Correspondence
Vol. 110, No.3
duced into the eye at the time of cataract surgery. Fungal contamination of either the irrigating solution or the implanted lens are possible but difficult to verify retrospectively in an isolated case.' Dematiaceous fungi have been recovered from unopened bottles of balanced salt solution." To date, this patient's infection appears to be an isolated case, the source of which has not been determined.
References 1. Hohl, T. E., Holley, H. P., Prevost, E., Ajello, 1., and Padhye, A. A.: Infections due to Wangiella dermatitidis in humans. Report of the first documented case from the United States and a review of the literature. Rev. Infect. Dis. 5:854, 1983. 2. Vartian, C. V., Shlaes, D. M., Padhye, A. A., and Ajello, L.: Wangiella dermatitidis endocarditis in an intravenous drug user. Am. J. Med. 78:703, 1985. 3. Levenson, J. E., Gardner, S. K., Duffin, R. M., and Pettit, T. H.: Dematiaceous fungal keratitis following penetrating keratoplasty. Ophthalmic Surg. 15:578,1984. 4. Stern, W. H., Tamura, E., Jacobs, R. A., Pons, V. G., Stone, T. D., O'Day, D. M., and Irvine, A. R.: Epidemic postsurgical Candida parapsilosis endophthalmitis. Clinical findings and management of 15 consecutive cases. Ophthalmology 92: 1701, 1985. 5. Isenberg, R. A., Weiss, R. 1., Apple, D. J., and Lowrey, D. B.: Fungal contamination of balanced salt solution. J. Am. Intraocul. Implant Soc. 11:485, 1985.
Correspondence Correspondence concerning recent articles or other material published in THE JOURNAL should be submitted within six weeks of publication. Correspondence must be typed double-spaced, on 8V2 x I l-inch bond paper with 1V2-inch margins on all four sides and should be no more than two typewritten pages in length. Every effort will be made to resolve controversies between the correspondents and the authors of the article before publication.
Safety of Fluorescein Angiography During Pregnancy EDITOR:
In the article "Safety of fluorescein angiography during pregnancy" by L. S. Halperin,
323
R. J. Olk, G. Soubrane, and G. Coscas (Am. J. Ophthalmol. 109:563, May 1990), although the authors' conclusion, that it may be reasonable to perform fluorescein angiography on a pregnant patient who has a sight-threatening vasculopathy, may be valid, we are concerned that their article does not establish the safety of the use of fluorescein angiography during pregnancy. We cannot agree with the conclusion that "fluorescein angiography does not result in a high rate of birth anomalies or complications when performed on a pregnant patient," since this conclusion is not supported by the data submitted by the authors. When evaluating the potential teratogenicity of agents in pregnancy, there are two primary concerns: the effect on organogenesis and the effect on the pregnancy itself. To evaluate the possible teratogenicity during organogenesis, one should evaluate exposures during the first trimester. In their review of either 399 or 403 respondents (the article is internally inconsistent), 90 specialists acknowledged performance of at least one fluorescein angiogram on at least one pregnant woman during the preceding ten years. Forty-five specialists could not provide any information on those subjects, and nine additional specialists could not be reached for further information. Fifty-four (60%) of these 90 specialists who stated that they had performed fluorescein angiography were unable to provide adequate information. Thus, apparently, more than half of the potential study sample was lost or unavailable. The article does not state whether any attempt was made to assess the medical status of outcomes of possible pregnancies among those women of reproductive age who were not knowingly pregnant and yet had fluorescein angiography performed (patients of the remaining 309 or 313 specialists, depending on one's reading of the article). Thus, a control population for this study might well have been the outcomes of pregnancies among women who inadvertently received fluorescein because they did not know that they were pregnant or they were not specifically asked whether they might be pregnant at the time of the procedure. The authors ascertained only 19 pregnancies with first trimester exposures, as well as 22 pregnancies that may have had multiple exposures, including a period during the first trimester. Thus, somewhere between 19 and 41 pregnancies were exposed to intravenous fluorescein during the first trimester. Because of
324
September, 1990
AMERICAN JOURNAL OF OPHTHALMOLOGY
this relatively small number of exposures in the first trimester, it is difficult, if not impossible, to detect an increase in the rate of malformations compared to an unspecified control population. Since the outcome of pregnancy after fluorescein exposure was solicited retrospectively and by questionnaire, it is difficult to determine the extent of the ascertainment and the diligence of the catamnesis. How often, for example, did the ophthalmologists update information on the outcome of pregnancy and on neonatal and postnatal development from their obstetric or pediatric colleagues to determine whether these infants were normal? Did that purported normality extend through the period of primary education, where subtle defects in learning abilities might become first apparent? Without this information, there could be either positive or negative bias of ascertainment. This interpretation is complicated further by this retrospective survey. Since 40 pregnant women were examined for diabetic retinopathy, and since women with insulin-dependent diabetes mellitus are at well-defined and significantly increased risk for various adverse outcomes of pregnancy, such as stillbirths, obstetric complications, and congenital malformations, these data should be analyzed separately. It is unclear why the authors decided to exclude the four neonatal or fetal deaths from their study. Although these may not be related to the exposure to fluorescein, it is unclear whether one fetal death and one spontaneous abortion may have occurred from the effect of fluorescein exposure or from the underlying primary medical condition. Only two offspring were reported to have birth defects. One child was reported to have an undescended testicle, for no apparent reason and without other stated association. The significance of this observation must be considered in the context of the infant's gestational age at the time of exposure, which is not stated. Another infant was described to have syndactyly. However, the authors do not state the type of syndactyly nor whether there was a family history of syndactyly. Since various syndromic associations of syndactyly have been documented, the diligence of ascertainment of other subtle malformations is critical to an understanding of this report; yet these data are missing. Lastly, without a suitable control group with which to compare their data, so that an adequate population-based or case-control study
can be done, the authors do not provide sufficient information to document incontrovertibly the safety of fluorescein angiography in pregnancy. Until these or other investigators are able to provide complete and prospective information, perhaps comparing the outcome of pregnancies in which fluorescein angiography was done and pregnancies in which it was indicated but not performed, the benefits and the risks of this procedure must be discussed individually with pregnant women and should not be performed arbitrarily. If the expected risk caused by fluorescein directly is low, then the sample sizes will need to be large to detect a statistically significant difference in the two populations, We hope that these better data will be forthcoming in the future. We look forward to a major national or international effort to design such a prospective protocol for this agent, which so long has been considered generally regarded as safe. FRANK GREENBERG, M.D. RICHARD A. LEWIS, M.D.
Houston, Texas
_ _ _ _ _ _ _ Reply EDITOR:
_
Drs. Greenberg and Lewis are correct in pointing out a transcription error in our abstract, which should have indicated that" 403 specialists responded ... " and "313 had never performed fluorescein angiography ...." The text was clear in pointing out that a total of 41 pregnancies were exposed to intravenous fluorescein during the first trimester (19 only in the first trimester and 22 with exposure in all three trimesters). It is clearly stated why we excluded the four neonatal or fetal deaths: two were because of complications related to eclampsia; one occurred months after injection of fluorescein; and "one spontaneous abortion occurred three days after fluorescein angiography in a four-week pregnancy of an otherwise healthy woman." We agree completely with Drs. Greenberg and Lewis that "the benefits and risks of this procedure must be discussed individually with pregnant women and should not be performed arbitrarily." Our concluding paragraph clearly states: "The decision to perform fluorescein angiography on a pregnant patient is left to the physician and patient, who should carefully weigh the risks and benefits of the procedure." We would further emphasize that one of the main purposes of this article was to
Vol. 110, No.3
duced into the eye at the time of cataract surgery. Fungal contamination of either the irrigating solution or the implanted lens are possible but difficult to verify retrospectively in an isolated case.' Dematiaceous fungi have been recovered from unopened bottles of balanced salt solution." To date, this patient's infection appears to be an isolated case, the source of which has not been determined.
References 1. Hohl, T. E., Holley, H. P., Prevost, E., Ajello, 1., and Padhye, A. A.: Infections due to Wangiella dermatitidis in humans. Report of the first documented case from the United States and a review of the literature. Rev. Infect. Dis. 5:854, 1983. 2. Vartian, C. V., Shlaes, D. M., Padhye, A. A., and Ajello, L.: Wangiella dermatitidis endocarditis in an intravenous drug user. Am. J. Med. 78:703, 1985. 3. Levenson, J. E., Gardner, S. K., Duffin, R. M., and Pettit, T. H.: Dematiaceous fungal keratitis following penetrating keratoplasty. Ophthalmic Surg. 15:578,1984. 4. Stern, W. H., Tamura, E., Jacobs, R. A., Pons, V. G., Stone, T. D., O'Day, D. M., and Irvine, A. R.: Epidemic postsurgical Candida parapsilosis endophthalmitis. Clinical findings and management of 15 consecutive cases. Ophthalmology 92: 1701, 1985. 5. Isenberg, R. A., Weiss, R. 1., Apple, D. J., and Lowrey, D. B.: Fungal contamination of balanced salt solution. J. Am. Intraocul. Implant Soc. 11:485, 1985.
Correspondence Correspondence concerning recent articles or other material published in THE JOURNAL should be submitted within six weeks of publication. Correspondence must be typed double-spaced, on 8V2 x I l-inch bond paper with 1V2-inch margins on all four sides and should be no more than two typewritten pages in length. Every effort will be made to resolve controversies between the correspondents and the authors of the article before publication.
Safety of Fluorescein Angiography During Pregnancy EDITOR:
In the article "Safety of fluorescein angiography during pregnancy" by L. S. Halperin,
323
R. J. Olk, G. Soubrane, and G. Coscas (Am. J. Ophthalmol. 109:563, May 1990), although the authors' conclusion, that it may be reasonable to perform fluorescein angiography on a pregnant patient who has a sight-threatening vasculopathy, may be valid, we are concerned that their article does not establish the safety of the use of fluorescein angiography during pregnancy. We cannot agree with the conclusion that "fluorescein angiography does not result in a high rate of birth anomalies or complications when performed on a pregnant patient," since this conclusion is not supported by the data submitted by the authors. When evaluating the potential teratogenicity of agents in pregnancy, there are two primary concerns: the effect on organogenesis and the effect on the pregnancy itself. To evaluate the possible teratogenicity during organogenesis, one should evaluate exposures during the first trimester. In their review of either 399 or 403 respondents (the article is internally inconsistent), 90 specialists acknowledged performance of at least one fluorescein angiogram on at least one pregnant woman during the preceding ten years. Forty-five specialists could not provide any information on those subjects, and nine additional specialists could not be reached for further information. Fifty-four (60%) of these 90 specialists who stated that they had performed fluorescein angiography were unable to provide adequate information. Thus, apparently, more than half of the potential study sample was lost or unavailable. The article does not state whether any attempt was made to assess the medical status of outcomes of possible pregnancies among those women of reproductive age who were not knowingly pregnant and yet had fluorescein angiography performed (patients of the remaining 309 or 313 specialists, depending on one's reading of the article). Thus, a control population for this study might well have been the outcomes of pregnancies among women who inadvertently received fluorescein because they did not know that they were pregnant or they were not specifically asked whether they might be pregnant at the time of the procedure. The authors ascertained only 19 pregnancies with first trimester exposures, as well as 22 pregnancies that may have had multiple exposures, including a period during the first trimester. Thus, somewhere between 19 and 41 pregnancies were exposed to intravenous fluorescein during the first trimester. Because of
324
September, 1990
AMERICAN JOURNAL OF OPHTHALMOLOGY
this relatively small number of exposures in the first trimester, it is difficult, if not impossible, to detect an increase in the rate of malformations compared to an unspecified control population. Since the outcome of pregnancy after fluorescein exposure was solicited retrospectively and by questionnaire, it is difficult to determine the extent of the ascertainment and the diligence of the catamnesis. How often, for example, did the ophthalmologists update information on the outcome of pregnancy and on neonatal and postnatal development from their obstetric or pediatric colleagues to determine whether these infants were normal? Did that purported normality extend through the period of primary education, where subtle defects in learning abilities might become first apparent? Without this information, there could be either positive or negative bias of ascertainment. This interpretation is complicated further by this retrospective survey. Since 40 pregnant women were examined for diabetic retinopathy, and since women with insulin-dependent diabetes mellitus are at well-defined and significantly increased risk for various adverse outcomes of pregnancy, such as stillbirths, obstetric complications, and congenital malformations, these data should be analyzed separately. It is unclear why the authors decided to exclude the four neonatal or fetal deaths from their study. Although these may not be related to the exposure to fluorescein, it is unclear whether one fetal death and one spontaneous abortion may have occurred from the effect of fluorescein exposure or from the underlying primary medical condition. Only two offspring were reported to have birth defects. One child was reported to have an undescended testicle, for no apparent reason and without other stated association. The significance of this observation must be considered in the context of the infant's gestational age at the time of exposure, which is not stated. Another infant was described to have syndactyly. However, the authors do not state the type of syndactyly nor whether there was a family history of syndactyly. Since various syndromic associations of syndactyly have been documented, the diligence of ascertainment of other subtle malformations is critical to an understanding of this report; yet these data are missing. Lastly, without a suitable control group with which to compare their data, so that an adequate population-based or case-control study
can be done, the authors do not provide sufficient information to document incontrovertibly the safety of fluorescein angiography in pregnancy. Until these or other investigators are able to provide complete and prospective information, perhaps comparing the outcome of pregnancies in which fluorescein angiography was done and pregnancies in which it was indicated but not performed, the benefits and the risks of this procedure must be discussed individually with pregnant women and should not be performed arbitrarily. If the expected risk caused by fluorescein directly is low, then the sample sizes will need to be large to detect a statistically significant difference in the two populations, We hope that these better data will be forthcoming in the future. We look forward to a major national or international effort to design such a prospective protocol for this agent, which so long has been considered generally regarded as safe. FRANK GREENBERG, M.D. RICHARD A. LEWIS, M.D.
Houston, Texas
_ _ _ _ _ _ _ Reply EDITOR:
_
Drs. Greenberg and Lewis are correct in pointing out a transcription error in our abstract, which should have indicated that" 403 specialists responded ... " and "313 had never performed fluorescein angiography ...." The text was clear in pointing out that a total of 41 pregnancies were exposed to intravenous fluorescein during the first trimester (19 only in the first trimester and 22 with exposure in all three trimesters). It is clearly stated why we excluded the four neonatal or fetal deaths: two were because of complications related to eclampsia; one occurred months after injection of fluorescein; and "one spontaneous abortion occurred three days after fluorescein angiography in a four-week pregnancy of an otherwise healthy woman." We agree completely with Drs. Greenberg and Lewis that "the benefits and risks of this procedure must be discussed individually with pregnant women and should not be performed arbitrarily." Our concluding paragraph clearly states: "The decision to perform fluorescein angiography on a pregnant patient is left to the physician and patient, who should carefully weigh the risks and benefits of the procedure." We would further emphasize that one of the main purposes of this article was to
