm) 13.4–16.8 13.9–16.8 13.4–16.2
Table 3. 
 
Birthweight, Axial Length, Age Parameters, and Birth Weight Small for Gestational Age (SGA) Standard Deviation Score
Table 3. 
 
Birthweight, Axial Length, Age Parameters, and Birth Weight Small for Gestational Age (SGA) Standard Deviation Score
BW
(g)
PCA at Exam (wk) PNA at Exam (wk) AL Measured (mm) ALw36 (mm) SGA
(SD Score)
GA ≤26 w (n = 19) 784 (1.45) 36.1 (2.82) 10.2 (2.48) 15.79 (0.47) 15.79 (0.65) −0.63 (1.36)
26.1–28 w (n = 20) 852 (246) 35.3 (1.18) 8.3 (1.44) 15.53 (0.50) 15.69 (0.53) −2.04 (1.63)
>28 w (n = 14) 1121 (285) 38.3 (1.51) 8.3 (1.25) 15.24 (0.78) 14.93 (0.76) −2.48 (1.54)
Table 4. 
 
Linear Regression Statistics, with Gestational Age at Delivery (weeks), Birth Weight (g), Age When Examined (PCA, weeks), and SGA Standard Deviation Score as Independent Variable, against the Parameters under Study
Table 4. 
 
Linear Regression Statistics, with Gestational Age at Delivery (weeks), Birth Weight (g), Age When Examined (PCA, weeks), and SGA Standard Deviation Score as Independent Variable, against the Parameters under Study
On x-Axis Cf. Figure Dependent Variable r = Calculated Regression Line P Value for Slope
GA (w) 1B PCA at exam (w) 0.34 y = 25.44 + 0.402 X 0.013
GA (w) 2A AL (mm) −0.25* y = 17.65 − 0.0775 X 0.07*
GA (w) 2B ALw36 (mm) 0.37 y = 19.20 − 0.135 X 0.007
GA (w) 1A BW (g) 0.51 y = −934 + 67.45 X 0.0001
GA (w) 1C PNA (w) 0.42 y = 20.71 − 0.433 X 0.0021
GA (w) 3A SGA (SDscore) 0.50 y = 0.104 − 0.424 X 0.0002
BW (g) PCA at exam (w) 0.10 y = 35.54 + 0.00091 X 0.46
BW (g) AL (mm) 0.24* y = 15.06 + 0.00055 X 0.089*
BW (g) ALw36 (mm) 0.14 y = 15.17 + 0.00039 X 0.31
PCA (w) 1D PNA (w) 0.56 y = −10.13 + 0.526 X <0.0001
PCA (w) 2C AL (mm) −0.09 y = 16.39 − 0.023 X 0.61
PCA (w) 2D ALw36 (mm) −0.09 y = 16.57 − 0.0286 X 0.52
PCA (w) ACD (mm) 0.38 y = 0.216 + 0.0513 X 0.026
PCA (w) LT (mm) −0.06 y = 4.14 − 0.0045 X 0.73
PCA (w) 3B SGA (SDscore) −0.18 y = −2.97 − 0.127 X 0.21
SGA SDscore 3C AL (mm) 0.49 y = 15.84 + 0.178 X 0.0002
SGA SDscore 3D AL36w (mm) 0.48 y = 15.87 + 0.208 X 0.0003
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×