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Ocular Manifestations in Children Born After In Vitro Fertilization
Arch Ophthalmol. 2001;119:1525-1529.
ABSTRACT
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Objective To report the ocular abnormalities found in children born after in vitro
fertilization.
Methods Forty-seven children (25 girls and 22 boys) born after an in vitro fertilization
pregnancy (mean ± SD birth weight, 2335 ± 817 g; range, 924-4300
g) and referred for ophthalmic evaluation were included in the study. All
underwent a thorough ocular examination. Obstetric history was gathered following
a detailed questionnaire with the mothers.
Results Of 70 eyes among nonverbal children, visual acuity was "normal for age"
in 60 (86%), "fair" in 4 (6%), and "poor" in 6 (9%). Visual acuity in 24 eyes
in verbal children ranged from 6/6 to no light perception, with 4 (17%) having
poor vision. Cycloplegic refraction disclosed an emmetropia in 22 (27%), hypermetropia
in 47 (57%), and myopia in 13 (16%) of the eyes. Anisometropia of more than
1.0 diopters was found in 8 children. Major ocular malformations were observed
in 12 (26%) of the 47 children. These malformations included Coats disease,
congenital cataract, congenital glaucoma, hypoplastic optic nerve head, idiopathic
optic atrophy, coloboma with microphthalmos, and retinoblastoma.
Conclusions Ocular anomalies were frequently observed in this cohort of offspring
born after in vitro fertilization. A diligent and prospective prenatal search
for such malformations should unveil the real prevalence of ocular malformations
in children born after in vitro fertilization.
INTRODUCTION
THE NUMBER of infants born after in vitro fertilization (IVF) is increasing
steadily as the techniques of micromanipulation and neonatal intensive care
evolve. The prevalence of neonatal and postnatal developmental abnormalities
among this fast-growing population of children remains, however, largely unknown.
Few prospective studies on this subject have been performed. It has been reported
that the rate of malformations detected in children born after IVF is similar
to that observed in the non-IVF newborn population.1-6
Some studies,7-9
however, disclosed an elevated rate of chromosomal aberrations among the IVF-born
offspring. These chromosomal abnormalities affected primarily sex chromosomes.
The purpose of the present study is to report the ocular findings (and
abnormalities) detected in 47 children born after IVF and evaluated in our
pediatric ophthalmology unit between July 1, 1994, and December 31, 1999.
The possible association of these ocular abnormalities with the intracytoplasmic
sperm injection (ICSI) method of micromanipulation is also examined.
PATIENTS AND METHODS
Forty-seven children (25 girls and 22 boys) born after IVF were examined
in the Pediatric Ophthalmology Unit at Hadassah University Hospital in Jerusalem,
Israel, between July 1, 1994, and December 31, 1999. Twenty children (43%)
were referred by their treating pediatrician, 18 (38%) were examined at the
request of the parents because of a heightened degree of anxiety, and 9 (19%)
were referred to our clinic for a second opinion because of the presence of
ocular abnormalities.
OBSTETRIC HISTORY
An attempt at careful and complete obstetric history taking was performed
in all cases. This included the presence or absence of previous pregnancies;
length of infertility period and its cause; ingestion of drugs before, during,
and after IVF; and type of IVF performed. Missing clinical obstetric and gynecologic
details were obtained in some cases through a telephone questionnaire with
the mothers.
OCULAR EXAMINATION
All children underwent a thorough ophthalmologic examination. In preverbal
children, assessment of the visual acuity was performed as previously described.10 In short, fixation behavior was assessed using the
smallest age-appropriate target. Monocular fixation was recorded for 3 separate
factors: (1) quality and accuracy (good, fair, poor), (2) location (central
vs eccentric), and (3) duration (maintained vs sporadic). For children with
poor fixation, the visual abilities were evaluated using an optokinetic drum.
In verbal children, this was based on identifying familiar pictures and shapes
either by single or linear optotypes. In older and cooperative children, the
Tumbling E or Snellen charts was used.
Ocular motility examination, including assessment of ductions and versions
in all cardinal positions of gaze, was also performed. In the very young or
inattentive children, the doll's head movement was used to rule out limitation
of movements. Strabismus was assessed by cover-uncover and alternate-cover
tests for near in all children and also for distance in older cooperative
ones. In cooperative children older than 3 years, binocular functions were
evaluated using the Titmus Fly Stereotest, whereas fusional capacity was assessed
by the Worth 4-dot test.
Survey of the external structures and anterior segment was carried out
at the slitlamp examination. Lens anatomy and anterior vitreous were reexamined
after maximal pupil dilation.
Cycloplegic refraction was carried out 30 minutes after instillation
of 1% cyclopentolate hydrochloride (Cyclogyl) and 0.5% tropicamide (Mydramide)
delivered twice at 10-minute intervals.
Fundus was examined by indirect ophthalmoscopy with special emphasis
on optic nerve anatomy and color, macula and foveal reflexes, and configuration
of retinal blood vessels in the posterior pole. Detailed examination of the
periphery was carried out only in eyes with unclear findings in the posterior
pole.
RESULTS
Data are given as mean ± SD.
OBSTETRIC PARAMETERS
The 47 children referred to our unit were the siblings of 68 children
born after 41 IVF-induced pregnancies. The remaining 21 siblings were reported
by the parents to have no ocular abnormality and therefore were not brought
to our unit. Thirty (64%) of the 47 children were part of a twin (27 or 57%)
or triplet (3 or 6%) pregnancy. The birth weight of the entire group was 2335
± 817 g (range, 924-4300 g). For the single fetus birth, the birth
weight was 2921 ± 922 g (range, 924-4300 g), and for multiple fetuses
birth, the single birth weight was 1990 ± 559 g (range, 1080-3470 g).
The birth weight was significantly lower for the multiple fetus pregnancies
(P = .002) (Table
1).
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Table 1. Birth Data of 47 Children Who Were Born After In Vitro Fertilization*
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The gestation age for the entire group was 35.0 ± 3.7 weeks (range,
28-40 weeks; median, 34 weeks). For the 9 single fetus pregnancies, the gestational
age was 37.7 ± 3.5 weeks (range, 29-40 weeks; median, 40 weeks). The
gestational age in multiple fetus pregnancies was significantly lower (33.8
± 3.1 weeks; range, 28-40 weeks; median, 33 weeks; P = .001) (Table 1).
Despite efforts, including telephone questionnaires, thorough and detailed
obstetric data regarding the type of IVF technique and pregnancy were only
obtained in 33 (80%) of the 41 pregnancies. The age of the mothers at time
of conception was 32.1 ± 4.7 years (range, 23-43 years). The fathers'
age was 34.8 ± 6.5 years (range, 26-51 years) (Table 2).
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Table 2. Patient Characteristics of 47 In Vitro Fertilization Offspring*
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The period of known infertility was 4.9 ± 4.6 years (range, 0-17
years; median, 3.5 years). Infertility was attributed to a combination of
causes in 8 of the women. Sperm quality and/or oligospermia were the probable
causes for infertility in 15 of 33 women for which reliable information was
available. Ovulation-related problems were implicated in 12 of 33 cases, and
mechanical-related abnormalities of the female reproductive system were the
cause of infertility in 11 of 33 cases. In 4 cases, the cause for the infertility
could not be ascertained.
The IVF technique was supplemented by ICSI in 16 cases (48%). Sperm
donations were used for 4 of the pregnancies. No intrauterine fetal reduction
was performed for any of the pregnancies in the study group.
Delivery was vaginal in 16 (47%) of 34 women, whereas a cesarean section
was performed in 18 (53%).
OCULAR FINDINGS
The children were first examined in our clinic at an age of 2 months
to 5 years (mean, 2.3 ± 5.8 years; median, 9.6 months). At the time
of examination, 12 children were verbal and 35 children were not. Of 70 eyes
of nonverbal children, 60 (86%) were classified as having vision "normal for
age", 4 (6%) had "fair" or "questionably normal", and 6 (9%) had "poor" or
"definitely abnormal" vision. In the 12 verbal children, visual acuity was
6/10 or better in 17 eyes, 6/12 to 6/30 in 2 eyes, 6/36 to 6/90 in 1 eye,
6/120 to light perception in 1 eye, and no light perception in 3 eyes.
Reliable cycloplegic refraction was achieved in 84 eyes. In 5 eyes no
retinoscopic reflex was obtained because of advanced intraocular pathologic
conditions, and in 5 eyes accurate refraction was not possible. Two eyes were
aphakic at the time of examination because they had undergone cataract surgery
without intraocular lens implantation elsewhere. The cycloplegic refraction
of the remaining 82 fully assessable eyes disclosed an emmetropia (spherical
equivalent refractive error of 0.00 to +1.00 diopters [D]) in 22 eyes (27%).
A hypermetropic refraction of more than +1.0 D was found in 47 eyes (57%),
and a myopic refraction (spherical equivalent refractive error of –0.50
D or more) was found in 13 (16%) eyes. In 20 eyes, the refractive error was
larger than ±3.0 D. Eight children had an anisometropia of more than
1.0 D.
In 43 of the children, a full assessment of ocular motility and cover
tests was achieved. Thirty-one were orthophoric (72%), 7 (16%) were esotropic,
and 5 (12%) were exotropic.
Major ocular malformations were observed in 12 (26%) of 47 children,
affecting 19 eyes (Table 3). The
conditions included Coats disease (2 eyes of 2 children), congenital cataract
(4 eyes of 2 children), coloboma of uvea (3 eyes of 2 children), hypoplastic
optic nerve heads (3 eyes of 2 children), frank idiopathic optic atrophy (4
eyes of 2 children), congenital glaucoma (2 eyes of 1 child), and retinoblastoma
(1 eye in 1 child).
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Table 3. Ocular Abnormalities in 47 Children Who Were Born After In
Vitro Fertilization Pregnancies
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Retinopathy of prematurity (ROP) was observed in 2 children. One child
with a gestational age of 29 weeks and a birth weight of 924 g reached ROP
stage II in both eyes that regressed spontaneously. One child, part of a triplet
(gestational age, 30 weeks; birth weight, 2060 g), was diagnosed as having
ROP stage V. Despite cryotherapy and several retinal surgical procedures,
visual function in both eyes of this child remained very poor.
Additional, sporadic pathologic conditions were observed in this group
of children. These included periocular hemangiomas in 3 children and Duane
retraction syndrome in 1 child.
COMMENT
Major ocular abnormalities were observed in 12 of the 47 children born
after IVF pregnancies. This 26% incidence of ocular pathologic conditions
in our cohort is higher than expected. Obviously, a certain referral bias
to our clinic and a heightened level of parent anxiety are most probably important
factors that affect these data, with an imbalance influence on this surprisingly
high number of ocular abnormalities in our group of children. Our institution
is a tertiary health care facility. Thus, referrals of the more severe and
complicated cases are more common. This skewed population bias is to be seriously
considered when evaluating the high rate of ocular malformations found in
our IVF population. The presence of ROP in 2 of the children is easily reconcilable
with the observations derived from the non-IVF population of premature infants.11-13 However, the many
other serious structural malformations, which included chorioretinal and optic
nerve colobomata, hypoplastic optic nerves, glaucoma, cataract, and retinoblastoma,
deserve thorough consideration. The facts that most of these structural abnormalities
were uniocular and there was no consanguinity or positive family history can
be interpreted to indicate that the pathologic condition is sporadic and not
due to an inherited trait. Taking into account the known higher rate of chromosomal
aberrations in children born after IVF,8-9
the observations made in this study should be weighed seriously. A suggestion
that these infants may experience a higher rate of ocular (and other organs)
structural abnormalities is inevitable. Consequently, although the prevalence
of 26% of ocular pathologic conditions in our cohort most probably does not
represent the true expected incidence of ocular abnormalities in IVF offspring
in general or their incidence in the population, it suggests that a higher
incidence of structural abnormalities is to be expected. Minor structural
abnormalities in other organs may remain "silent" and undetected. In the eye,
however, not only are structural abnormalities readily detected, they also
cause an impairment of visual function.
One of the children in our study developed a unilateral retinoblastoma.
The possibility that this manifestation is due to a de novo deletion occurring
as a "second hit" during early embryogenesis, as it occurs in the population
of children at large, may be a plausible explanation for this phenomenon.
An alternative reason for the occurrence of unilateral retinoblastoma may
be that the 2-hit deletions have occurred in the retinal cells due to the
higher tendency of chromosomal breakage and deletions in IVF-born children.8-9 Unfortunately, a closer examination
of the problem was not possible in this case because the IVF was carried out
with a donor sperm. This has precluded us from collecting useful genetic data,
which could be of help for the elucidation of this enigmatic case.
The structural abnormalities observed in the children born after IVF
have not been detected in utero. All mothers underwent periodic ultrasound
surveys of the fetuses during the entire period of gestation. Modern ultrasound
techniques and instruments can detect ocular abnormalities in utero.14 This is particularly applicable for microphthalmia,15 retinoblastoma,16
and congenital cataract.17-19
The lack of prenatal detection of these major ocular structural abnormalities
in our study group may be attributed to the fact that the eyes are not carefully
and routinely surveyed during ultrasound examination, leaving these malformations
veiled.
Despite the limitations of our study, which include its retrospective
design, lack of randomization, and incomplete obstetric survey, the results
of our study should stimulate a heightened awareness about the possible higher
incidence of ocular malformations in children born after IVF. Detection of
these ocular structural malformations in high-risk pregnancies, such as after
IVF in particular and in uncomplicated pregnancies in general, is feasible.
Ophthalmologists and, particularly, obstetricians and gynecologists must be
aware of the potential increased incidence of ocular abnormalities in IVF
offspring. Early detection and treatment may be sight saving and are mandatory.
AUTHOR INFORMATION
Accepted for publication May 24, 2001.
Corresponding author: Irene Anteby, MD, Pediatric Ophthalmology Unit,
Department of Ophthalmology, Hadassah University Hospital, PO Box 12000, Jerusalem
91120, Israel (e-mail: irene{at}hadassah.org.il).
Irene Anteby, MD;
Evelyne Cohen, CO;
Eyal Anteby, MD;
David BenEzra, MD, PhD
From the Pediatric Ophthalmology Unit, Department of Ophthalmology
(Drs I. Anteby, Cohen, and BenEzra) and Department of Obstetrics and Gynecology
(Dr E. Anteby), Hadassah University Hospital, Jerusalem, Israel. None of the
authors have any proprietary interest in the products mentioned in this article.
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