INTRAOCULAR PRESSURE OF PREMATURE NEWBORNS – A SYSTEMATIC REVIEW WITH META-ANALYSIS

Authors: Kalina Trifonova, Kiril Slaveykov, Hristo Mumdzhiev

Abstract

The intraocular pressure (IOP) ranges of premature newborns are not the same as those in full-term newborns and adult population. The exact ranges and causes, however, differ depending on the measurement techniques used and analysis. Our study aimed to summarize and analyze available information in the up-to-date literature concerning IOP values in premature newborns. We performed a systematic literature review with meta-analysis. Our research showed the mean IOP in premature newborns to range from 10 to 29 mmHg according to different authors, and its mean values were higher in premature compared to full-term newborns. The most commonly analyzed factor that probably affected IOP measurement was central corneal thickness. Longitudinal studies showed that IOP and central corneal thickness declined with maturation of the newborn and both factors were probably correlated. Additional studies with larger sample sizes and better differentiated sample groups need to be performed.

Introduction

Premature infants have serious health issues from the day they are born. It is important to know their anatomical and physiological differences from full-term newborns so that we do not misdiagnose, overtreat or underestimate an existing problem. The visual system can suffer serious consequences from prematurity, as most widely discussed matter in the literature is the threat of developing retinopathy of prematurity. However, other problems often occur such as strabismus (1), refractive errors, particularly myopia (2), and cerebral vision impairment (3). Thiagarajah et al. found in a retrospective study that included 247 premature patients that 2% had congenital glaucoma, which is significantly higher than the general population (4). The authors think that the premature birth led to termination of the development of the trabecular meshwork or angle. Other authors (5, 6) did not find a connection between primary congenital glaucoma and prematurity. However, those two conditions can coexist (5), and both are potentially blinding and need to be diagnosed and treated on time. Nakakura et al. presented a clinical case in 2021 that posed a difficulty in differentiating primary congenital glaucoma and large disks cupping which can be common in premature infants (7). Ricci speculated that even the slightly increased intraocular pressure (IOP) in premature newborns could facilitate the development of retinopathy of prematurity because it can lead to significant reduction in the ocular perfusion pressure (8). Everything mentioned so far makes it even more important to know the normal IOP ranges in premature infants. Our study aimed to summarize and analyze the available information in the up-to-date literature.

Material and Methods

We performed a systematic literature review using the key words “intraocular pressure”, “preterm”, “premature”, “infants”, “newborns”, “neonates” in Pubmed, Google Scholar, and free search. It included 20 articles with information on IOP measurement in premature newborns, 10 of which were cross-sectional, 4 of them case-control studies comparing IOP between prematurely born and full-term infants, and 6 longitudinal studies. A meta-analysis of the four case-control studies was performed using Review Manager 5.4.

Results

Many teams have tried to estimate the mean IOP in premature newborns throughout the years. However, there have been great variations among the results of different studies. The first group of studies that we included in our review were cross-sectional studies (9-18) (Table 1), in which the authors had measured IOP in premature newborns at a certain point after birth (usually trying to do the measurement within the first week after birth and/or when the newborn is sufficiently stable) without following its changes with the growth of the infant. Their results showed serious variance, from 10 mmHg to 29 mmHg. All those studies were insufficient in count (from 21 to 70 patients) and were performed on premature newborns with different gestational age and birth weight. Even though some of the studies were done with the same type of devices (3, 6, 7, 9) (Tono-pen, Reichart technologies, United States), their results still showed significant variation (from 10.3 mmHg to 24 mmHg). When using Tono-pen, local anesthesia and lid speculum were also used and the authors claimed that the infants were calm during the measurement. The oldest study that we found in the literature was published by Blockhurst (9) et al. in 1955. The measurements were performed with McLean tonometer (E. B. Meyrowitz, United States) and showed a medium value of 24.5 mmHg. Musarella and Morin (10) measured IOP with Perkins applanation tonometer (Haag-Streit UK, United Kingdom**)** and showed a value of 18 mmHg. Tucker et al. (11) and Spierer et al. (12) showed IOP of 10 mmHg and did not find correlation with gestational age and birth weight of the infants. The other two recent studies (17, 18) showed much higher IOP values, i.e., 24 mmHg and 29±9 mmHg, respectively, which correlated with gestational age and birth weight of the newborns. The more so, Khaja et al. (17) found a weak but positive correlation with the central corneal thickness (CCT) but Grover et al. (18) did not. McKibben et al. (13) were the first to measure IOP with an ocular blood flow tonograph. In their study, the newborns were sedated and eye speculum was not used. The mean IOP that they found was 15.4 mmHg. Haus et al. (14) were the first to compare the mean IOP measured with ICare (Icare Finland Oy) rebound tonometer and Tono-pen XL tonometer in premature newborns. They found a significant difference between the results achieved with those two devices, i.e., 9 mmHg for ICare rebound tonometer (SD 2.2 mmHg) and 16 mmHg for Tono-pen(SD 4.4 mmHg). IOP values were significantly lower when evaluated by ICare rebound tonometer than by Tono-pen. According to these authors, ICare rebound tonometer reflected IOP better. They thought that Tono-pen measurements were probably falsely elevated due to defense and discomfort reactions to the anesthetic eye drops and bigger size of eyelid opening.

Another group of studies that we analyzed were four case-control cross-sectional studies (19-22) (Table 2) performed in a prospective manner, which compared CCT and IOP values between premature and full-term newborns. All infants were examined only once during the study period, not multiple times on different dates. All the studies from this group showed that IOP and CCT were higher in premature newborns compared to full-term newborns. Only the results of Muslubas et al. (20) showed no difference between IOP in premature and full-term infants, probably because of the higher gestational age (36.3±0.9 gestational age) of the premature infants included in the study. All studies showed that CCT was higher in premature infants compared to full-term newborns. Uva et al. (19) and Acar et al. (22) showed that there was a correlation between CCT and IOP, which both declined with maturation of the infant. However, Muslubas et al. (20) and Karahan et al. (21) found no such correlation. All the mentioned studies had several limitations, i.e., small sample size; different characteristics of examined infants (postconceptual age, birth weight, age after birth, etc.); and cross-sectional design.

To analyze and combine data from the four case-control studies, we performed a meta-analysis using Rev Man 5.4. We used two variables, IOP and CCT, and compared the mean difference between their mean values in premature and full-term newborn babies. We used a random effect model due to the small size of the studies included. The mean difference in IOP (Fig. 1) between premature and full-term newborns was 1.83 mmHg (CI 0.91-2.74), which was slightly but significantly higher in preterm newborns. The mean difference of CCT according to our meta-analysis (Fig. 2) was 17.57 μm (CI 7.93-27.22), significantly higher in premature newborns. The test for the overall effect showed statistical significance for the two forest plots. To avoid heterogeneity, we excluded the study by Muslubas et al. (20) in the first forest plot (Fig. 1) and the study by Acar et al. (22) in the second forest plot (Fig. 2).

We also included six longitudinal studies (8, 23-27) in our systematic review (Table 3) following the measurement of IOP in premature newborns. In each of them, the measurements were performed in the same infant on different dates at different time intervals. This type of studies gave the most accurate information considering IOP changes after birth. All authors used Tono-pen for measuring IOP, except for Ricci (8) who used ProTon (Tomey, Japan). Balci et al. (27) and Acar et al. (26) included a very homogeneous group of newborns, 26 weeks and 28 weeks of gestational age at birth, respectively. All studies (8, 23-27) showed a statistically significant (p<0.01) decline of IOP values with negative correlation to the post conceptual age and birth weight of infants. All these studies (8, 23-27) used local anesthesia and all of them except for Balci et al. (27) used eyelid speculum. Balci et al. (27) gently separated the eyelids manually without applying pressure to the globe. The results reported by Ng et al. (23) show that IOP was also negatively associated with the mean blood pressure, Apgar score at 1 minute, and use of inhaled corticosteroids, but correlated positively with high-frequency oscillatory ventilation. They also failed to show correlation between IOP and stage of retinopathy of prematurity (23). Sekeroglu et al. (25) examined not only IOP but also CCT in premature newborns. This was the first longitudinal study to follow both values in different post conceptual ages in the same infant. The CCT and IOP were positively correlated with each other, and both were negatively correlated with gestational age, chronological age, and birth weight during first and second visits. Acar et al. (26) have also reported similar results later.

Discussion

Measuring IOP is a primary diagnostic method in assessing pediatric glaucoma patients and following the effects of their treatment. However, in pediatric patients measuring IOP with Goldman tonometry, which is the gold standard, is not possible, so other methods have been introduced. Studies (28, 29) have shown that Tono-Pen and ICare are suitable devices in measuring IOP in newborns because they are better in measuring IOP in edematous corneas. Gandhi et al. (30) showed slightly higher measurement of IOP with Tono-Pen than with Goldman applanation tonometer. However, Iester et al. (31) did not find significant difference between the two devices and showed enough precision for accurate screening. ICare rebound tonometer does not require topical anesthetic and is well tolerated by children. However, in the study performed by McKee et al. (32), ICare showed results by 2 mmHg lower than with Tono-pen and this difference was greater in corneas with edema. The study by Haus et al. (14) also showed significantly lower measurement of IOP in premature newborns with ICare compared to Tono-pen. Since CCT (Table 2) is significantly thicker in premature compared to full-term newborns, Tono-pen might still be a better device to measure IOP in this age group. Shiotz tonometry is rarely used in modern ophthalmic practice because it is less accurate in children due to decreased scleral rigidity. It is no longer considered acceptable method for measuring IOP in children except if no other devices are available (33).

Artificial IOP increase may develop due to increased venous pressure caused by Valsalva maneuver produced by resisting examination, forced closure of the eyelids, or use of eyelid speculum. Epley et al. (34) showed that using eyelid speculum in measuring IOP in children elevated it by an average of 4 mmHg. They performed the measurement under general anesthesia in order to exclude other factors such as vigorous resistance and forced eyelid closure. In 2022, Çiçek et al. (35) also showed average IOP rise by 2.6 mmHg caused by the use of eyelid speculum. They used ICare rebound tonometer under topical anesthesia. That is why the effects of using eyelid speculum need to be considered when measuring IOP in children. The use of general anesthesia, however, also has effects on IOP, mostly by decreasing it. According to Mikhail et al. (33), midazolam needs to be used for sedation if necessary because most of the studies do not show effect on IOP. If intubation is performed, then 3-5 minutes need to pass before measuring IOP.

The meta-analysis that we performed showed a 1.27 mmHg IOP difference between premature and full-term infants, and all the longitudinal studies also showed negative correlation of IOP measurement with postconceptual age of the infant. There are different theories trying to explain this phenomenon. According to Ricci (8) as one of the first authors to analyze this problem, it might be a result of the maturation of the aqueous drainage system induced by transition from the intrauterine to extrauterine environment. Karahan et al. (21) discussed whether this phenomenon represented a programmed maturation process related to an increase in dimensions of ocular structures under the influence of complex neuroendocrine control. Most recent studies have shown that the decrease in IOP with growth of the newborn is possibly due to a decrease in CCT. The gradual decrease in CCT after birth is due to better control of corneal hydration (36, 37), corneal remodeling, and stretching of collagen fibers (3).

Other factors also need to be considered when measuring IOP in a newborn, such as mode of delivery, especially when measured in the first 24 hours after birth. Some authors (38, 39) found a significant decrease in IOP in the first 12-24 hours after birth. They also found higher IOP in vaginally delivered newborns than those born with cesarean section. This difference might be caused by blood hormonal changes and physical stress (40).

Conclusion

The exact reference ranges of IOP in premature newborns have not been established so far. Our meta-analysis showed that IOP was significantly higher in premature infants compared to full-term newborns with a mean difference of 1.27 mmHg. All longitudinal studies showed significant negative correlation between the postconceptual age of infants and IOP. According to most authors, the method of choice for measuring IOP has been Tono-pen but the use of eyelid speculum needs to be avoided to prevent artificial increase. The exact causes of IOP decrease are not completely clear up to this point. Most probably, it is related to gradual CCT decrease with maturation of the newborn. Additional studies performed in a longitudinal pattern of larger sample sizes and better differentiated sample groups need to be performed and to follow changes in both IOP and CCT. Other factors such as mode of delivery, Apgar score, blood pressure, and medications need to be included in further analysis as well.