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\begin{document}

\title{Advisability of primary intraocular lens implantation for infants under
2: A systematic review and meta-analysis}



\author[1]{Shanshan  Jin}%
\author[2]{Jing Shang Zhang}%
\author[2]{Jin Da Wang}%
\author[2]{Yusufu  Mayinuer}%
\author[1]{Kai Cao}%
\author[1]{Guyu Zhu}%
\author[1]{Hailong He}%
\author[1]{Xiu Wan}%
\affil[1]{Beijing Institute of Ophthalmology}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Purposes: The present meta-analysis compared the postoperative visual
performance of primary intraocular lens (IOL) implantation and primary
aphakia in cataract infants. Methods: We performed a systematic
literature search in PubMed, EMBASE and Science Direct. Postoperative
visual acuity (VA) and complications were extracted and pooled. Results:
Four randomized controlled trails (RCTs) and seven retrospective studies
were included. The postoperative VA in primary IOL group was better than
that in primary aphakia group {[}MD=-0.12, 95\% CI: (-0.19, -0.05),
p=0.91{]}. There was no significant difference in the incidence of
glaucoma, retinal detachment and nystagmus between primary IOL group and
primary aphakia group {[}OR=1.27, 95\% CI: (0.79, 2.05), p=0.84 for
glaucoma; OR=0.49, 95\%CI: (0.07, 3.30), p=0.34 for retinal detachment;;
OR=1.11, 95\%CI: (0.62, 1.98), p=0.73 for nystagmus{]}. Analysis of
unilateral subgroup indicated there were fewer infants with strabismus
in primary IOL group compared with primary aphakia group {[}OR=0.40,
95\% CI: (0.21, 0.79), p=0.46{]}. The primary IOL group needed more
visual axis opacification (VAO) clearing than primary aphakia group
{[}OR=9.33, 95\%CI: (5.21, 16.73), p=0.27{]}. Conclusion: Primary IOL
implantation provided more visual benefits. IOL implantation may
decrease the incidence of strabismus in comparison with primary aphakia
in unilateral subgroup. However, these advantages could be offset by a
higher VAO clearing surgery.%
\end{abstract}%



\sloppy


\textbf{Extra information}

\textbf{How did you gather the information you considered in your
review?}

We performed a systematic search in PubMed, Science Direct, EMBASE and
Cochran Library. One or a combination terms was used in the search. The
publication time of the literature was restricted from January 1, 2000
to August 2, 2020. Two investigators searched and screened the articles
independently. In case of disagreement about the literature search, a
third reviewer would engage in the discussion until a consensus was
reached.

\textbf{What is the 'take-home' message for the clinician?}

We found the postoperative VA of primary IOL group was better than that
of primary aphakia group. Actually, constant optical correction during
this crucial period is very important for children. Moreover, previous
studies indicated primary IOL implantation was a protective factor of
secondary glaucoma. Whereas we found there was no difference in the
incidence of glaucoma surgery between this two groups. These two
critical findings help the surgeons to weigh the visual benefits and the
risks of surgery when they choose IOL implantation for a children
younger than 2 years.

\textbf{Keywords} \textbf{:} Primary intraocular lenses, Primary
aphakia, Cataract surgery, Cataract infant;

\textbf{Introduction}

Approximate 1.4 million children suffer from blindness around the
world.\textsuperscript{1} Childhood preventable blindness has been
identified as a priority of the Vision 2020: ``The Right to
Sight''\textsuperscript{2}. Pediatric cataract is the leading cause of
treatable childhood blindness and accounts for 5 - 20\% of childhood
blindness\textsuperscript{3-5}. IOL implantation is the main option for
optical rehabilitation in children after cataract surgery. There are two
main surgical procedures for IOL implantation in cataract infants, i.e.
primary IOL implantation and primary aphakia followed by secondary IOL
implantation. Due to the risk of postoperative complications, such as
inflammatory responses, VAO and secondary glaucoma, IOL implantation in
cataract children older than 2 years has been a consensus among
pediatric cataract surgeons around the world\textsuperscript{6-9}. But
in other cases, children with aphakic spectacles or contact lenses are
susceptible to VA issues, corneal problems, compliance with lens-wearing
and high cost.

Many studies had reported the clinical performance (including VA and
postoperative complications) after congenital cataract
surgery\textsuperscript{7,10-12}. However, given the elongation of axial
length, change of corneal curvature and high incidence of additional
surgery, the benefits and risks of primary IOL implantation in cataract
infants, especially in those younger than 2 years, still remains a
controversial issue\textsuperscript{13-15}. Surgeons need to weigh the
visual benefits agains risk (such as inflammatory response, VAO and
secondary glaucoma associated with the procedure) of surgery when they
choose IOL implantation for a children younger than 2 years.

Glaucoma is the main complication of congenital cataract surgery and has
been discussed in many studies\textsuperscript{16-18}. However, there is
no consistent conclusion on which type of surgery can decrease the
incidence of glaucoma. Some studies suggested that primary IOL
implantation was a protective factor of glaucoma after cataract
surgery\textsuperscript{19,20}. Whereas, other studies suggested that
the incidences of glaucoma were comparable in primary IOL group and
primary aphakia group \textsuperscript{11,21,22}. Similarly, previous
studies didn't reach consensus on which type of procedure would be
better in terms of postoperative VA and
complications\textsuperscript{23,24}. Therefore, the present
meta-analysis aims to compare the postoperative performance of primary
IOL implantation and primary aphakia in cataract infants younger than 2
years, and provide solid evidence for better clinical practice.

\textbf{Materials and methods}

\textbf{Search strategy}

A systematic search was performed in PubMed, Science Direct, EMBASE and
Cochran Library. One or a combination of the following terms was used in
the search: congenital, infant, child, pediatric, cataract, intraocular
lens, IOL, primary, secondary, pseudophakia, aphakia, cataract surgery,
comparison and compare. The publication time was restricted from January
1, 2000 to August 2, 2020. Two investigators (Shanshan Jin and Jingshang
Zhang) searched and screened the articles independently. In case of
disagreement about the literature search, a third reviewer (Xiuhua Wan)
would engage in the discussion until a consensus was reached. Figure 1
showed the selection process.

\textbf{Inclusion and exclusion criteria}

Inclusion and exclusion criteria: (i) The subjects should be cataract
infants younger than 2 years (P) who received cataract extraction with
primary IOL implantation (I) or primary aphakia (C); (ii) The clinical
outcomes on postoperative VA, complications (glaucoma, strabismus,
nystagmus and visual axial opacity) (O) should be evaluated; (iii) Given
the age at the surgery and the age at the last visit were significant
factors for the postoperative outcomes in congenital cataract patients,
studies in which the age at the surgery or last visit in these two
groups did not match were excluded; (iv) Studies without detailed
outcome on the postoperative visual performance were excluded; (v)
Studies reporting data on individual patient rather than individual
surgery eye were excluded; (vi) (potentially) overlapping study
populations that reported same outcome were excluded; (vii) Non-English
publications were excluded.

\textbf{Data extraction}

Data were extracted using pre-defined data fields from each study by two
investigators independently. If there were inconsistencies between two
investigators, a third reviewer would extract results and engage in
discussion until a consensus was reached. VA reported as log MAR VA were
extracted as the primary outcome. Second outcomes including glaucoma,
strabismus, nystagmus and VAO were extracted. The results of
postoperative visual performance at last visit were extracted from
studies with multiple postoperative follow-up data. As for the
retrospective studies, age-matched outcome would be extracted if
reported. Continuous data reported as mean \selectlanguage{ngerman}± SD were extracted directly.
Those data reported as median and interquartile ranges would be
converted into mean and SD based on the formula\textsuperscript{25}.

\textbf{Quality assessment}

The quality of the included RCTs was assessed with the Cochrane Risk of
Bias Tool\textsuperscript{26}. It contained six domains: randomization
process, intervention deviation, missing outcome data, outcome
measurement, selective outcome reporting. The retrospective studies were
assessed by the Newcastle-Ottawa Scale (NOS) in the following 3 aspects:
cohort selection, cohort comparability, assessment of
outcome\textsuperscript{27}. Details of NOS were available in Appendix
1.

\textbf{Data synthesis and statistical analysis}

The statistical analysis was performed with the statistical software
open source R program (Version 3.41). Categorical outcomes were
estimated by odds ratio (OR) with 95\% CI. If ``1'' falls into the CI,
the outcome would be considered ``not statistically significant''. The
mean difference (MD = mean of primary IOL -- mean of primary aphakia)
with a 95\% confidence interval (CI) was adopted for continuous
outcomes. If ``0'' falls into the CI, the outcome would be considered
``not statistically significant''.

Heterogeneity across studies was tested with Q test and
I\textsuperscript{2} statistic. If there was no heterogeneity across
these studies (I\textsuperscript{2}\selectlanguage{english}<50\% ), the Mantel--Haenszel
fixed-effect model would be used. I\textsuperscript{2} above 50\% and
the P-value below 0.1 would constitute a significant heterogeneity among
these studies, and possible reasons would be explored by reviewing the
included studies. Three approaches were used to detect the source of
heterogeneity in this meta-analysis: sensitive analysis, subgroup
analysis and meta regression. Through sensitivity analysis, we could
determine whether the heterogeneity would decrease following exclusion
of each study one by one. Subgroup analysis and meta regression would be
performed according to the clinical characteristics of the included
studies. Through these two approaches, we could identify the factor that
induced heterogeneity in the meta-analysis. If sensitivity analysis and
subgroup analysis did not decrease the heterogeneity, the random-effects
model (DerSimonian-Laird) would be adopted to calculate pooled effect
size.\textsuperscript{28,29}.

\textbf{Results}

\textbf{Characteristics of included studies}

Four randomized controlled trails (RCTs) and seven retrospective studies
were included. Table 1 describes the characteristics of the 11 included
studies that were published during 2001-2018. The surgery age of
subjects ranged from 1.8-7.5 mouth. The follow-up duration ranged from
0.5-5 years.

\textbf{Risk of bias assessment}

Three RCT studies reported the randomization process, intervention
deviation, yet none of them had selective reporting and outcome data
missing. The study of Qian L\textsuperscript{30} did not describe the
approach of random sequence generation and potential intervention
deviation. Vasavada et al.\textsuperscript{22} reported that the surgery
type was revealed to the surgeon and outcome examiner in their study.
The details of risk assessment for these RCTs were presented in the
Figure 2.

Retrospective studies were assessed based on NOS. Five studies described
the detailed process of cohort selection, and were assessed to be of low
risk in cohort selection. The study by Autrata et
al.\textsuperscript{31} did not report the source of study subjects, and
was assessed to be of medium risk in cohort selection. High risk was
found in the cohort selection in the study by Trivedi et
al\textsuperscript{32}, as the source and preoperative data on patients
were not described. Given the age at the surgery and the age at the last
visit were significant factors for the postoperative outcomes in
cataract infants, these two factors were used to assess the cohort
comparability. According to our inclusion and exclusion criteria, all
these retrospective studies have similar age at surgery and last visit
in both groups. So, all these studies were assessed to be of low risk in
the cohort comparability. The study by Trivedi et
al\textsuperscript{32}. was assessed to be of high risk since they did
not report the duration of follow up and rate of follow-up loss. Except
for the above study, all the other studies gave detailed information on
outcome assessment. The details of risk assessment for these
retrospective studies were shown in the Figure 3.

\textbf{Visual acuity}

There were 7 studies reporting VA\textsuperscript{11,22,30,31,33-35},
and the VA of primary IOL group was similar to that of primary aphakia
group {[}MD=-0.12, 95\%CI: (-0.19, -0.05), p=0.91{]}. There was no
heterogeneity (I\textsuperscript{2} =0\%)(Figure 4). No publication bias
was found (Table 2).

\textbf{Glaucoma}

Glaucoma was reported in 7
studies\textsuperscript{11,22,30,32,34,36,37}, there was no
heterogeneity (I\textsuperscript{2}=0\%). Therefore, the fixed effect
model was applied. As shown in Figure 5, there was no difference in the
incidence of glaucoma between primary IOL group and primary aphakia
group {[}OR=1.27,95\%CI: (0.79, 2.05), p=0.84{]}.

\textbf{Strabismus}

As Figure 6 shows, 6 studies reported the data on
strabismus\textsuperscript{11,22,31,33-35}. There were much fewer
infants with strabismus in primary IOL group compared with primary
aphakia group after the surgery {[}OR=0.53, 95\% CI: (0.31, 0.90),
p=0.19{]}. Given the unilateral cases or bilateral cases will be a
critical factor that contribute to strabismus incidence after congenital
cataract surgery, a subgroup analysis was performed. There were much
fewer infants with strabismus in primary IOL group compared with primary
aphakia group in the unilateral subgroup {[}OR=0.40, 95\% CI: (0.21,
0.79), p=0.46{]}. No difference was found in the bilateral subgroup.

\textbf{Nystagmus}

Four studies reported the outcome on nystagmus
incidence\textsuperscript{22,34,35,38}, and no heterogeneity was found
(I\textsuperscript{2} = 0\%). No statistically difference was found
between the primary IOL and primary aphakia group in terms of nystagmus
{[}OR=1.11,95\%CI: (0.62, 1.98), p=0.73{]} (Figure 7).

\textbf{Retinal detachment}

As shown in Figure 8, only 2 studies reported data on
RD\textsuperscript{11,34}, and there was no statistical heterogeneity
among these studies (I\textsuperscript{2} = 0\%). No statistically
significant difference was found between the two groups {[}OR=0.49,
95\%CI: (0.07, 3.30), p=0.34{]}.

\textbf{Visual axial opacity clearing}

VAO clearing was reported in 5 studies\textsuperscript{11,22,34,37}, and
the I\textsuperscript{2} was 23\%. As shown in Figure 9, the primary IOL
had a significantly higher incidence of VAO clearing compared with
primary aphakia, {[}OR=9.33, 95\%CI: (5.21, 16.73), p=0.27{]}.

\textbf{Discussion}

The present meta-analysis demonstrated that the postoperative VA in
primary IOL group was better than that in primary aphakia group. These
results were consistent with previous studies. Birch et al showed that
IOL may support better VA development when a cataract was extracted
after age 1, while the difference would taper off with the age reaching
4 years\textsuperscript{39,40}. Vasavada et al\textsuperscript{22}.
reported that more infants in primary IOL group had documentable VA than
aphakia group during early postoperative follow-up, and this trend
continued until age 5. This result indicated that the visual
rehabilitation was faster in pseudophakia group, especially in early
postoperative follow-up. However, in the IATS study, the VA was similar
in IOL group and contact lens group both in the first (1 year
old)\textsuperscript{6} and last follow-up (4.5 years
old)\textsuperscript{11}. This could be explained by better compliance
of contact lenses or spectacles in the aphakia group. The IATS study
offered free contact lenses and spectacles for the enrolled subjects.
Moreover, trained personnel assessed the vision and monitored the
compliance through regular home visits. \textsuperscript{41} This may
not be carried out in the real world, particularly in developing
countries. Actually, constant optical correction during this crucial
period is very important for children. A faster visual rehabilitation
will impact the activity and overall functional development of the
children. Therefore, primary IOL implantation may provide better VA for
pediatric patients, especially those under age 5.

Our meta-analysis did not see any difference in glaucoma incidence. Many
hypotheses proposed the mechanisms of glaucoma after infantile cataract
surgery. However, there is no unanimous conclusion. The mechanisms of
secondary glaucoma of pseudophakia eyes and aphakic eyes might be
different. The filtration angle of infants is susceptible to
postoperative inflammation. Thus, IOL implantation in infants will cause
chronic inflammations that induce changes of iris root or trabecular
meshwork (TM)\textsuperscript{42-44}. This might explain the glaucoma in
pseudophakia eyes. As for aphakic glaucoma, since the mechanical absence
of lens in the eye, TM cells would be exposed to the lens epithelial
cells (LEC). Michael et al. specified that LEC induced changes in TM
cells that resembled changes in primary open-angle
glaucoma\textsuperscript{45,46}. It is worth noting that the mechanism
of glaucoma is still unclear. But we could not make any attempt to
investigate the mechanisms of secondary glaucoma after infantile
cataract surgery in this meta-analysis.

Analysis of unilateral subgroup indicated there were much fewer infants
with strabismus in primary IOL group compared with primary aphakia
group. This was consistent with the studies by Autrata et
al\textsuperscript{31}. and Lambert et al. Previous studies also
suggested that the incidence of strabismus in IOL group was relatively
low\textsuperscript{47-49}. The absence of natural lens in unilateral
eye will lead to anisometropia and aniseikonia, which are related to
secondary strabismus following congenital cataract surgery. Primary IOL
implantation offers a stable retinal image with minimal aniseikonia as
well as full-time optical correction for surgery eye. Moreover, children
have to wear contact lenses or spectacles to get optical correction in
case of absent lenses. The compliance of wearing contact lenses will be
affected by the complications associated with contact lenses like
corneal infection. Hence, this might explain the higher incidence of
strabismus in primary aphakia group.

Postoperative VAO is very common in infants after congenital cataract
surgery. According to the previously published literatures, IOL
implantation is associated with higher VAO incidence in congenital
cataract children, especially those younger than 6
months\textsuperscript{50-52}. The average incidence of VAO after IOL
implantation is 44.0\%, while the incidence is up to 80\% when the
patient is younger than 6 mouths\textsuperscript{53}. The IOL in
capsular bag acts as an obstacle and prevents the anterior and posterior
capsule leaflets from fusing, while the capsule edges will seal more
effectively in aphakic eye. In our meta-analysis, primary IOL group had
a noticeably higher incidence of VAO clearing than primary aphakic
group, which was consistent with the RCT study conducted by IATS and
other previous studies.\textsuperscript{11,34,54,55}.

Our meta-analysis has some limitations. First, even though this
meta-analysis is the first systematic review on this topic, it included
retrospective studies rather than just RCTs. Thus, the level of evidence
will be weakened by the inclusion of retrospective studies. However,
there is no denying that it is very difficult to conduct RCT among
paediatric cataract children. Second, the pooled effect of complication,
especially the glaucoma incidence, might be affected by the inconsistent
diagnostic criteria adopted in these studies. Third, the control group
of these included studies was either primary aphakia followed by contact
lens or primary aphakia followed secondary IOL implantation. Third,
given the number of patients in each study is relatively small, we could
not draw explicit conclusion on the difference in postoperative visual
performance.

\textbf{Conclusions}

In summary, the postoperative VA in primary IOL group was better than
that in primary aphakia group. Primary IOL implantation may be of lower
incidence of strabismus than those with primary aphakia. However, these
advantages could be offset by higher surgery incidence especially VAO
clearing.

\textbf{Contributorship statement}

We thank for support by the sources of funding in this study. Study
design and concept of this meta-analysis were carried out by Xiu Hua
Wan, Jingshang Zhang, Jinda Wang and Shanshan Jin; Shanshan Jin and
Jingshang Zhang conducted the data collection; Shanshan Jin and Kai Cao
performed the data analysis; Ying Xiong, Guyu Zhu, Jing Li and Hailong
He provided interpretation of the data. Shanshan Jin performed the first
draft of the manuscript; Shanshan Jin, Jingshang Zhang, Jinda Wang and
Xiu Hua Wan revised the manuscript and produced the final version;
English polishing was done by Mayinuer Yusufu.

\textbf{Competing interests}

There is no conflict of interest

\textbf{Funding}

Beijing new star of science and technology (H020821380190,
Z131102000413025), Fund of work committee for women and children of
China State department (2014108), National natural science fund
(30471861), Beijing Institute of Ophthalmology leading program (201515).

\textbf{Acknowledgements}

During the preparation of this systematic review, Prof. Ningli Wang and
Prof. Ailian Hu of Beijing Institute of Ophthalmology authorized the
authors to access the database and put together the whole team to work
on this manuscript.

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\textbf{Table 1. Characteristics of the included studies (n = 10).}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
Study & Year & Designs & Primary IOL & Primary IOL & Primary IOL &
Primary aphakia & Primary aphakia & Primary aphakia\tabularnewline
\midrule
\endhead
& & & N(eye) & Age at Surgery (months) & Age at last visit (years) &
N(eye) & Age at Surgery (months) & Age at last visit
(years)\tabularnewline
IATS group & 2014 & RCT & 57 & 1.8 & 4.5 & 57 & 1.8 & 4.5\tabularnewline
Vasavada A R & 2018 & RCT & 29 & 6.3 & >5 & 25 & 8.1 &
>5\tabularnewline
Felius J & 2014 & RCT & 57 & 1.8 & 4.5 & 57 & 1.9 & 4.5\tabularnewline
Lambert SR & 2001 & RS & 12 & 2.8 & 1.5 & 13 & 2.3 & 1.7\tabularnewline
Trivedi R H & 2006 & RS & 41 & 1.9 & <1 & 42 & 1.6 & <1\tabularnewline
Magli A & 2013 & RS & 30 & 7.2 & 9.5 & 36 & 5.4 & 7.4\tabularnewline
Lambert SR & 2004 & RS & 12 & 2.8 & 4.3 & 13 & 2.3 & 4.4\tabularnewline
Autrata R & 2005 & RS & 18 & 3.4 & 4.9 & 23 & 2.9 & 5.5\tabularnewline
Joshaghani M & 2015 & RS & 23 & 7.5 & 7.0 & 32 & 6.0 &
6.5\tabularnewline
Wong B & 2009 & RS & 37 & 4.3 & <3 & 61 & 2 & <3\tabularnewline
Qian L & 2014 & RCT & 30 & <24 & <3 & 30 & <24 & <3\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Indicators} & \textbf{t} & \textbf{df} &
\textbf{p}\tabularnewline
\midrule
\endhead
VA & 1.904 & 5 & 0.115\tabularnewline
Glaucoma & 1.075 & 5 & 0.331\tabularnewline
Strabismus & -0.345 & 4 & 0.748\tabularnewline
Nystagmus & -0.832 & 2 & 0.493\tabularnewline
Retinal detachment & -0.438 & 1 & 0.737\tabularnewline
Glaucoma surgery & 87.023 & 1 & 0.007\tabularnewline
Strabismus surgery & -0.879 & 2 & 0.472\tabularnewline
VAO clearing & -2.586 & 3 & 0.081\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2. Egger's test for each outcomes}

\par\null

\textbf{Figure legend}

Figure 1. Flow chart of study selection

Figure 2. Risk of bias graph of RCT studies.

Figure 3. Risk of bias graph of retrospective studies.

Figure 4. Forest plot of VA.

Figure 5. Forest plot of glaucoma.

Figure 6. Forest plot of strabismus after subgroup analysis.

Figure 7. Forest plot of nystagmus.

Figure 8. Forest plot of retinal detachment.

Figure 9. Forest plot of VAO clearing.\selectlanguage{english}
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