Postoperative Complications and Axial Length Growth after Bilateral Congenital Cataract Surgery: Eyes with Microphthalmos Compared to a Comparison Group

Purpose: To investigate the postoperative clinical outcomes and axial length (AL) growth of infants with congenital cataracts and microphthalmos following rst-stage cataract surgery. Design: Retrospective case control study Methods: Setting: Single center. Infants with congenital cataract that met the inclusion criteria were classi�ed into two groups: the microphthalmos and comparison groups. All infants underwent a thorough ophthalmologic examination before surgery, and one week, 1 month, 3 months, and every 3 months after surgery. Results: This study enrolled 21 infants (42 eyes) in the microphthalmos group and 29 infants (58 eyes) in the comparison group. More glaucoma-related adverse events were observed in the microphthalmos group (7 eyes, 16.7%) than in the comparison group (0 eyes, 0%) (p<0.001). At each subsequent follow-up, the comparison group had a greater AL than the microphthalmos group (all p<0.001), and AL growth was signi�cantly higher in the comparison group than in the microphthalmos group (all p=0.035). Visual acuity improved in both groups. Conclusion: Early surgical intervention improves visual function in infants with congenital cataracts and microphthalmos although with a higher incidence of glaucoma-related adverse events. After cataract removal, the AL growth of microphthalmic eyes is slower than that of normally developed eyes.


Introduction
3][4][5] Microphthalmos has been described as eyes with an axial length (AL) 2 standard deviations below the age-adjusted mean, 6 typically resulting in an AL below 20.5 mm in adult eyes. 7,8 infants with congenital cataracts, early cataract surgery is essential to prevent amblyopia and improve visual functions.Although pediatric cataract surgery techniques and postoperative management have consistently improved in recent years, postoperative complications remain important factors that may obstruct visual rehabilitation.Multiple studies have reported the incidence of postoperative complications after congenital cataract surgery.In postoperative glaucoma, Zhang et al. 9 reported that the incidence of glaucoma-related adverse events was 8.10% during a 4-year follow-up.Wang et al. 10 observed that the cumulative incidence of suspected and de nitive glaucoma was 9.97% during a 5-year follow-up.
For pediatric ophthalmologists, surgeries on infants with microphthalmos can be more challenging because of the crowded anterior segment and the high risk of intraoperative and postoperative complications.In a 37-year longitudinal follow-up, Belitsky et al. 11 reported that the total glaucoma prevalence was 14.8%, including late-(10.7%)and early-onset (4.1%) glaucoma, and that most patients with late-onset glaucoma had microphthalmos.Although various postoperative complications (glaucoma-related adverse events, visual axis obscuration, and posterior synechiae) have been reported in previous studies which investigated clinical outcomes after congenital cataract surgery, a minority of them focused on microphthalmic eyes.On the other hand, different de nitions of microphthalmos and complications might have affected the results, and most of them did not include a comparison group.AL development is an important factor affecting prognosis, close to selection of an appropriate timing and target refraction of second-stage intraocular lens (IOL) implantation.However, AL growth after rst-stage cataract surgery (cataract removal) has been disputed in previous studies due to different study populations and follow-up periods.In rare cases of microphthalmos, AL growth has not been well studied, and the comparison between children with and without microphthalmos in the same age group requires further study.Therefore, we investigated the postoperative clinical outcomes and AL growth of infants with congenital cataracts and microphthalmos following rst-stage cataract surgery and compared these results with those of contemporary infants without microphthalmos to evaluate postoperative complications and bene ts from surgery.Analysis of the postoperative AL growth in the two groups helped us understand the developmental trends of microphthalmic eyes.

Patients selection
This retrospective study enrolled infants with bilateral congenital cataracts who underwent lensectomy combined with limited anterior vitrectomy without primary IOL implantation at the Eye Hospital of Wenzhou Medical University (Hangzhou Branch) between January 2016 and October 2020.This retrospective study was approved by the Institutional Review Board/Ethics Committee of Wenzhou Medical University (Optometry Hospital of Wenzhou Medical University, 2021-051-K-43).This study was conducted in accordance with the tenets of the Declaration of Helsinki.Legal guardians of pediatric patients signed informed consent before their being included in the study.
The inclusion criteria were as follows: (1) bilateral congenital cataract, (2) all surgical procedures performed by the same ophthalmologist (Yun-e Zhao), (3) age at surgery ≤ 12 months, and (4) followed up for ≥ 12 months.The exclusion criteria were as follows: (1) eyes concurrent with glaucoma, uveitis, retinopathy of prematurity, traumatic cataract, aniridia, steroid-induced cataract, posterior persistent fetal vasculature causing stretching of the ciliary process, or tractional retinal detachment before surgery; (2) patients with systemic disorders such as Down's syndrome, which is independently associated with glaucoma 12 and probably causes growth retardation, and Marfan syndrome; and (3) history of previous ocular surgery.
All patients were classi ed into two groups: the microphthalmos and comparison groups.Microphthalmos was de ned as a total AL at least two standard deviations below the mean age, 6, 13 equating to 19.2 mm at 1 year and 20.9 mm at adulthood. 14The microphthalmos group was further classi ed into the microcornea group (horizontal corneal diameter < 9.0 mm) and the relative normal-size cornea group (horizontal corneal diameter ≥ 9.0 mm).

Surgical technique
All surgeries were performed by the same experienced congenital cataract surgeon (Yun-e Zhao) under general anesthesia using the Accurus or Centurion system (Alcon Laboratories, Inc., Fort Worth, TX, USA) with a cut-rate of 2,000 per minute and vacuum of 350 mmHg.Two 0.8-mm precise corneal incisions were created at 10 and 2 o'clock using a MANI ophthalmic knife (MANI, Inc., Tochigi, Japan); lens aspiration was performed after anterior vitrectorhexis with a diameter of about 4.5-5.0mm, followed by posterior vitrectorhexis about 3-3.5 mm and limited anterior vitrectomy with a 23-gauge vitrector and 23-guage irrigating cannula via two cornea incisions.The incisions were closed using 10-0 absorbable Vicryl sutures (Ethicon, Somerville, NJ, USA).Peripheral iridectomy was performed prophylactically in several cases to decrease the possibility of a pupillary block and in ammatory peripheral anterior synechiae.Without primary IOL implantation, all patients remained aphakic after surgery.The interval between the binocular surgeries was within 7 days.
Postoperative topical treatment included levo oxacin (0.5%) eye drops four times a day for two weeks, tobramycin dexamethasone eye ointment once a day for two weeks and tobramycin dexamethasone eye drops four times a day, which were tapered for four to six weeks postoperatively.Atropine (1.0%) was administered once a day for 1 week and later changed to tropicamide phenylephrine eye drops (Mydrin®-P) once a day for one month.Optical correction using aphakic spectacles was prescribed for all patients.

Primary outcome measures
All pediatric patients underwent a thorough ophthalmologic examination before surgery, and one week, 1 month, 3 months, and every 3 months after surgery.The examination included slit-lamp bio-microscopy, dilated fundus examination, A-scan ultrasound examination (Axis Nano, Quantel Medical, Cournon, France), and estimation of IOP (iCare, Vantaa, Finland).

Ocular biological parameters and demographic features
AL, anterior chamber depth (ACD), and lens thickness (LT) were measured using an contact ultrasonic A-scan (Axis Nano, Quantel Medical, Cournon, France) under sedation.The horizontal corneal diameter (HCD) was measured at the beginning of surgery using calipers.IOP was evaluated using an iCare (Vantaa, Finland) rebound tonometer under anesthesia, if not cooperatively.Furthermore, AL, ACD, and LT were measured 10 times, and IOP was measured 6 times for each eye; the mean values were recorded.All the measurements were performed by the same technician.
All surgical videos were reviewed by three experienced congenital cataract doctors (Y.E.Z., Y.Y.Z., D.D.W.) to identi ed preexisting posterior capsule defects (PPCD), which included 3 types of PPCD.Type I showed large defect with sinking cortex in anterior vitreous, type II cluster of brotic spots in posterior capsule, and type III with concurrent persistent fetal vasculature (PFV). 15

Visual function assessment
Before surgery, due to the young age (< 12 months) and poor cooperation, an objective visual assessment was not possible.In the subjective evaluation, we classi ed infants' visual function into inability, instability, and stability of xation, depending on their ability to xate on or follow a light source or toys of different colors, and the results were recorded.
After surgery, patients with poor cooperation were assessed in the same manner as described above, and the two results were compared.The Teller acuity card (Stereo Optical Co., Inc., USA) procedure was performed on cooperative patients by the same technician.Visual acuity was recorded at the patient's last follow-up.

Postoperative complications
The main postoperative complications were glaucoma-related adverse events, posterior synechiae, and visual axis opaci cation (VAO).
According to the IATS 16 and the Childhood Glaucoma Research Network (CGRN) 17 , glaucoma-related adverse events were de ned as glaucoma plus glaucoma suspect.A study eye was diagnosed as having glaucoma if the IOP was > 21 mmHg with one or more of the following anatomical changes: (1) corneal enlargement; (2) asymmetrical progressive myopic shift coupled with enlargement of the corneal diameter and/or AL; (3) increased optic nerve cupping de ned as an increase of ≥ 0.2 in the cup-to-disc ratio; or (4) a surgical procedure was performed for IOP control.A study eye was diagnosed as a glaucoma suspect if there were either (1) recordings of two consecutive IOP measurements > 21 mmHg on different dates after topical corticosteroids had been discontinued without any of the anatomical changes listed above for glaucoma, or (2) glaucoma medication was used to control IOP without any of the anatomical changes listed above.
The existence of posterior synechiae was evaluated using slit-lamp microscopy and de ned as adhesion of the posterior iris plane and the margin of the anterior vitrectorhexis or pupil deformation.The VAO examination consisted of retroillumination with slit-lamp microscopy.Any obscuration of the visual axis area requiring an Nd:YAG laser 18 or surgical intervention was recorded as VAO.

Statistical analysis
All statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).Descriptive statistics were used to analyze individual-and eyelevel characteristics.The normality of data distribution was analyzed using the Kolmogorov-Smirnov test, and abnormalities in data distribution were analyzed using non-parametric statistical analyses.Values are expressed as the mean ± standard deviation (SD), range, or median (interquartile range [IQR]).The Mann-Whitney U-test, Chi-Square Test, or UNIANOVA was employed to compare the parameters among the different groups.The Chi-square test, Fisher's exact test or generalized estimating equation (GEE) was used to compare the differences in complication incidence between the different groups.
The UNIANOVA or GEE was used to adjust binocular correlation in uence.A GEE was used to adjust for the difference in AL and AL increments between the different groups in each postoperative period.Logistic regression analysis was used to analyze potential risk factors for postoperative complications, generating odds ratios (ORs) and associated 95% con dence intervals (CIs).Statistical signi cance was set at p < 0.05.
In Table 4, the results of the logistic regression analysis were used to evaluate the potential risk factors for postoperative glaucoma-related adverse events in the microphthalmos group.In the univariate analysis, no factor exhibited signi cant association with glaucoma-related adverse events in the microphthalmos group (all p > 0.05), although LT provided an approximate p-value (p = 0.067).

The axial length growth
Excluding cases that developed glaucoma-related adverse events, AL and AL growth were compared between the microphthalmos and comparison groups at 3, 6, 12, 18, and 24 months postoperatively.At each subsequent follow-up, the comparison group had a greater AL than the microphthalmos group (all p < 0.001), and AL growth was signi cantly higher in the comparison group than in the microphthalmos group (all p = 0.035) (Table 5).

The visual function
Visual acuity improved in both groups compared to the preoperative conditions (Table 6).At the last follow-up, 27 of 42 eyes (64.3%) in the microphthalmos group gained visual acuity ≥ 0.5, whereas the comparison group showed a higher proportion, 40 of 58 eyes (69.0%).

Microcornea eyes in the microphthalmos group
The microphthalmic eyes were divided into two subgroups according to the diameter of the cornea: the microcornea group (< 9 mm) and the normal cornea group (≥ 9 mm).Three infants (6 eyes) whose pairs were divided into different groups were excluded.As shown in 5.91 ± 0.95 mm; p = 0.004) than the normal cornea group (Tables 7a and b).As for postoperative complications, two groups showed no signi cant difference in total incidence of the three complications (9 eyes, 50.0% vs. 5 eyes, 27.8%; p = 0.746).When each postoperative complication was analyzed separately, no signi cant differences were observed between the two groups (all p > 0.05) (Table 8).

Discussion
The present study investigated the postoperative complications and axial length growth after bilateral congenital cataract surgery on microphthalmic eyes, and compared these with normally developed ones.The results showed that compared with infants without microphthalmos, infants with contemporary microphthalmos had a higher incidence of glaucoma-related adverse events and a slower AL growth rate, although 12 eyes in the microphthalmos group had grown to normal AL.However, both groups showed considerable improvements in visual acuity.
Glaucoma-related adverse events are vision-threatening complications in patients with congenital cataracts during the postoperative period due to optic nerve damage if not handled promptly and properly.In previous studies, the incidence of glaucoma after pediatric cataract surgery has been reported to vary from 3-41%. 19,20  few studies have reported the incidence of glaucoma in children with congenital cataracts and microphthalmos (Table 9).Vasavada et al. 21observed that the prevalence of aphakic glaucoma after cataract surgery was 30.9% (13 of 42 eyes), while Prasad et al. 22 reported a prevalence of 13.5% (5 of 37 eyes).In our study, the incidence of glaucoma-related adverse events was 16.7% in 42 microphthalmic eyes of 21 infants.This discrepancy might re ect differences in the follow-up duration, de nition employed, surgeons, and study populations among studies.Postoperative glaucoma was classi ed into two types based on its bimodal onset 20,23 : early-onset closure-angle type and late-onset open-angle type.In a study by Kim et al., 24 all patients with glaucoma had late-onset open-angle glaucoma.In our study, two of seven eyes developed postoperative early-onset closure-angle glaucoma, two eyes had late-onset open-angle glaucoma and the other three cases were diagnosed as glaucoma suspects based on the standard of diagnosis mentioned in the postoperative complications subheading of the methods section.The crowded anterior segment of microphthalmos, in ammatory reaction, along with iris stacking by using mydriatics might cause the early-onset closure-angle glaucoma.It is important to note that open-angle glaucoma was diagnosed in one of our patients (Pt 2, Table 2) who showed bilateral persistently high IOP with an open angle, four years after the operation, and was diagnosed as a glaucoma suspect before we found anatomical changes.This suggests that more late-onset open-angle glaucoma cases might be detected in our cohort in future follow-ups.Previous studies revealed potential risk factors for congenital cataract patients after cataract removal.In a 5-year follow-up study enrolled 686 eyes, Wang et al. 10 reported that microcornea, FHCC and initial anterior vitrectomy were risk factors for glaucoma.The Pediatric Eye Disease Investigator Group 25 reported a higher risk for glaucoma-related adverse events was associated with age at surgery less than 3 months, abnormal anterior segment, intraoperative complications at time of lensectomy, and bilaterality, among 443 aphakic eyes.Although different risk factors mentioned, the abnormality of eye structure has been quite obvious.The effect of microphthalmos on the risk of developing glaucoma in patients with congenital cataracts is well established. 16,26 or example, Belitsky et al. 11 reported that microphthalmos was a signi cant risk factor for developing glaucoma.Some studies have further investigated the risk factors for postoperative glaucoma in patients with congenital cataracts and microphthalmos and reported that surgery at an early age is a risk factor in both normal and microphthalmic eyes of infants. 16, 21-23, 27-29Kim et al. 24 reported that patients with shorter ALs have a higher risk of developing glaucoma.However, our results showed that earlier surgical age and shorter AL were not associated with a higher incidence of glaucoma, which is inconsistent with the ndings of previous studies.This could have been because (1) the age at surgery in our study was quite centralized; (2) a few patients had glaucoma; and (3) the follow-up period of this study was relatively limited, which is insu cient for some factors to show their in uence.Besides, our study found that smaller dilated pupil size during surgery was nor a risk factor, though some considered its probable association with glaucoma after congenital cataract surgery.We supposed that the abnormality of eye structure might be the leading reason for higher postoperative glaucoma incidence in microphthalmos, and in such a cohort it might be hard to nd other independent risk factors.Thus, we believe that an extended follow-up period would be valuable for evaluating the longterm incidence of glaucoma, particularly in microphthalmic eyes, and exploring the related risk factors.
In addition, in the study by Prasad et al., 22 all infants with microphthalmos underwent peripheral iridectomy during rst-stage cataract surgery, following a 13.5% incidence of glaucoma.4][35] In this study, peripheral iridectomy was performed in two microphthalmic eyes at the primary lens removal procedure, considering the HCD and anterior chamber conditions and risk evaluation; none of the two eyes developed glaucoma.After excluding cases that combined peripheral iridectomy with cataract surgery, the incidence of glaucoma-related adverse events was 17.5% in 40 microphthalmic eyes of 20 infants.Two eyes that did not undergo peripheral iridectomy at the rst stage developed angle-closure glaucoma and underwent peripheral iridectomy at the secondary IOL implantation.We believe that combining peripheral iridectomy with cataract surgery would prevent confounding risk factors affect the development of early-onset glaucoma.
A high incidence of in ammatory responses obstructs early visual rehabilitation after pediatric cataract surgery and may cause complex chain reactions.
Increased vascular permeability in pediatric patients can easily cause brinoid in ammation, 36 causing the iris to adhere to the lens capsule membrane, known as posterior synechiae.Severe in ammatory reactions can produce excessive brin exudation, forming brinous membranes. 36When the membrane fully covers the pupil area or the posterior synechiae block the fully circumferential pupil, secondary glaucoma associated with pupillary occlusion ensues.The brous membrane contributes to the formation of VAO.In addition, due to the drastic proliferation and migration of lens epithelial cells, clouding of the visual axis area forms in the middle and late postoperative stages. 18However, adequate anterior vitrectomy could reduce this possibility.
Posterior synechiae were the most frequently observed complication in our study, occurring in 21.4% of 42 microphthalmic eyes and 19.0% of normally developed eyes.In the study by Praveen et al., 37 the incidence of posterior synechiae was 27.8%, whereas Vasavada et al. 21reported a higher incidence of 35.7%.In the present study, one eye in the microphthalmos group developed glaucoma due to pupillary atresia caused by posterior synechiae.Our team routinely prescribed topical steroids and mydriatic immediately after surgery to prevent posterior synechiae and pupillary occlusion.However, in infants with microcorneas, excessive mydriasis might cause goniosynechia and even angle closing of the anterior chamber, which implies the need for a close follow-up and monitoring by the doctors.Moreover, infants with immature or incompletely mature dilator pupillary muscles cannot fully respond to medication, and some develop posterior synechiae due to stimulation by chronic in ammation.
0][41][42][43][44] In the present study, the incidence of VAO was 14.3% in the microphthalmos group, which was similar to that in previous studies on microphthalmos, ranging from 5.2-16.7%. 21,37,45,46 Th incidence of postoperative VAO may also vary according to differences in the individual development of pupil and surgical experience and technique among surgeons.
Early cataract surgery is essential for preventing amblyopia and improving visual function in infants with cataracts.The visual acuity results of the microphthalmos group in our study were satisfactory and similar to those of the comparison group.Previous studies reported similar results. 21,22,47 Dspite the increased risk of complications that threaten visual function after surgery, we believe that infants with congenital cataracts and microphthalmos will still bene t from early surgical intervention based on a timely and accurate postoperative optical correction.
In a previous study by our team, 48 we established an AL estimate formula for children aged ≤ 2 years with congenital cataracts who underwent cataract surgery; however, for infants with microphthalmos, the formula might be more complicated.This study found that AL growth was slower in the microphthalmos group than in the comparison group after excluding seven eyes with glaucoma-related adverse events.Our study showed results divergent from those of previous studies.In the study of Sun et al., 49 the growth rate was higher in the microphthalmos group, while there was a signi cant difference in age at surgery between the microphthalmos group and the comparison group (3.2 ± 1.3 vs. 5.9 ± 3.0 months, p < 0.001), which could affect results.Seven et al. 50found a signi cantly negative correlation between age at surgery and changes in AL and the monthly growth rate.Therefore, our study, with no signi cant difference in age at surgery between the two groups (4.09 ± 1.87 vs. 4.84 ± 2.08 months, p = 0.068), might be more convincing.
At the last follow-up, 12 eyes (34.3% of 35 eyes) in the microphthalmos group had progressed to age-matched normal AL.AL is related to hereditary factors, 51 physical development, 45,52 nutrition, and other environmental factors.Various factors can affect axial elongation.We hypothesized that some patients with microphthalmos might suffer more from form deprivation caused by their cataracts, which probably inhibit eyeball development rather than genetic defects.Previous studies built postoperative AL prediction models for children undergoing congenital cataract surgery, based on baseline AL, age at surgery and IOL status. 48,53 owever, the postoperative AL of our microphthalmos patients deviate from these models.One hand, patients with microphthalmos occupy a relatively small proportion in congenital cataracts, leading large error in prediction.The other hand, the mechanism of axial elongation in microphthalmos could be more complex, and future AL growth in microphthalmic eyes remains di cult to predict, which requires a larger sample size and a longer follow-up period for further investigation.
The results of this study should be viewed in light of these limitations.First, it was a retrospective study with a small sample size.Second, the follow-up period was relatively short; a longer follow-up period may reveal the development of glaucoma, especially the late-onset open-angle type, in some eyes.Further prospective studies with larger sample sizes and longer follow-up periods are warranted.

Conclusions
In conclusion, early surgical intervention improves visual function in infants with congenital cataracts and microphthalmos.And microphthalmic eyes had a higher incidence of postoperative glaucoma than normally developed eyes.After cataract removal, the AL growth of microphthalmic eyes is slower than that of normally developed eyes, providing an important basis for surgeons to choose the timing of secondary IOL implantation.

Table 1 a
Demographic features (individual-level characteristics) a Mann-Whitney U Test, b Chi-Square Test, c Fisher's Exact Test FHCC, Family history of Congenital Cataracts.

Table 2
Postoperative glaucoma-related adverse events in the microphthalmos group p-value adjusted for binocular correlation in uence by generalized estimating equation † Individually included eyes with glaucoma-related adverse events, posterior synechiae, VAO, and any combination of these three postoperative complications. *

Table 4
Univariate Logistic regression analysis of risk factors for glaucoma-related adverse events in the microphthalmos group * p-value adjusted for binocular correlation in uence by generalized estimating equation.AL, Axial length; HCD, Horizontal corneal diameter; LT, Lens thickness; ACD, Anterior chamber depth; Intra-op Intraoperative.

Table 5
a p-value adjusted for binocular correlation in uence by UNIANOVA, b values adjusted for sample size difference at every postoperative follow-up, and binocular correlation in uence by generalized estimating equation By the last follow-up, 12 of 35 eyes (excluding 7 eyes that developed glaucoma-related adverse events) in the microphthalmos group had grown to normal AL, while the other 23 eyes remained microphthalmos.

Table 6
Postoperative decimal visual acuity outcomes* * Tested using the Teller acuity card procedure

Table 7 a
Demographic features of the microphthalmos subgroups (individual-level characteristics)

Table 7 b
Ocular characteristics in the microphthalmos group subgroups (eye-level characteristics)

Table 8
Incidence of postoperative complications between the microphthalmos subgroups * p-value adjusted for binocular correlation in uence by generalized estimating equation † Individually included eyes with glaucoma-related adverse events, posterior synechiae, VAO, and any combination of these three postoperative complications.VAO, Visual axis opaci cation.

Table 9
Studies on infants with microphthalmos following cataract surgery