Purpose
To follow up children born after in vitro fertilization (IVF) with respect to eye malformations and poor visual acuity.
Design
Observational cohort study based on Swedish health registers.
Methods
Congenital eye malformations were studied in 32 091 children born from 1982 through 2007 and severe visual impairment was studied in 24 628 children born from 1985 through 2005 after IVF in Sweden. Comparisons were made with all children born in Sweden during corresponding periods with adjustment for various confounders. The main outcome measure was the presence of a congenital eye malformation and poor visual acuity.
Results
Thirty-six (1.1 per 1000) IVF infants with ocular malformations were identified, and the risk, compared with non-IVF children, was not increased when adjusted for maternal age, parity, smoking, and body mass index (odds ratio, 1.05; 95% confidence interval, 0.75 to 1.47). Severe visual impairment was identified in 25 cases (1.0 per 1000), and the risk increase was statistically significant (odds ratio, 1.65; 95% confidence interval, 1.12 to 2.45) and was only slightly reduced when adjustment as above was made (odds ratio, 1.55; 95% confidence interval, 1.04 to 2.32). When adjustment was made for known length of unwanted childlessness, the OR decreased to 1.15 (95% confidence interval, 0.61 to 2.16). Only 3 of the 25 children with visual impairment had ocular malformations.
Conclusions
Although there is an increased risk for visual impairment among children born after IVF, the individual risk is small and may be secondary to parental characteristics. No increased risk for eye malformations was found.
Relatively little has been published on visual acuity of infants born after in vitro fertilization. A Russian study found visual disorders among 6 of 11 investigated infants conceived by in vitro fertilization and born at 1 Moscow hospital. A study from Israel described 47 children born after in vitro fertilization and referred to ophthalmologic examination and found various eye anomalies in a high percentage and ocular malformations in 12 children. A German study identified 1 child with congenital glaucoma among 30 infants born after in vitro fertilization. A recent study from Sweden found abnormal retinal vessel morphologic features in boys born after intracytoplasmatic sperm injection, but no further eye anomalies.
Most interest has been paid to the occurrence of retinoblastoma after a report from the Netherlands, where an increased risk was thought to exist. An expanded study could not verify the increase. Bradbury and Jick found no case of retinoblastoma among 176 children conceived after in vitro fertilization. We found one case of retinoblastoma among 16 280 children born after in vitro fertilization, and the expected number of retinoblastomas from the population rate was 0.8.
The present study provides an opportunity to study the effect of in vitro fertilization on ocular malformations and severe visual impairment in a relatively large population, adjusting for putative confounding factors. A previous analysis of visual impairment that was published based on the first part of this material found an excess risk, but it did not reach statistical significance.
Methods
Children born in Sweden after in vitro fertilization performed from 1982 (when the first child was born) up to and including 2006 were studied for the presence of eye malformations. Treated women were identified from all centers for in vitro fertilization in Sweden as described in previous reports. After linkage with the Medical Birth Register data on the 31 850 children born from 1982 through 2007 were obtained. Further information on the presence of congenital malformations was obtained from the Swedish Register of Birth Defects (previously called the Register of Congenital Malformations) from 1982 through 2007 and the Patient Register (previously called the Hospital Discharge Register) from 1987 through 2007. By comparison with the Register of Visually Impaired Children, children born in 1988 or later and with a visual impairment (visual acuity ≤ 0.3, a visual field defect, or both) were identified up to February 1, 2009. The latter register covers the entire country, but from one area, patients are reported without complete identification, which made analysis of these children conceived after in vitro fertilization impossible. This part of the study therefore was restricted to 24 628 children conceived after in vitro fertilization and born from 1988 through 2005 (only 17 infants born after 2005 were registered in the Register of Visually Impaired Children). To be able to adjust for maternal characteristics, only children reported to the Medical Birth Register were included in the study.
Statistical analysis was made using Mantel-Haenszel procedures and risks were estimated as odds ratios (ORs) and 95% confidence intervals (95% CI), which were determined with the Miettinen test-based method. Adjustments were made for various putative confounders: year of birth (1-year intervals), maternal age (5-year intervals, < 20, 20 to 24, etc.), parity (1 to 4+), smoking (unknown, none, < 10 cigarettes daily, 10 cigarettes or more per day), and body mass index (unknown, < 19.8, 19.8 to 25.9, 26 to 29.9, ≥ 30) or years of involuntary childlessness when known (1 to 4+). This information was retrieved in early pregnancy by interviews at the first antenatal care center visit. Information on smoking was missing in approximately 7% of all records.
Results
Presence of Ocular Malformations
Using the 3 health registers, 36 infants were identified with an eye malformation among the 31 850 children conceived after in vitro fertilization (0.11%). Among all infants born in these years, 2830 infants with eye malformations were registered among 2 638 918 children born (also 0.11%). Table 1 summarizes the observed malformations and divides them into 3 groups: relatively severe eye malformations, iris malformations (mainly coloboma), and minor eye malformations.
| Eye Malformation | Total | Standard IVF | ICSI | Standard IVF + ICSI |
|---|---|---|---|---|
| Relatively severe | 14 | 5 | 9 | 0 |
| An/microphthalmia | 4 | 1 | 3 | 0 |
| Congenital cataract | 7 | 3 | 4 | 0 |
| Congenital lens luxation | 1 | 1 | 0 | 0 |
| Corneal opacity | 1 | 0 | 1 | 0 |
| Macrophthalmos | 1 | 0 | 1 | 0 |
| Iris malformations | 6 | 3 | 2 | 1 |
| Colobomas | 5 | 2 | 2 | 1 |
| Other iris malformations | 1 | 1 | 0 | 0 |
| Minor eye malformations | 16 | 12 | 5 | 0 |
| Congenital ptosis | 3 | 1 | 2 | 0 |
| Eye lid anomaly | 3 | 3 | 0 | 0 |
| Lacrimal duct stenosis | 10 | 8 | 2 | 0 |
| Total | 36 | 20 | 15 | 1 |
The OR for having an eye malformation registered after in vitro fertilization was 1.10 (95% CI, 0.79 to 1.53) when adjustment was only made for year of birth of the child. When adjustment was made also for maternal age, parity, smoking habits, and body mass index, the OR decreased slightly to 1.05 (95% CI, 0.75 to 1.47), and when adjustment was made instead for the number of years of involuntary childlessness (when known), it decreased further: OR, 1.04; 95% CI, 0.64 to 1.68.
Visually Impaired Children
Among the children conceived after in vitro fertilization and born from 1988 through 2005, 25 had been registered in the Registry of Visually Impaired Children. The OR for being registered (adjusted only for year of birth) was 1.65 (95% CI, 1.12 to 2.45). When adjustment was made for year of birth and maternal age, the OR was 1.64; for year of birth and parity, it was 1.62; for year of birth and smoking, it was 1.66; and for year of birth and body mass index, it was 1.65. If adjustment was made for year of birth, maternal age, parity, smoking, and body mass index, the OR changed slightly, to 1.55 (95% CI, 1.04 to 2.32). When adjustment was made for known number of years of involuntary childlessness instead of for body mass index, the OR decreased to 1.15 (95% CI, 0.61 to 2.16). Among the 25 children ( Table 2 ), 13 were born prematurely (52%). Among all children listed in the Register of Visually Impaired Children, 24% (368/1545) were born prematurely. After excluding preterm children, the OR (after adjustment for maternal age, parity, smoking, and body mass index) was 1.41 (95% CI, 0.81 to 2.45). Eleven of the 25 children (44%) born after in vitro fertilization and with visual impairment were twins whose twin sibling was unaffected. Among all children registered in the Register of Visually Impaired Children, 5.4% (83/1545) were twins. Both preterm birth and twins are well-known characteristics of children conceived after in vitro fertilization.
| Diagnosis | Pregnancy Week | Singleton/Twin | Visual Acuity | Additional Handicap/Condition |
|---|---|---|---|---|
| Fundus & optic coloboma | 37 | Twin | 2 | None |
| Fundus coloboma | 41 | Singleton | 1 | Down syndrome |
| CVI | 30 | Singleton | 4 | Severe CNS malformation, mental & motor impairment |
| CVI* | 37 | Twin | 4 | Lissencephaly, mental impairment |
| CVI | 39 | Twin | 2 | Neonatal asphyxia, mental & motor impairment |
| CVI | 41 | Singleton | 2 | Intrauterine asphyxia, mental impairment |
| CVI | 28 | Twin | 4 | Cerebral hemorrhage, mental & motor impairment |
| CVI a | 28 | Singleton | 4 | Mental & motor impairment |
| CVI | 41 | Singleton | 2 | Microcephaly, mental impairment |
| CVI + ROP a | 23 | Singleton | 4 | CP, mental impairment |
| CVI + optic atrophy a | 41 | Singleton | 4 | Hydrocephaly after IVH, mental & motor impairment |
| CVI + severe myopia + nystagmus | 34 | Twin | 9 | Encephalopathy, mental & motor impairment |
| CVI + bilateral retinal detachment + optic nerve hypoplasia a | 24 | Twin | 5 | Prenatal hydrocephaly, mental & motor impairment |
| Optic atrophy | 32 | Singleton | 9 | CMV infection, mental impairment |
| Optic atrophy | 24 | Twin | 1 | Motor impairment |
| Optic atrophy | 27 | Twin | 1 | Mental & motor impairment |
| Optic atrophy | 27 | Twin | 2 | None |
| Optic atrophy (mild ROP) | 26 | Singleton | 4 | Mental & motor impairment |
| Nystagmus | 40 | Singleton | 4 | Neonatal asphyxia, mental & motor impairment |
| ROP | 25 | Twin | 2 | None |
| ROP + congenital cataract + optic nerve hypoplasia | 24 | Twin | 9 | Periventricular leukomalacia, mental & motor impairment |
| Retinal dystrophy b | 41 | Singleton | 3 | Joubert syndrome |
| Leber’s congenital amaurosis | 40 | Singleton | 5 | None |
| Albinism | 40 | Singleton | 9 | None |
| Optic glioma | 40 | Singleton | 1 | None |
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