European Journal of Ophthalmology / Vol. 6/ no. 2. 1996/ pp.

187-191

- - - --~~---_.~~-_._-_.-

Review of experience with retinopathy of

prematurity from the Pavia registry (1990-1993)
P.E. BIANCHI 1, R. SALAT/I, R. GUAGLIANO t, G.P. TRASELLl I, G. RONDINI2, F. TRIMARCHI 1

1 Department of Ophthalmology, University of Pavia, Pavia

2 Neonatal Intensive Care Unit, I.R.C.C.S. Policlinico San Matteo, Pavia - Italy

ABSTRACT: In this retrospective study we analysed the prevalence of retino-pathy of

prematurity (ROP) and its sequelae in a sample of premature infants with birth weight less
than 1500 grams.
From 1 January 1990 to 31 October 1993, we studied 160 surviving premature infants with
very low birth weight (<1.500 g) referred to the Neonatal Intensive Care Unit of the I.R. C.C. S.
Policlinico San Matteo, Pavia, Italy. Thirty percent of these infants suffered from ROP, and
13.7%, with severe ROP, underwent cryotherapy. These latter had very-very low birth weight
(<1.000 g) and low gestational age «28 weeks).
Follow-up of 69 infants at 12 months for retinal sequelae, refraction defects, bin-ocular vi-
sion and ocular motility impairments gave the following results: 1) strabismus 20.3%; 2) >30
hyperopia 3%; 3) myopia 30.4%; 4) >50 myopia 3.7%. The incidence of refraction and oc-
ular motility anomalies in patients with acute ROP with spontaneous remission was similar
to that of unaffected premature infants. Conversely, in the patients treated with cryothera-
py the incidence of strabismus and >50 myopia was greater than for untreated infants: 30%
vs 15.4% (n.s.) and 14.7% vs 0% (p=0.05), respectively. Cryotherapy was successful in
91.9% of cases and in 37.8% of cases the cicatricial sequelae were limited to peripheral
chorioretinal scars. (Eur J Ophthalmol 1996; 6: 187-91)

KEY WORDS: ROP, Cryotherapy, Epidemiology

INTRODUCTION and with ROP treated by cryotherapy; d) evaluation of

The most frequent visual disorders of prematurity
are retinopathy of prematurity (ROP), errors of re-
fraction, nystagmus and strabismus (1-3). Despite
progress in neonatal intensive care, ROP is still a fre-
quent cause of blindness or hypovision in premature
infants with low birth weight (4, 5).
This survey comprised the following items: a) ret-
rospective study on the prevalence of ROP in a large
sample of premature infants with birth weight less than
1500 g; b) analysis of the incidence of refractive er-
rors, oculomotor and retinal anomalies in a reduced group
of compliant patients after a one-year follow-up; c)
comparison of the ocular sequelae of the premature
infants without ROP, with spontaneously regressing ROP
the therapeutic success rate.
MATERIALS AND METHODS
Two hundred and thirty-two premature infants with
birth weight less than 1500 g and low gestational age
(GA) were admitted to the Neonatal Intensive Care
Unit of the I.R.C.C.S. Policlinico San Matteo, Pavia,
from 1 January 1990 to 31 October 1993. Sixty-five (28%)
died during the perinatal period. Seven (3%) of the
167 surviving infants were excluded from the study
because they had malformations or congenital dis-
eases (chromosomal aberrations, cranio-facial mal-
formations, etc.) or because they had developed ROP

This paper was presented at the Xth Congress of the European © by Wichtig Editore, 1996 1120-6721/187-05 $02.50/0
Society of Ophthalmology, Milano, Italy 25-29 June 1995.
Review of experience with retinopathy from the Pavia Registry (1990-1993)
at other hospitals (ROP out). Our study therefore com-
prised 160 infants who underwent ophthalmological
examination with particular attention to ROP.
The mean GA of the sample was 30 weeks, and the
mean birth weight 1147 g. All the infants underwent pe-
riodic indirect binocular ophthalmoscopy of the fun-
dus oculi during their stay in the Neonatal Intensive Care
Unit. The date of the first examination and the fre-
quency of those that followed were fixed according to
the GA, birth weight and identification of ROP. Points
in time after birth are expressed as post-conception-
al age (PA): PA=GA + weeks of life.
Acute stage III ROP was treated by cryotherapy (6).
We decided to treat stage III or III plus ROP extend-
ing to zone II continuously for more than 4-5 hours. The
cryotherapy was performed at the edge of the avas-
cular retina and on the arterio-venous shunts, con-
trolled by an ophthalmoscope with a CO 2 cryode, ap-
plied across the conjunctiva as far as the retinal white
spot appeared. The operation was performed in gen-
eral anesthesia. In those cases in which, because of
the patient's bad general conditions tracheal intuba-
tion was not possible, anesthesia was induced with
intravenous ketamine (1 mg/kg).
We used a classification agreed upon by the Italian
ROP Study Group (2) for the assessment of retinal
sequelae after cryotherapy. In this classification it was
judged appropriate also to consider the peripheral
damage due to cryotherapy. Each stage of this clas-
sification corresponds to the Reese stage (Tab. I) with
the same number, to which the peripheral scars due
to the cryotherapy are added. Stage CO is when the
retinopathy has left no traces, apart from the periph-
eral cicatricial areas due to its treatment. In the high-
er stages the scars are difficult to identify, since the
cryotherapy has failed to stop the progression of the
retinopathy. We summarize the proposed classification
in Table I.
We followed the little patients after they left hospi-
tal with periodic check-ups according to birth weight
and GA or the presence of spontaneously remitted
ROP. We examined the fundus oculi and refraction
under anesthesia in infants who had undergone cryother-
apy.
Only 69 (43.1 %) of the 160 children we followed in
the Neonatal Intensive Care Unit turned up for regu-
lar ophthalmological examinations for at least one
year. Most of the loss from follow-up was of subjects
188
TABLE I - CLASSIFICATION OF THE CICATRICIAL
STAGES AFTER CRYOTHERAPY (according
to the Italian ROP Study Group)
Stage co: Chorioretinal scars in correspondance with the areas that
underwent cryotherapy
Stage C1: Reese stage I + chorioretinal scars due to cryotherapy
Stage C2: Reese stage II + chorioretinal scars due to cryotherapy
Stage C3: Reese stage III + chorioretinal scars due to cryotherapy
Stage C4: Reese stage IV + chorioretinal scars due to cryotherapy
Stage C5: Complete retrolental fibroplasia
who did not develop ROP while in the Neonatal In-
tensive Care Unit. Each infant underwent an orthop-
tic examination and examination of refraction, of the
anterior segment and of the fundus oculi. We assessed
the errors of refraction and the retinal sequelae in
terms of the number of eyes rather than of patients.
RESULTS
ROP epidemiology
Forty-eight (30%) of the premature infants exam-
ined suffered from acute ROP and 22 (13.7%) had
reached a threshold ROP (Fig. 1). The mean GA of the
48 infants was 27.1 weeks.
When the overall sample was divided into three GA
categories (between 33 and 34 weeks; between 27
and 32 weeks; 26 weeks or less) the incidence of ROP
was as follows: no ROP in the group between 33 and
34 wks (0 out of 37); 26.3% (20 out of 76) in the group
between 27 and 32 wks; much higher at 59.5% in the
group :0;26 wks (28 out of 47) (X 2 (2df)=38.36; p<0.00001).
On average, ROP was first found at the 34th week
PA and the highest stage at the 36th week PA. In 26
of the 48 infants affected by ROP (54.2%) ROP re-
mitted spontaneously. The mean GA of these subjects
was 27.4 weeks.
Since some Authors consider the postnatal age of ROP
onset to be inversely proportional to GA, we divided
the 48 subjects with ROP into two groups on the ba-
sis of their GA: those with a GA of 26 weeks or less
(20 premature infants) and those with GA between 26
and 32 weeks (28 premature infants). In the first sub-
group, whose mean GA was 25 weeks, ROP was first
found on average at 7 weeks from birth (PA 32 wks),
while the highest stage of ROP was found at 10 weeks
Bianchi et al
Fig ..1
(PA 35 wks). In the second subgroup, whose mean
GA was 29 weeks, ROP was first found at 6 weeks
from birth (PA 35 wks), while the highest stage of ROP
was at 8 weeks (PA 37 wks). These data confirm that
newborns with a lower GA, hence less mature retinal
vascularization at birth, develop ROP later than those
with a higher GA.
Twenty-two subjects (45.8% of those suffering from
ROP) developed a threshold ROP and were there-
fore treated with cryotherapy. Their average GA was
26.7 weeks; we subdivided the cases on the basis of
their GA: 15 of the 22 treated by cryotherapy (68.2%)
had GA :0; 26 weeks, while the other 7 (31.8%) had GA
between 27 and 32 weeks and none between 33 and
34 weeks (X 2(2df)=23.05; p<0.00001) (Fig. 2). On average,
the treatment was done at 38 weeks PA. Cicatricial
stabilization of the ROP was seen on average at 42
weeks PA.
Follow-up
Sixty-nine children were followed up for at least one
year. Twenty had undergone cryotherapy, for a total
of 37 eyes treated. Seventeen patients were treated
bilaterally and three unilaterally. Thirteen developed
ROP which regressed spontaneously, while 36 had
no ROP.
The retinal sequelae among those who received
cryotherapy can be divided as follows: three eyes pre-
sented a cicatricial ROP at stage C5, one eye stage
C3, five stage C2, 14 stage C1 and 14 stage CO. Since
up to stage C3 the outcome of the cryotherapy may be
considered favourable as the ROP has been halted,
our success rate was 91.9% (34 eyes out of 37). In three
eyes (8.1 %) the retinopathy had evolved to stage C5.
We found no funduscopic anomalies during follow-
up in the 26 eyes in which the ROP regressed spon-
Fig. 2
taneously.
The overall incidence of strabismus in the 69 chil-
dren we followed for at least a year was 20.3% (14
heterotropias). We found six cases of strabismus among
the 20 ROP treated by cryotherapy (five esotropias, one
exotropia), equivalent to 30%, and two cases among
the 13 spontaneously remitted ROP (one esotropia,
one exotropia), equivalent to 15.4%. The incidence of
strabismus in the remaining 36 children, who did not
have ROP, was 16.6% (6 out of 36) (X2(2df)=1.65; p-ris).
We followed Fulton's criteria for refractive values
and considered subjects whose refraction ranged be-
tween -0.50 and +3.00 to be emmetropes. The inci-
dence of myopia was 30.3% (41/135 eyes). Myopia
above 50 was found in 3.7% of cases (five eyes) and
hyperopia above 30 in 3% of cases (four eyes).
We studied myopia in relation to the presence/absence
of ROP and we found in the 34 eyes which underwent
cryotherapy (excluding the three at stage C5), 17 my-
opic eyes (50%), of which five had myopia >50 (14.7%);
in the 26 eyes whose ROP remitted we observed 13
myopic eyes (50%), but no myopia >50; in the 72 eyes
that had no ROP we observed 11 cases of myopia
(15.2%), and no cases of myopia >50 (X2(2df)=19.26;
p<0.00001. The incidence of high myopia in those who
underwent cryotherapy was significantly higher than
that of infants without ROP or whose ROP sponta-
neously remitted (p=0.05).
DISCUSSION
The incidence of ROP in our sample of premature in-
fants (30%) with birth weight :0;1500 g does not differ
from that found in similar studies (1,3,7). In a recent
study by the Italian ROP Study Group the incidence
of ROP was 37.9% (8).
189
Review of experience with retinopathy from the Pavia Registry (1990-1993)
The incidence of ROP is inversely proportional to
GA. In our sample therefore children with GA :0;26
weeks had significantly higher incidence of ROP than
the other two subgroups (59.5% vs 26.3% vs 0%)
(p<0.00001) and the more serious forms of ROP are
in fact found among preterms with lower GA.
Palmer made a clinically important observation (7)
that the moment of onset of ROP is more closely linked
to the date of conception than to the moment in which
pregnancy is interrupted by the premature birth. On-
set of ROP is thus correlated more to postconcep-
tional age than to post-natal age. This is because ROP
seems to be linked to the stage of maturation of reti-
nal vascularization, which is best expressed in terms
of postconceptional age. This appears to be confirmed
by our sample of children with ROP, divided into two
subgroups, the first with GA :0;26 weeks, the second with
GA ;:::27 weeks, if postnatal age is considered; in the
first subgroup the first observation of ROP was at the
seventh week of life and the highest stage of ROP
was reached at the tenth week of life. In the second
subgroup these times were 6 and 8 weeks.
On the other hand, if we consider their postcon-
ceptional age the opposite would seem to be true: in
patients with GA :0;26 weeks the onset and highest
stage of ROP were at 32 and 35 weeks PA, respec-
tively, while in the subgroup with a higher GA these
conditions were found at 35 and 37 weeks PA. We be-
lieve that the small size of our sample, compared to
that presented by Palmer, may in part be the reason.
However, more careful diagnosis of the smaller in-
fants (meaning above all the frequency of examinations),
even if they are more difficult to examine, might also
explain the difference between our data and Palmer's.
Despite this, the difference is not real because the
age at onset of the ROP in our sample lies within the
range he proposes.
Preterms with a lower GA, as well as having a high-
er incidence of ROP, also present a larger number of
serious forms of retinopathy: 15 (68%) of the 22 infants
who underwent cryotherapy for stage III ROP belonged
to the subgroup of neonates with a GA of 26 weeks or
less and only 7 (32%) belonged to the subgroup with
a higher GA. These findings agree with those in oth-
er publications (1, 7).
As regards the follow-up, above all, we had an enor-
mous drop-out rate: only 69 (43.1 %) of the 160 in-
fants returned for the periodic ophthalmological ex-
190
aminations in our protocol, a loss of 91 patients (56.9%).
This may be partly because most of them had not pre-
sented any eye complaints during their stay in hospi-
tal, and were therefore probably "healthy". However this
loss during the follow-up falsifies the "quality" of our
sample of preterms and contributes to increasing the
incidence of the pathologies examined (2, 3).
Our first significant finding is that the incidences of
myopia and strabismus in our sample of premature
infants differed widely from the population born at
term; strabismus has an incidence of 20% in preterms
compared to 4% in the normal population, and my-
opia has an incidence of 29.7% compared to 6% (1,
4, 9-17).
In infants with spontaneously regressed ROP the
incidence of strabismus was the same as in preterms
with no ROP. However, myopia had a higher incidence
in patients with spontaneously regressed ROP than
in those with no ROP (50% vs 15.2%) (p<0.00001). This
difference disappears if high myopia is considered (in
either group), and this condition was only found in the
group of patients who underwent cryotherapy.
In this latter group, the incidence of strabismus was
almost double that of the other two groups (30% vs 15.4%
and 16.6%); myopia in general (low myopia + high my-
opia) had the same incidence as in the preterms with
spontaneously regressed ROP (50% in both); 14.7%
of the cases had myopia >50, which was absent in
the other two groups.
We can therefore draw a number of conclusions.
Firstly, the high incidence of myopia in infants with
ROP, whether or not they were treated with cryother-
apy, leads us to assume that, for reasons still to be as-
certained, this error of refraction is closely correlated
to prematurity and particularly to the ROP of which, in
most cases, it can be considered a sequela. Con-
versely, the fact that strabismus is equally present in
subjects with spontaneously remitted ROP and in those
without ROP would seem to indicate that "mild" ROP
is not an important risk factor of prematurity for this
pathology, while serious ROP requiring cryotherapy
certainly is.
The explanation of this greater incidence is to be
sought in two principal factors, one sensorial, the oth-
er motor. The sensorial factor is the seriousness of
the retinopathy and the retinal sequelae which inter-
fere in the earliest months of life with the visual afferences
and, therefore, with the development of monocular
Bianchi et al

sensorial function and binocular sensory-motor func- tients with spontaneously remitted ROP (12). In those
tions. The motor factor may be identified at either a cen- treated by cryotherapy, however, 91.9% of sequelae
tral or a peripheral level. The very premature infant, were compatible with an acceptable visual function: we
besides developing more serious ROP, is more ex- can thus conclude that treatment gave a very high
posed to hypoxic or hemorrhagic damage to the eNS success rate.
with a consequent effect on the cortical, supranucle-
ar and nuclear centres which exercise oculomotor con-
Reprint requests to:
trol (3, 4, 14). Furthermore the direct application of Prof. P.E. Bianchi
the cryode on the tendinous and muscular structures Clinica Oculistica
during treatment might induce a mechanical peripheral Universita di Pavia
IRCCS Policlinico S. Matteo
motorial anomaly. Piazzale Golgi, 2
No retinal cicatrical outcomes were observed in pa- 27100 Pavia, Italy

REFERENCES ma: Editeam 1995; 281-96.

1. Cryotherapy for Retinopathy of Prematurity Cooperative
Group. Multicenter trial of cryotherapy for retinopathy
of prematurity. One-year outcome. Arch Ophthalmol
1990; 108: 1408-16.
2. Bianchi PE, Marsili MT, Anselmetti R. Follow up dopo crio-
trattamento. Atti VIII Congresso Nazionale S.I.O.P. Boll
Ocul 1992; 5: 191-7.
3. Robinson R, O'Keefe M. Follow up study on premature
infants with and without retinopathy of prematurity. Br J
Ophthalmol 1993; 77: 91-4.
4. Topilow HW, Ackerman AL. Cryotherapy for stage III
plus retinopathy of prematurity: visual and anatomic re-
sults. Ophthalmic Surg 1989; 12: 864-71.
5. Ben Sira I, Nissenkorn I, Weinberger D. Long term re-
sults of cryotherapy for active stages of retinopathy of
prematurity. Ophthalmology 1986; 93: 1423-8.
6. Committee on classification of the late stages of ROP.
An international classification of retinopathy of prema-
turity. II the classification of retinal detachment. Arch
Ophthalmol 1987; 105: 906-12.
7. Palmer EA, Flynn JT, Hardy RJ, et al. Incidence and
early course of retinopathy of prematurity. Ophthalmol-
ogy 1991; 98: 1628-40.
8. Bianchi PE. Ricerca multicentrica sulla ROP. Dati oculis-
tici. In: Atti del I congresso societa italiana di neona-
tologia, Proceedings of the First Italian Congress of
Neonatology, Montecatini Terme, 21-24 June 1995. Ro-
9. Birch EE, Spencer R. Visual outcome in infants with ci-
catricial retinopathy of prematurity. Invest Ophthalmol Vis
Sci 1991; 32: 410-5.
10. Bianchi PE, Guagliano R, Chirico G, Rondini G. Le se-
quele non retiniche della R.O.P .. Boll Ocul 1991; 70:
273-83.
11. Kushner BJ. Strabismus and amblyopia associated with
regressed retinopathy of prematurity. Arch Ophthalmol
1982; 100: 256-61.
12. Shaffer DB, Quinn GE, Johnson L. Sequelae of arrest-
ed mild retinopathy of prematurity. Arch Ophthalmol
1984; 102; 373-6.
13. Snir M, Nissenkorm I, Sherf MO, et al. Visual acuity,
strabismus and amblyopia in premature babies with and
without retinopathy of prematurity. Ann Ophthalmol 1988;
20: 256-8.
14. Seiberth V, Knorz MC, Trinkmann R. Refractive errors
after cryotherapy in retinopathy of prematurity. Oph-
thalmologica 1990; 201: 5-8.
15. The Cryotherapy for Retinopathy of Prematurity Coop-
erative group. The natural ocular outcome of premature
birth and retinopathy. Status at one year. Arch Oph-
thalmol1994; 112: 903-12.
16. Flynn JT, Sola A, Good WV, Phibbs RH. Screening for
retinopathy of prematurity - a problem solved? (Editori-
al). Pediatrics 1995; 95: 755-7.
17. Phelps DL. Retinopathy of prematurity. Pediatr-Rev 1995;
16: 50-6.

191