MINI REVIEW - “What Is The Safety Of Fluoroquinolones For... Dorothy Koech

 MINI REVIEW - “What Is The Safety Of Fluoroquinolones For Children?”
Dorothy Koech
Newton Opiyo
Mike English
This review addresses the question “What is the safety of fluoroquinolones for children?”
The WHO Pocketbook of Hospital Care for Children recommends the use of the following
quinolone antibiotics:
1. Ciprofloxacin: Oral 10-15mg/kg per dose given twice per day for five days (maximum
500mg/dose). Use in children is only warranted if the benefits outweigh the risk of
arthropathy. (Pocketbook Appendix 2, pg. 333).
2. Nalidixic acid: oral 15mg/kg 4 times a day for five days (Pocketbook Appendix 2,
Ciprofloxacin is recommended as a suitable first line agent for the treatment of dysentery. It
further recommends the possible use of ciprofloxacin for typhoid fever, but not as first line
therapy. (Pocket Book Pg. 160)
The WHO pocket book does not mention the use of ciprofloxacin in neonates but studies reveal
that ciprofloxacin has been safely used as second line treatment for neonatal sepsis with good
Quinolones first became available in 1962 and their fluorinated derivatives, characterized by
broad-spectrum antimicrobial activity, were developed in the early 1980s[1]. Since their
development, fluoroquinolones have emerged as an important group of antibiotics particularly
ciprofloxacin, a 2nd generation fluoroquinolone.
The fluoroquinolones are characterized by a broad spectrum of antibacterial activity including
against Staphylococci, Shigella and Pseudomonas and are often useful where there are many
multiply-resistant bacterial strains. They act through the inhibition of bacterial DNA gyrase and
have good oral bioavailability, extensive tissue penetration, low protein binding and long
elimination half-lives.
Numerous clinical trials have shown that these compounds are effective and well tolerated in the
treatment of adult patients with various infections[2] .However, occasional toxicities among
paediatric populations, particularly cartilage toxicity[3] have limited fluoroquinolone use in this
Common reported adverse effects associated with fluoroquinolones are gastrointestinal, such as
nausea and diarrhoea, and central nervous system effects .Less common adverse effects include
dermatologic reactions, hepatic enzyme elevation, hypersensitivity, nephrotoxicity,
hematological reactions, tendonitis, and tendon rupture [4]. A potentially serious adverse effect
is the prolongation of the QTc interval [5] which can lead to cardiac arrhythmias.
To date, clinical experience gained with fluoroquinolones in pediatric infections has been mainly
from a compassionate-use basis. Potential indications include Pseudomonas infections (mainly
exacerbations of cystic fibrosis), urinary tract, gastrointestinal and central nervous system
infections, infections in immunocompromised patients, certain otorhinolaryngeal infections and
neonatal infections caused by multiply-resistant pathogens. There is currently no
recommendation for the use of ciprofloxacin for neonates.
The data on safety of quinolone antibiotics was summarized in a recently published ICHRC
review by Mitchell RC et al who evaluated a large number of studies
(n=29, 9 reviews; 7 RCTs;11 cohorts;1 case control and 1 case report) on the safety of
fluoroquinolones for children. They concluded that they are safe and efficacious for paediatric
populations when used for specific indications. Although preliminary reports of juvenile
arthropathy were a cause of concern such adverse reactions have proven to be very rare.
As the WHO and the government of Kenya now recommend Ciprofloxacin as first line treatment
of childhood dysentery we wished to update the Mitchell review with any new data relevant to
the safety of this drug.
Search Strategy
To update the searches run by Mitchell et al’s ICHRC review [6] the search was rerun through
pubmed-clinical queries using the search terms ((ciprofloxacin OR quinolones) AND
safety.))The searches were limited to “Newborn: birth – 1 month, Infant 1- 23 months, Preschool
Child: 2-5 years, Child: 6 – 12 years with only work on human subjects and published in
English included.
The studies to be included had to meet the following criteria:
(a) Intervention: use of fluoroquinolones - irrespective of the dose or route of administration
or indication.
(b) Control groups -Other antibiotic (irrespective of the dose or route of administration),
placebo, or no drug.
c) Participants: children (0-5 years)
d) Type of study: RCTs and observational studies
Any studies whose primary outcome measure was efficacy but contained safety data were
included. PubMed: under therapy, broad sensitive search, 82 articles were retrieved 40 of which were
relevant. Most of the studies had been appraised in the ICHRC review [6] .Eight recent and
relevant studies were initially identified for inclusion after two reviewers independently
reviewed the titles and abstracts of identified articles for relevance. However, three included
adult patients as participants and were excluded leaving the ICHRC review and 5 further
publications. In addition, some studies included in the review had data that the review did not
capture and we felt it wise to include these additional data. Supplementary searches then carried
out in pubmed related articles and the WHOLIS database reference lists of key articles retrieved
3 extra studies. The Cochrane Library was also searched using mesh terms ‘quinolones’,
‘ciprofloxacin’ and ‘safety’. No further studies were retrieved. The search process identified no
clinical practice guideline on fluoroquinolone use in neonatal and young infant sepsis. Full texts
of the eight articles not included in the prior review were sourced in addition to the ICHRC
review itself.
Summary of the previous review
Mitchell et al in her recent review on the safety of quinolones analysed a large number of
studies. All the controlled trials included in the review included a total of 1349 participants
while observational data were available on 4,343. The total additional participants within the
included reviews was not clear.
Most of the side effects reported in Mitchell et al’s review were found to be mild and transient.
The rates of arthralgia reported in the review ranged from 0% in 4 cohort studies, 1.5% in the
largest cohort (N=1795) and between 1% and 5% in the reviews .Arthropathy rates reported were
< 1% in the reviews. All these episodes of arthropathy resolved with cessation of treatment. An
exception were cohorts of children with cystic fibrosis, in Phillip et al and Salam et al (4% in
children through to 7-8% in adolescents) who reported unusually high rates of arthralgia in both
the treatment and control group (therefore implying no association with use of ciprofloxacin).
The RCTs (arguably providing the best evidence) in general reported only few, mild
arthropathies that resolved with cessation of treatment or no arthropathies at all. The most
frequently reported adverse effects in the RCTs were gastrointestinal, and CNS related,
(headache, dizziness.) with a frequency ranging from 2%-20%. All included reviews reported an
overall adverse events rate in children between 13 – 20%, which is comparable to rates seen for
many other antimicrobial agents. The range was however affected by the duration of treatment
and the particular fluoroquinolone used. All the cohort studies included in the review had results
consistent to those of RCTs and the reviews.
Based on the above data , Mitchell et al considers the adverse effect profiles as acceptable when
considered in light of the severity of the conditions for which the drugs are used in children.
However, caution should still be exercised and continued adverse event surveillance carried out.
New data
The following results are findings of publications not previously included in the review as well
as previously unreported neonatal data from two previously included neonatal studies to add to
one new study reporting the safety and efficacy of fluoroquinolones when used among neonates.
Included in this update are five prospective studies [3, 7-10],one retrospective study[11], one
RCT [12] and one review. Ciprofloxacin in Paediatric patients (General)
Leone et al [11] analyzed safety data on quinolones particularly and other antibacterial agents
from the passive surveillance system database (that relies on clinicians spontaneously reporting
adverse events) of three regions in Italy .The adverse effects being measured ranged from
musculoskeletal, skin, CNS, and gastrointestinal. The reported musculoskeletal events ranged
from 1.4% to 5.9 % for all the quinolones with an exception of levofloxacin and pefloxacin
whose rates were 25.9% to 22.5% respectively. Age specific results indicated that use of
fluoroquinolones in children was rare. Other limitations of such passive reporting are a bias
towards reporting immediate and not long term adverse effects and the inadequacies of
information concerning the fluoroquinolone prescription rates. However they concluded the
safety profiles of fluoroquinolones differed and should be accounted for during prescription of
the same.
A more recent prospective multicentre study [10] carried out in 8 countries compared children
taking levofloxacin with those taking other antibiotics and monitored them for adverse effects
for 1 year . Safety assessment was based on the incidence of musculoskeletal disorders,
relationship to therapy, and severity and on changes in physical exam. Levofloxacin was well
tolerated during and for 1 month after therapy as evidenced by similar incidence and character of
adverse events compared with other antibiotics. Differences between the incidences of reported
adverse effects involving weight-bearing joints in levofloxacin group and control group were,
however, statistically significant 2 months post therapy (P = 0.03) and 1 year post therapy (P=
0.047). Subsequently, evaluation of a larger experience that included this trial and 2 other
prospective clinical trials demonstrated that incidence of one or more of these disorders is greater
in levofloxacin-exposed children than in children treated with non fluoroquinolone antibiotics.
Singh et al[3]carried out a prospective study of 219 children aged 5days -14 years admitted in
paediatric wards, and receiving both oral and intravenous ciprofloxacin for various reasons.
Radiographs and MRI of the joints of these children were taken during therapy and were
repeated after 6 months, along with thorough physical examinations and lab investigations. The
X-rays and MRI did not reveal any abnormalities. Adverse drug reactions were noted in 35/219
(15.98%) children with arthropathy rates being only (0.9%) (2/219 children). The results of this
study also apply to neonates >5 day but the number of neonatal participants is not clear.
Dolecek et al [12], in a multicentre open label RCT carried out in Vietnam assessed the efficacy
and tolerability of gatifloxacin a third generation quinolone against azithromycin for treatment of
uncomplicated typhoid fever. The results of this study indicate that gatifloxacin was well
tolerated. No adverse effect related to gatifloxacin was observed. Gastrointestinal side effects
that were probably typhoid related were relatively frequent in both treatment arms and they did
not require interruption of therapy. This data adds to the evidence that fluoroquinolones are a
safe class of antibiotics in paediatric populations.
Ciprofloxacin for Neonates
A prospective observational study carried out at a special care nursery in a children’s hospital in
Bangladesh [7] administered ciprofloxacin to neonates with neonatal sepsis (n=48) and later
enrolled a matched group of neonates with neonatal sepsis (N= 66) that had been treated with
other antibiotics for comparison for follow up purposes. The neonates were then monitored for
any adverse effects. Physical examination was normal in both groups during follow-up. No
osteoarticular problems or joint deformities were observed in both groups. Treatment was not
interrupted at any one time since no side effects were detected. Normal development was
observed in 35.6%, mild impairments were found in 41.1% and serious impairments in 23.3%.
No differences in development (physical and cognitive) were apparent between the groups.
An additional prospective observational study that was carried out in India [8]involved thirty
neonates with multi drug resistant septicaemia, who were treated with ciprofloxacin for a period
of 14 days and another thirty with neonatal sepsis received other antibiotics formed the
comparison group. Serial ultrasonographic measurements of the knee cartilage taken after one
and six months indicated no difference in the two groups. The femoral cartilage showed an
increase of 78.8% and 78.4% in the mean longitudinal area after 6 months in the study group and
control group respectively indicating that growth and development rates were the same for the
two groups.
In a third prospective observational study neonates with sepsis [9] aged approximately 2-4 weeks
received either ciprofloxacin (n=116) or other antibiotics (n=100) . The decision on the kind of
antimicrobial to be used was left purely on the attending physician. The neonates were followed
up for a period of one year and monitored for adverse effects. No clinical evidence of
arthropathies was reported both during the hospitalization and follow-up period. No potential
effects on growth were observed, although height may be totally independent of cartilage
damage. Moreover, this study concluded that ciprofloxacin administration to neonates with
sepsis is not associated with increased risk for hematologic, hepatic or renal dysfunction neither
is it associated with clinical arthropathy or growth impairment of the treated infants during the
first year of life.
The fluoroquinolone class of antimicrobials has been in clinical use for over 17 years now [14].
For a long time quinolones had not been approved for use in children, primarily because of
concerns they could cause irreversible damage to growing cartilage in weight bearing joints,
concerns resulting from effects in immature animals [15]. In some cases drugs in this class have
been withdrawn for safety reasons (namely, trovafloxacin and grepafloxacin and temafloxacin)
however other agents have been extensively prescribed, such as ciprofloxacin and levofloxacin.
Most of the data present is on ciprofloxacin but in all it is clear that fluoroquinolones cannot be
considered interchangeable in terms of efficacy or tolerability and safety [1]. A large recent
study[10] on exposure to levofloxacin indicated it was associated with a small but statistically
significant increased risk of developing a set of musculoskeletal disorders. These disorders
however were typically transient and all resolved without apparent sequelae over the 1-year
period of observation. Some caution must be used in interpreting these findings as are based on
somewhat subjective observational data linking the drug administered 1 to 12 months before the
side effect. Thus, although relatively reassuring, the limited ability to detect very rare events
should also be considered in using these data to assess overall risk of using levofloxacin in
Despite this, the results reported by Dolecek et al’s trial[12] on gatifloxacin a newer
fluoroquinolone, are comparable to the excellent clinical outcomes achieved with ofloxacin in
Vietnam in the early 1990s when S. typhi isolates were still susceptible to nalidixic acid [16]. No
adverse effect related to gatifloxacin was observed. Another very large comprehensive
review[17] including over 7000 children and adolescents who received ciprofloxacin, ofloxacin
or nalidixic acid failed to show any association between quinolone use and arthropathy.
Three prospective observational studies included in this review [3, 7, 8] suggest that
ciprofloxacin may be a safe therapeutic option for newborns with sepsis produced by multiple
resistant organisms...In view of this, there seems to be no reason to withhold short courses of
ciprofloxacin from neonates when alternative unrestricted therapies are either unavailable or
A recent ICHRC review [6] -on which this update is based- indicated, on the basis of numerous
paediatric studies worldwide, that fluoroquinolones, particularly ciprofloxacin are safe and they
will therefore play an important role in the treatment of a variety of severe paediatric infections
where any risk is outweighed by potential benefit. Ciprofloxacin is a particularly useful
fluoroquinolone for dysentery and typhoid and a role may emerge for treatment of highly
resistant infections in the neonatal period. There is less experience with other fluoroquinolones
and in the case of levofloxacin a suggestion of marginally higher rates of arthropathy.
The attrition levels of the studies included in this review was large, Ahmed et al reported
a death rate of 57% of the neonates enrolled and a dropout level of 13% although the
death rate was lower in the ciprofloxacin group. The neonates who died before the 15th
day after the initiation of the treatment or who did not complete the laboratory follow-up
were excluded from the study.
The absence of ultrasonographic evidence to support the clinically observed finding s in
three of these studies warrants the need of larger and methodologically reliable studies
for fluoroquinolone use in neonates
Overall, the validity of the findings of this review is limited by the small sample sizes in
the included studies
Some of the studies [3, 8, 12] had a short follow up period compared to the rest and this
complicates the comparability among them..
There is no evidence that permanent arthritis is induced by quinolone use in humans. All studies
utilizing radiographic techniques, or monitoring growth and joints over long time periods have
noted only rare development of transient and mild arthralgia or arthritis. Most experience is with
Ciprofloxacin which therefore appears safe for use in the paediatric age group. Some data
indicate safety in the neonatal period too but more and better data are required for any definitive
There is no evidence that permanent arthritis is
induced by quinolone use in humans.
Adverse effects rate for most fluoroquinolones
is comparable to other antimicrobial agents, and
that most they are mild and transient.
This adverse effects profile is acceptable in light
of severity of the conditions
Most data refer to the safety of Ciprofloxacin in
Fluoroquinolones cannot be considered
interchangeable in terms of efficacy or
tolerability and safety; Safety data of each
drug varies.
Levofloxacin has the highest rates of adverse
effects-particularly musculoskeletal and the
probability of them developing increased
with time-after exposure- within 1 year.
However they are mild and transient and
resolved without sequelae within a year.
Ciprofloxacin may be a safe therapeutic
option for newborns with sepsis produced by
multiply resistant organisms especially where
REFERENCES [1] Ball P. The quinolones: History and overview The Quinolones3rd ed San Diego, Calif: . 2000. [2] Dagan R. Fluoroquinolones in paediatrics‐‐1995. Drugs. 1995;49 Suppl 2:92‐9. [3] Singh UK, Sinha RK, Prasad B, Chakrabarti B, Sharma SK. Ciprofloxacin in children: is arthropathy a limitation? Indian J Pediatr. 2000 May; 67(5):386‐7. [4] Fish DN. Fluoroquinolone adverse effects and drug interactions. Pharmacotherapy. 2001 Oct;21(10 Pt 2):253S‐72S. [5] Congeni BL, Thomson RB, Jr. Fluoroquinolones: considerations for future use. Pediatr Infect Dis J. 2002 Apr;21(4):345‐6. [6] Mitchell R CN. Are quinolones safe to use in children? International child Health Review Collaboration. 2008. [7] Ahmed AS, Khan NZ, Saha SK, Chowdhury MA, Muslima H, Law P, et al. Ciprofloxacin treatment in preterm neonates in Bangladesh: lack of effects on growth and development. Pediatr Infect Dis J. 2006 Dec;25(12):1137‐41. [8] Chaudhari S, Suryawanshi P, Ambardekar S, Chinchwadkar M, Kinare A. Safety profile of ciprofloxacin used for neonatal septicemia. Indian Pediatr. 2004 Dec;41(12):1246‐51. [9] Drossou‐Agakidou V, Roilides E, Papakyriakidou‐Koliouska P, Agakidis C, Nikolaides N, Sarafidis K, et al. Use of ciprofloxacin in neonatal sepsis: lack of adverse effects up to one year. Pediatr Infect Dis J. 2004 Apr;23(4):346‐9. [10] Noel GJ, Bradley JS, Kauffman RE, Duffy CM, Gerbino PG, Arguedas A, et al. Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders. Pediatr Infect Dis J. 2007 Oct;26(10):879‐91. [11] Leone R, Venegoni M, Motola D, Moretti U, Piazzetta V, Cocci A, et al. Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three italian regions. Drug Saf. 2003;26(2):109‐20. [12] Dolecek C, Tran TP, Nguyen NR, Le TP, Ha V, Phung QT, et al. A multi‐center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PLoS ONE. 2008;3(5):e2188. [13] Forsythe CT, Ernst ME. Do fluoroquinolones commonly cause arthropathy in children? Cjem. 2007 Nov;9(6):459‐62. [14] Mandell L, Tillotson G. Safety of fluoroquinolones: An update. Can J Infect Dis. 2002 Jan;13(1):54‐61. [15] Krasula RW, Pernet AG. Comparison of organ‐specific toxicity of temafloxacin in animals and humans. Am J Med. 1991 Dec 30;91(6A):38S‐41S. [16] Vinh H, Wain J, Vo TN, Cao NN, Mai TC, Bethell D, et al. Two or three days of ofloxacin treatment for uncomplicated multidrug‐resistant typhoid fever in children. Antimicrob Agents Chemother. 1996 Apr;40(4):958‐61. [17] Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone arthropathy in animals versus children. Clin Infect Dis. 1997 Nov;25(5):1196‐204. [18] Childs S. Safety of the fluoroquinolone antibiotics; focus on the molecular structure. Infect Urol 2000;13::3‐10. SUMMARY OF EVIDENCE
Dolecek et
al 2008
open label
N = 358
No. of children
109 vs. 101 in
treatment and
control groups
3 hospitals in
the south of
Patients with clinically
suspected or culture
confirmed uncomplicated
typhoid fever.
(Median age =11years)
Oral treatment with either
20 mg/kg azithromycin
(n=101) or
10 mg/kg gatifloxacin
(n=109) once daily for
seven days.
Patients were followed up
for six months
Noel G et
al 2007
, Brazil
and USA
87 centers in
8 countries
from August
‘02 to
8 countries
Children who took at least
1 dose of levofloxacin or
comparator as part of any
of the previous efficacy
trials described above
were eligible
children randomized
to receive levofloxacin versus
were compared and followed
up 1 year post therapy.
Both treatments were well tolerated. One adverse
event related to azithromycin reported, a
maculopapular rash.
Gastrointestinal side-effects -probably typhoid
related were relatively frequent in both treatment
arms at the start of treatment.
In the gatifloxacin group, one patient experienced
vomiting on day 2 & 3 and one patient diarrhoea
(4 episodes/day) on day 4 &5 of treatment.
These episodes were self-limiting and did not
require the interruption of therapy.
Safety assessment was based on the incidence of
musculoskeletal disorders, relationship to
therapy, and severity and on changes in physical
Levofloxacin was well tolerated during and for 1
month after therapy but had higher rates of
adverse events than other fluoroquinolones.
Differences between the AE incidences of
reported AE involving weight-bearing joints in
levofloxacin group and control group were
statistically significant 2 months post therapy (P
= 0.03)&1 year post therapy (P= 0.047).
Leone et
al 2003
(all age groups)
Spontaneous adverse
effects reports collected
between January 1999
and December 2001 were
Complete adverse effects
reports between January
1999-December 2001
All ages.
Children had lowest reporting rates , along with
the lowest consumption, this could however be
indicative of absence of adverse effects among
children.22.5% involved fluoroquinolones.
Most reactions involved the skin (25%)
significantly lower (p < 0.01) than other systemic
antimicrobials (58.5%). CNS reactions (12.2 vs.
3.6%) musculoskeletal (14.7 vs. 0.3%) &
psychiatric (9.3 vs. 1.8%) were significantly
higher (p< 0.01).
All reports of ADRs
occurring in association
with fluoroquinolones
during the study period
were analyzed in detail.
Individual safety profiles: ciprofloxacin-more
skin reactions noted (p < 0.01), levofloxacin and
pefloxacin - musculoskeletal (p < 0.01), Toxic
epidermal necrolysis and Stevens-Johnson
syndrome were seen only ciprofloxacin.
Singh et al
Children admitted for a
variety of infections
Age range (5 -14 days)
ciprofloxacin doses:
20 mg/kg/day and
10mg/kg/day orally and
respectively in two divided
Physical &lab
investigations &
ultrasonography done to
monitor adverse effects .
ADR was observed in 15.98% of the children.
and arthropathy observed in 0.9% of children
The X-rays and M.R.I. of involved joints did not
reveal any abnormality either during treatment or
six months after discontinuation of therapy.
Ciprofloxacin was completed successfully in all
other children.
Ahmed et al
Chaudhari al 2004
N = 492
Special Care
size N
Newborn infants <72
hours old and (preterm
neonates; <33 weeks)
Excluded: major
congenital anomaly,
generalized skin disease,
ciprofloxacin for ≥ 5 days (n=92)
Other antibiotics, mainly cefotaxime,
gentamicin & ampicillin.(n=400)
Physical examination normal in both groups
during follow up.
No evidence of acute joint toxicity in form of
swelling, tenderness or restricted movement
during or after treatment. No joint deformities
Similar weight, length or head circumference in
both groups at any of the ages studied.
Normal development was observed in 35.6%,
mild impairments found in 41.1% and serious
impairments in 23.3%.
No differences in development (physical and
cognitive) between the groups.
Treatment with ciprofloxacin started
between the 3rd &16th days of age.
structural defect >5%
BSA &admission for
major surgery.
Length of treatment (range, 5-17days).
No side effects detected during treatment.
Neonates with
(Age not clear)
Ciprofloxacin 20 mg/kg in 2 divided doses
as a slow intravenous infusion over a
period of 30 minutes, for 14 days (n=30)
Other antibiotics (cefotaxime, amikacin),
enrolled for comparison (n = 30)
Treatment with ciprofloxacin started on
days 5-13
No difference noted in the mean serum
electrolytes, hepatic, renal and hematologic
parameters of the two groups. Serial
ultrasonography of knee cartilage after 1 and 6
months showed no difference in the two groups.
Increase in femoral cartilage-78.8% & 78.4% (
mean longitudinal area) after 6 months in the
study group & control group respectively.
Tibial cartilage - no difference in the % increase
in size in both groups at the end of 6 months.
After control for birth weight & gestation,
cartilage size was not affected by ciprofloxacin.
Drossou et
al 2004
N =216
Admitted neonates with
proven/ probable sepsis;
The age range 14±19
(range, 1 to 44) days and
12 ±8 (range, 1 to 31)
Excluded :
Any deaths ≥15th day
after initiation or failure
to complete the lab
Ciprofloxacin was administered in a
dosage of 10 mg/ kg/day in 2 divided
doses (N=116 [89 preterm; 27 term])
A broad range of antimicrobials
(N=100 [88 preterm; 12 term])
[ampicillin penicillin gentamicin/amikacin
imipenem,vancomycin amphotericin B
metronidazole and
No significant differences in the hematologic
indices and the biochemical markers of hepatic
and renal function in the two groups
Although no ultrasound and MRI of the joints
was performed, no clinical evidence of
arthropathy was observed during either the
initial hospitalization or follow-up.
One neonate from each group developed
greenish discoloration of the teeth during 1st year
of life. Growth rate was comparable in the two
groups studied