Increased Risk of Cerebral Palsy in IVF/ICSI Babies: Meta analysis of Current Literature

Increased Risk of Cerebral Palsy in IVF/ICSI Babies: Meta analysis of Current Literature | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Increased Risk of Cerebral Palsy in IVF/ICSI Babies: Meta analysis of Current Literature Halil Bulut, Merve Bastopcu, Omer Altin, Ali This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4000589/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 Background: The correlation between assisted reproductive therapies (ARTs) and congenital or developmental anomalies has been acknowledged by prominent obstetric and reproductive science authorities. However, the orthopedic perspective on this aspect of ARTs remains largely unexplored. This meta-analysis aims to examine a plausible association between cerebral palsy and in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) therapies within the realm of assisted reproductive technologies (ARTs). Methods: The literature spanning from 1980 to February 2024 was systematically reviewed within the MEDLINE, Scopus, and Embase databases, adhering to the PRISMA guidelines. Data synthesis was conducted using the Jamovi program. Results: The literature review involved an initial search that yielded 192 articles, which were subsequently refined to 21 articles following the removal of duplicates and screening for relevance. These articles, selected according to the PRISMA model, collectively included data from 8,657,973 patients. Upon analyzing the dataset, it was found that among 8,400,080 control patients, there were 14,518 cases of cerebral palsy, while among 237,873 patients who underwent IVF or ICSI, 736 cases of cerebral palsy were documented. This analysis revealed that the incidence of cerebral palsy was approximately 1.9 times higher in IVF and ICSI cases compared to control groups (p < 0.001, adjusted odds ratio = 1.9, 95% confidence interval: 1.570–2.323). Conclusion As a result, the risk of developing cerebral palsy, as in many other congenital anomalies and pediatric diseases, in babies born with assisted reproductive techniques is statistically significantly higher than in normal babies. This, together with the sensitive monitoring of the neonatal period and perinatal period in women conceived with ART. It is recommended that teams collaborate with pediatric orthopedic surgeons. Orthopedic Surgery Orthopedics Obstetrics & Gynecology Cerebral Palsy IVF ICSI Orthopedic surgery Figures Figure 1 Figure 2 Figure 3 Introduction In vitro fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI) have revolutionized the field of reproductive medicine, enabling millions of individuals and couples to overcome infertility and start families (1,2). While IVF and ICSI significantly increase pregnancy success, they also raise important ethical and medical issues, particularly regarding the potential for congenital anomalies in children born via IVF/ICSI (3–5). Congenital anomalies, also known as birth defects, are structural or functional abnormalities that are present at birth. They can range from minor cosmetic issues to serious or life-threatening conditions that require significant medical attention (3–5). The causes of congenital anomalies are complex and multifactorial, including genetic, environmental, and random factors. Over the years, extensive research has been conducted to understand the relationship between in vitro fertilization and congenital anomalies (3–5). Several studies suggest that the prevalence of certain congenital anomalies is higher in children born via IVF/ICSI compared to children born naturally (3–5). However, this situation has not been comprehensively investigated specifically in orthopedic problems or cerebral palsy, which are the most common congenital or prematurity-related problems. In this study, we comprehensively discussed the relationship between cerebral palsy and ICSI/IVF. Methods 2.1 Study Designing This study was designed as a meta-analysis, spanning 44 years of literature from 1980 to 2024. The primary endpoint of this study was to determine the difference in the incidence of cerebral palsy between natural conception and IVF/ICSI. 2.2 Search Strategy and Study Criteria The search methodology involved querying the PUBMED and Scopus databases using two distinct search strategies: (1) (IVF) AND (Cerebral Palsy) and (2) (ICSI) AND (Cerebral Palsy). Studies meeting the following inclusion criteria were considered: (1) inclusion of either IVF or ICSI groups, (2) presence of a control group for comparison, (3) provision of the total number (n) of "AT LEAST ONE" of the cp case in both the IVF/ICSI groups and the control group, (4) publication in English, and (5) inclusion of at least 10 patients in each group. Exclusion criteria encompassed reviews, meta-analyses, case series, and case reports, with a focus solely on original research articles that met the criteria for comprehensive analysis. During this selection process we followed PRISMA guideline(6). 2.3 Data Extraction Relevant data, including bibliographic details such as publication year and author surname, were extracted from each publication selected based on detailed criteria. Additionally, information regarding the total cohort size and the number of patients affected by cerebral palsy was meticulously documented. 2.4 Endpoint definition Data analysis was structured into two principal stages. In the pre-processing phase, meticulous examination of the data was conducted to ascertain the patient count within both the control and assisted reproductive technology (ART) groups. Following this, the occurrence of cerebral palsy within each group was meticulously documented. The primary emphasis during analysis was placed on calculating the percentage of patients afflicted with cerebral palsy within the respective groups. 2.5 Data Synthesis The synthesis of data was meticulously carried out by two seasoned academics proficient in statistics and epidemiology. Given the extensive number of patients expected to be included and the likelihood of encountering low study quality and missing patient data, the anticipated heterogeneity of results was carefully considered. However, despite these challenges, the results were presented per study alongside their corresponding 95% confidence intervals (95% CIs) to effectively illustrate the incidence of cerebral palsy in assisted reproductive technologies (ARTs). Each study was meticulously weighted based on sample size and data distribution, ensuring an accurate representation of the rates observed. These aggregated rates were subsequently combined and consistently reported. To evaluate the degree of heterogeneity among the studies, the I2 statistic was employed, with values exceeding 50% and their corresponding P-values indicating significant heterogeneity. The synthesis process utilized Jamovi, a freely available software program, to ensure robust analysis and interpretation of the data(7). Results 3.1 literature A thorough search utilizing pertinent keywords yielded a total of 192 articles from the designated database systems. Following the removal of duplicates and screening for relevance based on titles, the analysis narrowed down to 76 abstracts, resulting in the exclusion of 50 articles. The final filtration process, conducted in accordance with the PRISMA model, ultimately included 21 articles for detailed analysis(8-28). These selected articles collectively encompassed data from 8,657,973 patients. For a comprehensive overview of the study selection process, please refer to Figure 1 and Table 1. 3.2 Comparison between ARTs and Control After conducting a comprehensive analysis of the dataset, it was observed that among 8,400,080 control patients, 14,518 cases of cerebral palsy were identified. In contrast, among 237,873 patients who underwent either in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), 736 cases of cerebral palsy were documented. Upon meticulous data synthesis, it became evident that the incidence of cerebral palsy was approximately 1.9 times higher in IVF and ICSI cases compared to other control groups. (p<0.001,95% confidence interval: 1.570-2.323) (figure 2 and figure 3). 3.3 Heterogeneity of the literature Following heterogeneity analysis, the I2 statistic was calculated to be 73.5%, which indicates a moderate to high level of heterogeneity among the studies included in the analysis. This suggests that there is a considerable amount of variability in the study results beyond what would be expected by chance alone. The p-value associated with this finding is less than 0.001, indicating that the observed heterogeneity is statistically significant. Additionally, the tau2 value, a measure of between-study variance, was calculated to be 0.1125. This further supports the presence of heterogeneity among the studies, as a tau2 value greater than zero suggests that the true effect size may vary across studies. Discussion As infertility rates and maternal ages continue to rise, the utilization of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) is steadily increasing (2). These assisted reproductive technologies (ART) have a well-established track record of success in helping couples conceive. (1-2) However, the topic of concern regarding the prevalence of congenital anomalies in pregnancies resulting from IVF and ICSI has been a topic of ongoing debate within the medical community (1-5). Potential hypotheses behind this phenomenon include factors such as maternal age at the time of IVF/ICSI, multiparity, and innate susceptibility to natural congenital pathologies (29-30). Some causes of female infertility can predispose embryos to malformations and increase the risk of prematurity (30-31). Moreover, the risk of prematurity is heightened by multiparity, which is more prevalent in IVF/ICSI cases (28-31). There are also more speculative theories, such as the potential for DNA damage during in vitro fertilization or intracytoplasmic injection (32). While meta-analyses have investigated the association between IVF/ICSI and pediatric problems such as chromosomal anomalies and congenital heart diseases, a comprehensive perspective on congenital orthopedic problems and musculoskeletal diseases has not yet been presented(3,5). Our study represents the most thorough examination of this topic to date. In the study, we meticulously searched two vital databases and sifted through over 100,000 studies on ICSI and IVF. Surprisingly, only 192 studies addressed cerebral palsy. However, after removing duplicates and applying stringent selection criteria, only 21 publications were deemed suitable for inclusion in our analysis (8-28). This limited literature pool is characterized by moderate to high levels of heterogeneity. Notably, studies like those by Norman et al and Kallen et al, involving more than 2 million individuals, as well as studies such as Kuiper et al and Ramoglu et al, which include only a few hundred individuals, exemplify this qualitative heterogeneity. This disparity underscores the untouched nature of this area, emphasizing the necessity for further evidence and the establishment of a consensus within the field. The most striking revelation of this study is that the likelihood of cerebral palsy after IVF/ICSI is 1.9 times higher than after natural conception. This finding underscores the comparable risk of cerebral palsy associated with IVF/ICSI to that of congenital heart diseases or chromosomal anomalies. It is imperative to investigate whether this observed relationship extends to other musculoskeletal and orthopedic problems as well. Conclusion The findings of this study shed light on the possible association between IVF/ICSI and an increased risk of cerebral palsy. Although the literature pool is limited, the significant increase in the likelihood of cerebral palsy after IVF/ICSI compared to natural conception warrants further exploration. Future studies should aim to elucidate the underlying mechanisms and explore potential interventions to mitigate this risk. It is also essential to investigate whether this observed relationship extends to other musculoskeletal and orthopedic problems, as this can inform clinical decision-making and patient counseling. References Mantikou E, Youssef MA, van Wely M, van der Veen F, Al-Inany HG, Repping S, Mastenbroek S. Embryo culture media and IVF/ICSI success rates: a systematic review. Hum Reprod Update. 2013 May-Jun;19(3):210-20. doi: 10.1093/humupd/dms061. Epub 2013 Feb 5. PMID: 23385469. Palermo GD, Neri QV, Takeuchi T, Rosenwaks Z. ICSI: where we have been and where we are going. Semin Reprod Med. 2009 Mar;27(2):191-201. doi: 10.1055/s-0029-1202309. Epub 2009 Feb 26. PMID: 19247922. Giorgione V, Parazzini F, Fesslova V, Cipriani S, Candiani M, Inversetti A, Sigismondi C, Tiberio F, Cavoretto P. Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2018 Jan;51(1):33-42. doi: 10.1002/uog.18932. PMID: 29164811. Tandulwadkar S, Lodha P, Kharb V. Congenital malformations and assisted reproductive technique: Where is assisted reproductive technique taking us? J Hum Reprod Sci. 2012 Sep;5(3):244-7. doi: 10.4103/0974-1208.106334. PMID: 23533070; PMCID: PMC3604829. Berntsen S, Laivuori H, la Cour Freiesleben N, Loft A, Söderström-Anttila V, B Oldereid N, Romundstad LB, Magnusson Å, Petzold M, Bergh C, Pinborg A. A systematic review and meta-analysis on the association between ICSI and chromosome abnormalities. Hum Reprod Update. 2021 Aug 20;27(5):801-847. doi: 10.1093/humupd/dmab005. PMID: 33956940. BMJ (OPEN ACCESS) Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71 The jamovi project (2023). jamovi (Version 2.3) [Computer Software]. Retrieved from https://www.jamovi.org Norrman E, Petzold M, Bergh C, et al. School performance in children born after ICSI. Human Reproduction 2020; 35: 340–354. Levin, Shai, et al. “Infertility Treatments and Long-Term Neurologic Morbidity of the Offspring.” American Journal of Perinatology, vol. 36, no. 09, 16 Nov. 2018, pp. 949–954, https://doi.org/10.1055/s-0038-1675159. Accessed 9 Jan. 2022. Davies, Michael J., et al. “Reproductive Technologies and the Risk of Birth Defects.” New England Journal of Medicine, vol. 366, no. 19, 10 May 2012, pp. 1803–1813, https://doi.org/10.1056/nejmoa1008095. Zhu, J. L., et al. “Parental Infertility and Cerebral Palsy in Children.” Human Reproduction, vol. 25, no. 12, 2 Nov. 2010, pp. 3142–3145, www.ncbi.nlm.nih.gov/pmc/articles/PMC2989872/#:~:text=BACKGROUND, https://doi.org/10.1093/humrep/deq206. Accessed 27 Apr. 2022. Dorte Hvidtjørn, et al. “Multiplicity and Early Gestational Age Contribute to an Increased Risk of Cerebral Palsy from Assisted Conception: A Population-Based Cohort Study.” Human Reproduction, vol. 25, no. 8, 16 June 2010, pp. 2115–2123, https://doi.org/10.1093/humrep/deq070. Accessed 31 Dec. 2023. Pinborg, Anja, et al. “Infant Outcome of 957 Singletons Born after Frozen Embryo Replacement: The Danish National Cohort Study 1995-2006.” Fertility and Sterility, vol. 94, no. 4, 1 Sept. 2010, pp. 1320–1327, www.ncbi.nlm.nih.gov/pubmed/19647236, https://doi.org/10.1016/j.fertnstert.2009.05.091. Källén AJB, Finnström OO, Lindam AP, et al. Cerebral palsy in children born after in vitro fertilization. Is the risk decreasing? European Journal of Paediatric Neurology 2010; 14: 526–530. Carlsen H, Vik T, Andersen GL, et al. Cerebral palsy in children born after assisted reproductive technology in Norway: Risk, prevalence, and clinical characteristics. Acta Obstetricia et Gynecologica Scandinavica 2023; 102: 1450–1458. Dorte Hvidtjørn, et al. ““Vanishing Embryo Syndrome” in IVF/ICSI.” Human Reproduction, vol. 20, no. 9, 12 May 2005, pp. 2550–2551, https://doi.org/10.1093/humrep/dei092. Accessed 13 Feb. 2024. Hvidtjørn D, Grove J, Schendel DE, et al. Cerebral Palsy Among Children Born After In vitro Fertilization: The Role of Preterm Delivery—A Population-Based, Cohort Study. Pediatrics 2006; 118: 475–482. Lidegaard, Øjvind, et al. “Imprinting Diseases and IVF: Danish National IVF Cohort Study.” Human Reproduction, vol. 20, no. 4, 1 Apr. 2005, pp. 950–954, https://doi.org/10.1093/humrep/deh714. Goldsmith S, Mcintyre S, Badawi N, et al. Cerebral palsy after assisted reproductive technology: a cohort study. Developmental Medicine & Child Neurology 2017; 60: 73–80. Neurological Sequelae in Twins Born after Assisted Conception: Controlled National Cohort Study.” BMJ, vol. 329, no. 7461, 15 July 2004, p. 311, https://doi.org/10.1136/bmj.38156.715694.3a. Accessed 25 Aug. 2021. Strömberg B, Dahlquist G, Ericson A, et al. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. The Lancet 2002; 359: 461–465. Mansoureh Farhangniya, et al. “Comparison of Congenital Abnormalities of Infants Conceived by Assisted Reproductive Techniques versus Infants with Natural Conception in Tehran.” DOAJ (DOAJ: Directory of Open Access Journals), no. 20080778, 1 Oct. 2013. Accessed 13 Feb. 2024. D’Souza, S. W., et al. “Children Conceived by in Vitro Fertilisation after Fresh Embryo Transfer.” Archives of Disease in Childhood - Fetal and Neonatal Edition, vol. 76, no. 2, 1 Mar. 1997, pp. F70–F74, fn.bmj.com/content/76/2/F70, https://doi.org/10.1136/fn.76.2.F70. Accessed 25 May 2022. Middelburg, Karin J., et al. “Mental, Psychomotor, Neurologic, and Behavioral Outcomes of 2-Year-Old Children Born after Preimplantation Genetic Screening: Follow-up of a Randomized Controlled Trial.” Fertility and Sterility, vol. 96, no. 1, July 2011, pp. 165–169, https://doi.org/10.1016/j.fertnstert.2011.04.081. Accessed 27 May 2020. Ramoğlu, Mehmet, et al. “Neurodevelopment of Preterm Infants Born after in Vitro Fertilization and Spontaneous Multiple Pregnancy.” Pediatrics International, vol. 58, no. 12, 10 Aug. 2016, pp. 1284–1290, https://doi.org/10.1111/ped.13012. Accessed 22 Mar. 2021. Kuiper, Derk, et al. “Developmental Outcome of 9-Year-Old Children Born after PGS: Follow-up of a Randomized Trial.” Human Reproduction, vol. 33, no. 1, 1 Jan. 2018, pp. 147–155, https://doi.org/10.1093/humrep/dex337. Accessed 22 May 2023. Klemetti, Reija, et al. “Health of Children Born after Ovulation Induction.” Fertility and Sterility, vol. 93, no. 4, Mar. 2010, pp. 1157–1168, https://doi.org/10.1016/j.fertnstert.2008.12.025. Accessed 25 Feb. 2020. Ginström Ernstad, Erica, et al. “Preimplantation Genetic Testing and Child Health: A National Register-Based Study.” Human Reproduction (Oxford, England), vol. 38, no. 4, 3 Apr. 2023, pp. 739–750, pubmed.ncbi.nlm.nih.gov/36749096/, https://doi.org/10.1093/humrep/dead021. Accessed 26 Aug. 2023. Zhu JL, Basso O, Obel C, et al. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ 2006; 333: 679. Sanders JN, Simonsen SE, Porucznik CA, et al. Fertility treatments and the risk of preterm birth among women with subfertility: a linked-data retrospective cohort study. Reproductive Health; 19. Epub ahead of print March 29, 2022. DOI: 10.1186/s12978-022-01363-4. Luke B, Brown MB, Wantman E, et al. Risk of prematurity and infant morbidity and mortality by maternal fertility status and plurality. Journal of Assisted Reproduction and Genetics 2018; 36: 121–138. Hervás I, Rivera-Egea R, Pacheco A, et al. Elevated Sperm DNA Damage in IVF–ICSI Treatments Is Not Related to Pregnancy Complications and Adverse Neonatal Outcomes. Journal of Clinical Medicine 2023; 12: 6802. Table Table 1: Author surname Publish date Procedure Control Group Count IVF/ICSI Group Count Cerebral palsy count in control Cerebral palsy count in IVF/ICSI Group Count Norrman (8) 2020 IVF/ ICSI 2022095 18666 812 17 Levin (9) 2019 IVF 242187 2603 201 2 Davies (10) 2012 IVF/ ICSI 308974 6163 579 33 Zhu (11) 2010 IVF/ICSI 90203 3617 165 17 Hvidtjørn (12) 2010 IVF 588967 33139 1146 63 Pinborg (13) 2010 IVF/ ICSI 4800 10329 8 42 Källen (14) 2010 IVF 2623517 31587 6225 138 Carlsen (15) 2023 IVF/ ICSI 808444 23548 1556 97 Hvidtjørn (16) 2006 IVF 394713 9255 1048 40 Hvidtjørn (17) 2005 IVF 395025 9444 1016 41 Lidegaard (18) 2005 IVF 448401 6052 839 20 Goldsmith (19) 2017 IVF/ICSI 208746 2914 514 21 Pinborg (20) 2004 IVF/ ICSI 18762 8523 65 24 Strömberg (21) 2002 IVF 11360 5680 17 31 Farhangniya (22) 2013 IVF 623 299 1 0 D'Souza (23) 1997 IVF 278 278 0 2 Middelburg (24) 2011 IVF 77 54 0 1 Ramoğlu (25) 2016 IVF 65 60 0 1 Kuiper (26) 2018 IVF 56 43 0 1 Klemetti (27) 2010 IVF 190368 4559 267 17 Ginström (28) 2023 IVF 42424 61060 59 128 Additional Declarations The authors declare no competing interests. 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field of reproductive medicine, enabling millions of individuals and couples to overcome infertility and start families (1,2). While IVF and ICSI significantly increase pregnancy success, they also raise important ethical and medical issues, particularly regarding the potential for congenital anomalies in children born via IVF/ICSI (3\u0026ndash;5).\u003c/p\u003e \u003cp\u003eCongenital anomalies, also known as birth defects, are structural or functional abnormalities that are present at birth. They can range from minor cosmetic issues to serious or life-threatening conditions that require significant medical attention (3\u0026ndash;5). The causes of congenital anomalies are complex and multifactorial, including genetic, environmental, and random factors. Over the years, extensive research has been conducted to understand the relationship between in vitro fertilization and congenital anomalies (3\u0026ndash;5). Several studies suggest that the prevalence of certain congenital anomalies is higher in children born via IVF/ICSI compared to children born naturally (3\u0026ndash;5).\u003c/p\u003e \u003cp\u003eHowever, this situation has not been comprehensively investigated specifically in orthopedic problems or cerebral palsy, which are the most common congenital or prematurity-related problems. In this study, we comprehensively discussed the relationship between cerebral palsy and ICSI/IVF.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Designing\u003c/h2\u003e \u003cp\u003eThis study was designed as a meta-analysis, spanning 44 years of literature from 1980 to 2024. The primary endpoint of this study was to determine the difference in the incidence of cerebral palsy between natural conception and IVF/ICSI.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Search Strategy and Study Criteria\u003c/h2\u003e \u003cp\u003eThe search methodology involved querying the PUBMED and Scopus databases using two distinct search strategies: (1) (IVF) AND (Cerebral Palsy) and (2) (ICSI) AND (Cerebral Palsy).\u003c/p\u003e \u003cp\u003eStudies meeting the following inclusion criteria were considered: (1) inclusion of either IVF or ICSI groups, (2) presence of a control group for comparison, (3) provision of the total number (n) of \"AT LEAST ONE\" of the cp case in both the IVF/ICSI groups and the control group, (4) publication in English, and (5) inclusion of at least 10 patients in each group.\u003c/p\u003e \u003cp\u003eExclusion criteria encompassed reviews, meta-analyses, case series, and case reports, with a focus solely on original research articles that met the criteria for comprehensive analysis.\u003c/p\u003e \u003cp\u003e During this selection process we followed PRISMA guideline(6).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data Extraction\u003c/h2\u003e \u003cp\u003eRelevant data, including bibliographic details such as publication year and author surname, were extracted from each publication selected based on detailed criteria. Additionally, information regarding the total cohort size and the number of patients affected by cerebral palsy was meticulously documented.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Endpoint definition\u003c/h2\u003e \u003cp\u003eData analysis was structured into two principal stages. In the pre-processing phase, meticulous examination of the data was conducted to ascertain the patient count within both the control and assisted reproductive technology (ART) groups. Following this, the occurrence of cerebral palsy within each group was meticulously documented. The primary emphasis during analysis was placed on calculating the percentage of patients afflicted with cerebral palsy within the respective groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Data Synthesis\u003c/h2\u003e \u003cp\u003eThe synthesis of data was meticulously carried out by two seasoned academics proficient in statistics and epidemiology. Given the extensive number of patients expected to be included and the likelihood of encountering low study quality and missing patient data, the anticipated heterogeneity of results was carefully considered. However, despite these challenges, the results were presented per study alongside their corresponding 95% confidence intervals (95% CIs) to effectively illustrate the incidence of cerebral palsy in assisted reproductive technologies (ARTs). Each study was meticulously weighted based on sample size and data distribution, ensuring an accurate representation of the rates observed. These aggregated rates were subsequently combined and consistently reported. To evaluate the degree of heterogeneity among the studies, the I2 statistic was employed, with values exceeding 50% and their corresponding P-values indicating significant heterogeneity. The synthesis process utilized Jamovi, a freely available software program, to ensure robust analysis and interpretation of the data(7).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA thorough search utilizing pertinent keywords yielded a total of 192 articles from the designated database systems. Following the removal of duplicates and screening for relevance based on titles, the analysis narrowed down to 76 abstracts, resulting in the exclusion of 50 articles. The final filtration process, conducted in accordance with the PRISMA model, ultimately included 21 articles for detailed analysis(8-28). These selected articles collectively encompassed data from 8,657,973 patients. For a comprehensive overview of the study selection process, please refer to Figure 1 and Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Comparison between ARTs and Control\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter conducting a comprehensive analysis of the dataset, it was observed that among 8,400,080 control patients, 14,518 cases of cerebral palsy were identified. In contrast, among 237,873 patients who underwent either in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), 736 cases of cerebral palsy were documented. Upon meticulous data synthesis, it became evident that the incidence of cerebral palsy was approximately 1.9 times higher in IVF and ICSI cases compared to other control groups. (p\u0026lt;0.001,95% confidence interval: 1.570-2.323) (figure 2 and figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Heterogeneity of the literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing heterogeneity analysis, the I2 statistic was calculated to be 73.5%, which indicates a moderate to high level of heterogeneity among the studies included in the analysis. This suggests that there is a considerable amount of variability in the study results beyond what would be expected by chance alone. The p-value associated with this finding is less than 0.001, indicating that the observed heterogeneity is statistically significant. Additionally, the tau2 value, a measure of between-study variance, was calculated to be 0.1125. This further supports the presence of heterogeneity among the studies, as a tau2 value greater than zero suggests that the true effect size may vary across studies.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs infertility rates and maternal ages continue to rise, the utilization of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) is steadily increasing (2). These assisted reproductive technologies (ART) have a well-established track record of success in helping couples conceive. (1-2) However, the topic of concern regarding the prevalence of congenital anomalies in pregnancies resulting from IVF and ICSI has been a topic of ongoing debate within the medical community (1-5). Potential hypotheses behind this phenomenon include factors such as maternal age at the time of IVF/ICSI, multiparity, and innate susceptibility to natural congenital pathologies (29-30). Some causes of female infertility can predispose embryos to malformations and increase the risk of prematurity (30-31). Moreover, the risk of prematurity is heightened by multiparity, which is more prevalent in IVF/ICSI cases (28-31). There are also more speculative theories, such as the potential for DNA damage during in vitro fertilization or intracytoplasmic injection (32). While meta-analyses have investigated the association between IVF/ICSI and pediatric problems such as chromosomal anomalies and congenital heart diseases, a comprehensive perspective on congenital orthopedic problems and musculoskeletal diseases has not yet been presented(3,5). Our study represents the most thorough examination of this topic to date.\u003c/p\u003e\n\u003cp\u003eIn the study, we meticulously searched two vital databases and sifted through over 100,000 studies on ICSI and IVF. Surprisingly, only 192 studies addressed cerebral palsy. However, after removing duplicates and applying stringent selection criteria, only 21 publications were deemed suitable for inclusion in our analysis (8-28). This limited literature pool is characterized by moderate to high levels of heterogeneity. Notably, studies like those by Norman et al and Kallen et al, involving more than 2 million individuals, as well as studies such as Kuiper et al and Ramoglu et al, which include only a few hundred individuals, exemplify this qualitative heterogeneity. This disparity underscores the untouched nature of this area, emphasizing the necessity for further evidence and the establishment of a consensus within the field.\u003c/p\u003e\n\u003cp\u003eThe most striking revelation of this study is that the likelihood of cerebral palsy after IVF/ICSI is 1.9 times higher than after natural conception. This finding underscores the comparable risk of cerebral palsy associated with IVF/ICSI to that of congenital heart diseases or chromosomal anomalies. It is imperative to investigate whether this observed relationship extends to other musculoskeletal and orthopedic problems as well.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe findings of this study shed light on the possible association between IVF/ICSI and an increased risk of cerebral palsy. Although the literature pool is limited, the significant increase in the likelihood of cerebral palsy after IVF/ICSI compared to natural conception warrants further exploration. Future studies should aim to elucidate the underlying mechanisms and explore potential interventions to mitigate this risk. It is also essential to investigate whether this observed relationship extends to other musculoskeletal and orthopedic problems, as this can inform clinical decision-making and patient counseling.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMantikou E, Youssef MA, van Wely M, van der Veen F, Al-Inany HG, Repping S, Mastenbroek S. Embryo culture media and IVF/ICSI success rates: a systematic review. Hum Reprod Update. 2013 May-Jun;19(3):210-20. doi: 10.1093/humupd/dms061. Epub 2013 Feb 5. PMID: 23385469.\u003c/li\u003e\n\u003cli\u003ePalermo GD, Neri QV, Takeuchi T, Rosenwaks Z. ICSI: where we have been and where we are going. Semin Reprod Med. 2009 Mar;27(2):191-201. doi: 10.1055/s-0029-1202309. Epub 2009 Feb 26. PMID: 19247922.\u003c/li\u003e\n\u003cli\u003eGiorgione V, Parazzini F, Fesslova V, Cipriani S, Candiani M, Inversetti A, Sigismondi C, Tiberio F, Cavoretto P. Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2018 Jan;51(1):33-42. doi: 10.1002/uog.18932. PMID: 29164811.\u003c/li\u003e\n\u003cli\u003eTandulwadkar S, Lodha P, Kharb V. Congenital malformations and assisted reproductive technique: Where is assisted reproductive technique taking us? J Hum Reprod Sci. 2012 Sep;5(3):244-7. doi: 10.4103/0974-1208.106334. PMID: 23533070; PMCID: PMC3604829.\u003c/li\u003e\n\u003cli\u003eBerntsen S, Laivuori H, la Cour Freiesleben N, Loft A, S\u0026ouml;derstr\u0026ouml;m-Anttila V, B Oldereid N, Romundstad LB, Magnusson \u0026Aring;, Petzold M, Bergh C, Pinborg A. A systematic review and meta-analysis on the association between ICSI and chromosome abnormalities. Hum Reprod Update. 2021 Aug 20;27(5):801-847. doi: 10.1093/humupd/dmab005. PMID: 33956940.\u003c/li\u003e\n\u003cli\u003eBMJ (OPEN ACCESS) Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71\u003c/li\u003e\n\u003cli\u003eThe jamovi project (2023). jamovi (Version 2.3) [Computer Software]. Retrieved from https://www.jamovi.org\u003c/li\u003e\n\u003cli\u003eNorrman E, Petzold M, Bergh C, et al. School performance in children born after ICSI. Human Reproduction 2020; 35: 340\u0026ndash;354.\u003c/li\u003e\n\u003cli\u003eLevin, Shai, et al. \u0026ldquo;Infertility Treatments and Long-Term Neurologic Morbidity of the Offspring.\u0026rdquo; American Journal of Perinatology, vol. 36, no. 09, 16 Nov. 2018, pp. 949\u0026ndash;954, https://doi.org/10.1055/s-0038-1675159. Accessed 9 Jan. 2022.\u003c/li\u003e\n\u003cli\u003eDavies, Michael J., et al. \u0026ldquo;Reproductive Technologies and the Risk of Birth Defects.\u0026rdquo; New England Journal of Medicine, vol. 366, no. 19, 10 May 2012, pp. 1803\u0026ndash;1813, https://doi.org/10.1056/nejmoa1008095.\u003c/li\u003e\n\u003cli\u003eZhu, J. L., et al. \u0026ldquo;Parental Infertility and Cerebral Palsy in Children.\u0026rdquo; Human Reproduction, vol. 25, no. 12, 2 Nov. 2010, pp. 3142\u0026ndash;3145, www.ncbi.nlm.nih.gov/pmc/articles/PMC2989872/#:~:text=BACKGROUND, https://doi.org/10.1093/humrep/deq206. Accessed 27 Apr. 2022.\u003c/li\u003e\n\u003cli\u003eDorte Hvidtj\u0026oslash;rn, et al. \u0026ldquo;Multiplicity and Early Gestational Age Contribute to an Increased Risk of Cerebral Palsy from Assisted Conception: A Population-Based Cohort Study.\u0026rdquo; Human Reproduction, vol. 25, no. 8, 16 June 2010, pp. 2115\u0026ndash;2123, https://doi.org/10.1093/humrep/deq070. Accessed 31 Dec. 2023.\u003c/li\u003e\n\u003cli\u003ePinborg, Anja, et al. \u0026ldquo;Infant Outcome of 957 Singletons Born after Frozen Embryo Replacement: The Danish National Cohort Study 1995-2006.\u0026rdquo; Fertility and Sterility, vol. 94, no. 4, 1 Sept. 2010, pp. 1320\u0026ndash;1327, www.ncbi.nlm.nih.gov/pubmed/19647236, https://doi.org/10.1016/j.fertnstert.2009.05.091.\u003c/li\u003e\n\u003cli\u003eK\u0026auml;ll\u0026eacute;n AJB, Finnstr\u0026ouml;m OO, Lindam AP, et al. Cerebral palsy in children born after in vitro fertilization. Is the risk decreasing? European Journal of Paediatric Neurology 2010; 14: 526\u0026ndash;530.\u003c/li\u003e\n\u003cli\u003eCarlsen H, Vik T, Andersen GL, et al. Cerebral palsy in children born after assisted reproductive technology in Norway: Risk, prevalence, and clinical characteristics. Acta Obstetricia et Gynecologica Scandinavica 2023; 102: 1450\u0026ndash;1458.\u003c/li\u003e\n\u003cli\u003eDorte Hvidtj\u0026oslash;rn, et al. \u0026ldquo;\u0026ldquo;Vanishing Embryo Syndrome\u0026rdquo; in IVF/ICSI.\u0026rdquo; Human Reproduction, vol. 20, no. 9, 12 May 2005, pp. 2550\u0026ndash;2551, https://doi.org/10.1093/humrep/dei092. Accessed 13 Feb. 2024.\u003c/li\u003e\n\u003cli\u003eHvidtj\u0026oslash;rn D, Grove J, Schendel DE, et al. Cerebral Palsy Among Children Born After In vitro Fertilization: The Role of Preterm Delivery\u0026mdash;A Population-Based, Cohort Study. Pediatrics 2006; 118: 475\u0026ndash;482.\u003c/li\u003e\n\u003cli\u003eLidegaard, \u0026Oslash;jvind, et al. \u0026ldquo;Imprinting Diseases and IVF: Danish National IVF Cohort Study.\u0026rdquo; Human Reproduction, vol. 20, no. 4, 1 Apr. 2005, pp. 950\u0026ndash;954, https://doi.org/10.1093/humrep/deh714.\u003c/li\u003e\n\u003cli\u003eGoldsmith S, Mcintyre S, Badawi N, et al. Cerebral palsy after assisted reproductive technology: a cohort study. Developmental Medicine \u0026amp; Child Neurology 2017; 60: 73\u0026ndash;80.\u003c/li\u003e\n\u003cli\u003eNeurological Sequelae in Twins Born after Assisted Conception: Controlled National Cohort Study.\u0026rdquo; BMJ, vol. 329, no. 7461, 15 July 2004, p. 311, https://doi.org/10.1136/bmj.38156.715694.3a. Accessed 25 Aug. 2021.\u003c/li\u003e\n\u003cli\u003eStr\u0026ouml;mberg B, Dahlquist G, Ericson A, et al. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. The Lancet 2002; 359: 461\u0026ndash;465.\u003c/li\u003e\n\u003cli\u003eMansoureh Farhangniya, et al. \u0026ldquo;Comparison of Congenital Abnormalities of Infants Conceived by Assisted Reproductive Techniques versus Infants with Natural Conception in Tehran.\u0026rdquo; DOAJ (DOAJ: Directory of Open Access Journals), no. 20080778, 1 Oct. 2013. Accessed 13 Feb. 2024.\u003c/li\u003e\n\u003cli\u003eD\u0026rsquo;Souza, S. W., et al. \u0026ldquo;Children Conceived by in Vitro Fertilisation after Fresh Embryo Transfer.\u0026rdquo; Archives of Disease in Childhood - Fetal and Neonatal Edition, vol. 76, no. 2, 1 Mar. 1997, pp. F70\u0026ndash;F74, fn.bmj.com/content/76/2/F70, https://doi.org/10.1136/fn.76.2.F70. 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Accessed 22 Mar. 2021. \u003c/li\u003e\n\u003cli\u003eKuiper, Derk, et al. \u0026ldquo;Developmental Outcome of 9-Year-Old Children Born after PGS: Follow-up of a Randomized Trial.\u0026rdquo; Human Reproduction, vol. 33, no. 1, 1 Jan. 2018, pp. 147\u0026ndash;155, https://doi.org/10.1093/humrep/dex337. Accessed 22 May 2023.\u003c/li\u003e\n\u003cli\u003eKlemetti, Reija, et al. \u0026ldquo;Health of Children Born after Ovulation Induction.\u0026rdquo; Fertility and Sterility, vol. 93, no. 4, Mar. 2010, pp. 1157\u0026ndash;1168, https://doi.org/10.1016/j.fertnstert.2008.12.025. Accessed 25 Feb. 2020.\u003c/li\u003e\n\u003cli\u003eGinstr\u0026ouml;m Ernstad, Erica, et al. \u0026ldquo;Preimplantation Genetic Testing and Child Health: A National Register-Based Study.\u0026rdquo; Human Reproduction (Oxford, England), vol. 38, no. 4, 3 Apr. 2023, pp. 739\u0026ndash;750, pubmed.ncbi.nlm.nih.gov/36749096/, https://doi.org/10.1093/humrep/dead021. Accessed 26 Aug. 2023.\u003c/li\u003e\n\u003cli\u003eZhu JL, Basso O, Obel C, et al. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ 2006; 333: 679.\u003c/li\u003e\n\u003cli\u003eSanders JN, Simonsen SE, Porucznik CA, et al. Fertility treatments and the risk of preterm birth among women with subfertility: a linked-data retrospective cohort study. Reproductive Health; 19. Epub ahead of print March 29, 2022. DOI: 10.1186/s12978-022-01363-4.\u003c/li\u003e\n\u003cli\u003eLuke B, Brown MB, Wantman E, et al. Risk of prematurity and infant morbidity and mortality by maternal fertility status and plurality. Journal of Assisted Reproduction and Genetics 2018; 36: 121\u0026ndash;138.\u003c/li\u003e\n\u003cli\u003eHerv\u0026aacute;s I, Rivera-Egea R, Pacheco A, et al. Elevated Sperm DNA Damage in IVF\u0026ndash;ICSI Treatments Is Not Related to Pregnancy Complications and Adverse Neonatal Outcomes. Journal of Clinical Medicine 2023; 12: 6802.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"688\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eAuthor surname\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003ePublish date\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eProcedure\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eControl Group Count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF/ICSI Group Count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eCerebral palsy count in control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eCerebral palsy count in IVF/ICSI Group Count\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eNorrman (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF/ ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2022095\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e18666\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e812\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eLevin (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e242187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2603\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e201\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eDavies (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF/ ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e308974\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e6163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e579\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eZhu (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF/ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e90203\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e3617\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e165\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eHvidtj\u0026oslash;rn (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e588967\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e33139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e1146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003ePinborg (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF/ ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e4800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e10329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eK\u0026auml;llen (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2623517\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e31587\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e6225\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e138\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eCarlsen (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF/ ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e808444\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e23548\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e1556\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eHvidtj\u0026oslash;rn (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e394713\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e9255\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e1048\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eHvidtj\u0026oslash;rn (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e395025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e9444\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e1016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eLidegaard (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e448401\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e6052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e839\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eGoldsmith (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF/ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e208746\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2914\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e514\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003ePinborg (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF/ ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e18762\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e8523\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eStr\u0026ouml;mberg (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e2002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e11360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e5680\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eFarhangniya (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e623\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eD\u0026apos;Souza (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e1997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e278\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e278\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eMiddelburg (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eRamoğlu (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eKuiper (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eKlemetti (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e190368\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e4559\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e267\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cu\u003eGinstr\u0026ouml;m\u0026nbsp;\u003c/u\u003e(28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e42424\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e61060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"bottom\"\u003e\n \u003cp\u003e128\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Istanbul University Cerrahpaşa","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":"Cerebral Palsy, IVF, ICSI, Orthopedic surgery","lastPublishedDoi":"10.21203/rs.3.rs-4000589/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4000589/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eThe correlation between assisted reproductive therapies (ARTs) and congenital or developmental anomalies has been acknowledged by prominent obstetric and reproductive science authorities. However, the orthopedic perspective on this aspect of ARTs remains largely unexplored. This meta-analysis aims to examine a plausible association between cerebral palsy and in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) therapies within the realm of assisted reproductive technologies (ARTs).\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003e The literature spanning from 1980 to February 2024 was systematically reviewed within the MEDLINE, Scopus, and Embase databases, adhering to the PRISMA guidelines. Data synthesis was conducted using the Jamovi program.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eThe literature review involved an initial search that yielded 192 articles, which were subsequently refined to 21 articles following the removal of duplicates and screening for relevance. These articles, selected according to the PRISMA model, collectively included data from 8,657,973 patients. Upon analyzing the dataset, it was found that among 8,400,080 control patients, there were 14,518 cases of cerebral palsy, while among 237,873 patients who underwent IVF or ICSI, 736 cases of cerebral palsy were documented. This analysis revealed that the incidence of cerebral palsy was approximately 1.9 times higher in IVF and ICSI cases compared to control groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, adjusted odds ratio\u0026thinsp;=\u0026thinsp;1.9, 95% confidence interval: 1.570\u0026ndash;2.323).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAs a result, the risk of developing cerebral palsy, as in many other congenital anomalies and pediatric diseases, in babies born with assisted reproductive techniques is statistically significantly higher than in normal babies. This, together with the sensitive monitoring of the neonatal period and perinatal period in women conceived with ART. It is recommended that teams collaborate with pediatric orthopedic surgeons.\u003c/p\u003e","manuscriptTitle":"Increased Risk of Cerebral Palsy in IVF/ICSI Babies: Meta analysis of Current Literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-05 16:20:54","doi":"10.21203/rs.3.rs-4000589/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":"23d36c53-2cc4-480b-9bdf-13e79cdd9fce","owner":[],"postedDate":"March 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":29060204,"name":"Orthopedic Surgery"},{"id":29060205,"name":"Orthopedics"},{"id":29060206,"name":"Obstetrics \u0026 Gynecology"}],"tags":[],"updatedAt":"2024-03-05T16:20:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-05 16:20:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4000589","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4000589","identity":"rs-4000589","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}