The incidence of both acute ROP, and of the more severe stages, varies inversely with gestational age at birth. ROP is unusual (except in the mildest forms) in infants of greater than 31 weeks gestation (Palmer 1991). However, 84% of infants less than 28 weeks gestation develop acute ROP, and close to 11% develop 'threshold ROP' and undergo ablative surgery (cryotherapy or laser photocoagulation) to the peripheral avascular retina to reduce the risk of disease progression to retinal detachment (CRYO-ROP 1990).
The pathophysiology is understood to start with injury to the incomplete developing retinal capillaries. This could potentially occur before or during birth, but is thought to primarily occur in the days following delivery. Once the developing vessels have been damaged, it is hypothesized that the retina responds with the production of vascular growth factors stimulating neovascularization (which is the observable retinopathy) which may successfully revascularize the retina (regression of the ROP), or progress to neovascular membranes in the vitreous and subsequent scarring (cicatrix) and retinal detachment. Recent research suggests that vascular endothelial growth factor (VEGF) is one of the more important growth factors involved in this process (Aiello 1996, Aiello 1997).
Interventions:
Efforts to reduce morbidity from ROP can be grouped into preventive
and interdictive categories. While prevention would be best aimed at preventing
premature birth, once that birth is inevitable, preventive efforts are
directed at reducing stressors that may lead to injury of the developing
retinal capillaries. To date, investigations have focused on the antioxidants
Vitamin E or D-penicillamine, reduction of light exposure (Phelps
1997), and control of exogenous oxygen delivery (Flynn
1987, Kinsey 1956; STOP-ROP
2000). Animal models or clinical data have suggested that each of these
mechanisms may cause retinal vascular injury. For purposes of determining
what preventive treatments to consider using, it is important to remember
that preventive interventions must be applied to all premature infants,
not just those infants who develop ROP, and therefore potential side effects
should be minimal.
Interdictive approaches target just those eyes that already have ROP of a defined severity. The goal is to control or arrest the progression of the neovascularization (even at the sacrifice of some of the retina) in order to preserve central vision. Cryosurgical or laser ablation of the peripheral avascular retina destroys the cells that are the putative source of the neovascular growth factors, thus allowing regression of the neovascularization and ablating retina that would need new vessels.
D-Penicillamine Prophylaxis:
Oxygen free radicals are candidates for causing the injury to developing
retinal capillaries in the premature infant. As a chelator of pro-oxidant
heavy metals, d-penicillamine has the potential to reduce the amount of
free radical activity in the tissues of the premature infant when given
soon after birth. In addition to its oxygen radical scavenger properties,
d-penicillamine is also known to alter the biological profile of native
peptides by acting on disulfide bonds. Since most of the vascular growth
factors depend on disulfide linkages, it could also act through reducing
the bioavailability of the growth factors VEGF, Endothelin-1, etc. (Hunt
1993, Matsubara 1989, Yoshida
1995, Pierraforte 1995, McBrien
1994, Siemeister 1996).
Over an eight year period (1974-1982) while studying the administration of intravenous d-penicillamine to prevent or treat hyperbilirubinemia, Lakatos and colleagues noted a low incidence of ROP among the treated infants (see references in the excluded studies section (Lakatos 1986 for a summary). Therefore, they investigated the efficacy and safety of d-penicillamine for preventing ROP.
Side effects of oral d-penicillamine therapy, which is used for rheumatoid arthritis, Wilson's disease and cystinuria, have been reported, and may be fatal. Many of these are similar to autoimmune disorders and include pruritis, membranous glomerulonephritis, lupus erythematosus (or similar skin eruptions), Goodpasture's syndrome, drug fever, myasthenia gravis, polymyositis, aplastic anemia, thrombocytopenia, and agranulocytosis. Drosos et al have reported the strong association of such side effects with circulating cryoglobulins or autoantibodies in rheumatoid arthritis patients (Drosos 1997). However, oral d-penicillamine in patients with Wilson's disease or cystinuria can also result in similar toxicity. Interruption of d-penicillamine therapy has to be balanced between the risk of interrupting the mother's therapy and the potential toxicity to the fetus. Infants born following in utero exposure have been reported with connective tissue disruption, poor wound healing or cutis laxa, although most infants exposed to d-penicillamine in utero have been normal.
Short courses of oral d-penicillamine therapy used in children or adults for acute heavy metal overdose have not been associated with such side effects. The only reports of intravenous use of d-penicillamine in humans come from the same group as have reported the ROP results. Among earlier studies on at least 140 term and preterm newborns for the treatment of hyperbilirubinemia, only three infants with side effects were observed: two had mild erythematous rashes that quickly resolved with antihistamines, and one had vomiting which resolved when the drug was stopped (Lakatos 1976, Koranyi 1978, Lakatos 1976a). Specific testing of renal and hepatic function were within normal limits on a few selected infants, and growth was not affected. Altogether, small numbers of infants have received intravenous d-penicillamine with few if any side effects. Few data are available on either the acute or long term outcomes of early, short course intravenous d-penicillamine treatment.
Previous Overviews of D-Penicillamine Administration:
A search of Medline, EMBASE, bibliographic references of published
research on d-penicillamine treatment, and personal discussion with investigators
involved in ROP research all carried out in 1997, uncovered only one previous
systematic review, published in the book Effective Care of the Newborn
Infant (Watts 1992). No meta-analysis was attempted
in that review as only one trial had been included. Subsequently, one additional
randomized controlled trial from the same group was identified. A Cochrane
review was undertaken and published in 1998 (Phelps/Lakatos
1998). This is an update of that review.
Validity: Trials were assessed for
Randomized or quasi-randomized assignment
Concealment of group assignment prior to randomization
Masking of ophthalmologists determining the outcome
Follow up rate >90%
Studies were excluded if there was no random or quasi-random assignment to study group.
Severe ROP outcomes in this review include complete retinal detachment (stage 5 in the International Classification of ROP), or cicatricial ROP defined as Reese classification of Grade II or worse (Reese 1953).
Death from any cause prior to discharge to home.
Acute side effects include rashes, vomiting, or other reported abnormalities other than death -- also iron deficiency, nephropathy, aplastic crises, or myasthenia gravis type syndrome.
Rehospitalizations were counted as the number of rehospitalizations in the group followed and include repeated hospitalizations in some of the children.
Abnormal neurodevelopment was defined as present if there was spasticity, seizures, cerebral palsy, or DQ<70 at one year corrected age.
Because so few citations were expected, the search was not limited by type of methodology used. In addition to the following databases, reports were retrieved from cross references to bibliographies from retrieved articles and interviews of expert informants. Databases searched included: The Cochrane Neonatal Group's Specialized Register of Controlled Trials, MEDLINE January 1966 - November 2000, CINAHL through July 1996, EMBASE January 1980 - August 2000, HealthSTAR to August 1996, Science Citation Index (Current Contents) Database from January 1984 through November 2000, CATLINE, CANCERLIT, the Oxford Database of Perinatal Trials, and the Cochrane Library, Issue 2, 2000. In addition, the authors of the trials located provided additional reference lists that they had compiled.
Data were extracted from the trials determined to be valid by all three authors independently, and consensus reached on the final data before entry into this report. Acute ROP was recorded as present if any stage of ROP was reported at any time during hospitalization or follow up. Severe ROP was considered as cicatricial grade II ROP or worse as classified by Reese (Reese 1953).
The final data, report and conclusions were approved by all authors. This update (2000) was prepared only by the first author as no new studies were identified.
If acute ROP was diagnosed at any stage, children in the control group were then given d-penicillamine 50mg/kg daily for three weeks. Therefore, the diagnosis of progression to severe ROP in this analysis, as well as other longer term morbidities occurs following administration of active drug to some of the infants in the control group after six weeks of age. Most neonatal deaths occur in the first week following birth, and remaining deaths are rare after six weeks. Therefore the outcome of death is unlikely to have been affected by administration of active drug to control infants who developed ROP, but this study design feature contaminates to some degree other long term outcomes such as growth and neurodevelopmental follow up.
204 infants were randomized. Deaths before discharge occurred at similar rates (29/100 in the treated infants, 34/104 in the controls), and ROP was diagnosed in none of the 71 treated survivors, and in six of the 70 control survivors. Two of the infants with ROP progressed to cicatricial stages; but neither of those cases progressed to blindness. No acute toxicity was reported in either group during hospitalization, but there was no prospective, systematic collection of potential side effects either.
1a. Vekerdy-Lakatos 1987 (follow up of above infants)
At one year of age, the infants from the study reported above were
evaluated in follow up. There were three deaths after discharge so that
69 treated (69%) and 69 controls (66%) survived to age one year. Of these,
87% in each group returned for evaluation. Spasticity or seizures occurred
in three (5%) of the treated infants and five (8%) of the children originally
randomized to the control group. There were no significant differences
in developmental quotients or growth parameters, but rehospitalizations
occurred more frequently in controls (59 times in 28 children) than in
the treated infants (23 times in 15 children). Recall that six of the control
infants (those that developed ROP) also received late d-penicillamine for
three weeks when their ROP was diagnosed.
2. Lakatos 1987 -- Included
77 infants of birth weights 751-1500g were randomized to receive d-penicillamine
or be controls between July 1, 1984 and March 1, 1985. Randomization was
designed to be weighted 2:1, treated:control, and the study was to end
when/if three infants in the control group developed ROP (personal communication
Lakatos). The dose was 300mg/kg/day (divided into three doses) for three
days, then 50mg/kg/day (single dose) through two weeks of age. Infants
in the control group who later developed acute ROP were then given active
drug, d-penicillamine, for three weeks (50mg/kg/day IV) starting at the
time of diagnosis of the ROP.
The results of this trial are reported by the authors in combination with the results of Lakatos 1986. Therefore, the results from this separate randomization have been derived by subtraction between the two publications. Tables of outcomes within the birth weight strata in Lakatos 1986 permitted a subgroup analysis for just those infants <1500g birth weight. The data extraction was confirmed by the original investigator, and all authors agreed upon the final data.
While a 2:1 randomization ratio was placed in the envelopes used, the envelopes were not randomized in blocks, so that when the study was terminated after three infants developed ROP in the control group, the actual numbers randomized were in a ratio of 1.4 to 1 (personal communication Lakatos). 18/45 d-penicillamine infants died, and 10/32 control infants. Acute ROP occurred in 0/27 d-penicillamine survivors, and in 3/22 control survivors. Two of the ROP infants progressed to cicatricial changes, and one had probable severe vision impairment.
Of additional interest, the investigators also reported one infant with total vision loss from ROP despite d-penicillamine prophylaxis treatment during the four month gap between the two trials.
Lakatos 1987:
Randomized assignment - yes
Concealed randomization? - yes, using sealed envelopes
Both groups otherwise treated similarly? - yes
Placebo controlled? - no
Outcome determined by masked investigators? - yes
International Classification of ROP - yes
All enrollees accounted for? - yes
Early follow up >90% - yes
Late follow up: not done
Thirty-nine articles reporting the use of d-penicillamine in neonates were identified. Two randomized controlled trials reporting ROP outcomes were identified in five publications, plus one additional publication reporting one year outcomes of the first trial. Publication of the results in different language journals permitted the review of each trial by all authors.
Treatment, populations and outcome determination were sufficiently similar that combining the results for meta-analysis was determined to be appropriate for death and ROP outcomes. The number of infants <1000g birth weight was too small (eight survivors) to justify a separate subgroup analysis.
ROP of some degree was observed in 9/62 or 14.5% of all control infants reported. The relative risk of developing acute ROP in the d-penicillamine group (all birth weights <2000g) was 0.09, [95% confidence interval 0.01-0.71]. When the subgroup of infants under 1500g birth weight was examined, the results were similar: relative risk 0.09, [95% confidence interval 0.01-0.68].
Death rates were similar for all infants <2000g, relative risk 0.99, [95% confidence interval 0.70-1.39], or the subgroup <1500g, relative risk 0.98, [95% confidence interval 0.68-1.39].
Long-term follow up was completed in 87% of the one year survivors of the first trial and revealed no significant differences in growth (weight, length or head circumference), developmental quotients, spasticity or survival.
Side effects associated with the intravenous use of d-penicillamine in neonates was sought in both the controlled trials reported above (none noted) and in the previously reported trials where the drug was used to treat hyperbilirubinemia. In the hyperbilirubinemia studies, either oral or intravenous d-penicillamine had been used for a duration of days. Looking across studies, at least 140 infants received intravenous treatment and only three were observed to have side effects -- one had vomiting, and two had erythematous skin rashes which resolved with stopping the drug and treatment with antihistamines.
Another antioxidant that has been studied for the prevention of ROP, vitamin E, has had less impact than hoped for on the incidence of ROP, but may reduce severe stages of ROP by as much as 50% relative risk and also warrants further study. A recent systematic review of the Vitamin E for ROP trials has been conducted by Raju and colleagues (Raju 1997).
There are clearly sufficient data to justify further investigation of this drug. Safety data to date do not raise concerns about side effects with this relatively short term intravenous use, although long term use in children and adults with other disorders is accompanied by frequent and sometimes severe side effects. A multicenter randomized, masked controlled trial of intravenous d-penicillamine appears justified. Pilot studies would be needed to determine if oral d-penicillamine should be tried.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Lakatos 1986 | Randomized controlled trial. Controls received drug if ROP developed | Premature infants, 751-2000g birth weight, 1/1/83 through 3/6/84 | From day of birth, d-penicillamine intravenously, 300mg/kg/day (divided
in 3 doses) x 3 days, then 50mg/kg/day until 2 weeks if <1500g. Infants
of 1500-2000 g received additional doses if they required oxygen beyond
3 days. No placebo was used in controls.
Once ROP developed after 6 weeks of age, d-penicillamine was given to any infants with ROP |
Death before discharge
Acute ROP in survivors |
Group assignment not concealed from pediatricians, but ophthalmologists doing ROP examinations were masked to study group. | A |
| Lakatos 1987 | Randomized controlled trial. 2 to 1 ratio of randomization of drug
to control
Controls received drug if ROP developed |
Premature infants of 751-1500 grams birth weight 7/1/84-3/1/85 | From day 1, d-penicillamine intravenously, 300mg/kg/day (divided in
3 doses) x 3 days, then 50mg/kg/day for 11 more days (to 2 weeks). No placebo
was used for controls.
d-penicillaine given after 6 weeks to all infants who developed ROP |
Death before discharge home
Acute ROP in survivors |
Pediatricians not masked to group assignment. Ophthalmologists determining ROP outcomes were masked. | A |
| Study | Reason for exclusion |
| Lakatos 1974-84 | Non random allocation, observed cohorts over years 1974-78, 1979-80, and 1981-82, making these historical comparisons. |
| Lakatos 1982 | Non-random allocation, cohort descriptions, multiple publications |
* Lakatos L, Hatvani I, Oroszlan G, Balla G, Karmazsin L, Alaka O, et al. Controlled trial of D-penicillamine to prevent retinopathy of prematurity. Acta Paediatr Hungar 1986;27:47-56.
Lakatos L, Hatvani I, Oroszlan GY, Balla G, Karmazsin L, Olubunmi A, et al. Prevention of retinopathy of premature infants with D-penicillamine [Hungarian]. Orvosi Hetilap 1985;126:1391-1396.
Vekerdy-Lakatos S, Lakatos L, Oroszlan G, Itzes B. One year longitudinal follow-up of premature infants treated with D-penicillamine in the neonatal period. Acta Paediatr Hungar 1987;28:9-16.
Lakatos L. D-penicillamine and retinopathy of prematurity [letter]. Pediatrics 1988;82:951-953.
Lakatos 1987 {published data only}
Lakatos L, Lakatos Z, Hatvani I, Oroszlan G. Controlled trial of use of D-Penicillamine to prevent retinopathy of prematurity in very low-birth-weight infants. In: Stern L, Oh W, Friis-Hansen B, editor(s). Physiologic Foundations of Perinatal Care. Elsevier, 1987:9-23.
Lakatos L. D-Penicillamine in the prevention of retinopathy of prematurity [German]. In: Die Retinopathie des Fruhgeborenen. Gustav Flscher Verlag, 1984:197-199.
Lakatos L, Hatvani I, Oroszlan GY, et al. Clinical Observations in the prevention of retrolental fibroplasia with D-penicillamine. In: Stern L, Xanthou M, Friis-Hansen B, editor(s). Physiologic Foundations of Perinatal Care. Elsevier, 1985:293-305.
Lakatos 1982 {published data only}
Lakatos L, Hatvani I, Karmazsin L, et a. Is the treatment of prematurely born infants with D. penicillinamine decreasing the frequency of retrolental fibroplasia? [Hungarian]. Szemeszet 1980;117:9-12.
Lakatos L, Hatvani I, Oroszlan GY, et al. Prevention of retrolental fibroplasia with D-penicillamine[Hungarian]. Gyermekgyogyaszat 1981;32:525-530.
Lakatos L, Hatvani I, Oroszlan G, Karmazsin L, Matkovics B. D-penicillamine in the prevention of retrolental fibroplasia. Acta Paediatr Acad Sci Hungar 1982;23:327-335.
Lakatos L, Hatvani I, Karmazsin L, Oroszlan G. Prevention of retrolental fibroplasia in very low birth weight infants by D penicillamine. Eur J Pediatr 1982;138:199-200.
Hatvani I. Prevention and treatment of retinopathy of prematurity (Retrolental Fibroplasia)[Hungarian]. Thesis and dissertation. Hungarian Academy of Science 1984.
Lakatos L. Antioxidant effects of d-penicillamine in the neonatal period. Magyar Pediater 1982;16:355-362.
* indicates the primary reference for the study
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Aiello LP: Vascular endothelial growth factor. 20th-century mechanisms, 21st-century therapies. Investig Ophthalmol Vis Sci 1997;38:1647-1652.
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Drosos AA, Geogriou P, Politi EN, Voulgari PV. D-penicillamine in early rheumatoid arthritis. Clin Exper Rheumatol 1997;15:580.
Flynn JT, Bancalari E, Bawol R, Goldberg R, Cassady J, Schiffman J, Feuer W, Roberts J, Gillings D, Sim E, Buckley E, Bachynski BN. Retinopathy of prematurity: A randomized, prospective trial of transcutaneous oxygen monitoring. Ophthalmology 1987;94:630-638.
Hunt JT, Lee VG, Liu ECK, et al. Control of peptide disulfide regioisomer formation by mixed cysteine-penicillamine bridges. Int J Peptide Protein Res 1993;42:249-258.
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Kinsey V, Jacobus J, Hemphill F. Retrolental Fibroplasia: Cooperative study of retrolental fibroplasia and the use of oxygen. Arch Ophthalmol 1956;56:481-547.
Koranyi G, Kovacs J, Voros I. Penicillamine treatment of hyperbilirubinemia in preterm infants. Acta Paediatr Acad Sci Hungar 1978;19:9-16.
Lakatos L, Kover B, Peter F. D-penicillamine therapy of neonatal hyperbilirubinemia. Acta Paediatr Acad Sci Hungar 1974;15:77-85.
Lakatos L, Kover B, Vekerdy ZS, Dvoracsdk E. D-Penicillamine therapy in neonatal jaundice: comparison with phototherapy. Acta Paediatr Acad Sci Hungar 1976;17:93-102.
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01.05 Rehospitalizations in survivors followed up
01.06 Abnormal neurodevelopment in survivors followed up
02.05 Rehospitalizations in survivors followed up (no data)
02.06 Abnormal neurodevelopment in survivors followed up
Prof Lajos Lakatos