Association of Birth Parameters with OCT Measured Macular and Retinal Nerve Fiber Layer Thickness

Abstract

Purpose.: To examine whether birth parameters have associations with macular and retinal nerve fiber layer (RNFL) thickness measurements.

Methods.: The Sydney Myopia Study examined secondary school children for ocular conditions, with all eligible year 7 students from 21 high schools invited to participate. Macular and RNFL measurements were acquired from optical coherence tomography (OCT) scans. Birth variables, including birth weight and gestational duration, were obtained from parental questionnaires and health records. Mixed linear models were used in analyses, after adjustment for age, sex, height, axial length, and ethnicity.

Results.: In children with complete gestational duration data, adequate quality scans of the RNFL and macula were obtained from 1756 and 1698 children, respectively. Children with low birth weight (<2500 g) had a thinner mean RNFL (98.2 μm vs. 103.5 μm; P < 0.0001) and a thicker mean foveal minimum (164.3 μm vs. 158.5 μm; P = 0.004) than did children of normal birth weight (2500–4000 g). With increasing birth weight, average RNFL thickness increased (mixed model coefficient, β = 2.97 μm/kg; P < 0.0001) and foveal minimum thickness decreased (β = −2.16 μm/kg; P = 0.008). Children born before 32 weeks' gestation had significantly thicker mean foveal minimum and central macular thickness (205.5 μm vs. 193.4 μm; P = 0.001) measurements than did children born after 37 weeks' gestation.

Conclusions.: Low birth weight and prematurity are associated with thickening of the fovea, and decreased birth weight is associated with decreased RNFL thickness, as measured by OCT. These findings suggest that premature birth and low birth weight impair retinal development and may predispose these children to ocular problems later in life.

Prematurity and low birth weight have been associated with many adverse sequelae in later life, including high blood pressure, ¹ metabolic syndrome, ² type 2 diabetes mellitus, ³ neurodevelopment disorders, ⁴ and chronic renal insufficiency. ⁵ Ophthalmic consequences of preterm birth and low birth weight include retinopathy of prematurity (ROP), myopia, strabismus, amblyopia, and cortical visual impairment. ^{6 –11} Low birth weight is also a marker of adverse intrauterine development, and animal studies have confirmed that placental insufficiency has long-term effects on retinal structure. ¹² Although several studies have described retinal changes in ROP, very few have examined the impact of birth parameters on macular and retinal nerve fiber layer (RNFL) thickness. ^{13 –15}  

In a brief report, we presented the association of birth parameters with the thicknesses of the macula and RNFL in 6-year-old children. ¹⁶ We found that there is increased thickness in the central macula in children born before 37 weeks and that the RNFL and outer macular thicknesses are increased in higher birth weight children. To ascertain whether these changes persist throughout childhood we sought to test these associations in the older cohort of the Sydney Myopia Study (SMS). An adolescent population is ideal for this study, as these subjects are relatively free of potentially confounding ocular conditions (e.g., diabetes, glaucoma, and cataract). In addition, fine retinal development is thought to be ongoing until 4 years of age ¹⁷ ; therefore, an ideal population in which to assess the outcome of abnormal development is that in the later years of childhood. 

Methods

The SMS examined eye conditions in secondary school children in Sydney, with all eligible year 7 students from 21 high schools invited to participate. Schools were selected based on socioeconomic status (SES) stratification of the Sydney metropolitan area. Two schools were randomly selected from the top SES decile with the remainder randomly selected from the bottom 9 deciles. The study was approved by the Human Research Ethics Committee, University of Sydney, and the Department of Education and Training and the Catholic Education Office, New South Wales, Australia, and adhered to the tenets of the Declaration of Helsinki. Study methods have been described in detail previously. ¹⁸  

Examinations

Ocular examinations were conducted in 2004 and 2005 and were performed by a team of ophthalmologists, other medical practitioners, optometrists, and orthoptists. Monocular visual acuity (VA) was assessed with a logarithm of minimal angle of resolution (logMAR) chart read at 244 cm (8 feet). ¹⁹ Axial length (AL) was measured by using noncontact partial coherence interferometry (IOLMaster; Carl Zeiss Meditec, Jena, Germany). Cyclopentolate (1%) and tropicamide (1%) were administered twice (5 minutes apart) to achieve cycloplegia; in addition, phenylephrine (2.5%) was used in some children, but only if adequate mydriasis (≥6 mm) was not achieved. Autorefraction (Canon RK-F1; Canon, Tokyo, Japan) was performed at least 25 minutes after the eye drops were administered. 

Optical Coherence Tomography

The Stratus OCT (Stratus OCT3; Carl Zeiss Meditec, Dublin, CA) obtains cross-sectional retinal tomographic scans that have been found to be highly reproducible. ^20,21 OCT scans were conducted after cycloplegia by using the fast scan protocol to measure macular and peripapillary RNFL parameters. The macular scans consisted of six radial scans each, with 128 A-scans over a 6-mm distance (visual angle, 20.94° [Durbin M, Carl Zeiss Meditec, personal communication, 2010]). This macular thickness map was divided into three concentric areas with diameters of 1, 3, and 6 mm, termed the central, inner, and outer macula, respectively (Fig. 1). In addition, the foveal minimum (the retinal thickness at the central point where the six radial scans intersect) and the total macular volume (an approximation of the volume of the macular area 6 mm in diameter) were calculated by the OCT software. An average of five scans were used in the analyses. The peripapillary RNFL was scanned, with 256 A-scans arranged in a 3.46-mm diameter circle (visual angle 12.08°) centered on the optic disc (Fig. 2). The Stratus OCT calculates average RNFL and quadrant-specific thicknesses based on the average of three circular scans. For both scan types, the OCT instrument assumes a standard AL (24.46 mm) and refraction (0 D). Although both eyes were scanned, only OCT scans of the right eye with signal strength greater than 5 were used in the analyses. 

Figure 1.

 

OCT output for macular scan showing (A) fundus image with scanning lines; (B) a cross-sectional image with positions of the foveal minimum (F), central macula (CM), inner macula (IM), and outer macula (OM) indicated; and (C) a topographic map of retinal thickness and the average thickness of the nine regions defined.

Figure 2.

 

OCT output for several (RNFL) showing (A) fundus image with scan circle, (B) cross-sectional image of a retina, and (C) average RNFL thicknesses in clock hours and quadrants.

Questionnaires

A 193-item questionnaire covering each child's demographic and ocular history was completed by the parents. In Australia, health professionals record birth variables, including birth weight, length, and head circumference in a booklet (Blue Book), which is provided to parents. Information on perinatal variables was provided by parents on the basis of information recorded in this booklet. 

Statistical Analysis

Analyses were performed (SAS, ver. 9.2; SAS Institute, Cary, NC) in which, according to the World Health Organization definition, ²² children less than 2500 g were deemed to have low birth weight. For the purposes of this report we created a category of high birth weight for children >4000 g. Gestational duration was divided into premature (≤32 weeks), modestly premature (33–36 weeks), and normal (≥37 weeks). The χ² test was used to test for heterogeneity of sex and ethnicity between birth weight categories. To test for heterogeneity of baseline characteristics (age, height, weight, body mass index [BMI], refractive error, and VA) between birth weight categories, we used mixed linear models, ²³ with school attended serving as a random effect. To compare OCT parameters between perinatal categories, we also used mixed linear models, after adjustment for covariates (age, sex, AL, height, and ethnicity) and including school attended as a random effect. Since birth weight and duration of gestation correlate strongly with each other, we did not adjust for these parameters together in the main analyses. However, to assess the relative importance of these two parameters in the observed associations with retinal thickness, we performed additional analyses, adjusting for birth weight in the gestational duration model and for gestational duration in the birth weight model. P < 0.05 was considered significant. 

Results

Of 3144 eligible children, 2353 (74.8%) were examined. The remainder (n = 791), did not provide parental consent for the study or were absent from school on days when testing was performed. Children with amblyopia (n = 44) and various eye conditions (n = 16) including congenital glaucoma, optic nerve hypoplasia, microphthalmos, congenital nystagmus, and cortical blindness due to cerebral palsy, were excluded from this report. Of the remaining 2293 children, 1756 (77%) and 1698 (74%), respectively, had adequate quality RNFL and macular scans and provided data for gestational duration. For birth weight analysis, 1591 (69%) and 1537 (67%) had adequate quality scans of RNFL and macula, respectively. Based on questionnaires and examinations no child was noted to have a history of ROP. 

Table 1 presents various characteristics for participants by birth weight category. There were significant differences in the sex, ethnicity, height, weight, BMI, and AL between birth weight categories. For example, height, BMI, and weight were higher and AL slightly longer in children with greater birth weight. Caucasian children were overrepresented in the >4000-g group, East Asian children were underrepresented in that group, and a larger proportion of South Asian children were in the low birth weight category. Table 2 presents the birth weight by duration of gestation. Children with a longer duration of gestation generally had greater birth weight. There was considerable overlap in the birth weights of the children in the three gestation groups. In the very premature group (≤32 weeks) the duration of gestation ranged from 23 to 32 weeks. 

Table 1.

 

Characteristics of Participants by Birth Weight Category

	Birth Weight (g)			P *
	<2500 (n = 94)	2500–4000 (n = 1366)	>4000 (n = 171)
Male, %	57.5	50.2	61.4	0.01
Age, y	12.7 ± 0.5	12.7 ± 0.4	12.7 ± 0.5	0.57
Ethnicity, n (%)				0.001
Caucasian	61 (5.7)	876 (82.0)	131 (12.2)
East Asian	15 (6.5)	211 (91.3)	5 (2.2)
South Asian	7 (9.1)	62 (80.5)	8 (10.4)
Middle Eastern	5 (7.0)	61 (85.9)	5 (7.0)
Others	6 (3.3)	156 (84.8)	22 (12.0)
Height, cm	155.3 ± 9.3	155.9 ± 7.8	158.4 ± 7.6	0.0001
Weight, kg	46.9 ± 10.7	49.5 ± 12.2	54.8 ± 16.3	<0.0001
BMI, kg/m2	19.3 ± 3.2	20.2 ± 4.0	21.6 ± 5.2	<0.0001
AL, mm	23.3 ± 0.8	23.4 ± 0.8	23.6 ± 0.7	0.001
Refractive error, D	0.56 ± 1.03	0.48 ± 1.24	0.65 ± 0.91	0.46
Visual acuity†	56.2 ± 6.2	56.4 ± 5.7	57.7 ± 3.6	0.13

 Data are expressed as the percentage, the number with the percentage, or the mean ± SD. BMI, body mass index.

*  Test for heterogeneity.

†  Letters correct (logMAR): 55 letters is 20/20 Snellen equivalent.

Table 2.

 

Birth Weight by Duration of Gestation

Gestational Duration (wk)	Mean ± SD	Range
≤32	1780 ± 461	1200–2650
33–36	2749 ± 597	1500–4880
≥37	3420 ± 500	1900–6500

 Body weight is expressed in mean grams ± SD.

Table 3 presents the means of retinal parameters in children stratified by birth weight. Children with low birth weight (<2500 g) had significantly thinner average, inferior, nasal, and superior RNFL compared with those of normal (2500–4000 g) birth weight. Foveal minimum and central macular thicknesses were significantly thicker in the low birth weight compared with the normal birth weight category. Children in the high birth weight category (>4000 g) had a significantly thicker average and nasal RNFL than did the children in the normal birth weight range. Inner macular thickness, outer macular thickness, and macular volume were also found to be significantly greater in the high birth weight than in the normal birth weight category. 

Table 3.

 

Retinal Parameters by Birth Weight Category and Comparison with Normal Birth Weight

	Birth Weight Category
	Low (<2500)	P *	Normal (2500–4000)	High (>4000)	P *
RNFL
n	91		1333	167
RNFL average, μm	98.2 (95.9–100.4)	<0.0001	103.5 (102.6–104.4)	105.9 (104.1–107.7)	0.006
RNFL inferior, μm	119.8 (115.8–123.7)	<0.0001	128.7 (127.1–130.3)	130.2 (127.0–133.3)	0.33
RNFL nasal, μm	73.0 (69.6–76.5)	0.0003	79.3 (77.8–80.8)	83.2 (80.4–86.0)	0.003
RNFL superior, μm	126.1 (122.4–129.8)	0.02	130.4 (128.9–131.9)	133.2 (130.2–136.2)	0.05
RNFL temporal, μm	73.8 (71.0–76.5)	0.19	75.6 (74.3–76.8)	76.8 (74.6–79.0)	0.21
Macula
n	92		1283	162
Foveal minimum, μm	164.3 (160.0–168.6)	0.004	158.5 (156.3–160.7)	155.8 (152.2–159.4)	0.09
Central macula, μm	197.8 (193.8–201.8)	0.02	193.7 (191.5–195.8)	192.7 (189.4–196.1)	0.51
Inner macula, μm	270.8 (267.7–274.0)	0.60	270.0 (268.4–271.7)	272.8 (270.1–275.5)	0.02
Outer macula, μm	236.5 (233.6–239.3)	0.2	238.4 (237.1–239.7)	241.1 (238.7–243.5)	0.01
Macular volume, mm3	6.89 (6.81–6.96)	0.39	6.92 (6.88–6.96)	6.99 (6.93–7.06)	0.01

 Data are the mean (confidence interval) adjusted for age, sex, height, AL, ethnicity, and cluster sampling.

*  In comparison to normal birth weight.

After adjusting for gestational duration, the difference in foveal minimum thickness between low birth weight and normal birth weight children was no longer significant (P = 0.49), while all other associations remained significant. 

Table 4 presents regression coefficients for birth weight, birth length, and head circumference with retinal parameters. Greater birth weight and birth length were significantly associated with greater average RNFL thickness, along with the inferior, nasal, and superior RNFL, after adjusting for age, sex, height, AL, and ethnicity. Larger head circumference was associated with only greater average, inferior, and nasal RNFL. For macular parameters, increased birth weight and birth length were found to be associated with reduced minimum foveal thickness. Larger birth weight was associated with a thicker inner and outer macula and with larger macular volume. 

Table 4.

 

Change in Retinal Characteristics Per Unit Increase in Birth Parameter

	Weight (kg)		Length (cm)		Head Circumference (cm)
	β	P	β	P	β	P
RNFL average, μm	2.97	<0.0001	0.28	0.0001	0.44	0.0003
RNFL inferior, μm	4.21	<0.0001	0.37	0.004	0.86	<0.0001
RNFL nasal, μm	4.39	<0.0001	0.35	0.001	0.39	0.03
RNFL superior, μm	2.37	0.001	0.30	0.01	0.33	0.08
RNFL temporal, μm	0.88	0.10	0.09	0.28	0.18	0.21
Foveal minimum, μm	−2.16	0.008	−0.29	0.03	−0.24	0.27
Central macula, μm	−0.98	0.19	−0.16	0.18	−0.18	0.38
Inner macula, μm	1.19	0.05	0.006	0.95	−0.098	0.55
Outer macula, μm	1.73	0.002	0.055	0.54	0.062	0.68
Macular volume, mm3	0.043	0.005	0.001	0.66	0.0006	0.88

 Data adjusted for age, sex, height, AL, ethnicity and cluster sampling. β, the regression coefficient from the mixed model.

Figure 3 demonstrates the RNFL average thickness, foveal minimal thickness and macular volume by birth weight quintiles. These data are not adjusted for covariates of age, sex, height, AL, and ethnicity. Children with larger birth weight tended to have greater average RNFL and macular volume than children in lower birth weight quintiles (P _trend < 0.0001 and 0.005, respectively). There was no trend observed between birth weight and minimum foveal thickness (P _trend = 0.72) in this unadjusted analysis. 

Figure 3.

 

Relationship of birth weight to (A) average RNFL thickness, (B) minimum foveal thickness, and (C) total macular volume. Error bars, 95% confidence interval. Birth weight quintile 1, 1058–2935 g; 2, 2940–3220 g; 3, 3225–3510 g; 4, 3515–3798 g; and 5, 3800–6500 g.

Table 5 presents the means of retinal parameters stratified by gestational duration. Children born before 32 weeks and those born between 33 and 36 weeks had significantly greater minimum foveal and central macular thicknesses compared with those born at 37 weeks or later, with the greater difference in the children born before 32 weeks. The temporal RNFL was found to be significantly thinner in the modestly premature group (32–36 weeks) compared with children born after 37 weeks. After adjustment for birth weight the foveal minimum and central macular thicknesses were still significantly greater in children born before 32 weeks than in those born after 37 weeks (P < 0.0001 and P = 0.0015, respectively). The findings for modest prematurity (33–36 weeks), however, were no longer significant after adjustment for birth weight. 

Table 5.

 

Retinal Parameters Stratified by Gestational Duration and Compared to Term Birth

	Gestational Duration (wk)
	≤32	P *	33–36	P *	≥37 (Term)
RNFL
n	19		130		1607
RNFL average, μm	98.9 (94.1–103.7)	0.37	102.5 (100.6–104.4)	0.37	103.4 (102.5–104.2)
RNFL inferior, μm	121.6 (113.3–129.9)	0.12	127.0 (123.6–130.3)	0.45	128.2 (126.8–129.6)
RNFL nasal, μm	73.1 (65.9–80.3)	0.07	80.8 (77.9–83.8)	0.44	79.7 (78.4–81.0)
RNFL superior, μm	126.5 (118.6–134.3)	0.37	129.5 (126.3–132.7)	0.74	130.0 (128.6–131.4)
RNFL temporal, μm	74.7 (69.1–80.2)	0.76	72.7 (70.4–75.0)	0.01	75.5 (74.4–76.6)
Macula
n	19		126		1553
Foveal minimum, μm	179.1 (170.4–187.8)	<0.0001	163.2 (159.3–167.0)	0.003	158.0 (155.8–160.2)
Central macula, μm	207.9 (199.9–215.9)	0.0003	197.0 (193.4–200.6)	0.02	193.3 (191.2–195.4)
Inner macula, μm	269.6 (263.1–276.0)	0.84	270.8 (268.0–273.6)	0.65	270.2 (268.7–271.7)
Outer macula, μm	235.5 (229.6–241.3)	0.30	238.6 (236.1–241.1)	1.00	238.6 (237.4–239.8)
Macular volume, mm3	6.86 (6.70–7.03)	0.47	6.93 (6.86–7.00)	0.83	6.92 (6.89–6.96)

 Data are expressed as the mean (confidence interval), adjusted for age, sex, height, AL, ethnicity, and cluster sampling.

*  Comparison to ≥37-weeks' gestation group.

Discussion

In this population-based study of predominantly 12-year-old children free of confounding ocular conditions, we found that prematurity was associated with thicker foveal and central macular parameters. Decreasing birth weight was associated with thinner average RNFL, outer macular thickness, decreased total macular volume, and a greater foveal thickness. Decreasing birth length was associated with thinner average RNFL thickness and greater foveal thickness, but not with other macular parameters. 

Macular Thickness

In our study the significance of a thicker fovea and central macula in low-birth-weight children became nonsignificant after adjustment for gestational duration. On the other hand, the association of prematurity (<32 weeks) and a thicker fovea and central macula persisted after adjustment for birth weight, suggesting that gestational duration is a stronger factor in this association. 

Ecsedy et al., ¹⁴ in a study of 10 children (age range, 7–10 years) born between 26 and 34 weeks' gestation, reported a thicker fovea, as measured by OCT, in the premature group compared with the full-term children, findings consistent with those in our study. Similarly, in our previous study of a 6-year-old cohort (SMS) we reported a thickening of the central macula in children born prematurely, but no association with birth weight was observed. ¹⁶ In ROP studies, foveal thickening has also been reported. Hammer et al., ¹³ in an OCT study of 5 subjects (age range, 14–26 years) born between 26 and 28 weeks' gestation with a history of mild ROP, reported a shallower foveal pit with thickened inner retinal layers compared with the controls. 

The central retina undergoes maturation later than the peripheral retina and is therefore more susceptible to the effects of the postnatal environment imposed on the infant after premature birth. ^6,24 In normal foveal development, cone cell nuclei and bipolar cells migrate away from the cone cell outer segments, which remain closely arranged at the fovea. This cell migration contributes to the formation of a normal foveal depression. ²⁵ Our finding of a thicker fovea in premature children may suggest that prematurity and its associated complications may impair cell migration and ultimately lead to abnormal retinal structure. The lack of formation of a normal foveal avascular zone may be another reason for the altered foveal pit formation. In premature or low-birth-weight children the fovea is traversed by capillaries that may alter the normal elasticity of this area and impair normal foveal pit formation during eye growth, ^13,25 and earlier studies have reported that gestational age and birth weight correlate with the size of the avascular zone of the fovea. ²⁶  

RNFL Thickness

The finding that larger birth weight is associated with increased RNFL thickness was also reported in our study of 6-year-old children. ¹⁶ To our knowledge, there are no other studies that have examined this association. Studies on optic disc morphology in low-birth-weight and premature individuals have shown a spectrum of findings including increased optic disc cupping ²⁷ and either increased ²⁸ or decreased optic disc area. ²⁹ We have reported a strong association between greater birth weight and reduced optic cup/disc ratio in this same population. ³⁰ At that time, we speculated that larger birth weight would probably be associated with a greater reserve of ganglion cells—a speculation that is supported by the finding of increased average RNFL thicknesses in the higher birth weight children in the present study. 

During the course of normal optic nerve development, approximately 2.85 million nerve fibers develop. In the third trimester, 1.85 million supernumerary fibers are eliminated. ¹⁷ This process of elimination is therefore susceptible to events occurring in the third trimester. One interesting finding from our study was the lack of RNFL thinning in our sample of premature children, even though these children had a reduced birth weight. In addition, the relationship of low birth weight and RNFL thinning was unaffected by adjustment for duration of gestation. Taken together, these results suggest that premature infants are less likely to have reduced RNFL thickness, regardless of their low birth weight, perhaps because of the early visual stimulation in these premature children, which prevents normal third trimester axon elimination. A study of cultured rat cells showed that retinal ganglion cells that receive electrical stimulation produce neurotrophic factors that may then stimulate growth of nearby neurons. ³¹ It has also been suggested that early visual stimulation in premature infants and the resulting growth-promoting electrical signals may interfere with the normal degeneration of retinal ganglion cell axons. ²⁸ This effect would then lead to a thicker RNFL in these premature children than expected for their birth weight. It should be noted that our sample only includes low numbers of premature children, with only 20 children born before 32 weeks and 135 born between 32 and 36 weeks. Studies are needed in larger cohorts of premature children, to determine whether there is any association between prematurity and RNFL thickness. 

Another factor to consider when examining the relationship of retinal parameters and birth weight is the reported association of birth weight with retinal vascular caliber. Children with low birth weight have been shown to have narrower arterioles ³² and arteriolar caliber is positively correlated with RNFL thickness and macular (inner/outer) thickness. ^{33 –35} Our current findings, therefore, are consistent with these previously reported relationships. It has been postulated that the development of wider vascular caliber reflects an increased vascular requirement in persons with a thicker RNFL and macula. ^34,35 A further consideration, and possibly a confounding factor around this issue, is the effect of a thicker vasculature causing an artifact of increased OCT measurement of retinal parameters. ³⁶ Further investigation including histologic studies would be necessary to determine the interrelationships between retinal structures, retinal vessel caliber, and birth weight. 

Study Limitations

The strengths of this study include its large population-based sample with high response rate (75.3%), an objective technique of measuring retinal structures, the use of a healthy adolescent sample with little confounding ocular or systemic disease and the use of documented data on birth parameters. A limitation is the relatively low number of children in the low-birth-weight and premature birth groups; however, most associations spanned the continuum of birth weight. Another limitation is the use of Stratus OCT, which does not allow adequate resolution to determine changes in specific retinal layers. 

In summary, we found that birth parameters have significant associations with both the macular and RNFL thickness of adolescents. Prematurity is associated with thickening of the fovea similar to that reported in ROP. Lower birth weight is associated with a decreased average RNFL, inner and outer macula thickness, and macular volume, but with increased foveal thickness. Further studies should observe preterm and low-birth-weight children into adulthood to determine whether these changes adversely affect the development of age-related retinal diseases. 

Footnotes

 Supported by Grant 253732 from the Australian National Health and Medical Research Council, Canberra, Australia.

Footnotes

 Disclosure: Y.M. Tariq, None; A. Pai, None; H. Li, None; S. Afsari, None; G.A. Gole, None; G. Burlutsky, None; P. Mitchell, None