Seasonal Trend in the Occurrence of Myelomeningocele in Nigeria: a Hypothesis of Climate-induced Oxidative Stress

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Okpara, Izuchukwu C. Iloabachie, Tochukwu H. Mbanugo, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3364036/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Nov, 2023 Read the published version in Child's Nervous System → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose Myelomeningocele is the most severe birth defect compatible with long-term survival. It accounts for 5.7% of neurological surgeries in Nigeria. However, the exact cause of this neural tube defect remains unidentified. This study aims to determine if seasonal variation is a potential environmental contributor. Method This study prospectively recruited 242 children diagnosed with myelomeningocele at the University of Nigeria Teaching Hospital (UNTH), Enugu, Nigeria, between January 2010 and December 2022. Our primary outcome was the seasonal occurrence of myelomeningocele, while covariates included gender, birth order, maternal folic acid supplementation (FAS), and parental age. The estimated month of conception was derived from the mother's last menstrual period (LMP), and the occurrence of myelomeningocele across the various seasons in which these babies were conceived was assessed using the Lorenz curve and the Gini coefficient. Results 242 patients were studied with a male-to-female ratio of 1.26. The majority of cases were lumbosacral (93.4%), and none of the mothers commenced FAS before conception. The highest proportion of cases (39.7%) occurred during the hottest period of the dry season (January–March), while the lowest proportion (15.7%) occurred during the early wet season (April–June). The Gini index of 0.29, and the Gini coefficient derived from 100,000 Monte Carlo simulations of 0.24, indicate a significant variation in the distribution of myelomeningocele cases across different seasons of conception. Conclusion The seasonal occurrence of myelomeningocele with a peak in January–March suggests a potential association with environmental factors including oxidative stress induced by solar radiation. Birth defects seasonal variation neural tube defect folic acid supplementation environmental factors Figures Figure 1 Figure 2 INTRODUCTION Myelomeningocele is a significant neural tube defect (NTD) that leads to chronic disability and is considered the most severe birth defect compatible with long-term survival.[1] It is an abnormal protrusion of a cystic sac containing the spinal cord-meningeal complex through a defect in the posterior vertebral arches. This common form of spina bifida presents with sphincteric, motor, and sensory disturbances below the level of the lesion, along with associated hydrocephalus, Chiari II anomalies, and foot disorder.[2, 3] The exact cause of myelomeningocele remains unidentified, but it is believed to involve a complex interplay of environmental and genetic factors.[4] Karyotypic abnormalities such as trisomies, a high concordance rate in monozygotic twins, altered folate and homocysteine genes, occurrence within families, gender predilection, and ethno-racial differences provide evidence in favor of a genetic influence.[1] On the other hand, seasonal variations have been suggested as an indicator of potential environmental contributors to the development of myelomeningocele, among other factors such as folate deficiency, hyperthermia, diabetes, and drugs.[5] Various epidemiological studies conducted in different countries, including the United Kingdom, Norway, Newfoundland, Germany, Algeria, and the United States, have investigated the seasonal variation of this defect, albeit with conflicting findings.[6–11] Interestingly, low- and medium-income countries in sub-Saharan Africa bear the largest burden of NTDs like myelomeningocele, with substantial attendant medical, aesthetic, and socioeconomic implications.[12, 13] In Nigeria, it accounts for a considerable proportion (5.7%) of neurological surgeries, and its prevalence has been reported to be 1.3 per 1,000 newborns.[2, 14] Despite the growing recognition of seasonal variations in exposure to teratogens, the impact of seasonal variation on myelomeningocele incidence in Nigeria remains poorly understood.[15] Understanding the seasonal variations in the occurrence of myelomeningocele can provide valuable insights into the role of peri-conception and prenatal care practices in its occurrence.[7] By analyzing the temporal distribution of myelomeningocele cases throughout the year, we can discern potential patterns and associations with specific seasons or climatic conditions such as sunlight exposure, temperature fluctuations, and related oxidative stress. This knowledge is essential for tailoring preventive interventions, optimizing resource allocation, and improving healthcare planning to mitigate the burden of myelomeningocele in Nigeria. Therefore, this study aims to identify the months of conception and investigate the seasonal trends in the occurrence of myelomeningocele in Nigeria. Moreover, the findings of this study will contribute to the existing body of knowledge on myelomeningocele and may have implications for other regions with similar environmental and socio-demographic characteristics. Research Questions: Is there a significant seasonal variation in the occurrence of myelomeningocele? METHODS Study Design : This is a prospective hospital-based observational study of 242 participants diagnosed with myelomeningocele between January 2010 and December 2022. Participants were consecutively recruited from the neurosurgery and newborn units of the University of Nigeria Teaching Hospital (UNTH), Enugu, Southeast Nigeria. Their month of conception was derived from their mothers' last menstrual period (LMP). The occurrence of myelomeningocele was compared across the various seasons in which these babies were conceived. Setting : The UNTH is a tertiary healthcare facility renowned for its specialized medical services. It serves as a referral center for Nigerians living within the southeast and south-south regions as well as surrounding locations.[16] With dedicated departments for newborn care, emergency medicine, and neurosurgery, the hospital provides an ideal setting for a comprehensive study on myelomeningocele. The study location, Enugu, a city in southeast Nigeria, is located at geographical coordinates of latitude 06º26'0''N and longitude 070º29'0''E. It lies between the southern tropical rainforest and the northern Guinea savanna belt. The region experiences a tropical savanna climate characterized by distinct wet and dry seasons. The annual rainfall ranges from 1500mm to 2500mm.[17] According to the Nigeria climate review, the temperatures in this region can vary throughout the year, with maximum ambient temperatures typically observed in February and March . The seasonal patterns in Nigeria are largely influenced by the Intertropical Discontinuity, which involves the seasonal oscillatory movement of the dry wind blowing north-easterly from the Sahara Desert and the moist south-westerly monsoon from the Atlantic Ocean. These climatic factors play a significant role in shaping the seasonal variations experienced in the region.[18] Participants, Study Size, and Data Collection : The eligibility criteria for the study included all children diagnosed with myelomeningocele at UNTH, whether ruptured or intact, whose parents or legal guardians’ consented to participate in the study. Stillbirths, newborns delivered before the 28 th gestational week, and children with incomplete data, such as those from mothers without an identifiable LMP required to determine the time of conception, were excluded from the study. Assuming an acceptable error level of 5% (d = 0.05), a power of 0.80, an estimated proportion of 0.195 from a pilot study (p = 0.195), and an alpha(α) value of 0.05, the survey required a sample size of 242 participants.[13] Data was collected prospectively using the study proforma to capture the month of conception derived from the LMP of the mother. Demographic factors, including gender, birth order, and parental age, as well as data on maternal folic acid supplementation (FAS) and other relevant clinical information, were obtained. The dependent variable was the occurrence of myelomeningocele, while the independent variables included the season of conception and demographic variables. Potential confounders were maternal folic acid supplementation, parental age, and birth order. Statistical Analysis : Descriptive statistics were used to summarize the proportions, means, and standard deviations of clinico-demographic variables, while inferential statistics were performed using ANOVA, Chi-square, or Fisher's exact tests. We evaluated the association between the above covariates and the determined season of conception of myelomeningocele. Analysis was achieved with SPSS Statistics 26.0.0 (IBM Corp., Armonk, New York, US). The myelomeningocele conception ratio (MCR) was calculated for each of the 12 months by dividing the number of cases occurring in a given month over the 12 years by the number of days in the corresponding month (Table 1). The Lorenz curve was constructed by plotting the cumulative percentage of myelomeningocele on the y-axis against the cumulative percentage of days on the x-axis. The Gini coefficient was the area between the equality line and the Lorenz curve, which quantified the seasonality. The 95th percentile Gini coefficient derived from the 100,000 Monte Carlo simulations was used to assess the statistical significance of the observed seasonal variation at an alpha(α) level of 0.05. The Gini index provides a quantitative measure that allows us to assess the degree of variation or inequality in myelomeningocele cases across seasons, while the Lorenz curve provides a visual representation of the distribution. This approach can help us identify if there is a significant seasonal disparity and quantify the extent of that disparity. Ethical Considerations : We obtained ethical approval from the Health Research Ethics Committee of UNTH (NHREC/05/01/2008B-FWA00002458-1RB00001247) . Participation in the study was voluntary, and informed consent was obtained from the parents or legal guardians of participants for data collection and publication. The study adhered to the latest version of the Helsinki Declaration for medical research.[19] RESULTS The study included a total of 242 out of 251 participants with myelomeningocele over 12 years. The main reason for the exclusion of nine participants was incomplete data. Therefore, the average number of presentations per year was approximately 20.2 ± 8.9. The study had a slightly higher representation of males (55.4%) compared to females (44.2%), with a male-to-female ratio of 1.26:1. There was a trend toward more female conception between April and June and more male conception between October and March. However, the seasonal variation was not statistically more profound in one gender than in the other (P = 0.124, Table 1 ). The majority of cases were classified as lumbosacral (93.4%). Other less common locations included cervical (n = 1, 0.4%), thoracic (n = 11, 4.5%), and sacral (n = 4, 2.5%). The anatomical location of the defect did not show significant differences among the seasons of conception (P = 0.09). Table 1 Clinical and demographic characteristics of the study participants Characteristics Overall (n = 242) Jan-Mar (n = 96) Apr-Jun (n = 38) Jul-Sep (n = 60) Oct-Dec (n = 48) P-value Gender, n (%) 0.12 Female 107 (44.2) 34 (35.4) 21 (55.3) 30 (50.0) 22 (45.8) Male 135 (55.8) 62 (64.6) 17 (44.7) 30 (50.0) 26 (54.2) Location, n (%) 0.09 Cervical 1 (0.4) 0 (0.0) 1 (2.6) 0 (0.0) 0 (0.0) Thoracic 11 (4.5) 5 (5.2) 0 (0.0) 6 (10.0) 0 (0.0) Lumbosacral 226 (93.4) 90 (93.8) 37 (97.4) 53 (88.3) 46 (95.8) Sacral 4 (2.5) 1 (1.0) 0 (0.0) 1 (1.7%) 2 (4.2) Folic acid supplementation No, n (%) 55 (22.7) 20 (20.8) 8 (21.1) 15 (25.1) 12 (25.0) 0.91 Yes, Mean Month (S.D.) 3.5 (1.3) 3.4 (1.3) 3.5 (1.5) 3.3 (1.3) 3.6 (1.4) 0.93 Age at conception Maternal age, Mean (S.D.) 26.8 (5.6) 26.9 (5.8) 25.8 (6.1) 27.4 (4.6) 26.4 (5.8) 0.52 Paternal age, Mean (S.D.) 38.2 (7.0) 38.1 (6.2) 39.2 (7.7) 38.9 (6.8) 37.0 (8.1) 0.46 Birth order, Mean (S.D.) 2.3 (1.4) 2.3 (1.2) 2.2 (1.5) 2.4 (1.4) 2.4 (1.5) 0.92 In terms of folic acid supplementation, none of the mothers of the affected children began supplementation before conception. Post-conception, we observed folic acid intake in only 187 mothers (77.3%) during the pregnancy, and their mean month of commencement was 3.5 ± 1.3 (range 4 weeks to 7 months), with similar proportions across all seasons (P = 0.9). Both the average maternal and paternal ages at the time of conception of the children with myelomeningocele (27 and 38 years, respectively) did not show significant differences among the various seasons. Similarly, the mean birth order of the affected children did not vary significantly among the seasons (P = 0.92). The highest number of conceptions of babies with myelomeningocele occurred in 2013, 2015, and 2021, with 32 (13.2%), 30 (12.4%), and 25 (10.3%) cases, respectively. The years 2012, 2019, and 2022 had the lowest number of myelomeningoceles, with 6 (2.5%), 9 (3.7%), and 9 (3.7%) cases, respectively. There was variation in the distribution of patients across birth months. Babies with myelomeningocele were more likely to be conceived in March and February, while months like April and May had lower numbers (Fig. 1 ). Table 2 Monthly myelomeningocele conception ratio from 2010 to 2022 Month of Conception No. of Myelomeningocele No. of Days Monthly Conception Ratio (MCR) of Myelomeningocele Percentage (%) Jan 23 372 0.0618 9.3 Feb 32 339 0.0944 14.2 Mar 41 372 0.1102 16.6 April 8 360 0.0222 3.3 May 15 372 0.0403 6.1 June 15 360 0.0417 6.3 July 19 372 0.0511 7.7 Aug 21 372 0.0565 8.5 Sep 20 360 0.0556 8.4 Oct 14 372 0.0376 5.7 Nov 21 360 0.0583 8.8 Dec 13 372 0.0349 5.3 Total 242 4383 0.6646 100.0 Among the 242 participants with myelomeningocele, a total of 96 (39.7%) were conceived during the hottest period of the dry season of the year (Jan-Mar), 38 (15.7%) during the early wet season (Apr-Jun), 60 (24.8%) during the late wet season (Jul-Sep), and 48 (19.8%) during the coldest period of the dry season (Oct-Dec). There was variation in the MCR of myelomeningocele across different months (Table 1 ). Months such as February and March (16.6%) had relatively higher MCR values, indicating a higher incidence of myelomeningocele during those periods. Conversely, months like April and December exhibited lower MCR values, indicating a comparatively lower incidence of myelomeningocele during those periods. Figure 2 represents the Lorenz curve of the seasonal inequality in the occurrence of myelomeningocele. The empirical Gini index for the conception of a baby with a myelomeningocele birth defect was 0.29, and the 100,000 Monte Carlo simulations derived a 95th percentile Gini coefficient value of 0.24, suggesting a significant seasonal variation at an alpha level of 0.05 and a rejection of the null hypothesis. DISCUSSION This hospital-based study found a slightly higher proportion of males than females conceived with myelomeningocele. However, the study did not identify a gender-specific factor in the seasonal variation of myelomeningocele. Nevertheless, there was a significant sinusoidal variation in the distribution of myelomeningocele cases across different seasons of conception based on the Gini index. The highest proportion of cases (39.7%) occurred during the hottest period of the dry season (Jan–Mar), while the lowest proportion (15.7%) occurred during the early wet season (Apr–Jun). These findings suggest a potential association between the season of conception and the occurrence of myelomeningocele. Other factors, such as the location of myelomeningocele defects, folic acid supplementation, and parental age at conception, had no significant association with the season of conception. Similarly, the birth order of affected children within the family did not influence the seasonal pattern of myelomeningocele occurrence. All the factors highlighted above did not influence the seasonal distribution of the conception of patients with myelomeningocele in our study. Our observation of a significantly more frequent myelomeningocele conception during the hottest dry season months of our study location and a very rapid falloff to the lowest occurrence during the adjoining early rainy season months is quite interesting and, in our opinion, informative. The varying temperature, humidity, and precipitation patterns in the study catchment area provide insights into a potential seasonal causal link to the etiology of myelomeningocele. In Nigeria, the seasons are categorized into dry and rainy seasons. The rainy season in Nigeria typically spans from April to October. During the transition from the harmattan season to the wet season between April and June, there is favorable precipitation, humidity, and temperature, which coincidentally is the period with the lowest percentage of patients conceived with myelomeningocele (15.7%). The months of January to March correspond to the harmattan season, characterized by lower precipitation, decreased humidity, dry and dusty conditions, and extreme temperature fluctuations. Early mornings are relatively cooler, around 19°C (66°F), while afternoon temperatures can rise to 33°C (91°F).[18] The higher proportion (39.7%) of babies conceived with myelomeningocele during this period lends credence to the idea that the human embryo may be most vulnerable to thermally-induced oxidative stress during the hottest dry season. For the cold, wet season, we wish to scientifically speculate on the absence of our proposed thermal phenomenon or perhaps a reversal of attributable oxidative effects on the human embryo. Additionally, the harmattan winds blowing from the Sahara Desert can create hazy conditions that are conducive for the aerosolization of infectious agents and environmental pollutants. Maternal influenza and respiratory tract infections are more prevalent during this period, and the resulting thermal changes could induce oxidative stress, potentially playing a role in the observed seasonal variation of myelomeningocele.[20] It is important to note that this period coincides with the off-season for the farming of green leafy vegetables, which are significant sources of folate in our sub-region. Adequate folate intake is a crucial public health strategy for preventing NTDs, including myelomeningocele. Early supplementation with folic acid has been shown to significantly reduce the risk of NTD by 24%. However, similar to previous studies, none of the mothers in our study cohort received folic acid supplementation one month before and after conception, despite the 1992 recommendations by the US Centers for Disease Control and Prevention (CDC).[12, 20] [21, 22] The earliest record of commencement of folate supplementation among mothers of our study participants was in the fourth week of gestation, at which point the neural tube would be closing, while 22.7% had no folic acid supplementation at all during pregnancy. According to Tyrrell, the intense solar radiation, which in our setting peaks in March, may contribute significantly to maternal oxidative stress. The blood levels of oxidant-stress factors, such as the enzyme heme oxygenase, can be affected systemically by UV wavelengths depleting skin glutathione.[23] The molecular and cellular processes of neural tube closure all appear to be amenable to alteration by the extraembryonic conditions associated with oxidative stress. Diabetes, a "free radical disease," and folate insufficiency, an illness that leads to the accumulation of the oxidant stressor homocysteine, are two important maternal causes of dysmorphogenesis that provide the basis for the evidence. Natural antioxidants like vitamin C, vitamin E, and superoxide dismutase could prevent neural tube defects. From our study, we hypothesize that maternal oxidative stress, which can increase with excessive exposure to sunlight, especially in the hottest months, hyperthermia, and folate deficiency, may prevent the closure of the neural tube and result in the formation of myelomeningocele.[24] Nonetheless, it is crucial to remember that oxidative stress is not the only deciding environmental factor. Unknown teratogens that may exhibit seasonal patterns throughout the year are possible alternative causal factors.[5] Our findings are corroborated by previous studies conducted in other countries, including Puerto Rico, South Africa, Newfoundland, and the United Kingdom.[5, 6, 8, 25] However, it contrasts with reports from studies from the United States, Jordan, Germany, Poland, Japan, and Algeria.[9–11, 20, 26] Among the Scandinavian countries, northern Finland and Sweden demonstrated a seasonal variation, while Norway did not find a seasonal pattern. In Norway, Hwang et al. conducted a population-based study and observed a significant seasonal variation for any birth defect, but not specifically for spina bifida.[7] Their study included term babies with various systemic anomalies diagnosed within the first week of life between 1993 and 1998. Unlike our study, their analysis was retrospective and involved a larger dataset of 326,560 births. However, they excluded 10% of babies due to incomplete data, which could introduce selection bias. It is important to note that the Norwegian study did not specifically evaluate newborns with myelomeningocele as a subgroup. Nevertheless, they did observe a higher occurrence of Down's syndrome in February and respiratory anomalies in March. They suggested a potential prenatal environmental exposure to viral pathogens or disinfectant by-products, which may exhibit seasonality and could be influenced by higher temperatures.[7] It is worth mentioning that fetal neural tissue, which begins to form in the first month of conception, is highly susceptible to viral infections. The lack of consistent findings regarding the seasonal variation of NTD can be attributed to several factors. Firstly, the studies were conducted on different populations with diverse genetic backgrounds, environmental exposures, and healthcare systems. For example, the impact of nutritional factors such as folic acid intake may differ among populations due to variations in dietary habits and the availability of fortified foods or supplements. Secondly, factors such as maternal age, socioeconomic status, and exposure to teratogenic agents can differ between populations and contribute to the variation in findings. Thirdly, regional variations in climate and seasonal patterns can affect exposure to environmental factors during critical periods of fetal development. Sunlight exposure, for instance, can vary with latitude and may influence the risk of myelomeningocele. Lastly, differences in the methods used for case identification and analysis among studies can contribute to a lack of consistency, thereby impacting the accuracy and comparability of the results.[11]. Our study's geographical scope is a limitation on the generalizability of our findings. Also, children with myelomeningocele who were born outside of the hospital and whose parents did not voluntarily report them were not captured. Considering these factors, it is important to interpret the findings of individual studies within the context of their specific populations and settings. Further research and collaborative efforts are needed to better understand the complex interplay between seasonal variation, genetic and environmental factors, and the development of myelomeningocele. Specifically, a larger multicenter study is required to validate our findings as well as delineate possible molecular processes or epigenetic pathways that may interplay to influence our salient observations. Conclusion This study found a significant sinusoidal variation in myelomeningocele cases across seasons, with a peak in the hottest season of our study location (January–March), suggesting a potential association with environmental factors such as solar radiation and thermally induced oxidative stress. Abbreviation NTD = neural tube defect; LMP = last menstrual period; FAS = folic acid supplementation; MCR = myelomeningocele conception ratio Declarations The authors have no competing interests or financial disclosure to declare. Availability of data and materials Available upon relevant requests. References Bowman RM, Boshnjaku V, McLone DG (2009) The changing incidence of myelomeningocele and its impact on pediatric neurosurgery: A review from the Children’s Memorial Hospital. Child’s Nerv Syst 25:801–806. https://doi.org/10.1007/s00381-009-0865-z Oumer M, Taye M, Aragie H, Tazebew A (2020) Prevalence of spina bifida among newborns in Africa: A systematic review and meta-analysis. Scientifica (Cairo) 2020:14–18. https://doi.org/10.1155/2020/4273510 McCarthy DJ, Sheinberg DL, Luther E, McCrea HJ (2019) Myelomeningocele-associated hydrocephalus: Nationwide analysis and systematic review. Neurosurg Focus 47:. https://doi.org/10.3171/2019.7.FOCUS19469 Greene NDE, Stanier P, Copp AJ (2009) Genetics of human neural tube defects. Hum Mol Genet 18. https://doi.org/10.1093/hmg/ddp347 De La Vega A, Ronald LC (2009) Seasonal variations in the incidence of some congenital anomalies in Puerto Rico based on the timing of conception. P R Health Sci J 28:121–125 Maclean MH, MacLeod A (1984) Seasonal variation in the frequency of anencephalus and spina bifida births in the United Kingdom. J Epidemiol Community Health 38:99–102. https://doi.org/10.1136/jech.38.2.99 Hwang B-F, Magnus P, Jaakkola JJK (2013) Seasonal variation of birth defects in Norway. BioMedicine 3:95–101. https://doi.org/10.1016/j.biomed.2013.04.002 Fraser FC, Frecker M, Allderdice P (1986) Seasonal variation of neural tube defects in Newfoundland and elsewhere. Teratology 33:299–303. https://doi.org/10.1002/tera.1420330307 Beyer DA, Diedrich K, Weichert J, et al (2011) Seasonality of spina bifida in Northern Germany. Arch Gynecol Obstet 284:849–854. https://doi.org/10.1007/s00404-010-1762-0 Houcher B, Begag S, Egin Y, Akar N (2012) Neural Tube Defects in Algeria. In: Neural Tube Defects - Role of Folate, Prevention Strategies and Genetics. InTech, pp 112–114 Siffel C, Alverson CJ, Correa A (2005) Analysis of seasonal variation of birth defects in Atlanta. Birth Defects Res Part A Clin Mol Teratol 73:655–662. https://doi.org/10.1002/bdra.20207 Onyia E, Chikani M, Mezue W, et al (2017) Myelomeningocele in Nigeria: Has There Been Any Change with Improved Neurosurgery Care? 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Br J Neurosurg 35:174–180. https://doi.org/10.1080/02688697.2020.1777259 Chinago AB (2015) Climatological Review of Enugu Rainfall from 1916–2012 and its Implications. Glob J Sci Front Res 15:111–180 Yusuf N, Okoh D, Musa I, et al (2017) A Study of the Surface Air Temperature Variations in Nigeria. Open Atmos Sci J 11:54–70. https://doi.org/10.2174/1874282301711010054 World Medical Association (2013) World Medical Association Declaration of Helsinki. JAMA 310:2191–2194. https://doi.org/10.1001/jama.2013.281053 Obeidat AZ, Amarin Z (2010) Neural tube defects in the north of Jordan: Is there a seasonal variation? J Child Neurol 25:864–866. https://doi.org/10.1177/0883073809347596 Rabiu TB, Adeleye AO (2013) Prevention of myelomeningocele: African perspectives. Child’s Nerv Syst 29:1533–1540. https://doi.org/10.1007/s00381-013-2126-4 Kshettry VR, Kelly ML, Rosenbaum BP, et al (2014) Myelomeningocele: Surgical trends and predictors of outcome in the United States, 1988–2010. Clinical article. J Neurosurg Pediatr 13:666–678. https://doi.org/10.3171/2014.3.PEDS13597 Tyrrell RM (1996) Activation of mammalian gene expression by the UV component of sunlight - From models to reality. BioEssays 18:139–148. https://doi.org/10.1002/bies.950180210 Marzullo G, Fraser FC (2005) Similar rhythms of seasonal conceptions in neural tube defects and schizophrenia: A hypothesis of oxidant stress and the photoperiod. Birth Defects Res Part A - Clin Mol Teratol 73:1–5. https://doi.org/10.1002/bdra.20100 Buccimazza SS, Molteno CD, Dunne TT, Viljoen DL (1994) Prevalence of neural tube defects in Cape Town, South Africa. Teratology 50:194–199. https://doi.org/10.1002/tera.1420500304 Pietrzyk JJ, Grochowski J, Kanska B (1983) CNS malformations in the Krakow region. I. Birth prevalence and seasonal incidence during 1979–1981. Am J Med Genet 14:181–188. https://doi.org/10.1002/ajmg.1320140124 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 10 Nov, 2023 Read the published version in Child's Nervous System → Version 1 posted Editorial decision: Accepted 29 Oct, 2023 Reviews received at journal 29 Oct, 2023 Reviewers agreed at journal 29 Oct, 2023 Reviewers invited by journal 28 Sep, 2023 Submission checks completed at journal 19 Sep, 2023 Editor assigned by journal 19 Sep, 2023 First submitted to journal 17 Sep, 2023 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-3364036","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":234673551,"identity":"25f3e93b-8ab9-444c-ac78-60e2a25d0240","order_by":0,"name":"Samuel E. 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Iloabachie","email":"data:image/png;base64,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","orcid":"","institution":"University of Nigeria Teaching Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Izuchukwu","middleName":"C.","lastName":"Iloabachie","suffix":""},{"id":234673553,"identity":"092b7397-53cf-4da7-83e0-a1bd1c7594eb","order_by":2,"name":"Tochukwu H. Mbanugo","email":"","orcid":"","institution":"University of Nigeria Teaching Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tochukwu","middleName":"H.","lastName":"Mbanugo","suffix":""},{"id":234673554,"identity":"3484e987-bea4-4df7-988c-e5947a869f78","order_by":3,"name":"Ephraim E. Onyia","email":"","orcid":"","institution":"University of Nigeria Teaching Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ephraim","middleName":"E.","lastName":"Onyia","suffix":""},{"id":234673555,"identity":"84c42599-dc07-4d22-8457-3077084c4fed","order_by":4,"name":"Amarachi C. Okpara","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amarachi","middleName":"C.","lastName":"Okpara","suffix":""},{"id":234673556,"identity":"3693e343-285e-432f-a48f-6c6a4d0d8a0f","order_by":5,"name":"Ikechi C. Mbaeri","email":"","orcid":"","institution":"University of Nigeria Teaching Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ikechi","middleName":"C.","lastName":"Mbaeri","suffix":""},{"id":234673557,"identity":"fbe37ffd-7c54-4f98-a838-27b7545fc126","order_by":6,"name":"Mesi Mathew","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mesi","middleName":"","lastName":"Mathew","suffix":""},{"id":234673558,"identity":"eccacc1c-692f-4692-b60a-5c8e5bdfac58","order_by":7,"name":"Enoch O. Uche","email":"","orcid":"","institution":"University of Nigeria Teaching Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Enoch","middleName":"O.","lastName":"Uche","suffix":""}],"badges":[],"createdAt":"2023-09-17 21:29:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3364036/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3364036/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00381-023-06211-9","type":"published","date":"2023-11-10T15:01:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":43705124,"identity":"e43d5915-3dd6-471d-8959-6bda68f51a73","added_by":"auto","created_at":"2023-09-26 14:45:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":33901,"visible":true,"origin":"","legend":"\u003cp\u003eMonthly variation in the conception of participants with myelomeningocele\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3364036/v1/0c50faa7217408c76def6ba4.png"},{"id":43705123,"identity":"b8032f5e-b638-4d7e-9164-2994e6f1a619","added_by":"auto","created_at":"2023-09-26 14:45:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37316,"visible":true,"origin":"","legend":"\u003cp\u003eLorenz curve of myelomeningocele conception from 2010 to 2022\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3364036/v1/eb66acd606cf8d21eb88099a.png"},{"id":46349180,"identity":"9c015c50-24e2-47e6-9788-b859312ee76b","added_by":"auto","created_at":"2023-11-13 15:09:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":368300,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3364036/v1/635c7b56-6a54-4a54-9576-689dfa65f3a7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSeasonal Trend in the Occurrence of Myelomeningocele in Nigeria: a Hypothesis of Climate-induced Oxidative Stress\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eMyelomeningocele is a\u0026nbsp;significant neural tube defect (NTD) that leads to chronic disability and is considered the most severe\u0026nbsp;birth\u0026nbsp;defect compatible with long-term survival.[1]\u0026nbsp;It is an abnormal protrusion of a cystic sac containing the spinal cord-meningeal complex through a defect in the posterior vertebral arches. This common form of spina bifida\u0026nbsp;presents with\u0026nbsp;sphincteric, motor, and sensory disturbances below the level of the lesion, along with associated hydrocephalus, Chiari II anomalies, and foot disorder.[2, 3]\u0026nbsp;The exact cause of myelomeningocele remains unidentified, but it is believed to involve a complex interplay of environmental and genetic factors.[4]\u0026nbsp;Karyotypic abnormalities such as trisomies, a\u0026nbsp;high concordance rate in monozygotic twins, altered folate\u0026nbsp;and homocysteine\u0026nbsp;genes, occurrence within families, gender predilection, and ethno-racial differences provide evidence in favor of a genetic influence.[1]\u0026nbsp;On the other hand, seasonal variations have been suggested as an indicator of potential environmental contributors to the development of myelomeningocele, among other factors such as folate deficiency, hyperthermia, diabetes, and drugs.[5]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVarious epidemiological studies conducted in different countries, including\u0026nbsp;the United Kingdom,\u0026nbsp;Norway,\u0026nbsp;Newfoundland, Germany, Algeria, and the United States,\u0026nbsp;have investigated the seasonal variation of this defect, albeit\u0026nbsp;with conflicting findings.[6\u0026ndash;11]\u0026nbsp;Interestingly, low- and medium-income countries in sub-Saharan Africa bear the largest burden of NTDs like myelomeningocele, with substantial attendant medical, aesthetic, and socioeconomic implications.[12, 13]\u0026nbsp;In Nigeria, it accounts for a considerable proportion (5.7%) of neurological surgeries, and its prevalence has been reported to be 1.3 per 1,000 newborns.[2, 14]\u0026nbsp;Despite the growing recognition of seasonal variations in exposure to teratogens, the impact of seasonal variation on myelomeningocele incidence in Nigeria remains poorly understood.[15]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUnderstanding the seasonal variations in the occurrence of myelomeningocele can provide valuable insights into the role of peri-conception and prenatal care practices in its occurrence.[7]\u0026nbsp;By analyzing the temporal distribution of myelomeningocele cases throughout the year, we can discern potential patterns and associations with specific seasons or climatic conditions such as sunlight exposure, temperature fluctuations, and related oxidative stress. This knowledge is essential for tailoring preventive interventions, optimizing resource allocation, and improving healthcare planning to mitigate the burden of myelomeningocele in Nigeria. Therefore, this study aims to identify the months of conception and investigate the seasonal trends in the occurrence of myelomeningocele in Nigeria. Moreover, the findings of this study will contribute to the existing body of knowledge on myelomeningocele and may have implications for other regions with similar environmental and socio-demographic characteristics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eResearch Questions:\u003c/u\u003e\u003c/strong\u003e Is there a significant seasonal variation in the occurrence of myelomeningocele?\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eStudy Design\u003c/u\u003e\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis is a prospective hospital-based observational study of 242 participants diagnosed with myelomeningocele between January 2010 and December 2022. Participants were consecutively recruited from the neurosurgery and newborn units of the University of Nigeria Teaching Hospital (UNTH), Enugu, Southeast Nigeria. Their month of conception was derived from their mothers' last menstrual period (LMP). The occurrence of myelomeningocele was compared across the various seasons in which these babies were conceived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eSetting\u003c/u\u003e\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe UNTH is a tertiary healthcare facility renowned for its specialized medical services. It serves as a referral center for Nigerians living within the southeast and south-south regions as well as surrounding locations.[16]\u0026nbsp;With dedicated departments for newborn care, emergency medicine, and neurosurgery, the hospital provides an ideal setting for a comprehensive study on myelomeningocele. The study location, Enugu, a city in southeast Nigeria, is located at geographical coordinates of latitude 06º26'0''N and longitude 070º29'0''E. It lies between the southern tropical rainforest and the northern Guinea savanna belt. The region experiences a tropical savanna climate characterized by distinct wet and dry seasons. The annual rainfall ranges from 1500mm to 2500mm.[17]\u0026nbsp;According to the Nigeria climate review, the temperatures in this region can vary throughout the year, with \u003cem\u003emaximum ambient temperatures typically observed in February and March\u003c/em\u003e. The seasonal patterns in Nigeria are largely influenced by the Intertropical Discontinuity, which involves the seasonal oscillatory movement of the dry wind blowing north-easterly from the Sahara Desert and the moist south-westerly monsoon from the Atlantic Ocean. These climatic factors play a significant role in shaping the seasonal variations experienced in the region.[18]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eParticipants, Study Size,\u003c/u\u003e\u003c/strong\u003e\u003cu\u003e\u0026nbsp;\u003cstrong\u003eand Data Collection\u003c/strong\u003e\u003c/u\u003e:\u003c/p\u003e\n\u003cp\u003eThe eligibility criteria for the study\u0026nbsp;included all\u0026nbsp;children diagnosed with myelomeningocele at UNTH, whether ruptured or intact, whose parents or legal guardians’ consented to participate in the study. Stillbirths, newborns delivered before the 28\u003csup\u003eth\u003c/sup\u003e gestational week, and children with incomplete data, such as those from mothers without an identifiable LMP required to determine the time of conception, were excluded from the study.\u0026nbsp;Assuming an acceptable error level of 5% (d = 0.05), a power of 0.80, an estimated proportion of 0.195 from a pilot study (p = 0.195), and an alpha(α) value of 0.05, the survey required a sample size of 242 participants.[13] Data was collected prospectively using the study proforma to capture the month of conception derived from the LMP of the mother. Demographic factors, including gender, birth order, and parental age, as well as data on maternal folic acid supplementation (FAS) and other relevant clinical information, were obtained. The dependent variable was the occurrence of myelomeningocele, while the independent variables included the season of conception and demographic variables. Potential confounders were maternal folic acid supplementation, parental age, and birth order.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eStatistical Analysis\u003c/u\u003e\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eDescriptive statistics were used to summarize the proportions, means, and standard deviations of clinico-demographic variables, while inferential statistics were performed using ANOVA, Chi-square, or Fisher's exact tests. We evaluated the association between the above covariates and the determined season of conception of myelomeningocele. Analysis was achieved with SPSS Statistics 26.0.0 (IBM Corp., Armonk, New York, US). The myelomeningocele conception ratio (MCR) was calculated for each of the 12 months by dividing the number of cases occurring in a given month over the 12 years by the number of days in the corresponding month (Table 1). The Lorenz curve was constructed by plotting the cumulative percentage of myelomeningocele on the y-axis against the cumulative percentage of days on the x-axis. The Gini coefficient was the area between the equality line and the Lorenz curve, which quantified the seasonality. The 95th percentile Gini coefficient derived from the 100,000 Monte Carlo simulations was used to assess the statistical significance of the observed seasonal variation at an alpha(α) level of 0.05.\u0026nbsp;The Gini index provides a quantitative measure that allows us to assess the degree of variation or inequality in myelomeningocele cases across seasons, while the Lorenz curve provides a visual representation of the distribution. This approach can help us identify if there is a significant seasonal disparity and quantify the extent of that disparity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eEthical Considerations\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe obtained ethical approval from the Health Research Ethics Committee of UNTH \u003cem\u003e(NHREC/05/01/2008B-FWA00002458-1RB00001247)\u003c/em\u003e. Participation in the study was voluntary, and informed consent was obtained from the parents or legal guardians of participants for data collection and publication. The study adhered to the latest version of the Helsinki Declaration for medical research.[19]\u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe study included a total of 242 out of 251 participants with myelomeningocele over 12 years. The main reason for the exclusion of nine participants was incomplete data. Therefore, the average number of presentations per year was approximately 20.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9. The study had a slightly higher representation of males (55.4%) compared to females (44.2%), with a male-to-female ratio of 1.26:1. There was a trend toward more female conception between April and June and more male conception between October and March. However, the seasonal variation was not statistically more profound in one gender than in the other (P\u0026thinsp;=\u0026thinsp;0.124, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The majority of cases were classified as lumbosacral (93.4%). Other less common locations included cervical (n\u0026thinsp;=\u0026thinsp;1, 0.4%), thoracic (n\u0026thinsp;=\u0026thinsp;11, 4.5%), and sacral (n\u0026thinsp;=\u0026thinsp;4, 2.5%). The anatomical location of the defect did not show significant differences among the seasons of conception (P\u0026thinsp;=\u0026thinsp;0.09).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical and demographic characteristics of the study participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;242)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJan-Mar\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eApr-Jun\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eJul-Sep\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOct-Dec\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eGender, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107 (44.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (35.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (55.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22 (45.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e135 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62 (64.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17 (44.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26 (54.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLocation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.09\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCervical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThoracic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLumbosacral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e226 (93.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90 (93.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37 (97.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e53 (88.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e46 (95.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSacral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFolic acid supplementation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (22.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (20.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15 (25.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.91\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, Mean Month (S.D.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.5 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.4 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.5 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.3 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.6 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.93\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge at conception\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMaternal age, Mean (S.D.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.8 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.9 (5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.8 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.4 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.4 (5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.52\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePaternal age, Mean (S.D.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.2 (7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.1 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39.2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38.9 (6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e37.0 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.46\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBirth order, Mean (S.D.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.3 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.2 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.4 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.4 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.92\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn terms of folic acid supplementation, none of the mothers of the affected children began supplementation before conception. Post-conception, we observed folic acid intake in only 187 mothers (77.3%) during the pregnancy, and their mean month of commencement was 3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 (range 4 weeks to 7 months), with similar proportions across all seasons (P\u0026thinsp;=\u0026thinsp;0.9). Both the average maternal and paternal ages at the time of conception of the children with myelomeningocele (27 and 38 years, respectively) did not show significant differences among the various seasons. Similarly, the mean birth order of the affected children did not vary significantly among the seasons (P\u0026thinsp;=\u0026thinsp;0.92).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe highest number of conceptions of babies with myelomeningocele occurred in 2013, 2015, and 2021, with 32 (13.2%), 30 (12.4%), and 25 (10.3%) cases, respectively. The years 2012, 2019, and 2022 had the lowest number of myelomeningoceles, with 6 (2.5%), 9 (3.7%), and 9 (3.7%) cases, respectively. There was variation in the distribution of patients across birth months. Babies with myelomeningocele were more likely to be conceived in March and February, while months like April and May had lower numbers (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMonthly myelomeningocele conception ratio from 2010 to 2022\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonth of Conception\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of Myelomeningocele\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo. of Days\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMonthly Conception Ratio (MCR) of Myelomeningocele\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePercentage (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFeb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e339\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.1102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApril\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0222\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0403\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJune\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0417\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJuly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAug\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0565\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0556\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOct\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0376\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNov\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0583\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0349\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e242\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e4383\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.6646\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e100.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the 242 participants with myelomeningocele, a total of 96 (39.7%) were conceived during the hottest period of the dry season of the year (Jan-Mar), 38 (15.7%) during the early wet season (Apr-Jun), 60 (24.8%) during the late wet season (Jul-Sep), and 48 (19.8%) during the coldest period of the dry season (Oct-Dec). There was variation in the MCR of myelomeningocele across different months (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Months such as February and March (16.6%) had relatively higher MCR values, indicating a higher incidence of myelomeningocele during those periods. Conversely, months like April and December exhibited lower MCR values, indicating a comparatively lower incidence of myelomeningocele during those periods.\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e represents the Lorenz curve of the seasonal inequality in the occurrence of myelomeningocele. The empirical Gini index for the conception of a baby with a myelomeningocele birth defect was 0.29, and the 100,000 Monte Carlo simulations derived a 95th percentile Gini coefficient value of 0.24, suggesting a significant seasonal variation at an alpha level of 0.05 and a rejection of the null hypothesis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis hospital-based study found a slightly higher proportion of males than females conceived with myelomeningocele. However, the study did not identify a gender-specific factor in the seasonal variation of myelomeningocele. Nevertheless, there was a significant sinusoidal variation in the distribution of myelomeningocele cases across different seasons of conception based on the Gini index. The highest proportion of cases (39.7%) occurred during the hottest period of the dry season (Jan\u0026ndash;Mar), while the lowest proportion (15.7%) occurred during the early wet season (Apr\u0026ndash;Jun). These findings suggest a potential association between the season of conception and the occurrence of myelomeningocele. Other factors, such as the location of myelomeningocele defects, folic acid supplementation, and parental age at conception, had no significant association with the season of conception. Similarly, the birth order of affected children within the family did not influence the seasonal pattern of myelomeningocele occurrence. All the factors highlighted above did not influence the seasonal distribution of the conception of patients with myelomeningocele in our study.\u003c/p\u003e\n\u003cp\u003eOur observation of a significantly more frequent myelomeningocele conception during the hottest dry season months of our study location and a very rapid falloff to the lowest occurrence during the adjoining early rainy season months is quite interesting and, in our opinion, informative. The varying temperature, humidity, and precipitation patterns in the study catchment area provide insights into a potential seasonal causal link to the etiology of myelomeningocele. In Nigeria, the seasons are categorized into dry and rainy seasons. The rainy season in Nigeria typically spans from April to October. During the transition from the harmattan season to the wet season between April and June, there is favorable precipitation, humidity, and temperature, which coincidentally is the period with the lowest percentage of patients conceived with myelomeningocele (15.7%). The months of January to March correspond to the harmattan season, characterized by lower precipitation, decreased humidity, dry and dusty conditions, and extreme temperature fluctuations. Early mornings are relatively cooler, around 19\u0026deg;C (66\u0026deg;F), while afternoon temperatures can rise to 33\u0026deg;C (91\u0026deg;F).[18]\u0026nbsp;The higher proportion (39.7%) of babies conceived with myelomeningocele during this period lends credence to the idea that the human embryo may be most vulnerable to thermally-induced oxidative stress during the hottest dry season. For the cold, wet season, we wish to scientifically speculate on the absence of our proposed thermal phenomenon or perhaps a reversal of attributable oxidative effects on the human embryo. Additionally, the harmattan winds blowing from the Sahara Desert can create hazy conditions that are conducive for the aerosolization of infectious agents and environmental pollutants. Maternal influenza and respiratory tract infections are more prevalent during this period, and the resulting thermal changes could induce oxidative stress, potentially playing a role in the observed seasonal variation of myelomeningocele.[20]\u003c/p\u003e\n\u003cp\u003eIt is important to note that this period coincides with the off-season for the farming of green leafy vegetables, which are significant sources of folate in our sub-region. Adequate folate intake is a crucial public health strategy for preventing NTDs, including myelomeningocele. Early supplementation with folic acid has been shown to significantly reduce the risk of NTD by 24%. However, similar to previous studies, none of the mothers in our study cohort received folic acid supplementation one month before and after conception, despite the 1992 recommendations by the US Centers for Disease Control and Prevention (CDC).[12, 20]\u0026nbsp;[21, 22]\u0026nbsp;The earliest record of commencement of folate supplementation among mothers of our study participants was in the fourth week of gestation, at which point the neural tube would be closing, while 22.7% had no folic acid supplementation at all during pregnancy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAccording to Tyrrell, the intense solar radiation, which in our setting peaks in March, may contribute significantly to maternal oxidative stress. The blood levels of oxidant-stress factors, such as the enzyme heme oxygenase, can be affected systemically by UV wavelengths depleting skin glutathione.[23]\u0026nbsp;The molecular and cellular processes of neural tube closure all appear to be amenable to alteration by the extraembryonic conditions associated with oxidative stress. Diabetes, a \u0026quot;free radical disease,\u0026quot; and folate insufficiency, an illness that leads to the accumulation of the oxidant stressor homocysteine, are two important maternal causes of dysmorphogenesis that provide the basis for the evidence. Natural antioxidants like vitamin C, vitamin E, and superoxide dismutase could prevent neural tube defects. From our study, we hypothesize that maternal oxidative stress, which can increase with excessive exposure to sunlight, especially in the hottest months, hyperthermia, and folate deficiency, may prevent the closure of the neural tube and result in the formation of myelomeningocele.[24]\u0026nbsp;Nonetheless, it is crucial to remember that oxidative stress is not the only deciding environmental factor. Unknown teratogens that may exhibit seasonal patterns throughout the year are possible alternative causal factors.[5]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur findings are corroborated by previous studies conducted in other countries, including Puerto Rico, South Africa, Newfoundland, and the United Kingdom.[5, 6, 8, 25]\u0026nbsp;However, it contrasts with reports from studies from the United States, Jordan, Germany, Poland, Japan, and Algeria.[9\u0026ndash;11, 20, 26]\u0026nbsp;Among the Scandinavian countries, northern Finland and Sweden demonstrated a seasonal variation, while Norway did not find a seasonal pattern. In Norway, Hwang et al. conducted a population-based study and observed a significant seasonal variation for any birth defect, but not specifically for spina bifida.[7]\u0026nbsp;Their study included term babies with various systemic anomalies diagnosed within the first week of life between 1993 and 1998. Unlike our study, their analysis was retrospective and involved a larger dataset of 326,560 births. However, they excluded 10% of babies due to incomplete data, which could introduce selection bias. It is important to note that the Norwegian study did not specifically evaluate newborns with myelomeningocele as a subgroup. Nevertheless, they did observe a higher occurrence of Down\u0026apos;s syndrome in February and respiratory anomalies in March. They suggested a potential prenatal environmental exposure to viral pathogens or disinfectant by-products, which may exhibit seasonality and could be influenced by higher\u0026nbsp;temperatures.[7]\u0026nbsp;It is worth mentioning that fetal neural tissue, which begins to form in the first month of conception, is highly susceptible to viral infections.\u003c/p\u003e\n\u003cp\u003eThe lack of consistent findings regarding the seasonal variation of NTD can be attributed to several factors. Firstly, the studies were conducted on different populations with diverse genetic backgrounds, environmental exposures, and healthcare systems. For example, the impact of nutritional factors such as folic acid intake may differ among populations due to variations in dietary habits and the availability of fortified foods or supplements. Secondly, factors such as maternal age, socioeconomic status, and exposure to teratogenic agents can differ between populations and contribute to the variation in findings. Thirdly, regional variations in climate and seasonal patterns can affect exposure to environmental factors during critical periods of fetal development. Sunlight exposure, for instance, can vary with latitude and may influence the risk of myelomeningocele. Lastly, differences in the methods used for case identification and analysis among studies can contribute to a lack of consistency, thereby impacting the accuracy and comparability of the results.[11]. Our study\u0026apos;s geographical scope is a limitation on the generalizability of our findings. Also, children with myelomeningocele who were born outside of the hospital and whose parents did not voluntarily report them were not captured. Considering these factors, it is important to interpret the findings of individual studies within the context of their specific populations and settings. Further research and collaborative efforts are needed to better understand the complex interplay between seasonal variation, genetic and environmental factors, and the development of myelomeningocele. Specifically, a larger multicenter study is required to validate our findings as well as delineate possible molecular processes or epigenetic pathways that may interplay to influence our salient observations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study found a significant sinusoidal variation in myelomeningocele cases across seasons, with a peak in the hottest season of our study location (January\u0026ndash;March), suggesting a potential association with environmental factors such as solar radiation and thermally induced oxidative stress.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviation","content":"\u003cp\u003eNTD = neural tube defect; LMP = last menstrual period; FAS = folic acid supplementation; MCR = myelomeningocele conception ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe authors have no competing interests or financial disclosure to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAvailability of data and materials\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAvailable upon relevant requests.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eBowman RM, Boshnjaku V, McLone DG (2009) The changing incidence of myelomeningocele and its impact on pediatric neurosurgery: A review from the Children\u0026rsquo;s Memorial Hospital. 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Am J Med Genet 14:181\u0026ndash;188. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ajmg.1320140124\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Birth defects, seasonal variation, neural tube defect, folic acid supplementation, environmental factors","lastPublishedDoi":"10.21203/rs.3.rs-3364036/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3364036/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eMyelomeningocele is the most severe birth defect compatible with long-term survival. It accounts for 5.7% of neurological surgeries in Nigeria. However, the exact cause of this neural tube defect remains unidentified. This study aims to determine if seasonal variation is a potential environmental contributor.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eThis study prospectively recruited 242 children diagnosed with myelomeningocele at the University of Nigeria Teaching Hospital (UNTH), Enugu, Nigeria, between January 2010 and December 2022. Our primary outcome was the seasonal occurrence of myelomeningocele, while covariates included gender, birth order, maternal folic acid supplementation (FAS), and parental age. The estimated month of conception was derived from the mother's last menstrual period (LMP), and the occurrence of myelomeningocele across the various seasons in which these babies were conceived was assessed using the Lorenz curve and the Gini coefficient.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e242 patients were studied with a male-to-female ratio of 1.26. The majority of cases were lumbosacral (93.4%), and none of the mothers commenced FAS before conception. The highest proportion of cases (39.7%) occurred during the hottest period of the dry season (January\u0026ndash;March), while the lowest proportion (15.7%) occurred during the early wet season (April\u0026ndash;June). The Gini index of 0.29, and the Gini coefficient derived from 100,000 Monte Carlo simulations of 0.24, indicate a significant variation in the distribution of myelomeningocele cases across different seasons of conception.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe seasonal occurrence of myelomeningocele with a peak in January\u0026ndash;March suggests a potential association with environmental factors including oxidative stress induced by solar radiation.\u003c/p\u003e","manuscriptTitle":"Seasonal Trend in the Occurrence of Myelomeningocele in Nigeria: a Hypothesis of Climate-induced Oxidative Stress","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-26 14:45:31","doi":"10.21203/rs.3.rs-3364036/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2023-10-29T17:35:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-10-29T11:29:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"085f04ca-c1be-48b5-b58d-56befb20afd1","date":"2023-10-29T10:59:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-09-28T09:48:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-09-19T12:08:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-09-19T12:08:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Child's Nervous System","date":"2023-09-17T21:15:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f0bbf89c-5609-4e72-b07d-2d23f3d8d101","owner":[],"postedDate":"September 26th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-11-13T15:06:19+00:00","versionOfRecord":{"articleIdentity":"rs-3364036","link":"https://doi.org/10.1007/s00381-023-06211-9","journal":{"identity":"childs-nervous-system","isVorOnly":false,"title":"Child's Nervous System"},"publishedOn":"2023-11-10 15:01:50","publishedOnDateReadable":"November 10th, 2023"},"versionCreatedAt":"2023-09-26 14:45:31","video":"","vorDoi":"10.1007/s00381-023-06211-9","vorDoiUrl":"https://doi.org/10.1007/s00381-023-06211-9","workflowStages":[]},"version":"v1","identity":"rs-3364036","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3364036","identity":"rs-3364036","version":["v1"]},"buildId":"wLkW0s4AflPzk-lpfg-fK","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}