Laser refractive surgery in pregnant or breastfeeding patients

1 Title Laser Refractive Surgery in Pregnancy or Breastfeeding Patients: A Systematic Review Authors Francisco Zamorano-Martín MD 1 José-María Sánchez-González OD PhD 2,3 María García-Lorente MD 1 Rahul Rachwani-Anil MD 1 Jorge Peraza-Nieves MD 4 Marina Rodríguez-Calvo-de-Mora MD PhD FEBO 1 Davide Borroni MD 5,6 Carlos Rocha-de-Lossada MD FEBO 7,8 1 Department of Ophthalmology, Regional Universitary Hospital of Malaga, Malaga, Spain 2 Department of Physics of Condensed Matter, Optics Area. University of Seville, Seville, Spain. 3 Department of Ophthalmology (Tecnolaser Clinic Vision®). Refractive Surgery Centre, Seville, Spain. 4 Department of Ophthalmology, Hospital Clinic de Barcelona, Barcelona, Spain 5 Department of Doctoral Studies, Riga Stradins University, Riga, Latvia. 6 Department of Ophthalmology, Royal Liverpool University Hospital, Liverpool, UK. 7 Department of Ophthalmology, Hospital Universitario Virgen de las Nieves, Granada, Spain 8 Department of Ophthalmology, University of Malaga, Malaga, Spain. Corresponding author José-María Sánchez-González Reina Mercedes Street, Seville, Spain 41012 +34 618 20 41 10 / [email protected] Revised Manuscript 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract This systematic review reported the outcomes of laser corneal refractive surgery in pregnant or breastfeeding patients. This study was carried out by searching in PubMed, Web of Science and Scopus databases, on June 15th, 2020. This review included 128 eyes from a total of 64 patients, mean maximum follow-up was 39.2 ± 36.14 months. Time from surgery to complication ranged from 1 to 67 months, with a mean value of 23.42 ± 22.23 months. PRK and LASIK surgery appear to be stable procedures which are not modified during pregnancy, and safe to complete during breastfeeding. Nevertheless, the lack of weight prospective research avoids having a greater certainty on this matter and. Due to transitory nature of pregnancy and breastfeeding, we could still contemplate surgery risk outweigh the benefits. Additional investigation will be necessary to clarify these issues. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 Introduction The prevalence of refractive errors, mainly myopia, has noticeably increased over the past years, and those who suffer from it seek for its correction.1 Moreover, ages between 20 and 30 years old represent the most common age range amongst the female gender population that seek refractive surgery, coinciding with the period in which they are most prone to getting pregnant.1 Currently, Laser-assisted in-situ keratomileusis (LASIK) is one of the most common laser refractive surgery technique, with excellent visual outcomes and safety profile.2 The introduction of the femtosecond laser has made LASIK even safer, with reduced intraoperative flap-related complications.3 Small incision lenticule extraction (SMILE) is a flapless minimally invasive technique where femtosecond laser is used during the entire procedure. Similarly, SMILE has demonstrated good refractive outcomes.3 Other procedures such as laser photorefractive keratectomy (PRK) or Laser assisted sub-epithelial keratomileusis (LASEK)4 are accepted as effective techniques in treating refractive errors, especially for the correction of low to moderate myopia, hyperopia and astigmatism.5 Post laser ectasia (PLE) was defined as a progressive weakening and bulging of the cornea that leads to corneal steepening and thinning, associated with a loss of visual acuity.6 Although uncommon, with an approximate incidence between 0.04% and 0.9%, PLE remains one of the major fearsome complications after refractive surgery.7 It has been reported that LASIK induces a higher PLE risk than PRK,6 especially when the procedure is performed with a mechanical microkeratome instead of using femtosecond laser.8 PLE has also been reported after SMILE procedure.9 Risk factors for PLE include abnormal preoperative tomography, patients’ age at the surgery moment, an elevated refraction, central corneal thickness (CCT) less than 500 microns, or residual stromal bed thickness (RSBT) less than 300 microns.10–13 Santhiago et al.14 introduced the percent tissue altered (PTA) formula as a risk factor for PLE, when PTA is > 40%. Recently, it has been found that similar to the development of keratoconus, a vigorous eye rubbing could also result in chronic biomechanical failure, hence leading to PLE.15 Currently, there is still an ongoing debate in the scientific community whether it is possible to correct refractive defects during pregnancy and/or breastfeeding due to possible refractive changes, particularly myopia progression. The latter may be caused by hormonal induced-changes inherent to pregnancy or breastfeeding, altering the biomechanical stability of the body’s connective tissues, hence an increased risk of PLE.16,17 In fact, it has been reported that it may be advisable to postpone any changes in eyeglass 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 prescriptions until several weeks postpartum.18 Traditionally, pregnancy has been considered as a contraindication for refractive surgery, and recommending female patients to avoid pregnancy one year post-surgery.19,20 Modern studies have reported favorable results of refractive surgery in pregnancy21, and in breastfeeding patients.22 Conversely, in a well-designed and large-longitudinal cohort study, Fernández- Montero et al.1 recently reported that pregnancy is inversely associated with myopia development or its progression. Therefore, the aim of this systematic review is to report the outcomes of laser corneal refractive surgery in pregnant or breastfeeding patients, currently available in the scientific literature, seeking to establish a scientific consensus. Methods This systematic review study was carried out by searching in PubMed, Web of Science and Scopus databases, on June 15th, 2020. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations.23 An initial search was conducted, focused on obtaining case studies of outcomes of laser corneal refractive surgery in pregnancy or breastfeeding patients. The keywords used were (pregnancy OR breastfeeding) AND (photorefractive keratectomy OR laser in-situ keratomileusis OR PRK OR LASIK OR SMILE OR Small incision lenticule extraction OR Laser assisted sub-epithelial keratomileusis OR LASEK). Among the results, a total of 150 articles were identified, which were evaluated and selected according to the inclusion and exclusion criteria. Inclusion criteria were: (1) experimental studies, original articles, case reports and cases series studies. The exclusion criteria were: (1) narrative reviews; (2) animal studies; (3) non-English publications; (4) Studies that excluded pregnant or breastfeeding patients. Subsequently, the following data was summarized in tables; (1) authors and year of publication, (2) study design, (3) follow-up, (4) number of patients, (5) number of eyes, (6) age, (7) time between surgery and complication expressed in months, (8) pregnant or breastfeeding period expressed in months, (9) type of refractive surgery, (10) best corrected visual acuity before surgery, (11) refraction expressed in spherical equivalent (SE) before surgery, (12) uncorrected distance visual acuity after surgery, (13) refraction 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 expressed in SE after surgery, (14) recurrence expressed in months, (15) slit-lamp findings, (16) complementary diagnostic test, (17) complications, (18) treatments, (19) favor or against. To assess risk of bias of the included studies, a summary table was created (Table 1) based on the Quality Assessment Tool for Case Series Studies from the National Heart, Lung, and Blood Institute.24 Questions included in the tool were: (1) Is the study oriented to a clear question?; (2) Were all the patients results taken into account?; (3) Was the follow-up complete?; (4) Were the same conditions used in surgical treatment?; (5) Was the intervention clearly described?; (6) Was the duration of follow-up adequate?; (7) Were the results described correctly? This analysis did not result in the elimination of any article. However, articles with a higher risk of bias had a lower weight for the data synthesis. Risk of bias was assessed by C- RL and JM.SG. No disagreement was encountered among the authors. Results The selection process of this systematic review was presented with a flow chart diagram in Figure 1. A total of ten articles,21,25–33 published between 1996 and 2020, were included. All of them were case series, case reports or cohort studies. We included pregnant and breastfeeding patients between 25 and 38 years old, with a preoperative manifest refractive spherical equivalent between -0.87 D and -11.75 D. The mean previous spherical equivalent was -5.27 ± 2.66 D. Best spectacle corrected distance visual acuity was 20/20 (Snellen scale). Patients’ and surgeries’ characteristics of the selected articles were reported in Table 2. This systematic review included 128 eyes from a total of 64 patients, and a maximum postoperative followup that ranged from 3 to 108 months, with the mean maximum follow-up of 39.2 ± 36.14 months. Time from surgery to complication ranged from 1 to 67 months, with a mean value of 23.42 ± 22.23 months. Pregnant or breastfeeding surgery period ranged from 1 to 7 months, and mean value was 4.60 ± 2.57 months. Regarding the surgical technique, four articles25–27,33 used PRK, and seven studies 21,28–33 used LASIK. Results after all refractive surgeries available in the scientific literature were presented in Table 3. In the postoperative period, uncorrected distance visual acuity changed to 20/32 ± 16.81. SE refraction changed to -1.62 ± 2.11 D. Recurrence time from surgery to the first evident clinical sign ranged from 1 to 67 months, with a mean value of 26.5 ± 22.60 months. RSBT mean value was 332.75 ± 52.06 µm. Within the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 6 complications, we observed that myopic regression was present in two studies,25,26 haze was present in two studies,26,27 overcorrection in only one study,27 visual acuity decrease and halos in two studies,27,28 and finally ectasia in four studies.27,28,30,31 Retreatment was performed in three studies.26,28,31 Sharif 26 retreated with PRK, while Hafezi et al.28,31 reported ectasia treatment with corneal crosslinking. In summary, only three studies21,25,33 were in favor, while the other seven studies26–32 were against refractive surgery procedures on pregnant or breastfeeding patients. Finally, the studies were grouped into three degrees, based on the risk of bias assessment tool: low evidence (yeses = 0 to 2); medium evidence (yeses = 3 to 5); high evidence (yeses = 6 to 7). Hefetz et al.25 and Hafezi et al.31 obtained a low evidence level. Starr27, Padmanabhan et al.29 and, López-Prats et al.32 achieved medium evidence level. Finally, Sharif26, Hafezi & Iseli28, Said et al.30, Alonso-Santander et al.33 and, Kanellopoulos & Vingopoulos21 obtained high evidence level. Discussion Refractive changes Ocular changes associated with pregnancy, such as the variation in tear production, intraocular pressure, and corneal and lens topographic alterations have been studied with inconclusive results in recent years. The role of estrogen receptors in corneal and lens modifications during pregnancy has been proposed.34 Morphological changes in the cornea may occur due to the development of corneal edema during pregnancy, therefore increasing the corneal curvature by one diopter (D) and increasing the central corneal thickness between 1 to 16 µm. Furthermore, the curvature of the lens appears to increase, leading to a loss of transient accommodation.34 However, these changes usually reverse after delivery or lactation, and some authors have proposed that these changes do not involve significant variations in visual acuity or refractive error during pregnancy.35,36 The effect of pregnancy on the progression of myopia has been studied in a recent publication1. A cohort of 10,401 women between 20 and 50 years old was prospectively evaluated since 1999. Pregnancies and myopia were repeatedly assessed in each biennial follow-up questionnaire during 14 years of follow-up. Authors conclude that pregnancy was inversely associated with the risk of myopia development or 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 7 progression during each of the two-year periods. Complications of corneal refractive surgery associated with pregnancy, such as myopic regression, PLE, and haze, have been reported. It has been proposed that these complications may be a result of pregnancy physiological variations in underlying biomechanically weakened corneas.35,37–39 PRK Hefetz et al.40 were the first to assess the effect of pregnancy on PRK. They studied 11 eyes of 8 women who became pregnant 1 to 5 months after surgery. Out of these, one woman experienced myopic regression in both eyes when she became pregnant 5 months after surgery. However, this study did not report whether these changes remained permanent after delivery. Subsequently, Sharif 41 studied the same effect in 18 eyes of 9 women who became pregnant in the first 12 months after PRK. Preoperative myopia ranged from - 1.25 to -6 D, and the follow-up was from 12 to 24 months. He observed that twelve eyes underwent myopic regression, of which ten also developed corneal haze. All of them became pregnant in the first 5 months after surgery. Both complications improved after delivery in 50% of the eyes and the other 50% required retreatment with PRK. Furthermore, they observed that these complications were more frequent the more complex the pregnancy was. However, this study did not report the degree of preoperative myopia of all patients, which some authors related with corneal haze development.42 There is also no reference to the degree of myopic regression and its clinical implication for the patient, although we presume it was substantial as a new surgery was required. The results of this study seem to indicate that there is a risk of myopic regression and haze development in patients who become pregnant in the first 5 months after PRK. In the same way, Starr43 reported a case of a woman who experienced a +3 D overcorrection and corneal haze during pregnancy after myopic PRK in her right eye (RE). Preoperative myopia was -5 D, and it was estimated that she became pregnant one week after surgery. The patient suffered an abortion in the third month of pregnancy and the overcorrection suffered a regression. In the tenth month after surgery, she had an uncorrected distance visual acuity (UDVA) of 20/20, a refraction of +0.25 D and the haze had disappeared. Although this study refers to an isolated case, the results are striking given the overcorrection in the short period of time between surgery and the beginning of pregnancy, as well as for the complete regression of the overcorrection after the abortion. It also seems to point out the risk of corneal haze and refractive changes in patients who become pregnant in a short period of time after PRK. We can conclude 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 8 that, although there are no weight studies that assess the effect of pregnancy in patients with PRK surgery, it seems reasonable to delay gestation between 6 and 12 months after the intervention. Likewise, the few published studies suggest that it is important to point out that refractive changes and corneal haze revert after the end of pregnancy in most patients, including those who become pregnant in the first 6 months after surgery. Therefore, it is recommended to wait several months before considering the possibility of retreatment in patients who continue with sequelae after delivery. LASIK LASIK can alter corneal biomechanics, which seems to suppose a greater risk of PLE than other refractive surgery corrections, such as PRK or SMILE.3 Hafezi and Iseli 37 reported a case of bilateral PLE in the third trimester of a woman's first pregnancy, 26 months after LASIK correction of -5.5 D in the RE and -5.25 D in the left eye (LE). According to the presurgical examination, the cornea had no pre-existing signs of disease, and 68 µm were ablated in the RE and 62 µm in the LE. After LASIK, the UDVA was 20/20 with normal topographies, and central corneal thickness was 410 µm in the RE and 400 µm in the LE. These parameters remained stable for two years. During the third trimester of the first pregnancy, PLE was developed, and the patient had a minimum corneal thickness of 370 µm in the RE and 360 µm in the LE. Two years later, during the second pregnancy, the patient suffered a sudden vision deterioration in her RE due to PLE progression. This case is distinctive due to the late onset of PLE, happening and progressing both times in the second trimester of pregnancy, and due to its stable behavior out of the pregnancy period. Changes in estrogen levels could play a role in LASIK-induced ectasia as they had been proposed to reduce corneal biomechanical stability in experimental studies.37 In the same way, Padmanabhan et al. reported another case of bilateral PLE in the first trimester of gestation, 18 months after myopic LASIK surgery. Similarly, the preoperative and tomographic clinical examinations did not suggest a presumable forme fruste or subclinical keratoconus in any eye. In this case, the patient had a 20/20 BCVA with a refractive error of -10.50 -2 x 10 in the RE, and -11.50 -1 x 160 in the LE. After the intervention, there was a RSBT of 305 µm in the RE and 282 µm in the LE, and a UDVA of 20/20. Eighteen months after surgery, during the first month of gestation, the patient was diagnosed with progressive PLE. Likewise, this article suggested the action of estrogens as a factor that modifies corneal biomechanics, and proposed that we should be cautious with arbitrary cut-off values, recalling that 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 9 preoperative corneal thickness and RSBT are not absolute predictive values for the development of ectasia. This case report and the previous one referred to the fact that there were no pre-existing factors of ectasia; however, the anterior and posterior elevation curvature values prior to the intervention were not reported, so it cannot be ruled out that there was any anomaly. Topographic features, such as asymmetry between the two eyes, skewed radial axis, inferior/superior ratio greater than 1.4, and young patients with against-the- rule astigmatism could indicate a subclinical risk for ectasia due to intrinsic biomechanical instability.44 Moreover, this case did not collected a complete history, that includes smoking, allergies and eye rubbing, which are known risk factors for PLE.10 Also Furthermore, Said et al.39 reported an association between late onset of PLE after LASIK surgery and pregnancy. They collected a series of 19 patients and 29 eyes that developed this complication. Of these, they studied five eyes of three were women, who became pregnant between 2 and 5 years after surgery, with a SE between -5 and -9 D, and with an average RSBT of 277 µm. This article attributed this fact to the effect of the relaxing hormone, which increases during pregnancy and inhibits collagen remodeling. Furthermore, they affirmed that ectasia may occur after successful LASIK procedures, even in the absence of apparent preoperative risk factors. Once again, they did not report data about corneal curvature or elevation map values before the intervention, therefore such preoperative risk factors cannot be ruled out. In the same year, Hafezi et al.17 performed a review of five patients who experienced visual impairment during pregnancy, and who had undergone LASIK surgery averagely 67 months before gestation. All patients, except one, were primiparous, and all presented a progressive PLE. They only reported the complete data of one patient, who was operated for -5 D in the RE and -4.5 D in the LE. The patients’ BCVA and UDVA was 20/20, and the minimum corneal thickness was 359 µm. This study provides the least information about the patients compared to the previous reports; therefore, its results should be carefully assessed. Furthermore, the authors emphasize “we cannot rule out that some of the cases could have had a pre-existing minimal corneal thickness at the lower end of the normal distribution (i.e., 505 µm), a minor asymmetry and elevation at the posterior pole (i.e., 12 µm at a reference sphere of 8 mm), or even keratoconus”. Subsequently, López-Prats et al.35 conducted a prospective study comparing a group consisting of 18 eyes from pregnant women who underwent LASIK prior to pregnancy, and a control group with 18 eyes from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 16 prospective clinical study. BMC Ophthalmol. 2004. doi:10.1186/1471-2415-4-12 43. Starr MB. Pregnancy-associated overcorrection following myopic excimer laser photorefractive keratectomy. Вестник Казнму. 1998;№3:с.30. 44. Jin SX, Dackowski E, Chuck RS. Risk factors for postlaser refractive surgery corneal ectasia. Curr Opin Ophthalmol. 2020;31(4):288-292. doi:10.1097/ICU.0000000000000662 45. Bower KS, Woreta F. Update on contraindications for laser-assisted in situ keratomileusis and photorefractive keratectomy. Curr Opin Ophthalmol. 2014;25(4):251-257. doi:10.1097/ICU.0000000000000055 46. Journal O, Moshirfar M, Motlagh MN, Murri MS, Momeni-Moghaddam H, Ronquillo YC, Phillip ;, Hoopes C. Medical Hypothesis, Discovery &Innovation Advances in Biomechanical Parameters for Screening of Refractive Surgery Candidates: A Review of the Literature, Part III. Med Hypothesis Discov Innov Ophthalmol. 2019;8(3). 47. Roy AS, Shetty R, Kummelil MK. Keratoconus: A biomechanical perspective on loss of corneal stiffness. Indian J Ophthalmol. 2013;61(8):392-393. doi:10.4103/0301-4738.116057 48. Scarcelli G, Besner S, Pineda R, Yun SH. Biomechanical characterization of keratoconus corneas ex vivo with brillouin microscopy. Investig Ophthalmol Vis Sci. 2014;55(7):4490-4495. doi:10.1167/iovs.14-14450 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 17 Figure Captions Figure 1 – Systematic review flowchart 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 Laser Refractive Surgery in Pregnant or Breastfeeding Patients Francisco Zamorano-Martín MD 1 José-María Sánchez-González OD PhD 2,3 María García-Lorente MD 1 Rahul Rachwani-Anil MD 1 Jorge Peraza-Nieves MD 4 Marina Rodríguez-Calvo-de-Mora MD PhD FEBO 1 Davide Borroni MD 5,6 Carlos Rocha-de-Lossada MD FEBO 7,8 1 Department of Ophthalmology, Regional Universitary Hospital of Malaga, Malaga, Spain 2 Department of Physics of Condensed Matter, Optics Area. University of Seville, Seville, Spain. 3 Department of Ophthalmology (Tecnolaser Clinic Vision). Refractive Surgery Centre, Seville, Spain. 4 Department of Ophthalmology, Hospital Clinic de Barcelona, Barcelona, Spain 5 Department of Doctoral Studies, Riga Stradins University, Riga, Latvia. 6 Department of Ophthalmology, Royal Liverpool University Hospital, Liverpool, UK. 7 Department of Ophthalmology, Hospital Universitario Virgen de las Nieves, Granada, Spain 8 Department of Ophthalmology, University of Malaga, Malaga, Spain. Corresponding author José-María Sánchez-González Reina Mercedes Street, Seville, Spain 41012 +34 618 20 41 10 / [email protected] Abstract This systematic review reported the outcomes of laser corneal refractive surgery in pregnant or breastfeeding patients. This study was carried out by searching in PubMed, Web of Science and Scopus Ms rev EO 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 databases, on June 15, 2020. Included were 128 eyes from a total of 64 patients, mean maximum followup was 39.2 ± 36.14 months. Time from surgery to complication ranged from 1 to 67 months, with a mean value of 23.42 ± 22.23 months. Photorefractive keratectomy and laser in situ keratomileusis surgery appear to be stable procedures which are not modified during pregnancy, and safe to complete during breastfeeding. Nevertheless, the lack of weight prospective research avoids having a greater certainty on this matter and. Due to transitory nature of pregnancy and breastfeeding, we could still contemplate surgery risk outweigh the benefits. Additional investigation will be necessary to clarify these issues. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 Introduction The prevalence of refractive errors, mainly myopia, has noticeably increased over the past years, and those who suffer from it seek for its correction.1 Moreover, ages between 20 and 30 years old represent the most common age range amongst the female gender population that seek refractive surgery, coinciding with the period in which they are most prone to getting pregnant.1 Currently, Laser-assisted in-situ keratomileusis (LASIK) is one of the most common laser refractive surgery technique, with excellent visual outcomes and safety profile.2 The introduction of the femtosecond laser has made LASIK even safer, with reduced intraoperative flap-related complications.3 Small incision lenticule extraction (SMILE) is a flapless minimally invasive technique where femtosecond laser is used during the entire procedure. Similarly, SMILE has demonstrated good refractive outcomes.3 Other procedures such as laser photorefractive keratectomy (PRK) or Laser assisted sub-epithelial keratomileusis (LASEK)4 are accepted as effective techniques in treating refractive errors, especially for the correction of low to moderate myopia, hyperopia and astigmatism.5 Post-laser ectasia (PLE) was defined as a progressive weakening and bulging of the cornea that leads to corneal steepening and thinning, associated with a loss of visual acuity.6 Although uncommon, with an approximate incidence between 0.04% and 0.9%, PLE remains one of the major fearsome complications after refractive surgery.7 It has been reported that LASIK induces a higher PLE risk than PRK,6 especially when the procedure is performed with a mechanical microkeratome instead of using femtosecond laser.8 PLE has also been reported after SMILE procedure.9 Risk factors for PLE include abnormal preoperative tomography, patients’ age at the surgery moment, an elevated refraction, central corneal thickness (CCT) less than 500 microns, or residual stromal bed thickness (RSBT) less than 300 microns.10–13 Santhiago et al.14 introduced the percent tissue altered (PTA) formula as a risk factor for PLE, when PTA is > 40%. Recently, it has been found that similar to the development of keratoconus, a vigorous eye rubbing could also result in chronic biomechanical failure, hence leading to PLE.15 Currently, there is still an ongoing debate in the scientific community whether it is possible to correct refractive defects during pregnancy and/or breastfeeding due to possible refractive changes, particularly myopia progression. The latter may be caused by hormonal induced-changes inherent to pregnancy or breastfeeding, altering the biomechanical stability of the body’s connective tissues, hence an increased risk of PLE.16,17 In fact, it has been reported that it may be advisable to postpone any changes in eyeglass 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 prescriptions until several weeks postpartum.18 Traditionally, pregnancy has been considered as a contraindication for refractive surgery, and recommending female patients to avoid pregnancy one year post-surgery.19,20 Modern studies have reported favorable results of refractive surgery in pregnancy21, and in breastfeeding patients.22 Conversely, in a well-designed and large-longitudinal cohort study, Fernández- Montero et al.1 recently reported that pregnancy is inversely associated with myopia development or its progression. Therefore, the aim of this systematic review is to report the outcomes of laser corneal refractive surgery in pregnant or breastfeeding patients, currently available in the scientific literature, seeking to establish a scientific consensus. Methods This systematic review study was carried out by searching in PubMed, Web of Science and Scopus databases, on June 15, 2020. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations.23 An initial search was conducted, focused on obtaining case studies of outcomes of laser corneal refractive surgery in pregnancy or breastfeeding patients. The keywords used were (pregnancy OR breastfeeding) AND (photorefractive keratectomy OR laser in-situ keratomileusis OR PRK OR LASIK OR SMILE OR Small incision lenticule extraction OR Laser assisted sub-epithelial keratomileusis OR LASEK). Among the results, a total of 150 articles were identified, which were evaluated and selected according to the inclusion and exclusion criteria. Inclusion criteria were: (1) experimental studies, original articles, case reports and cases series studies. The exclusion criteria were: (1) narrative reviews; (2) animal studies; (3) non-English publications; (4) Studies that excluded pregnant or breastfeeding patients. Subsequently, the following data was summarized in tables; (1) authors and year of publication, (2) study design, (3) follow-up, (4) number of patients, (5) number of eyes, (6) age, (7) time between surgery and complication expressed in months, (8) pregnant or breastfeeding period expressed in months, (9) type of refractive surgery, (10) corrected distance visual acuity (CDVA) before surgery, (11) refraction expressed in spherical equivalent (SE) before surgery, (12) uncorrected distance visual acuity after surgery, (13) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 refraction expressed in spherical equivalent (SE) after surgery, (14) recurrence expressed in months, (15) slitlamp findings, (16) complementary diagnostic test, (17) complications, (18) treatments, (19) favor or against. To assess risk of bias of the included studies, a summary table was created (Table 1) based on the Quality Assessment Tool for Case Series Studies from the National Heart, Lung, and Blood Institute.24 Questions included in the tool were: (1) Is the study oriented to a clear question?; (2) Were all the patients results taken into account?; (3) Was the follow-up complete?; (4) Were the same conditions used in surgical treatment?; (5) Was the intervention clearly described?; (6) Was the duration of follow-up adequate?; (7) Were the results described correctly? This analysis did not result in the elimination of any article. However, articles with a higher risk of bias had a lower weight for the data synthesis. Risk of bias was assessed by C.R.L. and J.-M.S.-G. No disagreement was encountered among the authors. Results The selection process of this systematic review was presented with a flow chart diagram in Figure 1. A total of 10 articles,21,25–33 published between 1996 and 2020, were included. All of them were case series, case reports or cohort studies. We included pregnant and breastfeeding patients between 25 and 38 years old, with a preoperative manifest refractive spherical equivalent between -0.87 diopter (D) and -11.75 D. The mean previous spherical equivalent was -5.27 ± 2.66 D. Spectacle CDVA was 20/20 (Snellen scale). Patient and surgery characteristics of the selected articles were reported in Table 2. This systematic review included 128 eyes from a total of 64 patients, and a maximum postoperative follow-up that ranged from 3 to 108 months, with the mean maximum follow-up of 39.2 ± 36.14 months. Time from surgery to complication ranged from 1 to 67 months, with a mean value of 23.42 ± 22.23 months. Pregnant or breastfeeding surgery period ranged from 1 to 7 months, and mean value was 4.60 ± 2.57 months. Regarding the surgical technique, four articles25–27,33 used PRK, and seven studies 21,28–33 used LASIK. Results after all refractive surgeries available in the scientific literature were presented in Table 3. In the postoperative period, uncorrected distance visual acuity changed to 20/32 ± 16.81. SE refraction changed to -1.62 ± 2.11 D. Recurrence time from surgery to the first evident clinical sign ranged from 1 to 67 months, with a mean value of 26.5 ± 22.60 months. RSBT mean value was 332.75 ± 52.06 µm. Within the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 6 complications, we observed that myopic regression was present in two studies,25,26 haze was present in two studies,26,27 overcorrection in only one study,27 visual acuity decrease and halos in two studies,27,28 and finally ectasia in four studies.27,28,30,31 Retreatment was performed in three studies.26,28,31 Sharif 26 retreated with PRK, while Hafezi et al.28,31 reported ectasia treatment with corneal crosslinking. In summary, only three studies21,25,33 were in favor, while the other seven studies26–32 were against refractive surgery procedures on pregnant or breastfeeding patients. Finally, the studies were grouped into three degrees, based on the risk of bias assessment tool: low evidence (yeses = 0 to 2); medium evidence (yeses = 3 to 5); high evidence (yeses = 6 to 7). Hefetz et al.25 and Hafezi et al.31 obtained a low evidence level. Starr27, Padmanabhan et al.29 and, López-Prats et al.32 achieved medium evidence level. Finally, Sharif26, Hafezi & Iseli28, Said et al.30, Alonso-Santander et al.33 and, Kanellopoulos & Vingopoulos21 obtained high evidence level. Discussion Refractive changes Ocular changes associated with pregnancy, such as the variation in tear production, intraocular pressure, and corneal and lens topographic alterations have been studied with inconclusive results in recent years. The role of estrogen receptors in corneal and lens modifications during pregnancy has been proposed.34 Morphological changes in the cornea may occur due to the development of corneal edema during pregnancy, therefore increasing the corneal curvature by 1 D and increasing the central corneal thickness between 1 to 16 µm. Furthermore, the curvature of the lens appears to increase, leading to a loss of transient accommodation.34 However, these changes usually reverse after delivery or lactation, and some authors have proposed that these changes do not involve significant variations in visual acuity or refractive error during pregnancy.35,36 The effect of pregnancy on the progression of myopia has been studied in a recent publication1. A cohort of 10,401 women between 20 and 50 years old was prospectively evaluated since 1999. Pregnancies and myopia were repeatedly assessed in each biennial follow-up questionnaire during 14 years of follow-up. Authors conclude that pregnancy was inversely associated with the risk of myopia development or 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 7 progression during each of the two-year periods. Complications of corneal refractive surgery associated with pregnancy, such as myopic regression, PLE, and haze, have been reported. It has been proposed that these complications may be a result of pregnancy physiological variations in underlying biomechanically weakened corneas.35,37–39 PRK Hefetz et al.40 were the first to assess the effect of pregnancy on PRK. They studied 11 eyes of 8 women who became pregnant 1 to 5 months after surgery. Out of these, one woman experienced myopic regression in both eyes when she became pregnant 5 months after surgery. However, this study did not report whether these changes remained permanent after delivery. Subsequently, Sharif 41 studied the same effect in 18 eyes of 9 women who became pregnant in the first 12 months after PRK. Preoperative myopia ranged from - 1.25 to -6 D, and the follow-up was from 12 to 24 months. He observed that twelve eyes underwent myopic regression, of which ten also developed corneal haze. All of them became pregnant in the first 5 months after surgery. Both complications improved after delivery in 50% of the eyes and the other 50% required retreatment with PRK. Furthermore, they observed that these complications were more frequent the more complex the pregnancy was. However, this study did not report the degree of preoperative myopia of all patients, which some authors related with corneal haze development.42 There is also no reference to the degree of myopic regression and its clinical implication for the patient, although we presume it was substantial as a new surgery was required. The results of this study seem to indicate that there is a risk of myopic regression and haze development in patients who become pregnant in the first 5 months after PRK. In the same way, Starr43 reported a case of a woman who experienced a +3 D overcorrection and corneal haze during pregnancy after myopic PRK in her right eye (RE). Preoperative myopia was -5 D, and it was estimated that she became pregnant one week after surgery. The patient suffered an abortion in the third month of pregnancy and the overcorrection suffered a regression. In the tenth month after surgery, she had an uncorrected distance visual acuity (UDVA) of 20/20, a refraction of +0.25 D and the haze had disappeared. Although this study refers to an isolated case, the results are striking given the overcorrection in the short period of time between surgery and the beginning of pregnancy, as well as for the complete regression of the overcorrection after the abortion. It also seems to point out the risk of corneal haze and refractive changes in patients who become pregnant in a short period of time after PRK. We can conclude 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 8 that, although there are no weight studies that assess the effect of pregnancy in patients with PRK surgery, it seems reasonable to delay gestation between 6 and 12 months after the intervention. Likewise, the few published studies suggest that it is important to point out that refractive changes and corneal haze revert after the end of pregnancy in most patients, including those who become pregnant in the first 6 months after surgery. Therefore, it is recommended to wait several months before considering the possibility of retreatment in patients who continue with sequelae after delivery. LASIK LASIK can alter corneal biomechanics, which seems to suppose a greater risk of PLE than other refractive surgery corrections, such as PRK or SMILE.3 Hafezi and Iseli 37 reported a case of bilateral PLE in the third trimester of a woman's first pregnancy, 26 months after LASIK correction of -5.5 D in the RE and -5.25 D in the left eye (LE). According to the presurgical examination, the cornea had no pre-existing signs of disease, and 68 µm were ablated in the RE and 62 µm in the LE. After LASIK, the UDVA was 20/20 with normal topographies, and central corneal thickness was 410 µm in the RE and 400 µm in the LE. These parameters remained stable for two years. During the third trimester of the first pregnancy, PLE was developed, and the patient had a minimum corneal thickness of 370 µm in the RE and 360 µm in the LE. Two years later, during the second pregnancy, the patient suffered a sudden vision deterioration in her RE due to PLE progression. This case is distinctive due to the late onset of PLE, happening and progressing both times in the second trimester of pregnancy, and due to its stable behavior out of the pregnancy period. Changes in estrogen levels could play a role in LASIK-induced ectasia as they had been proposed to reduce corneal biomechanical stability in experimental studies.37 In the same way, Padmanabhan et al. reported another case of bilateral PLE in the first trimester of gestation, 18 months after myopic LASIK surgery. Similarly, the preoperative and tomographic clinical examinations did not suggest a presumable forme fruste or subclinical keratoconus in any eye. In this case, the patient had a 20/20 CDVA with a refractive error of -10.50 -2 x 10 in the RE, and -11.50 -1 x 160 in the LE. After the intervention, there was a RSBT of 305 µm in the RE and 282 µm in the LE, and a UDVA of 20/20. Eighteen months after surgery, during the first month of gestation, the patient was diagnosed with progressive PLE. Likewise, this article suggested the action of estrogens as a factor that modifies corneal biomechanics, and proposed that we should be cautious with arbitrary cut-off values, recalling that 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 15 Ophthalmol. 2011;25(3):225-230. doi:10.1016/j.sjopt.2011.05.003 31. Hafezi F, Koller T, Derhartunian V, Seiler T. Pregnancy may trigger late onset of keratectasia after LASIK. J Refract Surg. 2012;28(4):242-243. doi:10.3928/1081597X-20120401-07 32. López-Prats MJ, Hidalgo-Mora JJ, Sanz-Marco E, Pellicer A, Perales A, Díaz-Llopis M. Influencia del embarazo sobre los parámetros refractivos tras cirugía laser in situ keratomileusis. Arch Soc Esp Oftalmol. 2012;87(6):173-178. doi:10.1016/j.oftal.2011.09.021 33. Alonso-Santander N, Ortega-Usobiaga J, Beltrán-Sanz J, Druchkiv V, Llovet-Osuna F, Baviera- Sabater J. Laser in Situ Keratomileusis and Surface Ablation in Breastfeeding Patients. Cornea. 2020;39(7):862-867. doi:10.1097/ICO.0000000000002276 34. Sharma S, Rekha W, Sharma T, Downey G. Refractive issues in pregnancy. Aust N Z J Obstet Gynaecol. 2006;46(3):186-188. doi:10.1111/j.1479-828X.2006.00569.x 35. López-Prats MJ, Hidalgo-Mora JJ, Sanz-Marco E, Pellicer A, Perales A, Díaz-Llopis M. Influencia del embarazo sobre los parámetros refractivos tras cirugía laser in situ keratomileusis. Arch Soc Esp Oftalmol. 2012;87(6):173-178. doi:10.1016/j.oftal.2011.09.021 36. Moshirfar M, Rosen DB, Heiland MB, Ronquillo YC, Hoopes PC. Should I Get LASIK If I’m Breastfeeding? Ophthalmol Ther. 2019;8(3):349-352. doi:10.1007/s40123-019-0195-5 37. Hafezi F, Iseli HP. Pregnancy-related exacerbation of iatrogenic keratectasia despite corneal collagen crosslinking. J Cataract Refract Surg. 2008;34(7):1219-1221. doi:10.1016/j.jcrs.2008.02.036 38. Padmanabhan P, Radhakrishnan A, Natarajan R. Pregnancy-triggered iatrogenic (post-laser in situ keratomileusis) corneal ectasia--a case report. Cornea. 2010;29(5):569-572. doi:10.1097/ICO.0b013e3181bd9f2d 39. Said A, Hamade IH, Tabbara KF. Late onset corneal ectasia after LASIK surgery. Saudi J Ophthalmol Off J Saudi Ophthalmol Soc. 2011;25(3):225-230. doi:10.1016/j.sjopt.2011.05.003 40. Hefetz L, Gershevich A, Haviv D, Krakowski D, Eshkoly M, Nemet P. Influence of pregnancy and labor on outcome of photorefractive keratectomy. J Refract Surg. 1996;12(4):511-512. 41. Sharif K. Regression of myopia induced by pregnancy after photorefractive keratectomy. J Refract Surg. 1997;13(5 Suppl):S445-6. 42. Hashemi H, Reza Taheri SM, Fotouhi A, Kheiltash A. Evaluation of the prophylactic use of mitomycin-C to inhibit haze formation after photorefractive keratectomy in high myopia: A 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 16 prospective clinical study. BMC Ophthalmol. 2004. doi:10.1186/1471-2415-4-12 43. Starr MB. Pregnancy-associated overcorrection following myopic excimer laser photorefractive keratectomy. Вестник Казнму. 1998;№3:с.30. 44. Jin SX, Dackowski E, Chuck RS. Risk factors for postlaser refractive surgery corneal ectasia. Curr Opin Ophthalmol. 2020;31(4):288-292. doi:10.1097/ICU.0000000000000662 45. Bower KS, Woreta F. Update on contraindications for laser-assisted in situ keratomileusis and photorefractive keratectomy. Curr Opin Ophthalmol. 2014;25(4):251-257. doi:10.1097/ICU.0000000000000055 46. Journal O, Moshirfar M, Motlagh MN, Murri MS, Momeni-Moghaddam H, Ronquillo YC, Phillip ;, Hoopes C. Medical Hypothesis, Discovery &Innovation Advances in Biomechanical Parameters for Screening of Refractive Surgery Candidates: A Review of the Literature, Part III. Med Hypothesis Discov Innov Ophthalmol. 2019;8(3). 47. Roy AS, Shetty R, Kummelil MK. Keratoconus: A biomechanical perspective on loss of corneal stiffness. Indian J Ophthalmol. 2013;61(8):392-393. doi:10.4103/0301-4738.116057 48. Scarcelli G, Besner S, Pineda R, Yun SH. Biomechanical characterization of keratoconus corneas ex vivo with brillouin microscopy. Investig Ophthalmol Vis Sci. 2014;55(7):4490-4495. doi:10.1167/iovs.14-14450 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 17 Figure Captions Figure 1 – Systematic review flowchart 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 PRK and LASIK appear to be stable procedures which are not modified during pregnancy, and safe to perform during breastfeeding. However, the lack of weight studies prevents having greater certainty. Synopsis Figure 1 Click here to access/download;Figure;Figure 1.tif Table 1. Quality assessment of articles Author and Date Q1 Q2 Q3 Q4 Q5 Q6 Q7 Hefetz et al.1 (1996) Yes No No Yes No No No Sharif2 (1997) Yes Yes Yes Yes Yes Yes No Starr3 (1998) Yes Yes No Yes Yes No No Hafezi & Iseli4 (2008) Yes Yes Yes Yes Yes Yes Yes Padmanabhan et al.5 (2010) Yes Yes No Yes Yes No No Said et al.6 (2011) Yes Yes Yes Yes Yes Yes Yes Hafezi et al.7 (2012) Yes No No No No No No López-Prats et al.8 (2012) Yes Yes No Yes Yes No Yes Alonso-Santander et al.9 (2020) Yes Yes Yes Yes Yes Yes Yes Kanellopoulos & Vingopoulos10 (2020) Yes Yes Yes Yes Yes Yes Yes Q= Question; (Q1): Is the study oriented to a clear question?; (Q2): Were all the patients results taken into account?; (Q3): Was the follow-up complete?; (Q4): Were the same conditions used in surgical treatment?; (Q5): Was the intervention clearly described?; (Q6): Was the duration of follow-up adequate?; (Q7): Were the results described correctly? Table Table 2. Study characteristics Autor (date) Design Followup (months) Patients Eyes Age Surgery to complication time POB Period Refractive Surgery Hefetz et al.1 (1996) SC 12 8 11 NR 5 NR PRK Sharif2 (1997) SC 12 9 18 25 5 NR PRK Starr3 (1998) CR 14 1 1 38 1 1 PRK Hafezi & Iseli4 (2008) CR 90 1 2 33 26 7 LASIK Padmanabhan et al.5 (2010) CR 25 1 2 20 18 2 LASIK Said et al.6 (2011) SC 108 3 5 32 42 NR LASIK Hafezi et al.7 (2012) SC 67 5 10 31 67 7 LASIK López-Prats et al.8 (2012) Cohort 6 9 18 27 NR 6 LASIK Alonso-Santander et al.9 (2020) SC 3 71 142 33 NR NR LASIK (131)/PRK (11) Kanellopoulos & Vingopoulos10 (2020) SC 55 64 128 32.5 NR No LASIK SC= Serie of Cases; LASIK: Laser assisted in-situ keratomileusis; PRK: Photorefractive keratectomy; CR: Case Report; POB: pregnant or breastfeeding; NR: not reported Table Table 3. Evaluation of the visual results after the laser refractive surgery on pregnant of breastfeeding patients Autor (date) Previous Posterior Recurrenc e (months) Slit-Lamp Findings Complementary Diagnostic Tests Complication Treatment Favor / Against BCVA Rx* UDVA Rx* Hefetz et al.1 (1996) NR -4.80 NR -0.80 NR NR NR Myopic regression NR Favor Sharif2 (1997) NR -3.50 NR NR 5 Haze NR Myopic regression, Haze PRK Against Starr3 (1998) 20/20 -5.00 20/20 +0.25 1 Haze NR Overcorrection, Haze NR Against Hafezi & Iseli4 (2008) 20/20 -5.75 20/63 -6.00 26 NR 405 µm VA decrease, halos, ectasia CCL Against Padmanabhan et al.5 (2010) 20/20 - 11.75 NR NR 18 NR 290 µm VA decrease, halos, ectasia NR Against Said et al.6 (2011) NR -7.00 NR NR 42 NR 277 µm Ectasia NR Against Hafezi et al.7 (2012) 20/20 -5.00 NR NR 67 NR 359 µm Ectasia CCL Against López-Prats et al.8 (2012) 20/20 -0.87 20/25 -1.37 NR NR NR NR NR Against Alonso-Santander et al.9 (2020) 20/20 -3.80 20/20 -0.20 NR NR NR NR NR Favor Kanellopoulos & Vingopoulos10 (2020) 20/20 -6.05 20/20 -0.37 NR NR NR NR NR Favor BCVA: Best corrected visual acuity; Rx: Refraction (*expressed in spherical equivalent); NR: not reported; UDVA: Uncorrected distance visual acuity; CCL: Corneal collagen Crosslinking; µm: micra (thinnest point) after LASIK Table Table 2. Study characteristics Autor (date) Design Followup (mo) Patients Eyes Age (y) Surgery to complication time POB period Refractive surgery Hefetz et al.1 (1996) CS 12 8 11 NR 5 NR PRK Sharif2 (1997) CS 12 9 18 25 5 NR PRK Starr3 (1998) CR 14 1 1 38 1 1 PRK Hafezi and Iseli4 (2008) CR 90 1 2 33 26 7 LASIK Padmanabhan et al.5 (2010) CR 25 1 2 20 18 2 LASIK Said et al.6 (2011) SC 108 3 5 32 42 NR LASIK Hafezi et al.7 (2012) SC 67 5 10 31 67 7 LASIK López-Prats et al.8 (2012) Cohort 6 9 18 27 NR 6 LASIK Alonso-Santander et al.9 (2020) SC 3 71 142 33 NR NR LASIK (131)/PRK (11) Kanellopoulos & Vingopoulos10 (2020) SC 55 64 128 32.5 NR No LASIK CR = case report; CS = case series; NR = not reported; POB = pregnant or breastfeeding; PRK = photorefractive keratectomy T2 EO Table 1. Quality Assessment of Articles. Author and Date Q1 Q2 Q3 Q4 Q5 Q6 Q7 Hefetz et al.1 (1996) Yes No No Yes No No No Sharif2 (1997) Yes Yes Yes Yes Yes Yes No Starr3 (1998) Yes Yes No Yes Yes No No Hafezi & Iseli4 (2008) Yes Yes Yes Yes Yes Yes Yes Padmanabhan et al.5 (2010) Yes Yes No Yes Yes No No Said et al.6 (2011) Yes Yes Yes Yes Yes Yes Yes Hafezi et al.7 (2012) Yes No No No No No No López-Prats et al.8 (2012) Yes Yes No Yes Yes No Yes Alonso-Santander et al.9 (2020) Yes Yes Yes Yes Yes Yes Yes Kanellopoulos & Vingopoulos10 (2020) Yes Yes Yes Yes Yes Yes Yes Q1 = Is the study oriented to a clear question?; Q2 = Were all the patients results taken into account?; Q3 = Was the follow-up complete?; Q4 = Were the same conditions used in surgical treatment?; Q5 = Was the intervention clearly described?; Q6 = Was the duration of follow-up adequate?; Q7 = Were the results described correctly? T1 EO