Maternal Night Blindness and Microphthalmos, Anophthalmos, and Coloboma (MAC) Disorders – Is there an Association?

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Ken Nischal, Ketaki Subhedar, Shailja Tibrewal, Chintan Shah, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5194389/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract OBJECTIVES Microphthalmos, Anophthalmos, and Coloboma (MAC) are common causes of childhood blindness. In 1996, World Health Organisation (WHO) proposed night blindness (NB) as a functional indicator of Vitamin A deficiency (VAD). We aimed to investigate the association of maternal antenatal NB, environmental risk factors and socioeconomic determinants with MAC. METHODS A case-control study was conducted between 2018 to 2021 comparing risk factors between MAC and control cases. Data regarding maternal antenatal NB, birth order, consanguinity, family history, maternal dietary habits during pregnancy, history of spontaneous abortions, and father’s income were collected retrospectively and through telephonic interviews with mothers. Bilateral anophthalmos, severe microphthalmos or a combination defined a severe MAC phenotype. RESULTS 220 children with MAC and 219 normal controls aged 0–3 years were included. Antenatal maternal NB was observed in 33.2% of MAC and 3.2% of controls (p < 0.001). A higher birth order (2nd or more), parental consanguinity, and a history of prior spontaneous abortions were also more common in MAC. A history of antenatal maternal NB was more common in severe MAC (67.3%) as compared to the less severe MAC (22.6%) (p < 0.001). CONCLUSIONS The study identified antenatal maternal NB, higher birth order, parental consanguinity, and history of spontaneous abortions as significant risk factors for MAC disorders, highlighting the influence of maternal nutrition and genetics. To the best of our knowledge, this is the largest case-control study to show an association of maternal NB and MAC. Maternal NB has been used as a functional indicator of VAD. Health sciences/Risk factors Health sciences/Pathogenesis Figures Figure 1 Figure 2 INTRODUCTION Childhood blindness poses a significant global health challenge, particularly in low to middle-income countries. 1 In India, the prevalence of childhood blindness is about 0.8 per 1000 children, with major causes being microphthalmos, anophthalmos, and phthisis bulbi. 2 Microphthalmos is defined as an eye size less than two standard deviations (SD) of average, anophthalmos is the absence of ocular structures, and coloboma refers to the incomplete closure of the optic fissure. These conditions, which often show clinical and genetic overlaps, are grouped as the 'MAC phenotype'. 3 The MAC disorders are influenced by genetic and environmental factors. 3 – 6 Certain causative genes like STRA6, ALDH1A3, RARB are involved in the retinoic acid (RA) pathway and are essential for eye development. 3 – 6 Pathogenic variations in these genes can cause severe forms of MAC. 7 Concurrently, maternal Vitamin A deficiency (VAD) during pregnancy has been speculated in MAC causation. 5 , 7 Both MAC and Vitamin A deficiency (VAD) are common in poor socioeconomic sections of the society. 8 , 9 MAC is also common in populations where consanguinity is higher. 4 , 9 It has been hypothesised that a genetic susceptibility may increase fetal vulnerability to the teratogenic effects of maternal VAD. 5 Animal studies have shown that Vitamin A deficient mothers gave birth to offsprings with defective eyeballs and that Vitamin A supplementation at a critical time during pregnancy could prevent the ocular anomalies from occurring. 10 – 12 In 2020, we analyzed the clinical features of MAC across three eye care institutes and noted regional variances in numbers and severity. 13 We postulated that these differences were linked to socioeconomic status and antenatal maternal VAD. The current study was conducted with the aim to compare antenatal maternal VAD (using a surrogate marker, namely maternal night blindness during pregnancy) and other risk factors in MAC patients versus age-matched controls and correlate them with the severity of MAC. Since night blindness is the main clinical consequence of VAD, the International Vitamin A Consultative Group (IVACG) 14 recommended that a night blindness prevalence of ≥ 5% during pregnancy observed in population studies is sufficient to classify VAD as a public health issue. For this reason, maternal VAD was assessed using the WHO’s night blindness questionnaire. 14 , 15 METHODS An observational, retrospective case-control study was conducted at three tertiary eye-care institutes in India from three neighbouring states: Dr. Shroff’s Charity Eye Hospital (SCEH, New Delhi, Delhi), Sadguru Netra Chikitsalaya (SNC, Chitrakoot, Madhya Pradesh) and Sitapur Eye Hospital (SEH, Sitapur, Uttar Pradesh). These three eye-care institutes are part of the Bodhya Eye Consortium, which includes seven eye-care institutes (SCEH, New Delhi; SNC, Chitrakoot; SEH, Sitapur; CL Gupta Eye Institute, Moradabad, Uttar Pradesh; MGM Eye Institute, Raipur, Chhattisgarh; Srikiran eye institute, Kakinada, Andhra Pradesh; and Pushpagiri Vitreoretina Institute, Hyderabad, Telangana) across India. This research consortium was formulated to develop evidence-based consensus led protocols and studies to provide consistent and robust big data from both urban and non-urban eye-care centres in India. Institutional review board approval was obtained at each of the three participating centres. The study conformed to the tenets of Helsinki. Standardized data collection forms were used across the three sites. We included consecutive patients of MAC between the ages of 0 to 3 years presenting between July 2018 to June 2021. The control group consisted of all consecutive patients of similar age group with a diagnosis of refractive error, allergic conjunctivitis, trauma, or congenital nasolacrimal duct obstruction presenting to the clinics within the same study duration. The number of the children in the control group was matched with the number of MAC cases from each of the participating centres to avoid any selection bias due to regional variations in the risk factors. Children with unclear antenatal histories or indistinct MAC diagnoses were excluded. Assuming the prevalence of maternal night blindness in MAC disorders to be 16% 4 and taking the upper limit of 95% CI for the same, a difference of 10% between the two groups, α error of 5% and power of 80%, the sample size in each group was calculated to be around 220. The data collected consisted of demographic data such as the age of the child, gender, and address/region of residence. The father's income was noted to determine the socioeconomic status of the family. Antenatal details like history of prior spontaneous abortions in the mother, diet of the mother during pregnancy (vegetarian /non-vegetarian, antenatal fever or rashes, use of antenatal medications or complications, antenatal NB and the month of the NB if present were documented. Any family history of MAC, presence of consanguinity, and the degree of consanguinity was enquired. Other natal factors like, term, preterm or post-term delivery, birth order, low birth weight (< 2.5 kg), and any history of delayed milestones were noted. The clinical features that were documented were presence or absence of systemic abnormalities, nature of the systemic problems if present, the best corrected visual acuity, size of the cornea (measured with scale, callipers or pupilometer), and the details of the coloboma, microphthalmos and anophthalmos. Age-appropriate tests for visual acuity were performed as per standard protocols for visual assessment in the participating eye institutes. In children less than 3 months of age, the presence of light perception was recorded by documenting the dazzle reflex. In children older than 3 months, fixing and following light and illuminated objects was evaluated. In co-operative children, preferential looking tests (Teller Acuity cards or Cardiff acuity test) were used for vision assessment. Clinical anophthalmos (A) was defined as ‘no visible sign of the globe’ and microphthalmos was defined as ‘visibly small eyes’. Additionally, those eyes in which the corneal diameter was < 4mm and only non-functional rudimentary eye structures were present were classified as severe microphthalmos (SMM). Isolated ocular coloboma (IC) was defined as coloboma without microcornea or microphthalmos. Isolated micropthalmos (IM) was defined as a visibly small eye with no coloboma or any other structural abnormality. Mixed microphthalmos (MM) was termed in the presence of coloboma with microcornea/microphthalmia. Complex microphthalmos (CM) was defined as the presence of microphthalmos or coloboma with other anterior segment anomalies such as corneal opacities, cataract, and anterior segment dysgenesis. Diagnosis relied mainly on clinical assessments, supplemented by B-scan ultrasound and A-scan biometry where available. Figure 1 shows the examples of phenotypic subtypes of MAC. Any missing data pertaining to history was obtained via telephonic conversations with the mother of the child in both the MAC and the control groups. The telephone calls were made by one of the team members at each of the participating centers and only the mother of the child was specifically questioned regarding the antenatal events. In 1996, World Health Organisation (WHO), provided guidelines for utilizing indicators of VAD for estimating the community burden focusing on children, pregnant and lactating women. Night blindness was used as a functional indicator of VAD. 15 They suggested an algorithm, which can be used for interviewing mothers to elicit reliable history. The questionnaire includes the following: (i) Do you/does your child have any problem seeing in the daytime? (ii) Do you/does your child have any problem seeing in the evening or in low levels of light? (iii) If (2) = yes: Is this problem different from most other children/ women in your community? (iv) Do you/Does your child have NB? (use the local term that describes symptoms). The same algorithm has been used by several studies with minor modifications. 16 , 17 We used the same algorithm to enquire about the history of NB during pregnancy during the in-person and telephonic conversations with the mothers of both the MAC and the control group patients in the study. We also asked if the NB persisted after the pregnancy and whether it was associated with poor vision and nystagmus, to rule out nyctalopia associated with retinal dystrophies. While poor vision can be associated with VAD, by excluding such cases we felt that the number of mothers with NB would be an underestimation and not an overestimation. The data was compiled in Excel, and analysis was performed using the R software (version 4.3.2). The descriptive statistics included calculation of numbers, percentages, mean and range. Univariate and multivariate logistic regression was used to compare the various demographic and risk factors among the cases and the controls. For analysis, a severe phenotype of MAC was defined as a bilateral affection with anophthalmos or severe microphthalmos or a combination of both. The various factors were compared between the severe MAC phenotype and others. A p value of less than 0.05 was considered statistically significant. RESULTS A total of 220 MAC cases and 219 controls were included in the study. Amongst the cases and the controls, females constituted 52.7% and 54.3% of the patients, respectively. Unilateral MAC was seen in 67 patients (30.4%) while 153 patients presented with bilateral MAC in various phenotypic combinations. Figure 1 shows the clinical images of phenotypes and Fig. 2 shows the distribution of the various MAC subtypes among the unilateral and bilateral cases. The diagnoses in the control group were, allergic conjunctivitis (79), congenital nasolacrimal duct obstruction (116), refractive error (9), acute microbial conjunctivitis (6), esotropia (2), no ocular pathology (6), and trauma (1). The distribution of cases varied amongst the three institutions. A total of 124 (56.3%) cases were from SEH, 66 (30.0%) cases from SCEH and 30 (13.6%) cases were from SNC. Out of these, the severe MAC phenotype was observed more in SEH, 46 out of the 124 cases (37.0%), as compared to 6 out of 66 cases from SCEH (9.0%) and none from SNC. A comparison of the demographic features and risk factors among the cases and the controls is shown in Table 1. Based on the validated WHO questionnaire, a positive history of night blindness was given by 73 (33.1%) mothers of the MAC patients and 7 (3.2%) mothers of controls (p value < 0.001). Only 45 women could provide details of the timing of night blindness. Among them 26 perceived night blindness in the 3rd trimester (57.7%), eight perceived in the 2nd trimester (17.7%) and four perceived in the first trimester (8.8%). In all the instances the night blindness was transient and recovered during pregnancy or shortly after it. A total of seven women recalled the presence of transient night blindness in all their pregnancies, out of that only 2 confirmed the timing in the 3rd trimester. A history of parental consanguinity was present in 11.9% of patients in the MAC group and 9.1% of patients in the control group. No instances of first-degree consanguinity were noted in either of the groups. Second-degree consanguinity was noted in 19 cases and 6 controls. Multivariate analysis revealed that antenatal night blindness (p value < 0.001, Odds ratio (OR) 16.47, 95% Confidence interval (CI) 4.78–87.62) and the birth order (p value < 0.001, OR 2.53, 95% CI 1.54–4.37) remained statistically different among the cases and controls. The analysis also revealed that parental consanguinity (p value 0.018, OR 71.39, 95% CI 1.90 – very high) and history of spontaneous abortions (p value 0.005, OR 6.31, 95% CI 1.69–33.99) were statistically different between the two groups, explained by the suppressor effect. A severe MAC phenotype was seen in 52 patients. Table no 2 shows the comparison of the various risk factors between severe and less severe MAC phenotypes using univariate analysis. Only age (p value 0.037, OR 0.928, 95% CI 0.86–0.99) and antenatal NB (p value 0.006, OR 5.043, 95% CI 1.64–16.86) retained statistical significance in the multivariate analysis. Among those patients with a positive history of night blindness, a severe MAC phenotype was seen in 47.9%. There was no statistically significant difference between unilateral and bilateral cases regarding their history of night blindness, consanguinity, or birth order. Systemic abnormalities were observed in 9 (4.1%) patients with MAC. Table no 3 describes the systemic abnormalities seen in the children with MAC. DISCUSSION Due to the progressive improvement in detection and treatment of the avoidable causes of blindness, non-avoidable causes like MAC disorders are now becoming important causes of childhood blindness. 18 , 19 Our study compared the demographic, socioeconomic, and environmental risk factors in MAC patients against controls to identify the potentially modifiable risk factors. We discovered a 10-fold increase in odds of a maternal history of transient NB during pregnancy in MAC patients compared to controls. Other significant risk factors included a higher birth order, maternal history of spontaneous abortions, and parental consanguinity. A higher MAC prevalence in economically disadvantaged areas and its regional differences suggest possible maternal nutritional factors. 9 , 19 We utilized maternal NB history as a functional indicator of VAD, in line with WHO recommendations 15 and those of the IVACG 14 (International vitamin A consultative Group). Although serum retinol is a more specific biological indicator, its variability with season, pregnancy trimester, and hemodilution complicates its utility as a measure. 15 The relationship between maternal VAD and MAC disorders has been speculative, with previous studies not conclusively establishing an association. 4 , 5 , 8 Retinoic acid (RA), derived from Vitamin A, is a crucial morphogen for embryogenesis, organ formation, limb development, optic vesicle and anterior segment formation, and embryonic sustainability. 7 Animal models have demonstrated the essential role of RA in eye development through evolutionary conserved mechanisms. 10 , 11 , 20 , 21 In 1937, Hale found porcine offsprings of Vitamin A-deprived mothers had severe eye defects or an absent eyes. 10 Warkany and Kalter's 1959 review revealed that over 90% of offspring from Vitamin A-deficient rodents displayed ocular and urogenital anomalies. 11 They noted that early gestational Vitamin A supplementation reduced the incidence of malformations, emphasizing that the timing is critical. Administration before key organogenesis could avert developmental aberrations, whereas late supplementation proved ineffective. Similarly, anecdotal reports in humans link congenital microphthalmia and ocular dysgenesis in neonates to maternal biliopancreatic surgery related VAD. 22 , 23 A case where a woman had repeated anophthalmia and systemic defects across two pregnancies, which was averted in the third by pre-conceptional daily intake of 5000 IU of Vitamin A has been reported. 24 Genetic variations affecting the RA pathway genes have also been linked to MAC disease. 3 , 6 , 12 , 25 – 27 The common genes of the retinoic acid pathway implicated in MAC disorders are STRA6 (MIM*610745), ALDH1A3 (MIM*600463), RARB (MIM*180220) and RBP4 (MIM*180250). The presence of deleterious genetic variants in the fetus may influence the consequences of maternal VAD. 5 , 12 , 25 , 28 , 29 Additionally, the differences in Vitamin A metabolism in mothers or fetuses and the timing of the expression of the gene may explain the phenotypic variability in MAC in some cases. 29 , 30 Hornby et al. reiterated the role of RA pathway gene signaling in MAC, based on their study in South India which showed high rates of consanguinity (44.6%) and familial occurrences (21.4%) among 56 visually impaired children with MAC recruited from blind schools, integrated schools for the visually impaired, eye hospital and community rehabilitation programs. 4 , 31 They proposed a gene-environment interaction where recessively inherited mutations in Vitamin A pathway genes might increase the fetal susceptibility to ocular anomalies in the presence of maternal VAD. 5 Our study recorded a lower consanguinity (11.9%) and familial history (6.3%), possibly due to different source of the sample population, differences in laterality of the disease in the sample, and regional variations in consanguineous marriages. Hornby et al. also investigated environmental risk factors in children with coloboma and found maternal history of antenatal NB in 16%. 4 Our current study observed a higher frequency of antenatal NB in MAC patients (33.2%). Unlike Hornby et al who recruited patients affected with bilateral MAC from schools for the blind, we included both bilateral and unilateral MAC patients from outpatient departments across three tertiary-eye-care centers. The authors of the former study did not mention the age range of the patients recruited in their study. There were only two patients less than two years of age. There is a possibility of recall bias in assessing a history of remote events. Thus, we included children below three years of age at the time of the presentation. The presence of an age-matched control group in the current study also strengthens its results. Our study found the majority of women experienced night blindness in the third trimester (57.7%), aligning with the results of Hornby et al. 4 VAD is more common in the third trimester due to the increased physiological demand by the growing fetus. 32 However, shortage of Vitamin A in diet and during infections or gestational diabetes may precipitate VAD in any time during pregnancy. 32 Other micronutrients like zinc can affect Vitamin A utilization. 33 Multiple pregnancies contribute to poor maternal nutrition, with nutritional status often declining in successive pregnancies. 34 Hornby et al. observed higher chances of second order birth in children with MAC 4 similar to our study, suggesting that occurrence of MAC was related to parity. Maternal malnutrition can also predispose to spontaneous abortions by affecting the morphology of germ cells. 35 The history of previous spontaneous abortions coupled with higher birth order in MAC cases in the current study, is suggestive of poor maternal nutrition with multiple micronutrient deficiencies including VAD. We also found that a history of maternal NB was more common (67.3%) in severe category of MAC as compared to less severe cases (22.6%). There is evidence that pathogenic variations in the RA pathway genes often lead to severe MAC phenotypes. 3 , 27 , 29 Whether the level of VAD in the mother influences the manifestation of RA pathway gene defects in a dose-dependent manner is a matter of future research. Our study faced limitations, including difficulties in obtaining detailed histories of socioeconomic status, diet, and antenatal medication use. Dietary intake was broadly classified as vegetarian or non-vegetarian due to the imprecision of maternal recall. While a history of NB serves as a proxy for Vitamin A deficiency (VAD), direct measurement of serum retinol would be more specific. 15 However, serum retinol and retinol binding protein levels may change throughout pregnancy and vary in stress and inflammation. 36 Apart from being expensive, it may underestimate the status of VAD in populations with high prevalence of infections and inflammation. Socioeconomic status was also challenging to determine, as many participants were reticent about disclosing family income, education, or occupation. Axial length or corneal diameter measurements were often infeasible due to the young age of the patients included in the study. Although, we restricted our sample to children under three years old, to reduce the recall bias, it could not have been eliminated. To conclude, to the best of our knowledge the current study is the first case-control study to evaluate the risk factors for MAC disorders. Maternal night blindness, lower birth order, history of consanguinity and prior spontaneous abortions in mothers were significantly more in children with MAC as compared to controls. The children with the severe phenotypes had higher chances of maternal night blindness. The true nature of possible gene-environment interactions needs to be explored in future research, but we feel this study establishes a correlation between maternal night blindness during pregnancy and MAC. SUMMARY Maternal night blindness (a surrogate for Vitamin A deficiency) is tenfold more prevalent in children with Microphthalmos, Anophthalmos & Coloboma (MAC) than in non-MAC children. What was known before MAC disorders cause childhood blindness and result from genetic and/or environmental factors. Animal studies have shown an association with maternal Vitamin A deficiency (VAD). Maternal night blindness is a marker for vitamin A deficiency for public health interventions. What This Study Adds This is first study in humans to show an increased prevalence of maternal night blindness (surrogate for VAD) in children with MAC versus age-matched unaffected children. The possible association of maternal VAD and MAC has research and health policy implications. Abbreviations MAC Microphthalmos Anophthalmos and Coloboma NB Night blindness SD Standard deviation VAD Vitamin A deficiency WHO World Health Organization CI Confidence interval A Anophthalmos SMM Severe microphthalmos CM Complex microphthalmos IM Isolated microphthalmos IC Isolated Coloboma MM Mixed microphthalmos RA Retinoic Acid SCEH Dr. Shroff’s Charity Eye Hospital SEH Sitapur Eye Hospital SNC Sadguru Netra Chikitsalaya INR Indian Rupee Declarations Acknowledgements The authors would like to thank Dr Jinal Gore from SCEH for helping with a small part of the data collection.The authors would also like to acknowledge the governing council of the Bodhya Eye Consortium consisting of Dr Umang Mathur, Dr Madhu Bhadauria, Dr Elesh Jain, Dr Ashi Khurana, Dr Deepshikha Agrawal and Dr Vikas Mittal.The remaining members of the Pediatric Ophthalmology subgroup of the Bodhya Eye Consortium- Dr Pradeep Agarwal, Dr Anupam Sahu, Dr Avinash Mahindrakar, Dr Monalisa Mohapatra, Dr Rajat Kapoor, Dr Soveeta Rath, Dr Richa Sharma, Dr Abhilasha Parkhe, Dr Shilpa Sonarkhann, Mr Samir Sutar, Ms Preeti Sharma, Ms Srivani, and Ms Dolly are also acknowledged. Funding/Support: No funding was secured for this study. Author Contribution Statements Ketaki Subhedar and Shailja Tibrewal equally conceptualized and designed the study, coordinated and supervised data collection, wrote the manuscript, critically reviewed and revised the manuscript for important intellectual content and proof reading. Chintan Shah, Ria Ratna, Atanu Majumdar, Subhajit Bhattacharya and Pradnya Sen contributed in designing the data collection methodology, collected data, carried out the initial analyses, and critically reviewed and revised the manuscript. Madhu Bhaduria and Suma Ganesh contributed to the implementation of the research, critically reviewed and revised the manuscript. Ken Nischal contributed to the study design, critically reviewed and revised the manuscript, and proofread it for the publication version. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. 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Hum Genet. 2019;138:831–846. doi: 10.1007/s00439-018-1949-1 Ch ou CM, Nelson C, Tarlé SA, Pribila JT, Bardakjian T, Woods S, et al. Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease. Cell. 2015;161:634–646. doi: 10.1016/j.cell.2015.03.006 Ch assaing N, Golzio C, Odent S, Lequeux L, Vigouroux A, Martinovic-Bouriel J, et al. Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia. Hum Mutat. 2009;30:E673-E681. doi: 10.1002/humu.21023 West B, Bove KE, Slavotinek AM. Two novel STRA6 mutations in a patient with anophthalmia and diaphragmatic eventration. Am J Med Genet A. 2009;149A:539–542. doi: 10.1002/ajmg.a.32682 Hornby SJ, Dandona L, Jones RB, Stewart H, Gilbert CE. The familial contribution to non-syndromic ocular coloboma in south India. Br J Ophthalmol. 2003;87:336–340. doi: 10.1136/bjo.87.3.336 B astos Maia S, Rolland Souza AS, Costa Caminha MF, Lins da Silva S, Callou Cruz RSBL, Carvalho Dos Santos C, et al. Vitamin A and Pregnancy: A Narrative Review. Nutrients. 2019;11:681. doi: 10.3390/nu11030681 Thorne-Lyman AL, Fawzi WW. Vitamin A and carotenoids during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol. 2012;26 Suppl 1(0 1):36–54. doi: 10.1111/j.1365-3016.2012.01284.x R amakrishnan U, Lowe A, Vir S, Kumar S, Mohanraj R, Chaturvedi A et al. Public health interventions, barriers, and opportunities for improving maternal nutrition in India. Food Nutr Bull. 2012;33(2 Suppl):S71-S92. doi: 10.1177/15648265120332S105 Ahmadi R, Ziaei S, Parsay S. Association between Nutritional Status with Spontaneous Abortion. Int J Fertil Steril. 2017;10:337–342. doi: 10.22074/ijfs.2016.4577 Tanumihardjo S.A. Assessing vitamin A status: Past, present and future. J Nutr. 004;134:290S–293S. doi: 10.1093/jn/134.1.290S . Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations There is no conflict of interest Supplementary Files Table1.xlsx Table 1 Table2.xlsx Table 2 Table3.xlsx Table 3 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5194389","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":370030455,"identity":"de35c3b9-ab95-441b-a5d2-5fe6ce5408e4","order_by":0,"name":"Ken Nischal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYBACCQYGZgYGAxBibnwAFODhI0ELY7MBSAsbcVoYwFraJEAMglok23sPGxcU1Mmbsx9sq/yaYyfDxsD88NENPFqkec4lJ88wOGy4syex7bbstmSgw9iMjXPwaJGTyDE+zGNwIMHgAFCL5DZmoBYeNmm8WuTfgLTUJRicf9hWLLmtnrAWaQke42QeA+YEgxuJbYwftx0mrEWyJ8fYmAfolw03HjZLM247zsPGTMAvEsfPGEvz/KmTNziffPDjz23V9vzszQ8f49OCAph5wCSxykGA8QcpqkfBKBgFo2DEAACIzUF1eMi2kAAAAABJRU5ErkJggg==","orcid":"","institution":"UPMC Children’s Hospital of Pittsburgh","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ken","middleName":"","lastName":"Nischal","suffix":""},{"id":370030456,"identity":"bac72411-1182-4988-861d-831c8363afef","order_by":1,"name":"Ketaki Subhedar","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ketaki","middleName":"","lastName":"Subhedar","suffix":""},{"id":370030457,"identity":"17ae37bb-8923-457b-a576-c240f6b9b997","order_by":2,"name":"Shailja Tibrewal","email":"","orcid":"","institution":"Dr Shroff's Charity Eye Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shailja","middleName":"","lastName":"Tibrewal","suffix":""},{"id":370030458,"identity":"b15cf0c7-eba5-496e-8134-95606ae1aad6","order_by":3,"name":"Chintan Shah","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chintan","middleName":"","lastName":"Shah","suffix":""},{"id":370030459,"identity":"7de0dee9-56b9-4e95-ba25-258897acab8f","order_by":4,"name":"Ria Ratna","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ria","middleName":"","lastName":"Ratna","suffix":""},{"id":370030460,"identity":"366dad83-bee9-4f9c-9d1c-fdcfd685f9ff","order_by":5,"name":"Atanu Majumdar","email":"","orcid":"","institution":"Dr. Shroff's Charity Eye Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Atanu","middleName":"","lastName":"Majumdar","suffix":""},{"id":370030461,"identity":"1e2541b0-a94f-4d52-84a7-70a2f12cc39d","order_by":6,"name":"Subhajit Bhattacharya","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Subhajit","middleName":"","lastName":"Bhattacharya","suffix":""},{"id":370030462,"identity":"f270ed3f-61f6-4d95-969a-3fb62a7cdbb9","order_by":7,"name":"Pradhnya Sen","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pradhnya","middleName":"","lastName":"Sen","suffix":""},{"id":370030463,"identity":"7d169ef8-fc19-4541-9751-c5e7ecdd9ccf","order_by":8,"name":"Madhu Bhaduria","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Madhu","middleName":"","lastName":"Bhaduria","suffix":""},{"id":370030464,"identity":"59a4c901-dab6-4570-9530-f59b728c55fe","order_by":9,"name":"Suma Ganesh","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Suma","middleName":"","lastName":"Ganesh","suffix":""}],"badges":[],"createdAt":"2024-10-02 17:50:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5194389/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5194389/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67779638,"identity":"920053ad-28e9-44d3-b077-686885af91f3","added_by":"auto","created_at":"2024-10-29 15:40:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1215951,"visible":true,"origin":"","legend":"\u003cp\u003eshows the various clinical phenotypes of microphthalmos, anophthalmos and coloboma (MAC) group of disorders. A shows a typical coloboma with lenticular opacification. B shows a complex MAC with microcornea, coloboma and corneal opacification. C shows a retinochoroidal coloboma involving the disc and the macula. D shows simple microphthalmos in the right eye. E shows anophthalmos. F shows severe microphthalmos with rudimentary eye structures. G shows bilateral anophthalmos with orbitopalpebral cyst in the left eye.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5194389/v1/4a0f1315057a1b8a360a7303.png"},{"id":67779640,"identity":"7d9a9e17-aabd-4b89-b82b-18f96925e55d","added_by":"auto","created_at":"2024-10-29 15:40:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":170079,"visible":true,"origin":"","legend":"\u003cp\u003eshows the graphical distribution of the microphthalmos, anophthalmos and coloboma (MAC) phenotype between the 440 eyes. A, anophthamos, SMM, severe microphthalmos, CM, complex microphthalmos, MM, mixed microphthalmos, IC, isolated coloboma, IM, isolated microphthalmos, and N, total numbers.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5194389/v1/28b1066ab269d97d041bce30.png"},{"id":69529498,"identity":"a84b693e-9df1-43d8-a755-4acbc6b8e110","added_by":"auto","created_at":"2024-11-21 10:23:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2556990,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5194389/v1/79f9c39f-fd26-4250-838d-27a670fc9ede.pdf"},{"id":67779722,"identity":"81814339-3c07-4756-bc72-029f1410c9ff","added_by":"auto","created_at":"2024-10-29 15:48:51","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10900,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5194389/v1/80c00a1cc8b5d53a0dbf37fb.xlsx"},{"id":67779637,"identity":"c6f23801-c904-4fba-8e86-3c2f3f22f7fd","added_by":"auto","created_at":"2024-10-29 15:40:51","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10610,"visible":true,"origin":"","legend":"Table 2","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5194389/v1/d124aaf2a6804fb4aed9adcc.xlsx"},{"id":67779721,"identity":"7321b5cb-9035-40fd-90ee-58a542f524c2","added_by":"auto","created_at":"2024-10-29 15:48:51","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":10397,"visible":true,"origin":"","legend":"Table 3","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5194389/v1/4fcb560ab832b056fcebf113.xlsx"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Maternal Night Blindness and Microphthalmos, Anophthalmos, and Coloboma (MAC) Disorders – Is there an Association?","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eChildhood blindness poses a significant global health challenge, particularly in low to middle-income countries.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e In India, the prevalence of childhood blindness is about 0.8 per 1000 children, with major causes being microphthalmos, anophthalmos, and phthisis bulbi.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Microphthalmos is defined as an eye size less than two standard deviations (SD) of average, anophthalmos is the absence of ocular structures, and coloboma refers to the incomplete closure of the optic fissure. These conditions, which often show clinical and genetic overlaps, are grouped as the 'MAC phenotype'.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe MAC disorders are influenced by genetic and environmental factors.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Certain causative genes like \u003cem\u003eSTRA6, ALDH1A3, RARB\u003c/em\u003e are involved in the retinoic acid (RA) pathway and are essential for eye development.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Pathogenic variations in these genes can cause severe forms of MAC.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Concurrently, maternal Vitamin A deficiency (VAD) during pregnancy has been speculated in MAC causation.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Both MAC and Vitamin A deficiency (VAD) are common in poor socioeconomic sections of the society.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e MAC is also common in populations where consanguinity is higher.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e It has been hypothesised that a genetic susceptibility may increase fetal vulnerability to the teratogenic effects of maternal VAD.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Animal studies have shown that Vitamin A deficient mothers gave birth to offsprings with defective eyeballs and that Vitamin A supplementation at a critical time during pregnancy could prevent the ocular anomalies from occurring.\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn 2020, we analyzed the clinical features of MAC across three eye care institutes and noted regional variances in numbers and severity.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e We postulated that these differences were linked to socioeconomic status and antenatal maternal VAD. The current study was conducted with the aim to compare antenatal maternal VAD (using a surrogate marker, namely maternal night blindness during pregnancy) and other risk factors in MAC patients versus age-matched controls and correlate them with the severity of MAC. Since night blindness is the main clinical consequence of VAD, the International Vitamin A Consultative Group (IVACG)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e recommended that a night blindness prevalence of \u0026ge;\u0026thinsp;5% during pregnancy observed in population studies is sufficient to classify VAD as a public health issue. For this reason, maternal VAD was assessed using the WHO\u0026rsquo;s night blindness questionnaire.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e An observational, retrospective case-control study was conducted at three tertiary eye-care institutes in India from three neighbouring states: Dr. Shroff\u0026rsquo;s Charity Eye Hospital (SCEH, New Delhi, Delhi), Sadguru Netra Chikitsalaya (SNC, Chitrakoot, Madhya Pradesh) and Sitapur Eye Hospital (SEH, Sitapur, Uttar Pradesh). These three eye-care institutes are part of the Bodhya Eye Consortium, which includes seven eye-care institutes (SCEH, New Delhi; SNC, Chitrakoot; SEH, Sitapur; CL Gupta Eye Institute, Moradabad, Uttar Pradesh; MGM Eye Institute, Raipur, Chhattisgarh; Srikiran eye institute, Kakinada, Andhra Pradesh; and Pushpagiri Vitreoretina Institute, Hyderabad, Telangana) across India. This research consortium was formulated to develop evidence-based consensus led protocols and studies to provide consistent and robust big data from both urban and non-urban eye-care centres in India.\u003c/p\u003e \u003cp\u003e Institutional review board approval was obtained at each of the three participating centres. The study conformed to the tenets of Helsinki. Standardized data collection forms were used across the three sites. We included consecutive patients of MAC between the ages of 0 to 3 years presenting between July 2018 to June 2021. The control group consisted of all consecutive patients of similar age group with a diagnosis of refractive error, allergic conjunctivitis, trauma, or congenital nasolacrimal duct obstruction presenting to the clinics within the same study duration. The number of the children in the control group was matched with the number of MAC cases from each of the participating centres to avoid any selection bias due to regional variations in the risk factors. Children with unclear antenatal histories or indistinct MAC diagnoses were excluded. Assuming the prevalence of maternal night blindness in MAC disorders to be 16% \u003csup\u003e4\u003c/sup\u003e and taking the upper limit of 95% CI for the same, a difference of 10% between the two groups, α error of 5% and power of 80%, the sample size in each group was calculated to be around 220.\u003c/p\u003e \u003cp\u003eThe data collected consisted of demographic data such as the age of the child, gender, and address/region of residence. The father's income was noted to determine the socioeconomic status of the family. Antenatal details like history of prior spontaneous abortions in the mother, diet of the mother during pregnancy (vegetarian /non-vegetarian, antenatal fever or rashes, use of antenatal medications or complications, antenatal NB and the month of the NB if present were documented. Any family history of MAC, presence of consanguinity, and the degree of consanguinity was enquired. Other natal factors like, term, preterm or post-term delivery, birth order, low birth weight (\u0026lt;\u0026thinsp;2.5 kg), and any history of delayed milestones were noted. The clinical features that were documented were presence or absence of systemic abnormalities, nature of the systemic problems if present, the best corrected visual acuity, size of the cornea (measured with scale, callipers or pupilometer), and the details of the coloboma, microphthalmos and anophthalmos. Age-appropriate tests for visual acuity were performed as per standard protocols for visual assessment in the participating eye institutes. In children less than 3 months of age, the presence of light perception was recorded by documenting the dazzle reflex. In children older than 3 months, fixing and following light and illuminated objects was evaluated. In co-operative children, preferential looking tests (Teller Acuity cards or Cardiff acuity test) were used for vision assessment.\u003c/p\u003e \u003cp\u003eClinical anophthalmos (A) was defined as \u0026lsquo;no visible sign of the globe\u0026rsquo; and microphthalmos was defined as \u0026lsquo;visibly small eyes\u0026rsquo;. Additionally, those eyes in which the corneal diameter was \u0026lt;\u0026thinsp;4mm and only non-functional rudimentary eye structures were present were classified as severe microphthalmos (SMM). Isolated ocular coloboma (IC) was defined as coloboma without microcornea or microphthalmos. Isolated micropthalmos (IM) was defined as a visibly small eye with no coloboma or any other structural abnormality. Mixed microphthalmos (MM) was termed in the presence of coloboma with microcornea/microphthalmia. Complex microphthalmos (CM) was defined as the presence of microphthalmos or coloboma with other anterior segment anomalies such as corneal opacities, cataract, and anterior segment dysgenesis. Diagnosis relied mainly on clinical assessments, supplemented by B-scan ultrasound and A-scan biometry where available. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the examples of phenotypic subtypes of MAC. Any missing data pertaining to history was obtained via telephonic conversations with the mother of the child in both the MAC and the control groups. The telephone calls were made by one of the team members at each of the participating centers and only the mother of the child was specifically questioned regarding the antenatal events. In 1996, World Health Organisation (WHO), provided guidelines for utilizing indicators of VAD for estimating the community burden focusing on children, pregnant and lactating women. Night blindness was used as a functional indicator of VAD.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e They suggested an algorithm, which can be used for interviewing mothers to elicit reliable history. The questionnaire includes the following: (i) Do you/does your child have any problem seeing in the daytime? (ii) Do you/does your child have any problem seeing in the evening or in low levels of light? (iii) If (2)\u0026thinsp;=\u0026thinsp;yes: Is this problem different from most other children/ women in your community? (iv) Do you/Does your child have NB? (use the local term that describes symptoms). The same algorithm has been used by several studies with minor modifications.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e We used the same algorithm to enquire about the history of NB during pregnancy during the in-person and telephonic conversations with the mothers of both the MAC and the control group patients in the study. We also asked if the NB persisted after the pregnancy and whether it was associated with poor vision and nystagmus, to rule out nyctalopia associated with retinal dystrophies. While poor vision can be associated with VAD, by excluding such cases we felt that the number of mothers with NB would be an underestimation and not an overestimation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe data was compiled in Excel, and analysis was performed using the R software (version 4.3.2). The descriptive statistics included calculation of numbers, percentages, mean and range. Univariate and multivariate logistic regression was used to compare the various demographic and risk factors among the cases and the controls. For analysis, a severe phenotype of MAC was defined as a bilateral affection with anophthalmos or severe microphthalmos or a combination of both. The various factors were compared between the severe MAC phenotype and others. A p value of less than 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 220 MAC cases and 219 controls were included in the study. Amongst the cases and the controls, females constituted 52.7% and 54.3% of the patients, respectively. Unilateral MAC was seen in 67 patients (30.4%) while 153 patients presented with bilateral MAC in various phenotypic combinations. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the clinical images of phenotypes and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the distribution of the various MAC subtypes among the unilateral and bilateral cases.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe diagnoses in the control group were, allergic conjunctivitis (79), congenital nasolacrimal duct obstruction (116), refractive error (9), acute microbial conjunctivitis (6), esotropia (2), no ocular pathology (6), and trauma (1).\u003c/p\u003e \u003cp\u003eThe distribution of cases varied amongst the three institutions. A total of 124 (56.3%) cases were from SEH, 66 (30.0%) cases from SCEH and 30 (13.6%) cases were from SNC. Out of these, the severe MAC phenotype was observed more in SEH, 46 out of the 124 cases (37.0%), as compared to 6 out of 66 cases from SCEH (9.0%) and none from SNC. A comparison of the demographic features and risk factors among the cases and the controls is shown in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eBased on the validated WHO questionnaire, a positive history of night blindness was given by 73 (33.1%) mothers of the MAC patients and 7 (3.2%) mothers of controls (p value\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Only 45 women could provide details of the timing of night blindness. Among them 26 perceived night blindness in the 3rd trimester (57.7%), eight perceived in the 2nd trimester (17.7%) and four perceived in the first trimester (8.8%). In all the instances the night blindness was transient and recovered during pregnancy or shortly after it. A total of seven women recalled the presence of transient night blindness in all their pregnancies, out of that only 2 confirmed the timing in the 3rd trimester. A history of parental consanguinity was present in 11.9% of patients in the MAC group and 9.1% of patients in the control group. No instances of first-degree consanguinity were noted in either of the groups. Second-degree consanguinity was noted in 19 cases and 6 controls.\u003c/p\u003e \u003cp\u003eMultivariate analysis revealed that antenatal night blindness (p value\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Odds ratio (OR) 16.47, 95% Confidence interval (CI) 4.78\u0026ndash;87.62) and the birth order (p value\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 2.53, 95% CI 1.54\u0026ndash;4.37) remained statistically different among the cases and controls. The analysis also revealed that parental consanguinity (p value 0.018, OR 71.39, 95% CI 1.90 \u0026ndash; very high) and history of spontaneous abortions (p value 0.005, OR 6.31, 95% CI 1.69\u0026ndash;33.99) were statistically different between the two groups, explained by the suppressor effect.\u003c/p\u003e \u003cp\u003eA severe MAC phenotype was seen in 52 patients. Table no 2 shows the comparison of the various risk factors between severe and less severe MAC phenotypes using univariate analysis. Only age (p value 0.037, OR 0.928, 95% CI 0.86\u0026ndash;0.99) and antenatal NB (p value 0.006, OR 5.043, 95% CI 1.64\u0026ndash;16.86) retained statistical significance in the multivariate analysis. Among those patients with a positive history of night blindness, a severe MAC phenotype was seen in 47.9%. There was no statistically significant difference between unilateral and bilateral cases regarding their history of night blindness, consanguinity, or birth order.\u003c/p\u003e \u003cp\u003eSystemic abnormalities were observed in 9 (4.1%) patients with MAC. Table no 3 describes the systemic abnormalities seen in the children with MAC.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eDue to the progressive improvement in detection and treatment of the avoidable causes of blindness, non-avoidable causes like MAC disorders are now becoming important causes of childhood blindness.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Our study compared the demographic, socioeconomic, and environmental risk factors in MAC patients against controls to identify the potentially modifiable risk factors. We discovered a 10-fold increase in odds of a maternal history of transient NB during pregnancy in MAC patients compared to controls. Other significant risk factors included a higher birth order, maternal history of spontaneous abortions, and parental consanguinity. A higher MAC prevalence in economically disadvantaged areas and its regional differences suggest possible maternal nutritional factors.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e We utilized maternal NB history as a functional indicator of VAD, in line with WHO recommendations\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and those of the IVACG\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e (International vitamin A consultative Group). Although serum retinol is a more specific biological indicator, its variability with season, pregnancy trimester, and hemodilution complicates its utility as a measure.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe relationship between maternal VAD and MAC disorders has been speculative, with previous studies not conclusively establishing an association.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Retinoic acid (RA), derived from Vitamin A, is a crucial morphogen for embryogenesis, organ formation, limb development, optic vesicle and anterior segment formation, and embryonic sustainability.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Animal models have demonstrated the essential role of RA in eye development through evolutionary conserved mechanisms.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e In 1937, Hale found porcine offsprings of Vitamin A-deprived mothers had severe eye defects or an absent eyes.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Warkany and Kalter's 1959 review revealed that over 90% of offspring from Vitamin A-deficient rodents displayed ocular and urogenital anomalies.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e They noted that early gestational Vitamin A supplementation reduced the incidence of malformations, emphasizing that the timing is critical. Administration before key organogenesis could avert developmental aberrations, whereas late supplementation proved ineffective. Similarly, anecdotal reports in humans link congenital microphthalmia and ocular dysgenesis in neonates to maternal biliopancreatic surgery related VAD.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e A case where a woman had repeated anophthalmia and systemic defects across two pregnancies, which was averted in the third by pre-conceptional daily intake of 5000 IU of Vitamin A has been reported.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eGenetic variations affecting the RA pathway genes have also been linked to MAC disease.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e The common genes of the retinoic acid pathway implicated in MAC disorders are \u003cem\u003eSTRA6\u003c/em\u003e (MIM*610745), \u003cem\u003eALDH1A3\u003c/em\u003e (MIM*600463), \u003cem\u003eRARB\u003c/em\u003e (MIM*180220) and \u003cem\u003eRBP4\u003c/em\u003e (MIM*180250). The presence of deleterious genetic variants in the fetus may influence the consequences of maternal VAD.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Additionally, the differences in Vitamin A metabolism in mothers or fetuses and the timing of the expression of the gene may explain the phenotypic variability in MAC in some cases.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e Hornby et al. reiterated the role of RA pathway gene signaling in MAC, based on their study in South India which showed high rates of consanguinity (44.6%) and familial occurrences (21.4%) among 56 visually impaired children with MAC recruited from blind schools, integrated schools for the visually impaired, eye hospital and community rehabilitation programs.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e They proposed a gene-environment interaction where recessively inherited mutations in Vitamin A pathway genes might increase the fetal susceptibility to ocular anomalies in the presence of maternal VAD.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Our study recorded a lower consanguinity (11.9%) and familial history (6.3%), possibly due to different source of the sample population, differences in laterality of the disease in the sample, and regional variations in consanguineous marriages. Hornby et al. also investigated environmental risk factors in children with coloboma and found maternal history of antenatal NB in 16%.\u003csup\u003e4\u003c/sup\u003e Our current study observed a higher frequency of antenatal NB in MAC patients (33.2%). Unlike Hornby et al who recruited patients affected with bilateral MAC from schools for the blind, we included both bilateral and unilateral MAC patients from outpatient departments across three tertiary-eye-care centers. The authors of the former study did not mention the age range of the patients recruited in their study. There were only two patients less than two years of age. There is a possibility of recall bias in assessing a history of remote events. Thus, we included children below three years of age at the time of the presentation. The presence of an age-matched control group in the current study also strengthens its results.\u003c/p\u003e \u003cp\u003eOur study found the majority of women experienced night blindness in the third trimester (57.7%), aligning with the results of Hornby et al.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e VAD is more common in the third trimester due to the increased physiological demand by the growing fetus.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e However, shortage of Vitamin A in diet and during infections or gestational diabetes may precipitate VAD in any time during pregnancy.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Other micronutrients like zinc can affect Vitamin A utilization.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Multiple pregnancies contribute to poor maternal nutrition, with nutritional status often declining in successive pregnancies.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Hornby et al. observed higher chances of second order birth in children with MAC \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e similar to our study, suggesting that occurrence of MAC was related to parity. Maternal malnutrition can also predispose to spontaneous abortions by affecting the morphology of germ cells.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e The history of previous spontaneous abortions coupled with higher birth order in MAC cases in the current study, is suggestive of poor maternal nutrition with multiple micronutrient deficiencies including VAD. We also found that a history of maternal NB was more common (67.3%) in severe category of MAC as compared to less severe cases (22.6%). There is evidence that pathogenic variations in the RA pathway genes often lead to severe MAC phenotypes.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Whether the level of VAD in the mother influences the manifestation of RA pathway gene defects in a dose-dependent manner is a matter of future research.\u003c/p\u003e \u003cp\u003eOur study faced limitations, including difficulties in obtaining detailed histories of socioeconomic status, diet, and antenatal medication use. Dietary intake was broadly classified as vegetarian or non-vegetarian due to the imprecision of maternal recall. While a history of NB serves as a proxy for Vitamin A deficiency (VAD), direct measurement of serum retinol would be more specific.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e However, serum retinol and retinol binding protein levels may change throughout pregnancy and vary in stress and inflammation.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Apart from being expensive, it may underestimate the status of VAD in populations with high prevalence of infections and inflammation. Socioeconomic status was also challenging to determine, as many participants were reticent about disclosing family income, education, or occupation. Axial length or corneal diameter measurements were often infeasible due to the young age of the patients included in the study. Although, we restricted our sample to children under three years old, to reduce the recall bias, it could not have been eliminated.\u003c/p\u003e \u003cp\u003eTo conclude, to the best of our knowledge the current study is the first case-control study to evaluate the risk factors for MAC disorders. Maternal night blindness, lower birth order, history of consanguinity and prior spontaneous abortions in mothers were significantly more in children with MAC as compared to controls. The children with the severe phenotypes had higher chances of maternal night blindness. The true nature of possible gene-environment interactions needs to be explored in future research, but we feel this study establishes a correlation between maternal night blindness during pregnancy and MAC.\u003c/p\u003e"},{"header":"SUMMARY","content":"\u003cp\u003eMaternal night blindness (a surrogate for Vitamin A deficiency) is tenfold more prevalent in children with Microphthalmos, Anophthalmos \u0026amp; Coloboma (MAC) than in non-MAC children.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat was known before\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eMAC disorders cause childhood blindness and result from genetic and/or environmental factors.\u003c/li\u003e\n \u003cli\u003eAnimal studies have shown an association with maternal Vitamin A deficiency (VAD).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMaternal night blindness is a marker for vitamin A deficiency for public health interventions.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat This Study Adds\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eThis is first study in humans to show an increased prevalence of maternal night blindness (surrogate for VAD) in children with MAC versus age-matched unaffected children.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe possible association of maternal VAD and MAC has research and health policy implications.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMicrophthalmos\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAnophthalmos and Coloboma\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNight blindness\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVAD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVitamin A deficiency\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWHO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWorld Health Organization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAnophthalmos\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSMM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSevere microphthalmos\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComplex microphthalmos\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIsolated microphthalmos\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIsolated Coloboma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMixed microphthalmos\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRetinoic Acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSCEH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDr. Shroff\u0026rsquo;s Charity Eye Hospital\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSEH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSitapur Eye Hospital\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSNC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSadguru Netra Chikitsalaya\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eINR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIndian Rupee\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Dr Jinal Gore from SCEH for helping with a small part of the data collection.The authors would also like to acknowledge the governing council of the Bodhya Eye Consortium consisting of Dr Umang Mathur, Dr Madhu Bhadauria, Dr Elesh Jain, Dr Ashi Khurana, Dr Deepshikha Agrawal and Dr Vikas Mittal.The remaining members of the Pediatric Ophthalmology subgroup of the Bodhya Eye Consortium- Dr Pradeep Agarwal, Dr Anupam Sahu, Dr Avinash Mahindrakar, Dr Monalisa Mohapatra, Dr Rajat Kapoor, Dr Soveeta Rath, Dr Richa Sharma, Dr Abhilasha Parkhe, Dr Shilpa Sonarkhann, Mr Samir Sutar, Ms Preeti Sharma, Ms Srivani, and Ms Dolly are also acknowledged.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo funding was secured for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution Statements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKetaki Subhedar and Shailja Tibrewal\u0026nbsp;equally conceptualized and designed the study, coordinated and supervised data collection, wrote the manuscript, critically reviewed and revised the manuscript for important intellectual content and proof reading.\u003c/p\u003e\n\u003cp\u003eChintan Shah, Ria Ratna, Atanu Majumdar, Subhajit Bhattacharya and Pradnya Sen contributed in designing the data collection methodology, collected data, carried out the initial analyses, and critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eMadhu Bhaduria and Suma Ganesh contributed to the implementation of the research, critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eKen Nischal contributed to the study design, critically reviewed and revised the manuscript, and proofread it for the publication version.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures (includes financial disclosures):\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone of the authors have any conflicts of interest to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePascolini D, Mariotti SP. 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J Nutr. 004;134:290S\u0026ndash;293S. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jn/134.1.290S\u003c/span\u003e\u003cspan address=\"10.1093/jn/134.1.290S\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5194389/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5194389/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eOBJECTIVES\u003c/h2\u003e \u003cp\u003eMicrophthalmos, Anophthalmos, and Coloboma (MAC) are common causes of childhood blindness. In 1996, World Health Organisation (WHO) proposed night blindness (NB) as a functional indicator of Vitamin A deficiency (VAD). We aimed to investigate the association of maternal antenatal NB, environmental risk factors and socioeconomic determinants with MAC.\u003c/p\u003e\u003ch2\u003eMETHODS\u003c/h2\u003e \u003cp\u003eA case-control study was conducted between 2018 to 2021 comparing risk factors between MAC and control cases. Data regarding maternal antenatal NB, birth order, consanguinity, family history, maternal dietary habits during pregnancy, history of spontaneous abortions, and father\u0026rsquo;s income were collected retrospectively and through telephonic interviews with mothers. Bilateral anophthalmos, severe microphthalmos or a combination defined a severe MAC phenotype.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e \u003cp\u003e220 children with MAC and 219 normal controls aged 0\u0026ndash;3 years were included. Antenatal maternal NB was observed in 33.2% of MAC and 3.2% of controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A higher birth order (2nd or more), parental consanguinity, and a history of prior spontaneous abortions were also more common in MAC. A history of antenatal maternal NB was more common in severe MAC (67.3%) as compared to the less severe MAC (22.6%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eCONCLUSIONS\u003c/h2\u003e \u003cp\u003eThe study identified antenatal maternal NB, higher birth order, parental consanguinity, and history of spontaneous abortions as significant risk factors for MAC disorders, highlighting the influence of maternal nutrition and genetics. To the best of our knowledge, this is the largest case-control study to show an association of maternal NB and MAC. Maternal NB has been used as a functional indicator of VAD.\u003c/p\u003e","manuscriptTitle":"Maternal Night Blindness and Microphthalmos, Anophthalmos, and Coloboma (MAC) Disorders – Is there an Association?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-29 15:40:47","doi":"10.21203/rs.3.rs-5194389/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c9295d0a-10d2-4743-a08a-8e784ca53fde","owner":[],"postedDate":"October 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":39380545,"name":"Health sciences/Risk factors"},{"id":39380546,"name":"Health sciences/Pathogenesis"}],"tags":[],"updatedAt":"2024-11-21T10:15:33+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-29 15:40:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5194389","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5194389","identity":"rs-5194389","version":["v1"]},"buildId":"CiT4i_kKBbxQbnFL0ufpk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}