Keywords retinopathy of prematurity - histological chorioamnionitis - funisitis - prematurity
- meta-analysis
Retinopathy of prematurity (ROP) is a sight-threatening retinal disorder in premature
neonates, accounting for up to 40% of worldwide childhood blindness.[1 ] This vasoproliferative disorder affects 10 to 25% of neonates born under 32 weeks
of gestation, with an even higher incidence of 30 to 70% in neonates with a birthweight
(BW) below 1,500 g.[2 ] The pathophysiology is primarily due to abnormal retinal vessel development and
occurs in two phases. The initial phase is induced by hyperoxia exposure and decreased
insulin-like growth factor-1 (IGF-1) levels due to placental disruption, followed
by decreased vascular endothelial growth factor (VEGF) levels, and results in attenuation
and cessation of retinal vessel growth.[1 ]
[3 ] The second phase is characterized by abnormal retinal vessel growth due to increased
VEGF concentrations following retinal hypoxia and increasing IGF-1 levels.[1 ]
[3 ]
Preterm birth, one of the leading causes of ROP, is associated with chorioamnionitis
(CA).[4 ] Histological chorioamnionitis (HCA) is an acute maternal inflammatory response in
the placental membranes, mainly due to ascending microorganisms, while funisitis (FUN)
is the fetal inflammatory response of the vessels in the umbilical cord.[5 ]
[6 ] The presence of HCA will not always lead to FUN, whereas the presence of FUN is
always equivalent to the presence of HCA. Clinical chorioamnionitis (CCA) has been
proven to be unreliable in diagnosing inflammation in the placenta due to high false-positive
rates.[7 ] In most cases, the role of HCA in neonatal morbidities is underestimated due to
lack of postpartum placental histological examination.[6 ]
The potential association between HCA and the development of ROP is believed to be
a result of proinflammatory cytokines production.[4 ]
[8 ] However, establishing its specific pathophysiology is found to be challenging due
to the simultaneous interplay of substantial confounders such as low gestational age
(GA) at birth and BW.[4 ] Additionally, most studies do not differentiate between HCA and FUN, even though
the presence of FUN is believed to have more impact on the risk of ROP development.[9 ]
Robust evidence regarding the effect of HCA and especially FUN on the development
of ROP is still lacking. Hence, we performed a systematic review and meta-analysis
to investigate the association between HCA with and without FUN and the risk of ROP
development in premature born neonates to further adjust the risk profile for ROP
screening.
Methods
Sources
This systematic review was conducted according to Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines and is registered in the International
Prospective Register of Systematic Reviews (PROSPERO) (CRD42022346582).[10 ] The online electronic databases PubMed, Embase, and Cochrane Library were searched
up until October 2023 by using combinations of the following keywords: “Placenta,”
“Chorioamnionitis,” “Risk Factors,” AND “Retinopathy of Prematurity.” Additionally,
various synonyms were added as Medical Subject Headings (MESH) terms and free text
words. Lastly, reference lists of key articles were manually reviewed to identify
relevant articles missed by PubMed.
Study Selection
All studies were assessed for eligibility by primarily screening the title and abstract
and subsequently evaluating the full text. Studies were eligible for inclusion when
(unadjusted) data were reported on HCA with or without FUN in preterm neonates (<37
weeks' GA and/or BW < 2,000 g) with ROP.[11 ]
[12 ] Articles were excluded when the study population consisted entirely of animals or
multiple pregnancies due to its confounding effect.[13 ] Additionally, articles were excluded when placenta reports were unavailable to histologically
confirm CA in cases with CCA, which is diagnosed by nonspecific clinical symptoms.[7 ] Further exclusion criteria were case reports, case series, reviews, editorials,
and unavailable full text. To identify eligibility of inclusion, three reviewers (S.E.,
E.J.S.J., and J.U.M.T.) independently assessed the search results and discrepancies
were resolved through discussion.
The primary outcome was ROP. Due to their known potential confounding effect on ROP,
the following clinical data were included: GA at birth (weeks), BW (grams) and maternal
steroid use, necrotizing enterocolitis (any stage), sepsis (suspected/proven), and
mechanical ventilation duration (days).[14 ] Studies were classified as any stage ROP or severe ROP (defined as ROP ≥ stage 3,
Type I ROP [treatment criteria], aggressive [posterior] ROP], plus disease or ROP
requiring treatment).[15 ] HCA was defined as an acute inflammation with presence of neutrophils in the placental
membranes (chorion and/or amnion) and chorionic plate.[5 ] FUN, also known in literature as fetal inflammatory response or acute fetal inflammation,
was defined as the presence of neutrophils in the umbilical vessel walls.[5 ]
[16 ]
The included neonates were categorized into four groups: HCA and any stage ROP, HCA
and severe ROP, FUN and any stage ROP, and FUN and severe ROP. Neonates with HCA were
compared with neonates without HCA, while neonates with FUN were compared with neonates
without FUN (HCA without FUN or no HCA).
Quality Assessment
The Newcastle–Ottawa Scale for case–control and cohort studies was used to assess
the validity and quality of the included studies.[17 ] This assessment includes three study aspects: selection (0–4 points), comparability
(0–2 points), and exposure/outcome (0–3 points). Scoring was based on the association
between HCA/FUN and ROP as the primary outcome. The comparability section relied on
GA and one additional potential confounder reported in our study.
Statistical Analysis
Statistical analyses were performed using R studio for Windows, version 4.2.1 (RStudio,
PBC, Boston, MA) with the metafor package, assisted by a statistician (J.J.G.).[18 ] Data are presented using n /N (%) and odds ratio (OR) with 95% confidence interval (CI). The OR and 95% CI for
the primary outcome were recalculated from unadjusted 2 × 2 table data provided in
the studies and combined using a logistic random-effects model due to anticipated
heterogeneity. Heterogeneity between studies was evaluated by the Q statistics and I
2 statistics, which is the total variation between studies due to heterogeneity beyond
chance. p -Values <0.05 were considered statistically significant. Publication bias was assessed
through funnel plots, failsafe number, and trim-and-fill function in R studio.
To explain observed between-study heterogeneity, the mean/median difference for continuous
variables and the incidence (%) difference for dichotomous outcomes were calculated
between the HCA/FUN and no HCA/FUN groups. No distinction was made between the median
and mean for continuous variables to include more studies. A univariate meta-regression
model was performed to identify variables that potentially influence the effect size
of HCA/FUN on ROP. The Bonferroni correction for multiple comparisons was used in
univariate analysis, in which a p -value of 0.05/number of included variables was considered statistically significant.
Subsequently, variables with significant associations found in univariate analysis
were included in multivariate meta-regression analysis. GA and BW are highly correlated
and adjusting for both variables in multivariate analysis will undermine the statistical
significance of each other. When both GA and BW are significant in univariate analysis,
only one variable should be included in multivariate analysis, preferably in combination
with the variable small for GA. Since data on small for GA were limited, only the
highest significant variable was included to prevent multicollinearity. Data are presented
using β-coefficient with 95% CI. Positive β-coefficients indicate that studies with
large between-group differences in potential confounders had higher associations between HCA/FUN and ROP, while negative β-coefficients indicate
the opposite.
Results
The search strategy yielded 6,536 articles. Nine additional articles were included
from manual search of reference lists for title and abstract screening. After excluding
duplicates, 3,697 titles and abstracts were screened. Primary assessment led to exclusion
of 3,597 articles based on inclusion and exclusion criteria. After full-text assessment
of the remaining 100 articles, 55 articles were excluded, resulting in a total of
45 included articles in this systematic review and meta-analysis ([Fig. 1 ]).
Fig. 1 PRISMA flowchart of study inclusion. PRISMA, Preferred Reporting Items for Systematic
Reviews and Meta-Analyses.
Quality Analysis
Validity and quality assessment of included studies are presented in [Supplementary Tables S1–S4 ] (available in the online version). Most studies (n = 32) had a moderate quality score (6–7 points), while 11 studies received a high
quality score (8–9 points), and only 2 studies had a low quality score (0–5 points).
Many studies lost points due to absence of confounder adjustment. Some studies that
adjusted for both GA and BW in multivariate analysis lost a point since these factors
are highly correlated and will undermine the statistical significance of each other.
Studies also did not receive points when the definition or reference of ROP and HCA/FUN
diagnosis were not reported.
Histological Chorioamnionitis and Any Stage Retinopathy of Prematurity
Seventeen studies assessing HCA in neonates with any stage ROP compared with neonates
without ROP were included, with the number of sample size ranging from 13 to 912 ([Supplementary Table S1 ], available in the online version).[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ]
[26 ]
[27 ]
[28 ]
[29 ]
[30 ]
[31 ]
[32 ]
[33 ]
[34 ]
[35 ] HCA was detected 1.8 times as frequently in neonates with any stage ROP compared
with neonates without ROP (OR 1.8, 95% CI 1.3–2.4, p = 0.0004; [Fig. 2 ]). Neither visual inspection and trim-and-fill number (n = 0) of the funnel plot nor the failsafe number (n = 223, Kendall's tau = 0.07, p = 0.7) showed indication of publication bias ([Supplementary Fig. S1 ], available in the online version). Significant moderate heterogeneity was observed
(Q : 50.7, I
2 : 68.5%, p < 0.0001).
Fig. 2 Forest plot of the association between HCA and any stage ROP. Heterogeneity: Q = 50.7, I
2 = 68.5%, p < 0.0001. HCA, histological chorioamnionitis; ROP, retinopathy of prematurity; RE,
random-effects.
To explore the observed heterogeneity and to analyze the possible influence of potential
confounders as moderators on the effect size of HCA on any stage ROP, univariate regression
meta-analysis was performed ([Table 1 ]). One factor was a significant moderator in univariate meta-regression analysis
for the association between HCA and any stage ROP: maternal steroids (β-coefficient
0.05, 95% CI 0.008–0.09, p = 0.02).
Table 1
Meta-regression regarding the influence of potential confounders on histological chorioamnionitis
and any stage retinopathy of prematurity
Univariate
N
Estimate
SE
Z-value
p -Value
CI lower
CI higher
R
2 (%)
I
2 (%)
Gestational age at birth
8
−0.3920
0.3068
−1.2775
0.2014
−0.9933
0.2094
3.26
74.02
Birthweight
8
−0.0014
0.0012
−1.1361
0.2559
−0.0037
0.0010
1.66
75.11
Maternal steroids
8
0.0482
0.0204
2.3574
0.0184
0.0081
0.0882
56.87
53.57
Necrotizing enterocolitis
4
0.0489
0.0728
0.6708
0.5023
−0.0939
0.1916
0.00
43.80
Sepsis
4
0.0381
0.0344
1.1090
0.2674
−0.0293
0.1055
33.56
53.57
Mechanical ventilation
3
−0.0231
0.0735
−0.3144
0.7532
−0.1672
0.1209
0.00
78.90
Abbreviations: SE, standard error; CI, confidence interval.
Histological Chorioamnionitis and Severe Retinopathy of Prematurity
Fifteen studies assessing HCA in neonates with severe ROP compared with neonates with
no/mild ROP were included, with the number of sample size ranging from 32 to 12,254
([Supplementary Table S2 ], available in the online version).[21 ]
[23 ]
[25 ]
[27 ]
[28 ]
[32 ]
[33 ]
[36 ]
[37 ]
[38 ]
[39 ]
[40 ]
[41 ]
[42 ]
[43 ] HCA was detected 1.5 times as frequently in neonates with severe ROP compared with
neonates with no/mild ROP (OR 1.5, 95% CI 1.2–1.8, p < 0.0001; [Fig. 3 ]). Publication bias ([Supplementary Fig. S2 ], available in the online version) was neither detected in visual inspection and
trim-and-fill number (n = 0) of the funnel plot, nor the failsafe number (n = 129, Kendall's tau = 0.1, p = 0.5). Low heterogeneity was observed (Q : 20.2, I
2 : 30.8%, p = 0.1230).
Fig. 3 Forest plot of the association between HCA and severe ROP. Heterogeneity: Q = 20.2, I
2 = 30.8%, p = 0.1230. HCA, histological chorioamnionitis; ROP, retinopathy of prematurity; RE,
random-effects.
While using the Bonferroni correction for multiple comparisons, one factor was a significant
moderator in univariate meta-regression analysis for the association between HCA and
severe ROP: GA (β-coefficient −0.4, 95% CI −0.7 to −0.04, p = 0.03) between the HCA group and non-HCA group ([Table 2 ]).
Table 2
Meta-regression regarding the influence of potential confounders on histological chorioamnionitis
and severe retinopathy of prematurity
Univariate
N
Estimate
SE
Z-value
p -Value
CI lower
CI higher
R
2 (%)
I
2 (%)
Gestational age at birth
9
−0.3910
0.1777
−2.2006
0.0278
−0.7393
−0.0428
74.19
16.81
Birthweight
8
−0.0031
0.0016
−1.9979
0.0457
−0.0062
−0.0001
99.85
0.07
Maternal steroids
9
0.0108
0.0344
0.3132
0.7542
−0.0567
0.0782
0.00
52.15
Necrotizing enterocolitis
8
0.0134
0.0317
0.4238
0.6717
−0.0487
0.0755
0.00
50.26
Sepsis
5
0.0310
0.0153
2.0254
0.0428
0.0010
0.0610
43.36
44.48
Mechanical ventilation
4
−0.0314
0.0563
−0.5588
0.5763
−0.1417
0.0788
0.00
61.30
Abbreviations: SE, standard error; CI, confidence interval.
Funisitis and Any Stage Retinopathy of Prematurity
Seventeen studies assessing FUN in neonates with any stage ROP compared with neonates
without ROP were included, with the number of sample size ranging from 29 to 2,009
([Supplementary Table S3 ], available in the online version).[24 ]
[25 ]
[26 ]
[27 ]
[28 ]
[32 ]
[33 ]
[44 ]
[45 ]
[46 ]
[47 ]
[48 ]
[49 ]
[50 ]
[51 ]
[52 ]
[53 ] FUN was detected 1.8 times as frequently in neonates with any stage ROP compared
with neonates without ROP (OR 1.8, 95% CI 1.4–2.2, p < 0.0001; [Fig. 4 ]). Neither visual inspection and trim-and-fill number (n = 1) of the funnel plot, nor the failsafe number (n = 472, Kendall's tau = 0.04, p = 0.8) showed indication of publication bias ([Supplementary Fig. S3 ], available in the online version). Significant moderate heterogeneity was observed
(Q : 45.8, I
2 : 65.1%, p < 0.0001).
Fig. 4 Forest plot of the association between FUN and any stage ROP. Heterogeneity: Q = 45.8, I
2 = 56.1%, p < 0.0001. FUN, funisitis; ROP, retinopathy of prematurity; RE, random-effects.
Secondary meta-regression analyses were performed to explore the heterogeneity found
in this analysis ([Table 3 ]). Two factors were significant moderators in univariate analysis for the association
between FUN and any stage ROP: GA at birth (β-coefficient −1.0, 95% CI −1.5 to −0.4,
p = 0.0004) and sepsis (β-coefficient 0.07, 95% CI 0.02–0.1, p = 0.006). In multivariate analysis, no independent factors were found.
Table 3
Meta-regression regarding the influence of potential confounders on funisitis and
any stage retinopathy of prematurity
N
Estimate
SE
Z-value
p -Value
CI lower
CI higher
R
2 (%)
I
2 (%)
Univariate
Gestational age at birth
6
−0.9577
0.2725
−3.5140
0.0004
−1.4918
−0.4235
100.00
0.00
Birthweight
6
0.0010
0.0032
0.2986
0.7653
−0.0053
0.0072
0.00
71.13
Maternal steroids
6
−0.0217
0.0273
−0.7953
0.4265
−0.0751
0.0318
16.23
73.71
Necrotizing enterocolitis
4
0.0337
0.1026
0.3289
0.7422
−0.1673
0.2348
0.00
0.00
Sepsis
4
0.0665
0.0241
2.7622
0.0057
0.0193
0.1137
100.00
0.00
Mechanical ventilation
2
–
–
–
–
–
–
–
–
Multivariate
Gestational age at birth
4
−0.3234
0.9318
−0.3471
0.7285
−2.1497
1.5029
100.00
0.00
Sepsis
0.0501
0.0530
0.9456
0.3443
−0.0538
0.1540
–
–
Abbreviations: SE, standard error; CI, confidence interval.
Funisitis and Severe Retinopathy of Prematurity
Twenty-two studies assessing FUN in neonates with severe ROP compared with neonates
with no/mild ROP were included, with the number of sample size ranging from 29 to
2,702 ([Supplementary Table S4 ], available in the online version).[25 ]
[27 ]
[32 ]
[33 ]
[36 ]
[40 ]
[43 ]
[44 ]
[45 ]
[46 ]
[50 ]
[53 ]
[54 ]
[55 ]
[56 ]
[57 ]
[58 ]
[59 ]
[60 ]
[61 ]
[62 ]
[63 ] FUN was detected more frequently in neonates with severe ROP compared with neonates
with no/mild ROP (OR 1.4, 95% CI 1.1–1.6, p = 0.0008; [Fig. 5 ]). Publication bias ([Supplementary Fig. S4 ], available in the online version) was neither detected in visual inspection and
trim-and-fill number (n = 0) of the funnel plot, nor the failsafe number (n = 151, Kendall's tau = 0.004, p = 1.0). Significant moderate heterogeneity was observed (Q : 38.4, I
2 : 45.4%, p = 0.0115).
Fig. 5 Forest plot of the association between FUN and severe ROP. Heterogeneity: Q = 38.4, I
2 = 45.4%, p = 0.0115. FUN, funisitis; ROP, retinopathy of prematurity; RE, random-effects.
In univariate meta-regression analysis, GA at birth (β-coefficient −0.7, 95% CI −1.2
to −0.3, p = 0.001), BW (β-coefficient −0.004, 95% CI −0.007 to −0.001, p = 0.007) and maternal steroids (β-coefficient 0.04, 95% CI 0.01–0.07, p = 0.009) were found to be significant moderators for the association between FUN
and severe ROP ([Table 4 ]). GA at birth was more significant compared with BW, which led to BW being omitted
from multivariate meta-regression analysis to avoid multicollinearity with GA. In
multivariate meta-regression analysis, lower GA at birth (β-coefficient −0.7, 95%
CI −1.4 to −0.1, p = 0.021) was found to be independently associated with the association between FUN
and severe ROP.
Table 4
Meta-regression regarding the influence of potential confounders on funisitis and
severe retinopathy of prematurity
N
Estimate
SE
Z-value
p -Value
CI lower
CI higher
R
2 (%)
I
2 (%)
Univariate
Gestational age at birth
8
−0.7285
0.2213
−3.2923
0.0010
−1.1622
−0.2948
100.0
0.00
Birthweight
8
−0.0043
0.0016
−2.7198
0.0065
−0.0073
−0.0012
100.0
0.00
Maternal steroids
8
0.0392
0.0149
2.6315
0.0085
0.0100
0.0683
87.69
11.42
Necrotizing enterocolitis
5
0.1269
0.0707
1.7952
0.0726
−0.0116
0.2654
100.0
0.00
Sepsis
6
0.0011
0.0491
0.0232
0.9815
−0.0951
0.0973
0.00
64.12
Mechanical ventilation
2
–
–
–
–
–
–
–
–
Multivariate
Gestational age at birth
7
−0.7429
0.3206
−2.3169
0.0205
−1.3713
−0.1144
100.00
0.00
Maternal steroids
0.0039
0.0198
0.1962
0.8445
−0.0349
0.0427
–
–
Abbreviations: SE, standard error; CI, confidence interval.
Summary
Neonates with HCA have a 1.8-fold increased risk for any stage ROP and 1.5-fold increased
risk for severe ROP, while neonates with FUN have a 1.8-fold increased risk for any
stage ROP and 1.4-fold increased risk for severe ROP. Multivariate regression analysis
suggests that lower GA increases the effect size between FUN and severe ROP.
Discussion
This systematic review and meta-analysis showed that neonates with HCA and/or FUN
have an increased risk for any stage ROP and severe ROP. To our knowledge, this is
the first meta-analysis with a relatively large number of studies demonstrating that
the additional presence of the fetal response results in an even higher risk for developing
ROP compared with only the maternal inflammatory response. Meta-regression analysis
suggests that lower GA increases the effect size between FUN and severe ROP.
The pathophysiology behind this increased risk of ROP is believed to be due to production
of proinflammatory cytokines, which play an important role in retinal angiogenesis,
either directly or indirectly by sensitizing the retina to the effects of postnatal
oxygen.[64 ]
[65 ] HCA stimulates the production of tumor necrosis factor-α and interleukin (IL)-1,
IL-6, and IL-8, which can disrupt the blood–brain barrier and in turn lead to increased
plasma protein influx and oligodendroglia damage.[66 ]
[67 ] Increased cytokine levels in the first 72 hours of life have been associated with
severe ROP.[68 ] Additionally, perinatal inflammation induces decreased levels of IGF-1, which inhibit
retinal vessel growth and, thus, increase the risk of ROP development.[46 ]
[69 ]
[70 ]
FUN is the histologic fetal inflammatory response of HCA, and its presence is believed
to increase risk of ROP development.[9 ] However, little is known about FUN since most studies do not differentiate between
HCA and FUN. HCA will not always lead to FUN, whereas FUN will always be the result
of HCA. Therefore, it is plausible to hypothesize that an additional fetal inflammatory
response would increase the risk of ROP compared with only the maternal inflammatory
response. Our meta-analyses showed that neonates with FUN indeed had an increased
risk for ROP compared with neonates without FUN (HCA without FUN or no HCA), which
is based on the most extensive overview of included articles to date.
ROP is a multifactorial disease and multiple hits of antenatal and postnatal inflammation
have been found to be associated with ROP.[64 ]
[71 ]
[72 ] Studies have shown that sepsis increases the risk of ROP—directly or indirectly—as
a consequence of FUN or prematurity.[73 ] GA < 30 weeks and BW < 1,250 g are the main risk factors in the ROP screening program
and could, therefore, partially influence the effect of HCA and FUN.[74 ] However, GA and BW could also be in the causal pathway, since HCA/FUN can lead to
premature birth. The exact pathophysiology remains complex, and several studies have
attempted to clarify this mechanism without conclusive evidence. Nevertheless, we
have demonstrated that HCA and FUN are associated with ROP and that this association
is increased when lower GA is present. Thus, GA is highly suggestive to be an effect
modifier.
Three previous meta-analyses have explored the association between CA and ROP and
showed opposing results.[4 ]
[9 ]
[75 ] Mitra et al reported no association between CA and ROP after adjusting for GA, while
Villamor-Martinez et al (OR 1.4, 95% CI 1.1–1.7) and Bahmani et al (OR 1.5, 95% CI
1.0–2.2) showed significant associations. Villamor-Martinez et al also performed a
subgroup analysis (n = 2) of FUN and found an increased risk of severe ROP (OR 2.3, 95% CI 1.2–4.3), but
not any stage ROP. Notably, our methods of inclusion differed substantially. While
the previous meta-analyses investigated the overall effect of CCA and HCA on ROP,
we only focused on HCA and the difference between HCA and FUN. Additionally, our meta-analysis
included a relatively larger number of studies (n = 17 for any stage ROP, n = 22 for severe ROP) with a longer study period (2002–2023) and, therefore, provides
stronger evidence.
Remarkably, most studies investigating CA and ROP did not make a distinction between
CCA and HCA, even though it has been reported that CCA is unreliable in diagnosing
inflammation in the placenta. Studies have shown that intra-amniotic inflammation
is only present in around 70% of patients with CCA and should, therefore not be used
in scientific publications due to this high false-positive rate.[76 ]
[77 ] Furthermore, recommendations have been proposed to restrict the term CA to pathologic
diagnosis, since substantial heterogeneity occurs in the criteria for CCA, and to
introduce positive Gram stain, positive amniotic fluid culture and placental histology
to the criteria of CA besides isolated maternal fever.[7 ] Excluding CCA cases provides stronger evidence and may explain the significantly
higher odds of ROP in neonates with HCA found in our study.
Several limitations should be considered while interpreting our results. This meta-analysis
mainly included retrospective studies, which may have introduced information bias
and resulted in limited data on potential confounders. Additionally, severe HCA cases
in the HCA group may also have had FUN, since some studies only examined the placenta
for HCA. Furthermore, moderate heterogeneity existed between included studies. Nevertheless,
our meta-analysis gives the most recent and elaborate overview of the association
between HCA and ROP, particularly for the subgroup FUN. Additionally, the differentiation
between maternal and fetal inflammatory response demonstrated the importance of recognizing
and diagnosing FUN. Lastly, by calculating unadjusted ORs from 2 × 2 tables reported
in studies, we have eliminated heterogeneity in confounder adjustment.
In conclusion, this meta-analysis confirms that HCA is a risk factor for any stage
ROP and severe ROP. Additionally, it demonstrates the increased odds of any stage
and severe ROP in neonates that have also been exposed to FUN. However, ROP is a multifactorial
disease and part of the found effect may be influenced by the lower GA found in FUN
cases. Future studies should define HCA based on histological placental diagnosis
and report additional information on the presence of FUN. Subsequently, meta-regression
analysis on potential confounders should be repeated. Nevertheless, our study introduces
structured placental examination of HCA and FUN shortly after birth as a potential
tool to further refine the ROP risk profile and to possibly tailor treatment interventions
in a very early stage to optimize the condition for these vulnerable neonates at risk.
