The safety of time-lapse incubation system for embryo culture in assisted reproductive laboratory: A systematic review and meta-analysis

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But only few randomized controlled trials (RCT) have been published that evaluated the safety of TLI, especially the neonatal outcomes. We conducted a systematic review and meta-analyses to evaluate the neonatal outcomes between TLI and standard incubators (SI). Methods: A literature search up to October 2021 was carried out to search for clinical trials from electronic databases comparing TLI versus SI on neonatal outcomes. The summary measures were reported as odds ratio (OR) with 95% confidence-interval (CI). Results: A total of 5905 live-born infants were included from fresh embryos transfer cycles. Only singleton pregnancies were analyzed, no statistical differences were found with respect to gestational weeks at delivery (Mean difference=0.09; 95%CI, -0.18 to 0.35; I 2 =33%; P =0.52), preterm births (<37weeks) (OR=0.98; 95%CI 0.78 to 1.24; I 2 =0%; P =0.86), and early preterm birth (<32 weeks) (OR=0.41; 95%CI, 0.11 to 1.50; I 2 =50%; P =0.18). Besides, no statistical significances were also observed in TLI group on birth weight (Mean difference=71.61; 95%CI, -30.55 to 173.77; I 2 =62%; P =0.17), low birth weight rate (<2,500g) (OR=0.85; 95%CI, 0.64 to 1.13; I 2 =0%; P =0.26), very low birth weight rate (<1,500g) (OR=0.58; 95%CI, 0.17 to 1.96; I 2 =50%; P =0.38), and macrosomia rate (≥4,000g) (OR=1.11; 95%CI, 0.84 to 1.47; I 2 =0%; P =0.48). Moreover, incidences of malformations of babies delivered from TLI and SI groups were also similar (OR=1.19; 95%CI, 0.66 to 2.14; I 2 =0%; P =0.56). And finally, sex ratio analysis still showed no differences between the two groups (OR=2.16; 95%CI, 0.53 to 8.81; I 2 =96%; P =0.28). Conclusions: The strategy of culturing embryo in time-lapse incubation systems would not increase adverse risks of neonatal outcomes comparing to SI. Trial registration: PROSPERO (2018: CRD42020186807) neonatal outcomes singleton pregnancy systematic review and meta-analysis standard incubator time-lapse incubation systems Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction In recent years, the methods of non-invasive embryo evaluation and selection have been greatly developed. One of these methods coming into the limelight is the time-lapse incubation systems [ 1 – 3 ]. It has been widely used in clinical practice for the continuous monitoring of human embryos and provided more information on embryo morphokinetics compared to standard culture incubators [ 4 , 5 ]. Time-lapse incubation systems offer at least two advantages over conventional culture methods: (a) it does not need to be taken out from the incubator for observation, therefore, perturbations to embryo culture environment were minimized [ 6 , 7 ]. (b) it allows development of algorithms based on the extensive morphokinetic markers which may facilitate selection of viable embryos for transfer [ 8 – 10 ]. Currently, it remains a controversial subject whether TLI is superior to conventional methods for human embryo incubation and clinical outcomes. However, several studies showed that such morphokinetic enhanced embryos selection method and “undisturbed” culture may help to identify embryos with high implantation potential to increase clinical outcome [ 11 – 14 ]. However, concerns have been raised regarding the safety of the time-lapse incubator, considering the more frequent exposure to light during the image acquisition. It has been reported that considerable light exposure may be detrimental to embryo development [ 15 ]. Furthermore, risk to embryo development may be raised by the presence of magnetic fields, the warmth created by moving parts, and the presence of lubricants inside the instrument near the culture dish [ 16 ]. Although several studies have provided reassurance that TLI does not have a detrimental effect on embryo development, implantation potential, and clinical pregnancy rates, there is still insufficient evidence regarding the impact of TLI on obstetric and perinatal outcomes [ 17 , 18 ]. Hence, for the purpose of evaluating the safety of TLI technique, we performed this meta-analysis to compare the neonatal outcomes of pregnancies resulting from embryos conceived in TLI and standard incubators. To our knowledge, this is the first systematic review and meta-analysis on this topic. Methods We registered this review in the international prospective register of systematic reviews (PROSPERO, registration number CRD42020186807). Data sources and search strategy Three reviewers independently identified the relevant articles by searching the PubMed, EMBASE, Cochrane library, ClinicalTrial.gov and BioMed Central databases up to October 2021. The following search terms and keywords were used: (“time-lapse” OR “time lapse” OR EmbryoScope OR “EEVA” OR “Primo Vision” OR “live cell imaging”) AND (“perinatal outcome” or “neonatal outcome”). No publication date, study design, or publication status restrictions were imposed. Eligibility criteria and study selection Three reviewers independently screened trial eligibility on the basis of titles, abstracts, and full-text publications. Potential articles had to satisfy the following eligibility criteria: (i) comparative studies including randomized and non-randomized controlled trials (NCTs), observational cohort studies and case-control studies; (ii) human studies; (iii) availability of obstetric and perinatal outcome data. Discrepancies were solved by group discussion. We contacted the original authors by e-mail when necessary. Data extraction and quality assessment Three reviewing authors independently extracted quantitative and qualitative data by using a standard data extraction form. For RCTs, the same investigators independently and systematically assessed the studies’ methodological quality using the Cochrane tool for risk of bias assessment [19]. For NCTs and observational studies, the Newcastle-Ottawa Scale (NOS) tool was used to evaluate items considered relevant to this review topic [20]. Any disagreement was resolved through discussion. Funnel plots were used to screen for potential publication bias. Data synthesis and data analysis Outcome measures The neonatal outcomes included gestational weeks at delivery, birth weight (BW), sex ratio, and the risk of preterm births (PTB, <37weeks), early preterm births (early PTB, <32weeks), low birth weight (LBW, <2,500g), very low birth weight (VLBW, <1,500g), macrosomia (≥4,000g), and congenital malformations. Statistical analysis For dichotomous outcomes, the odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the overall effects. All meta-analysis were conducted with Review Manager Version 5.3 (Cochrane Collaboration, Software Update, Oxford, United Kingdom, 2014) in a random-effect model or the fixed-effect model. Statistical heterogeneity among the study results was examined by the P value and I 2 statistic. Statistical significance was set at a P values40%), we applied the random-effects model. Results Search results After removal of 70 duplicates, a total of 216 citations were hit. We excluded 206 articles by reviewing titles and abstracts as they were considered non-relevant screened. We retrieved a further two articles through hand-searching. Therefore, 10 remaining studies were selected to undergo further full-text review. Among these studies, 5 were excluded for absence of quantitative data. In total, we included a total of two RCTs and three Retrospective cohort studies involving 5905 live-born infants in the quantitative synthesis. Study selection process is shown in PRISMA flow diagram ( Fig.1 ). Study characteristics and bias assessment Five studies assessing neonatal outcomes of singleton pregnancies after TLI versus SI meeting the inclusion criteria. Studies were conducted in various regions including Hungary, Spain, America, England and China. Both in vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI) cycles were performed in TLI and standard culture groups in our study. Further, both day 3 embryos and blastocysts transferred were included in our meta-analysis. The age of patients and mature oocytes might lead to bias in the results, so in one of our included studies [21], we only selected data matched the ages and oocytes of the TLI group. Among the 3 eligible retrospective cohort studies, we use NOS for quality assessment. The main trial and patient characteristics of the included studies were summarized in Table 1 . Finally, Fig.6 showed a funnel plot of four studies included in this meta-analysis that reported low birth weight. All studies lay inside the 95% CIs, with an even distribution around the vertical, indicating no obvious publication bias. Main outcomes Gestational weeks at delivery There were four studies analyzing gestational weeks at delivery in singleton pregnancies between TLI group and SI group, including 2399 live births in the TLI group, and 1845 live births in the SI group and no significant difference was observed (Mean difference=0.09; 95%CI, -0.18 to 0.35; I 2 =33%; P =0.52; n TLI =2399, n SI =1845; Fig.2A ). Preterm birth (PTB, <37 weeks) Four studies (two RCTs and two retrospective cohort studies) reported PTB, including 2399 live births in the TLI incubation group, and 1845 live births in the SI group. There were no significant differences between the two groups with the overall odds ratio (OR) for preterm birth was 0.98 (95%CI, 0.78 to 1.24; I 2 =0%; P =0.86; n TLI =2399, n SI =1845; Fig.2B ). Early preterm birth (early PTB, <32 weeks) Two RCTs and two retrospective cohort studies reported early PTB, but a RCT (Insua et al. [22]) was excluded for its early PTB was defined as before 34 gestational weeks, not fulfilled our criteria which was defined as before 32 weeks. In total, 2250 singleton live births were included in the TLI incubation group and 1723 singleton live births in the SI group. There were also no significant differences between the two groups (OR=0.41; 95%CI, 0.11 to 1.50; I 2 =50%; P =0.18; n TLI =2250, n SI =1723; Fig.2C ). Live birth weight Four studies (Bingxin et al. [21] Kovacs et al. [2]; Insua et al. [22]; Mascarenhas et al. [23]) were included for meta-analysis to investigate overall impact on the singleton live birth weight (BW), low birth weight (LBW, <2,500g), and very low birth weight (VLBW, <1,500g). Overall, our meta-analysis included 2399 live births in the TLI group, and 1845 in the SI group. The results showed no significant differences on birth weight in TLI group comparing to standard group (Mean difference=71.61; 95%CI, -30.55 to 173.77; I 2 =62%; P =0.17; n TLI =2399, n SI =1845; Fig.3A ). Low birth weight (<2,500g) Four studies reported low birth weight, including 2399 singleton live births in the TLI group, and 1845 singleton live births in the SI group. The overall OR was of 0.85 (OR=0.85; 95%CI, 0.64 to 1.13; I 2 =0%; P =0.26; Fig.3B ) when comparing LBW rate between different groups. Our result showed that TLI group would not increase risks of LBW compared with SI group in fresh ET (Embryo transfer, ET) cycles. Very low birth weight (<1,500g) 4244 babies were reported about VLBW, including 2399 in the TLI group, and 1845 in the SI group. But no significant difference was observed between the TLI group and the SI group in fresh cycles (OR=0.58; 95%CI, 0.17 to 1.96; I 2 =50%; P =0.38, n TLI =2399, n SI =1845; Fig.3C ). The results of fresh ET cycles indicated that TLI group would not increase the risk of VLBW rate. Macrosomia ( ≥4,000g ) As for macrosomia rate, only two studies involving 3913 live-born infants were included. Our meta-analysis showed that TLI group would not increase risks of macrosomia rate compared with SI group in fresh ET cycles (OR=1.11; 95%CI, 0.84 to 1.47; I 2 =0%; P =0.48, n TLI =2216, n SI =1697; Fig.4A ). Malformations With respect to the risk of congenital malformations, three studies involving 5252 live-born infants were included. We found no differences in incidence of congenital malformations between the TLI and SI groups (OR=1.19; 95%CI, 0.66 to 2.14; I 2 =0%; P =0.56; n TLI =2971, n SI =2281; Fig.4B ). Sex ratio Sex ratio analysis of newborn babies also showed that there was no difference between the two groups (OR=2.16; 95%CI, 0.53 to 8.81; I 2 =96%; P =0.28; n TLI =2024, n SI =1567; Fig.5 ). Discussion To our knowledge this is the first and only one systematic review and meta-analysis to evaluate the neonatal outcomes after incubation in TLI vs. SI, and found no increased risk of abnormal events when comparing the two types of incubation. Birth weight is associated with morbidity and mortality, therefore, it is commonly used for the assessment of neonatal outcomes [ 24 ]. In our meta-analysis, the mean birth weight of the TLI group was similar to the SI group without any significant differences (Fig. 3 A). It is determined that birth weight was related to many factors. Firstly, birth weight increases with the increasing of gestational age, with an upward trend in the late stage of pregnancy. It tends to stabilize after 40 gestational weeks [ 25 ]. We only found four studies considering birth weight, but no significant difference was observed in gestational weeks at delivery between TLI group and SI group. Secondly, birth weight has been linked to infant gender, with boys having heavier birth weights than girls at every gestational age [ 25 ]. In our study, only two studies compared the gender ratio of the infants, and no significant differences were found ( P = 0.28). Furthermore, birth weight is somewhat positively associated with maternal body mass index (BMI) [ 26 ], for the value of BMI was mainly represent maternal healthy and nutritional status. Of the four articles included in our meta-analysis, three had no statistical difference and one did not mention BMI. Since a higher birth weight was found in live-born infants with frozen ET cycles in comparison to fresh ET cycles [ 27 , 28 ], we excluded frozen embryo transfer cycles. Actually, animal studies have shown that culture media constituents are responsible for changes in birthweight of offspring [ 29 ]. In human IVF, Nelissen et al. showed that the type of embryo culture medium had a significant effect on birthweight of the baby [ 30 ]. In contrast, Vergouw et al. demonstrated that there was no significant association between the type of embryo culture medium and birthweight adjusted for gestational age, gender and parity of singletons born after a fresh or frozen-thawed SET [ 31 ]. But in our four studies about birthweight included in meta-analysis, all embryos were cultured in sequential culture medium. Low birth weight had been associated with neonatal morbidity, mortality and long term health outcomes [ 32 , 33 ]. With regard to VLBW, it likely related to disease and treatment contributing to postnatal growth failure [ 34 ]. However, no clinically relevant neonatal risks were found in our analysis concerning LBW rate and VLBW rate ( P > 0.05). Infants born preterm are recognized to be at increased risk of many adverse health outcomes, leading to perinatal mortality and a considerable burden of complications [ 35 ]. While comparing preterm birth and early preterm birth rate, we did not find any significant differences between TLI and SI group, which indicated that culturing embryo in TLI would not increase risks of PTB and early PTB. Maybe, it was showed that blastocyst stage transfer was associated with an increased risk of preterm birth [ 36 ]. However, four studies in our analysis all transferred cleavage embryos and blastocysts. When comparing the rate of congenital malformations, our study showed that TLI group would not increase risk of malformations. One of our included studies didn't make it clear whether birth defect rates were divided into singletons or twin pregnancies. As is well known, twins or multiple pregnancies in comparison to singletons, show a higher risk to have chromosomal disorders, prenatal death, prematurity, perinatal mortality, morbidity or other congenital malformations [ 37 – 39 ]. Moreover, the smaller twin significantly increase risks for malformations like patent ductus arteriosus, retinopathy of prematurity, and neurodevelopmental impairment [ 40 ]. Therefore, stable culture and the selection of single viable embryo for transfer by TLI technology are crucial in reducing multiple pregnancies [ 41 ]. What’s more, only one trial with data on neonatal height, pregnancy-induced hypertension and Apgar score outcomes of pregnancies conceived with embryos cultured in a time-lapse monitoring system has been published (Insua et al. [ 22 ]), no significant differences were found between the two groups. Our review included significant sample sizes, 3346 singleton live births by TLI and 2559 by SI group. Therefore, this relatively large sample size will significantly increase the validity of our findings. Besides, to avoid bias and accurately examine the impact of TLI on neonatal outcomes, we only focused on newborns delivered from singleton pregnancies to reduce skewing of the data due to vanishing twins. Moreover, we also excluded frozen ET cycles in terms of BW, LBW, VLBW and macrosomia in our study. Our study had some limitations. First, only five studies, two RCTs and three retrospective cohort studies, were included. Although several studies adjusted for confounding factors (including age and stage of the embryos transferred), other unknown confounding factors could be influencing the outcomes during this meta-analysis. What’s more, Only ICSI patients (Insua et al. [ 22 ]) or only IVF patients (Zaninovic et al. [ 42 ]) were included, which may limit the generality of the results. In addition, some retrospective data were partially obtained through medical questionnaires or contacted patients again to clarify any inaccuracies whenever necessary. Furthermore, the baseline characteristics of singleton pregnancies in some retrospective data were not described separately, and vanishing twin pregnancies could have also influenced the results. Last but not the least, we should emphasize that studies included in our meta-analysis were all using the EmbryoScope systems. Therefore, our results could not generalize to the other different time-lapse incubation systems. Different time-lapse devices may bring different clinical results. There are at least three time-lapse incubation systems available in the IVF laboratory, including Primo Vision, EmbryoScope, and Eeva [ 18 ]. Each of them was designed with different parameters. For example, different light source, different ways of embryos are brought into the field of view, and different culture environment. Conclusion To sum up, our data indicated that TLI in assisted reproductive laboratory would not increase adverse risks on neonatal outcomes. However, further RCT studies with large sample size are definitely needed to draw a conclusion. Abbreviations TLI: Time-lapse incubation systems; SI: standard incubators; OR: Odds ratio; CI: confidence-interval; RCT: Randomized controlled trial; NCT: Non-randomized controlled trial; NOS: Newcastle-Ottawa Scale; BW: birth weight; PTB: preterm births; LBW: low birth weight; VLBW: very low birth weight; IVF: in vitro fertilization; ICSI: intra cytoplasmic sperm injection; BMI: body mass index; ET: Embryo transfer. Declarations Acknowledgements The authors are grateful for the support received from the First Affiliated Hospital, Sun Yat-sen University, Guangzhou. Authors' contributions Design of the study: LYX; literature search and screening: LYX, SGH, and HGL; data extraction and risk of bias assessment: LYX, SGH and HGL; data analysis: LYX, SGH, HGL, WHH and CB; results visualization: LYX, SGH and HGL; manuscript draft and modification: LYX, SGH, HGL, WHH, CB, ZSH and XYW; funding acquirement: XYW. All authors reviewed and approved the final version of the manuscript. Funding This work was supported by National Natural Science Foundation of China (Grant no. 81771588). Availability of data and materials The datasets supporting the conclusions of this article are included within the article. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no conflict of interest. References Barrie A, Homburg R, McDowell G, Brown J, Kingsland C, Troup S. Embryos cultured in a time-lapse system result in superior treatment outcomes: a strict matched pair analysis. Hum Fertil (Camb). 2017; 20(3):179–85. Kovacs P, Matyas S, Forgacs V, Sajgo A, Molnar L, Pribenszky C. Non-invasive embryo evaluation and selection using time-lapse monitoring: Results of a randomized controlled study. Eur J Obstet Gynecol Reprod Biol. 2019; 233:58–63. Meseguer M, Rubio I, Cruz M, Basile N, Marcos J, Requena A. Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study. Fertil Steril. 2012; 98(6):1481-9.e10. Adolfsson E, Porath S, Andershed AN. External validation of a time-lapse model; a retrospective study comparing embryo evaluation using a morphokinetic model to standard morphology with live birth as endpoint. JBRA Assist Reprod. 2018; 22(3):205–14. Zaninovic N, Nohales M, Zhan Q, de Los Santos ZMJ, Sierra J, Rosenwaks Z, et al. A comparison of morphokinetic markers predicting blastocyst formation and implantation potential from two large clinical data sets. J Assist Reprod Genet. 2019; 36(4):637–46. Wale PL, Gardner DK. The effects of chemical and physical factors on mammalian embryo culture and their importance for the practice of assisted human reproduction. Hum Reprod Update. 2016; 22(1):2–22. Zhang JQ, Li XL, Peng Y, Guo X, Heng BC, Tong GQ. Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate. Reprod Biomed Online. 2010; 20(4):510–5. Desai N, Goldberg JM, Austin C, Falcone T. Are cleavage anomalies, multinucleation, or specific cell cycle kinetics observed with time-lapse imaging predictive of embryo developmental capacity or ploidy? Fertil Steril. 2018; 109(4):665–74. Gazzo E, Pena F, Valdez F, Chung A, Bonomini C, Ascenzo M, et al. The Kidscore(TM) D5 algorithm as an additional tool to morphological assessment and PGT-A in embryo selection: a time-lapse study. JBRA Assist Reprod. 2020; 24(1):55–60. Goodman LR, Goldberg J, Falcone T, Austin C, Desai N. Does the addition of time-lapse morphokinetics in the selection of embryos for transfer improve pregnancy rates? A randomized controlled trial. Fertil Steril. 2016; 105(2):275 – 85.e10. Kalleas D, McEvoy K, Horne G, Roberts SA, Brison DR. Live birth rate following undisturbed embryo culture at low oxygen in a time-lapse incubator compared to a high-quality benchtop incubator. Hum Fertil (Camb). 2020:1–7. Rubio I, Galan A, Larreategui Z, Ayerdi F, Bellver J, Herrero J, et al. Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope. Fertil Steril. 2014; 102(5):1287-94.e5. Wang S, Ding L, Zhao X, Zhang N, Hu Y, Sun H. Embryo Selection for Single Embryo Transfer on Day 3 Based on Combination of Cleavage Patterns and Timing Parameters in in Vitro Fertilization Patients. J Reprod Med. 2016; 61(5–6):254–62. Wu L, Han W, Wang J, Zhang X, Liu W, Xiong S, et al. Embryo culture using a time-lapse monitoring system improves live birth rates compared with a conventional culture system: a prospective cohort study. Hum Fertil (Camb). 2018; 21(4):255–62. Oh SJ, Gong SP, Lee ST, Lee EJ, Lim JM. Light intensity and wavelength during embryo manipulation are important factors for maintaining viability of preimplantation embryos in vitro. Fertil Steril. 2007; 88(4 Suppl):1150–7. Sciorio R, Thong JK, Pickering SJ. Comparison of the development of human embryos cultured in either an EmbryoScope or benchtop incubator. J Assist Reprod Genet. 2018; 35(3):515–22. Armstrong S, Bhide P, Jordan V, Pacey A, Marjoribanks J, Farquhar C. Time-lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database Syst Rev. 2019; 5(5):Cd011320. Racowsky C, Kovacs P, Martins WP. A critical appraisal of time-lapse imaging for embryo selection: where are we and where do we need to go? J Assist Reprod Genet. 2015; 32(7):1025–30. Zeng X, Zhang Y, Kwong JS, Zhang C, Li S, Sun F, et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med. 2015; 8(1):2–10. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010; 25(9):603–5. Ma BX, Zhang H, Jin L, Huang B. Neonatal Outcomes of Embryos Cultured in a Time-Lapse Incubation System: an Analysis of More Than 15,000 Fresh Transfer Cycles. Reprod Sci. 2021; Insua MF, Cobo AC, Larreategui Z, Ferrando M, Serra V, Meseguer M. Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time-lapse monitoring system. Fertil Steril. 2017; 108(3):498–504. Mascarenhas M, Fox SJ, Thompson K, Balen AH. Cumulative live birth rates and perinatal outcomes with the use of time-lapse imaging incubators for embryo culture: a retrospective cohort study of 1882 ART cycles. Bjog. 2019; 126(2):280–6. Land J. How should we report on perinatal outcome? Human reproduction (Oxford, England). 2006; 21(10):2638–9. Oken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC Pediatr. 2003; 3:6. Stamnes Koepp U, Frost Andersen L, Dahl-Joergensen K, Stigum H, Nass O, Nystad W. Maternal pre-pregnant body mass index, maternal weight change and offspring birthweight. Acta obstetricia et gynecologica Scandinavica. 2012; 91(2):243–9. Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update. 2019; 25(1):2–14. Sha T, Yin X, Cheng W, Massey IY. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis. Fertil Steril. 2018; 109(2):330 – 42.e9. Young LE, Sinclair KD, Wilmut I. Large offspring syndrome in cattle and sheep. Rev Reprod. 1998; 3(3):155–63. Nelissen EC, Van Montfoort AP, Coonen E, Derhaag JG, Geraedts JP, Smits LJ, et al. Further evidence that culture media affect perinatal outcome: findings after transfer of fresh and cryopreserved embryos. Hum Reprod. 2012; 27(7):1966–76. Vergouw CG, Kostelijk EH, Doejaaren E, Hompes PG, Lambalk CB, Schats R. The influence of the type of embryo culture medium on neonatal birthweight after single embryo transfer in IVF. Hum Reprod. 2012; 27(9):2619–26. S G, T F, E A, D H, G G, Z D, et al. Factors associated with low birthweight among newborns delivered at public health facilities of Nekemte town, West Ethiopia: a case control study. BMC pregnancy and childbirth. 2019; 19(1):220. M H, NK K, HG T. Long-term developmental outcomes of low birth weight infants. The Future of children. 1995; 5(1):176–96. A L, E T, K M, E W, Y K, M O. Growth in high risk infants < 1500 g birthweight during the first 5 weeks. Early human development. 2008; 84(10):645–50. Williams T, Drake A. Preterm birth in evolutionary context: a predictive adaptive response? Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2019; 374(1770):20180121. Kalra SK, Ratcliffe SJ, Barnhart KT, Coutifaris C. Extended embryo culture and an increased risk of preterm delivery. Obstet Gynecol. 2012; 120(1):69–75. G C, E P. The world of twins: an update. The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2010:59–62. Babatunde OA, Adebamowo SN, Ajayi IO, Adebamowo CA. Neurodevelopmental Outcomes of Twins Compared With Singleton Children: A Systematic Review. Twin Res Hum Genet. 2018; 21(2):136–45. Piro E, Schierz IAM, Serra G, Puccio G, Giuffrè M, Corsello G. Growth patterns and associated risk factors of congenital malformations in twins. Ital J Pediatr. 2020; 46(1):73. Branum A, Schoendorf K. The effect of birth weight discordance on twin neonatal mortality. Obstetrics and gynecology. 2003; 101(3):570–4. Johnston J, Gusmano MK, Patrizio P. Preterm births, multiples, and fertility treatment: recommendations for changes to policy and clinical practices. Fertil Steril. 2014; 102(1):36–9. Zaninovic N, Zhan Q, Clarke R, Ye Z, Malmsten J, Rosenwaks Z. Perinatal outcome using time-lapse system and reduced oxygen culture in IVF patients. Fertility and Sterility. 2015; 104(3) Table Table 1: Description of included studies in the meta-analysis Study and year Country Study design Period of enrollment TLI group, live births SI group, live births Type of ART Embryo stage Inclusion criteria Exclusion criteria Neontatal outcomes Quality score Kovacs et al . (2019) Hungary RCT Oct 2012 to Apr 2015 Fresh: 34 Fresh: 26 IVF/ICSI D3/Blastocyst age <36 years 1st/2nd cycle autologous oocyte use normal ovarian reserve eSET advanced stage endometriosis polycystic ovary syndrome surgical sperm extraction PGD birthweight low birthweight (<2500g) very low birthweight(<1500g) gestational age (GA) at delivery preterm delivery(<37w) very preterm delivery(<32w) RCT Insua et al . (2017) Spain RCT Oct 2012 to Apr 2014 Fresh: 216 Fresh: 162 ICSI D3/Blastocyst Age 20-38 years 1st/2nd cycle BMI 18-25kg/m 2 severe male factor hydrosalpinx acquired or congenital uterine abnormalities endocrinopathies recurrent pregnancy losses endometriosis low-responder patients Birthweight low birthweight (<2500g) very low birthweight(<1500g) gestational age (GA) at delivery preterm delivery(<37w) Malformations Neonatal height RCT Zaninovic et al . (2015) The USA Retrospective cohort study 2012 to May 2014 Fresh: 947 Fresh: 714 IVF D3 Not mentioned Frozen ET and PGD/S Malformations ***** Mascarenhas et al . (2018) The UK Retrospective cohort study Jan 2014 to Oct 2015 Fresh: 341 Frozen: 150 Fresh: 252 Frozen: 132 IVF/ICSI D3/Blastocyst Not mentioned Not mentioned Birthweight low birthweight (<2500g) very low birthweight(<1500g) gestational age (GA) at delivery preterm delivery(<37w) very preterm delivery(<32w) Macrosomia ******* Bingxin et al. (2021) China Retrospective cohort study January 2016 to December 2019 Fresh: 1875 Fresh: 1445 IVF/ICSI D3/Blastocyst SI group were selected to match the ages and oocytes of the TLI group Not mentioned Birthweight low birthweight (<2500g) very low birthweight(<1500g) gestational age (GA) at delivery preterm delivery(<37w) very preterm delivery(<32w) Macrosomia (≥4000g) Sex ratio Malformations ******* Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-1637133","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":108133248,"identity":"b3bda4e9-0b20-4045-9b18-cac7f1aa9d8c","order_by":0,"name":"Yongxiang Liu","email":"","orcid":"","institution":"the First Affiliated Hospital of Guangzhou University of Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yongxiang","middleName":"","lastName":"Liu","suffix":""},{"id":108133249,"identity":"f178eb05-53e6-4787-9ca5-cd6a6a77d828","order_by":1,"name":"Gaohui Shi","email":"","orcid":"","institution":"Kunming University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gaohui","middleName":"","lastName":"Shi","suffix":""},{"id":108133251,"identity":"4958833c-9708-45bb-beea-5f1c8d6344b3","order_by":2,"name":"Guilan Huang","email":"","orcid":"","institution":"The First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guilan","middleName":"","lastName":"Huang","suffix":""},{"id":108133255,"identity":"c8ae22f5-8dfa-4aa5-bd3d-e5bc055297e1","order_by":3,"name":"Wenhui Hou","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wenhui","middleName":"","lastName":"Hou","suffix":""},{"id":108133256,"identity":"a3d9bb50-5abd-439c-95ce-8c6fb6fa22c3","order_by":4,"name":"Bing Cai","email":"","orcid":"","institution":"The First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Cai","suffix":""},{"id":108133258,"identity":"e897452e-ac97-49a9-ae15-066fb41c5992","order_by":5,"name":"Shaohu Zhou","email":"","orcid":"","institution":"the First Affiliated Hospital of Guangzhou University of Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shaohu","middleName":"","lastName":"Zhou","suffix":""},{"id":108133264,"identity":"d6aa8352-cae2-4b24-a84a-0d4ab61688ff","order_by":6,"name":"Yanwen Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIiWNgGAWjYDADfiA+8ADG4yFGi2QDUEsCSVoMDgAJorQY3Mgx/FzYZpNnfO3wQ6AtdYnzZyQwPnjbxiBvjss9M3KMpWe2pRWb3U4zAGo5nLjhRgKz4dw2BsOdDdi18EvkGEjzbjucuO12AkjLgcQNEgls0rxtDAlgp2IBbBI5xr95t/1P3Dw7/QPMYey/8WkB2mIGtAVouHQOyBbmxIYbCWzM+LRI9jwrs+b9l5w443ZOwYEEg8PGG848bJacc07CcAMOLQbHkzff5jljl9g/O33zhw8VdbLz25MPfnhTZiOPyxYGBg4DZBMYHBsYGBuALAlc6oGA/QEK1x6P0lEwCkbBKBihAACkYF/Ar2KbQwAAAABJRU5ErkJggg==","orcid":"","institution":"The First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yanwen","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2022-05-09 07:29:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1637133/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1637133/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":22092407,"identity":"13eb0fa2-81ed-44e2-8cb2-bb7469b623c7","added_by":"auto","created_at":"2022-05-31 18:05:34","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":383690,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA flow diagram of study selection. \u003cspan class=\"ql-cursor\"\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1637133/v1/b6991ebc139356efd52bf6cd.jpg"},{"id":22092924,"identity":"1a9ef695-a8ab-4513-930e-86aba542bdd2","added_by":"auto","created_at":"2022-05-31 18:10:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":135513,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots comparing gestational weeks at delivery with TLI and SI.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e(A) Forest plot of weeks at delivery per randomized singleton pregnancy woman in the studies comparing time-lapse vs. standard incubator. (B) Forest plot of preterm birth per randomized singleton pregnancy woman in the studies comparing time-lapse vs. standard incubator. (C) Forest plot of early preterm birth per randomized singleton pregnancy woman in the studies comparing time-lapse vs. standard incubator.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-1637133/v1/fb141b1e5a204a3769fdfcc3.png"},{"id":22092409,"identity":"5d8fa999-abad-486d-bc78-235f38f0e04b","added_by":"auto","created_at":"2022-05-31 18:05:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":145265,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of mean birth weight, low birth weight, and very low birth weight comparing TLI vs. SI.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e(A) Forest plot of mean birth weight per randomized singleton pregnancy woman in the studies comparing time-lapse vs. standard incubator. (B) Forest plot of low birth weight per randomized singleton live-born infant in the studies comparing time-lapse vs. standard incubator. (C) Forest plot of very low birth weight per randomized singleton live-born infant in the studies comparing time-lapse vs. standard incubator.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-1637133/v1/1ca0a10df36c8c3e2e061313.png"},{"id":22092412,"identity":"6b7940b7-b3df-4e14-b439-482ae17e33c0","added_by":"auto","created_at":"2022-05-31 18:05:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":97365,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of macrosomia and the incidence of malformations in the studies comparing TLI vs. SI.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e(A) Forest plot of macrosomia rate per randomized singleton pregnancy woman in the studies comparing time-lapse vs. standard incubator. (B) Forest plot of incidence of congenital malformations per randomized singleton live-born infant in the studies comparing time-lapse vs. standard incubator.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-1637133/v1/c423839d0d45cc3fe8ea790c.png"},{"id":22092923,"identity":"67e64129-553a-4cff-97e4-7a17cec7a2e3","added_by":"auto","created_at":"2022-05-31 18:10:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":49711,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of sex ratio in the studies comparing TLI vs. SI.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-1637133/v1/3df9be8a7d153276eba8b1fd.png"},{"id":22092411,"identity":"8d57cc35-09b5-4714-af15-a873514a263e","added_by":"auto","created_at":"2022-05-31 18:05:34","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":47240,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plots illustrating meta-analysis of live birth weight.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eSE=standard error; OR= odds ratios\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-1637133/v1/f4977d3c42c4eb2353504eb5.png"},{"id":26158829,"identity":"9214c9a3-87ff-456d-8d71-3963875eae2a","added_by":"auto","created_at":"2022-09-07 07:30:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1664017,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1637133/v1/0e67c5c5-ff5c-4c81-85c7-7d1aa5e6d3db.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The safety of time-lapse incubation system for embryo culture in assisted reproductive laboratory: A systematic review and meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn recent years, the methods of non-invasive embryo evaluation and selection have been greatly developed. One of these methods coming into the limelight is the time-lapse incubation systems [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It has been widely used in clinical practice for the continuous monitoring of human embryos and provided more information on embryo morphokinetics compared to standard culture incubators [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTime-lapse incubation systems offer at least two advantages over conventional culture methods: (a) it does not need to be taken out from the incubator for observation, therefore, perturbations to embryo culture environment were minimized [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. (b) it allows development of algorithms based on the extensive morphokinetic markers which may facilitate selection of viable embryos for transfer [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrently, it remains a controversial subject whether TLI is superior to conventional methods for human embryo incubation and clinical outcomes. However, several studies showed that such morphokinetic enhanced embryos selection method and \u0026ldquo;undisturbed\u0026rdquo; culture may help to identify embryos with high implantation potential to increase clinical outcome [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, concerns have been raised regarding the safety of the time-lapse incubator, considering the more frequent exposure to light during the image acquisition. It has been reported that considerable light exposure may be detrimental to embryo development [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Furthermore, risk to embryo development may be raised by the presence of magnetic fields, the warmth created by moving parts, and the presence of lubricants inside the instrument near the culture dish [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough several studies have provided reassurance that TLI does not have a detrimental effect on embryo development, implantation potential, and clinical pregnancy rates, there is still insufficient evidence regarding the impact of TLI on obstetric and perinatal outcomes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHence, for the purpose of evaluating the safety of TLI technique, we performed this meta-analysis to compare the neonatal outcomes of pregnancies resulting from embryos conceived in TLI and standard incubators. To our knowledge, this is the first systematic review and meta-analysis on this topic.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe registered this review in the international prospective register of systematic reviews (PROSPERO, registration number CRD42020186807).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sources and search strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree reviewers independently identified the relevant articles by searching the PubMed, EMBASE, Cochrane library, ClinicalTrial.gov and BioMed Central databases up to October 2021. The following search terms and keywords were used: (\u0026ldquo;time-lapse\u0026rdquo; OR \u0026ldquo;time lapse\u0026rdquo; OR EmbryoScope OR \u0026ldquo;EEVA\u0026rdquo; OR \u0026ldquo;Primo Vision\u0026rdquo; OR \u0026ldquo;live cell imaging\u0026rdquo;) AND (\u0026ldquo;perinatal outcome\u0026rdquo; or \u0026ldquo;neonatal outcome\u0026rdquo;). No publication date, study design, or publication status restrictions were imposed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria and study selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree reviewers independently screened trial eligibility on the basis of titles, abstracts, and full-text publications. Potential articles had to satisfy the following eligibility criteria: (i) comparative studies including randomized and non-randomized controlled trials (NCTs), observational cohort studies and case-control studies; (ii) human studies; (iii) availability of obstetric and perinatal outcome data. Discrepancies were solved by group discussion. We contacted the original authors by e-mail when necessary.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData extraction and quality assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree reviewing authors independently extracted quantitative and qualitative data by using a standard data extraction form. For RCTs, the same investigators independently and systematically assessed the studies\u0026rsquo; methodological quality using the Cochrane tool for risk of bias assessment [19]. For NCTs and observational studies, the Newcastle-Ottawa Scale (NOS) tool was used to evaluate items considered relevant to this review topic [20]. Any disagreement was resolved through discussion. Funnel plots were used to screen for potential publication bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData synthesis and data analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe neonatal outcomes included gestational weeks at delivery, birth weight (BW), sex ratio, and the risk of preterm births (PTB, \u0026lt;37weeks), early preterm births (early PTB, \u0026lt;32weeks), low birth weight (LBW, \u0026lt;2,500g), very low birth weight (VLBW, \u0026lt;1,500g), macrosomia (\u0026ge;4,000g), and congenital malformations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor dichotomous outcomes, the odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the overall effects. All meta-analysis were conducted with Review Manager Version 5.3 (Cochrane Collaboration, Software Update, Oxford, United Kingdom, 2014) in a random-effect model or the fixed-effect model. Statistical heterogeneity among the study results was examined by the \u003cem\u003eP\u003c/em\u003e value and I\u003csup\u003e2\u003c/sup\u003e statistic. Statistical significance was set at a \u003cem\u003eP\u003c/em\u003e values\u0026lt;0.05.When the clinical and methodological heterogeneity was greater than 40% (I\u003csup\u003e2\u003c/sup\u003e\u0026gt;40%), we applied the random-effects model.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSearch results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter removal of 70 duplicates, a total of 216 citations were hit. We excluded 206 articles by reviewing titles and abstracts as they were considered non-relevant screened. We retrieved a further two articles through hand-searching. Therefore, 10 remaining studies were selected to undergo further full-text review. Among these studies, 5 were excluded for absence of quantitative data. In total, we included a total of two RCTs and three Retrospective cohort studies involving 5905 live-born infants in the quantitative synthesis. Study selection process is shown in PRISMA flow diagram (\u003cstrong\u003eFig.1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy characteristics and bias assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFive studies assessing neonatal outcomes of singleton pregnancies after TLI versus SI meeting the inclusion criteria. Studies were conducted in various regions including Hungary, Spain, America, England and China. Both in vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI) cycles were performed in TLI and standard culture groups in our study. Further, both day 3 embryos and blastocysts transferred were included in our meta-analysis. The age of patients and mature oocytes might lead to bias in the results, so in one of our included studies [21], we only selected data matched the ages and oocytes of the TLI group. Among the 3 eligible retrospective cohort studies, we use NOS for quality assessment. The main trial and patient characteristics of the included studies were summarized in \u003cstrong\u003eTable 1\u003c/strong\u003e. Finally, \u003cstrong\u003eFig.6\u003c/strong\u003e showed a funnel plot of four studies included in this meta-analysis that reported low birth weight. All studies lay inside the 95% CIs, with an even distribution around the vertical, indicating no obvious publication bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGestational weeks at delivery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were four studies analyzing gestational weeks at delivery in singleton pregnancies between TLI group and SI group, including 2399 live births in the TLI group, and 1845 live births in the SI group and no significant difference was observed (Mean difference=0.09; 95%CI, -0.18 to 0.35; I\u003csup\u003e2\u003c/sup\u003e=33%; \u003cem\u003eP\u003c/em\u003e=0.52; n\u003csub\u003eTLI\u003c/sub\u003e=2399, n\u003csub\u003eSI\u003c/sub\u003e=1845; \u003cstrong\u003eFig.2A\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreterm birth (PTB, \u0026lt;37 weeks)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour studies (two RCTs and two retrospective cohort studies) reported PTB, including 2399 live births in the TLI incubation group, and 1845 live births in the SI group. There were no significant differences between the two groups with the overall odds ratio (OR) for preterm birth was 0.98 (95%CI, 0.78 to 1.24; I\u003csup\u003e2\u003c/sup\u003e=0%; \u003cem\u003eP\u003c/em\u003e=0.86; n\u003csub\u003eTLI\u003c/sub\u003e=2399, n\u003csub\u003eSI\u003c/sub\u003e=1845; \u003cstrong\u003eFig.2B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEarly preterm birth (early PTB, \u0026lt;32 weeks)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo RCTs and two retrospective cohort studies reported early PTB, but a RCT (Insua et al. [22]) was excluded for its early PTB was defined as before 34 gestational weeks, not fulfilled our criteria which was defined as before 32 weeks. In total, 2250 singleton live births were included in the TLI incubation group and 1723 singleton live births in the SI group. There were also no significant differences between the two groups (OR=0.41; 95%CI, 0.11 to 1.50; I\u003csup\u003e2\u003c/sup\u003e=50%; \u003cem\u003eP\u003c/em\u003e=0.18;\u0026nbsp;n\u003csub\u003eTLI\u003c/sub\u003e=2250, n\u003csub\u003eSI\u003c/sub\u003e=1723; \u003cstrong\u003eFig.2C\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLive birth weight\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour studies (Bingxin et al. [21] Kovacs et al. [2]; Insua et al. [22]; Mascarenhas et al. [23]) were included for meta-analysis to investigate overall impact on the singleton live birth weight (BW), low birth weight (LBW, \u0026lt;2,500g), and very low birth weight (VLBW, \u0026lt;1,500g). Overall, our meta-analysis included 2399 live births in the TLI group, and 1845 in the SI group. The results showed no significant differences on birth weight in TLI group comparing to standard group (Mean difference=71.61; 95%CI, -30.55 to 173.77; I\u003csup\u003e2\u003c/sup\u003e=62%; \u003cem\u003eP\u003c/em\u003e=0.17; n\u003csub\u003eTLI\u003c/sub\u003e=2399, n\u003csub\u003eSI\u003c/sub\u003e=1845; \u003cstrong\u003eFig.3A\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLow birth weight (\u0026lt;2,500g)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour studies reported low birth weight, including 2399 singleton live births in the TLI group, and 1845 singleton live births in the SI group. The overall OR was of 0.85 (OR=0.85; 95%CI, 0.64 to 1.13; I\u003csup\u003e2\u003c/sup\u003e=0%; \u003cem\u003eP\u003c/em\u003e=0.26; \u003cstrong\u003eFig.3B\u003c/strong\u003e) when comparing LBW rate between different groups. Our result showed that TLI group would not increase risks of LBW compared with SI group in fresh ET (Embryo transfer, ET) cycles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVery low birth weight (\u0026lt;1,500g)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e4244 babies were reported about VLBW, including 2399 in the TLI group, and 1845 in the SI group. But no significant difference was observed between the TLI group and the SI group in fresh cycles (OR=0.58; 95%CI, 0.17 to 1.96; I\u003csup\u003e2\u003c/sup\u003e=50%; \u003cem\u003eP\u003c/em\u003e=0.38,\u0026nbsp;n\u003csub\u003eTLI\u003c/sub\u003e=2399, n\u003csub\u003eSI\u003c/sub\u003e=1845; \u003cstrong\u003eFig.3C\u003c/strong\u003e). The results of fresh ET cycles indicated that TLI group would not increase the risk of VLBW rate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMacrosomia (\u003c/strong\u003e\u0026ge;4,000g\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs for macrosomia rate, only two studies involving 3913 live-born infants were included. Our meta-analysis showed that TLI group would not increase risks of macrosomia rate compared with SI group in fresh ET cycles (OR=1.11; 95%CI, 0.84 to 1.47; I\u003csup\u003e2\u003c/sup\u003e=0%; \u003cem\u003eP\u003c/em\u003e=0.48, n\u003csub\u003eTLI\u003c/sub\u003e=2216, n\u003csub\u003eSI\u003c/sub\u003e=1697; \u003cstrong\u003eFig.4A\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMalformations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith respect to the risk of congenital malformations, three studies involving 5252 live-born infants were included. We found no differences in incidence of congenital malformations between the TLI and SI groups (OR=1.19; 95%CI, 0.66 to 2.14; I\u003csup\u003e2\u003c/sup\u003e=0%; \u003cem\u003eP\u003c/em\u003e=0.56;\u0026nbsp;n\u003csub\u003eTLI\u003c/sub\u003e=2971, n\u003csub\u003eSI\u003c/sub\u003e=2281; \u003cstrong\u003eFig.4B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSex ratio\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSex ratio analysis of newborn babies also showed that there was no difference between the two groups (OR=2.16; 95%CI, 0.53 to 8.81; I\u003csup\u003e2\u003c/sup\u003e=96%; \u003cem\u003eP\u003c/em\u003e=0.28;\u0026nbsp;n\u003csub\u003eTLI\u003c/sub\u003e=2024, n\u003csub\u003eSI\u003c/sub\u003e=1567; \u003cstrong\u003eFig.5\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge this is the first and only one systematic review and meta-analysis to evaluate the neonatal outcomes after incubation in TLI vs. SI, and found no increased risk of abnormal events when comparing the two types of incubation.\u003c/p\u003e \u003cp\u003eBirth weight is associated with morbidity and mortality, therefore, it is commonly used for the assessment of neonatal outcomes [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In our meta-analysis, the mean birth weight of the TLI group was similar to the SI group without any significant differences (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). It is determined that birth weight was related to many factors. Firstly, birth weight increases with the increasing of gestational age, with an upward trend in the late stage of pregnancy. It tends to stabilize after 40 gestational weeks [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. We only found four studies considering birth weight, but no significant difference was observed in gestational weeks at delivery between TLI group and SI group. Secondly, birth weight has been linked to infant gender, with boys having heavier birth weights than girls at every gestational age [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In our study, only two studies compared the gender ratio of the infants, and no significant differences were found (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.28). Furthermore, birth weight is somewhat positively associated with maternal body mass index (BMI) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], for the value of BMI was mainly represent maternal healthy and nutritional status. Of the four articles included in our meta-analysis, three had no statistical difference and one did not mention BMI. Since a higher birth weight was found in live-born infants with frozen ET cycles in comparison to fresh ET cycles [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], we excluded frozen embryo transfer cycles. Actually, animal studies have shown that culture media constituents are responsible for changes in birthweight of offspring [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In human IVF, Nelissen et al. showed that the type of embryo culture medium had a significant effect on birthweight of the baby [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In contrast, Vergouw et al. demonstrated that there was no significant association between the type of embryo culture medium and birthweight adjusted for gestational age, gender and parity of singletons born after a fresh or frozen-thawed SET [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. But in our four studies about birthweight included in meta-analysis, all embryos were cultured in sequential culture medium.\u003c/p\u003e \u003cp\u003eLow birth weight had been associated with neonatal morbidity, mortality and long term health outcomes [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. With regard to VLBW, it likely related to disease and treatment contributing to postnatal growth failure [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, no clinically relevant neonatal risks were found in our analysis concerning LBW rate and VLBW rate (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eInfants born preterm are recognized to be at increased risk of many adverse health outcomes, leading to perinatal mortality and a considerable burden of complications [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. While comparing preterm birth and early preterm birth rate, we did not find any significant differences between TLI and SI group, which indicated that culturing embryo in TLI would not increase risks of PTB and early PTB. Maybe, it was showed that blastocyst stage transfer was associated with an increased risk of preterm birth [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. However, four studies in our analysis all transferred cleavage embryos and blastocysts.\u003c/p\u003e \u003cp\u003eWhen comparing the rate of congenital malformations, our study showed that TLI group would not increase risk of malformations. One of our included studies didn't make it clear whether birth defect rates were divided into singletons or twin pregnancies. As is well known, twins or multiple pregnancies in comparison to singletons, show a higher risk to have chromosomal disorders, prenatal death, prematurity, perinatal mortality, morbidity or other congenital malformations [\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Moreover, the smaller twin significantly increase risks for malformations like patent ductus arteriosus, retinopathy of prematurity, and neurodevelopmental impairment [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Therefore, stable culture and the selection of single viable embryo for transfer by TLI technology are crucial in reducing multiple pregnancies [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. What\u0026rsquo;s more, only one trial with data on neonatal height, pregnancy-induced hypertension and Apgar score outcomes of pregnancies conceived with embryos cultured in a time-lapse monitoring system has been published (Insua et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]), no significant differences were found between the two groups.\u003c/p\u003e \u003cp\u003eOur review included significant sample sizes, 3346 singleton live births by TLI and 2559 by SI group. Therefore, this relatively large sample size will significantly increase the validity of our findings. Besides, to avoid bias and accurately examine the impact of TLI on neonatal outcomes, we only focused on newborns delivered from singleton pregnancies to reduce skewing of the data due to vanishing twins. Moreover, we also excluded frozen ET cycles in terms of BW, LBW, VLBW and macrosomia in our study.\u003c/p\u003e \u003cp\u003eOur study had some limitations. First, only five studies, two RCTs and three retrospective cohort studies, were included. Although several studies adjusted for confounding factors (including age and stage of the embryos transferred), other unknown confounding factors could be influencing the outcomes during this meta-analysis. What\u0026rsquo;s more, Only ICSI patients (Insua et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]) or only IVF patients (Zaninovic et al. [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]) were included, which may limit the generality of the results. In addition, some retrospective data were partially obtained through medical questionnaires or contacted patients again to clarify any inaccuracies whenever necessary. Furthermore, the baseline characteristics of singleton pregnancies in some retrospective data were not described separately, and vanishing twin pregnancies could have also influenced the results. Last but not the least, we should emphasize that studies included in our meta-analysis were all using the EmbryoScope systems. Therefore, our results could not generalize to the other different time-lapse incubation systems. Different time-lapse devices may bring different clinical results. There are at least three time-lapse incubation systems available in the IVF laboratory, including Primo Vision, EmbryoScope, and Eeva [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Each of them was designed with different parameters. For example, different light source, different ways of embryos are brought into the field of view, and different culture environment.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo sum up, our data indicated that TLI in assisted reproductive laboratory would not increase adverse risks on neonatal outcomes. However, further RCT studies with large sample size are definitely needed to draw a conclusion.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTLI: Time-lapse incubation systems; SI: standard incubators; OR: Odds ratio; CI: confidence-interval; RCT: Randomized controlled trial; NCT: Non-randomized controlled trial; NOS: Newcastle-Ottawa Scale; BW: birth weight; PTB: preterm births; LBW: low birth weight; VLBW: very low birth weight; IVF: in vitro fertilization; ICSI: intra cytoplasmic sperm injection; BMI: body mass index; ET: Embryo transfer.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful for the support received from the First Affiliated Hospital, Sun Yat-sen University, Guangzhou.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos;\u0026nbsp;contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDesign of the study: LYX; literature search and screening: LYX, SGH, and HGL; data extraction and risk of bias assessment: LYX, SGH and HGL; data analysis: LYX, SGH, HGL, WHH and CB; results visualization: LYX, SGH and HGL; manuscript draft and modification: LYX, SGH, HGL, WHH, CB, ZSH and XYW; funding acquirement: XYW. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Natural Science Foundation of China (Grant no. 81771588).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets supporting the conclusions of this article are included within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBarrie A, Homburg R, McDowell G, Brown J, Kingsland C, Troup S. Embryos cultured in a time-lapse system result in superior treatment outcomes: a strict matched pair analysis. Hum Fertil (Camb). 2017; 20(3):179\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKovacs P, Matyas S, Forgacs V, Sajgo A, Molnar L, Pribenszky C. Non-invasive embryo evaluation and selection using time-lapse monitoring: Results of a randomized controlled study. Eur J Obstet Gynecol Reprod Biol. 2019; 233:58\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeseguer M, Rubio I, Cruz M, Basile N, Marcos J, Requena A. Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study. Fertil Steril. 2012; 98(6):1481-9.e10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdolfsson E, Porath S, Andershed AN. External validation of a time-lapse model; a retrospective study comparing embryo evaluation using a morphokinetic model to standard morphology with live birth as endpoint. JBRA Assist Reprod. 2018; 22(3):205\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZaninovic N, Nohales M, Zhan Q, de Los Santos ZMJ, Sierra J, Rosenwaks Z, et al. A comparison of morphokinetic markers predicting blastocyst formation and implantation potential from two large clinical data sets. J Assist Reprod Genet. 2019; 36(4):637\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWale PL, Gardner DK. The effects of chemical and physical factors on mammalian embryo culture and their importance for the practice of assisted human reproduction. Hum Reprod Update. 2016; 22(1):2\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang JQ, Li XL, Peng Y, Guo X, Heng BC, Tong GQ. Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate. Reprod Biomed Online. 2010; 20(4):510\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesai N, Goldberg JM, Austin C, Falcone T. Are cleavage anomalies, multinucleation, or specific cell cycle kinetics observed with time-lapse imaging predictive of embryo developmental capacity or ploidy? Fertil Steril. 2018; 109(4):665\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGazzo E, Pena F, Valdez F, Chung A, Bonomini C, Ascenzo M, et al. The Kidscore(TM) D5 algorithm as an additional tool to morphological assessment and PGT-A in embryo selection: a time-lapse study. JBRA Assist Reprod. 2020; 24(1):55\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoodman LR, Goldberg J, Falcone T, Austin C, Desai N. Does the addition of time-lapse morphokinetics in the selection of embryos for transfer improve pregnancy rates? A randomized controlled trial. Fertil Steril. 2016; 105(2):275 \u0026ndash; 85.e10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKalleas D, McEvoy K, Horne G, Roberts SA, Brison DR. Live birth rate following undisturbed embryo culture at low oxygen in a time-lapse incubator compared to a high-quality benchtop incubator. Hum Fertil (Camb). 2020:1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRubio I, Galan A, Larreategui Z, Ayerdi F, Bellver J, Herrero J, et al. Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope. Fertil Steril. 2014; 102(5):1287-94.e5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang S, Ding L, Zhao X, Zhang N, Hu Y, Sun H. Embryo Selection for Single Embryo Transfer on Day 3 Based on Combination of Cleavage Patterns and Timing Parameters in in Vitro Fertilization Patients. J Reprod Med. 2016; 61(5\u0026ndash;6):254\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu L, Han W, Wang J, Zhang X, Liu W, Xiong S, et al. Embryo culture using a time-lapse monitoring system improves live birth rates compared with a conventional culture system: a prospective cohort study. Hum Fertil (Camb). 2018; 21(4):255\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOh SJ, Gong SP, Lee ST, Lee EJ, Lim JM. Light intensity and wavelength during embryo manipulation are important factors for maintaining viability of preimplantation embryos in vitro. Fertil Steril. 2007; 88(4 Suppl):1150\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSciorio R, Thong JK, Pickering SJ. Comparison of the development of human embryos cultured in either an EmbryoScope or benchtop incubator. J Assist Reprod Genet. 2018; 35(3):515\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmstrong S, Bhide P, Jordan V, Pacey A, Marjoribanks J, Farquhar C. Time-lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database Syst Rev. 2019; 5(5):Cd011320.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRacowsky C, Kovacs P, Martins WP. A critical appraisal of time-lapse imaging for embryo selection: where are we and where do we need to go? J Assist Reprod Genet. 2015; 32(7):1025\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeng X, Zhang Y, Kwong JS, Zhang C, Li S, Sun F, et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med. 2015; 8(1):2\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010; 25(9):603\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa BX, Zhang H, Jin L, Huang B. Neonatal Outcomes of Embryos Cultured in a Time-Lapse Incubation System: an Analysis of More Than 15,000 Fresh Transfer Cycles. Reprod Sci. 2021;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInsua MF, Cobo AC, Larreategui Z, Ferrando M, Serra V, Meseguer M. Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time-lapse monitoring system. Fertil Steril. 2017; 108(3):498\u0026ndash;504.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMascarenhas M, Fox SJ, Thompson K, Balen AH. Cumulative live birth rates and perinatal outcomes with the use of time-lapse imaging incubators for embryo culture: a retrospective cohort study of 1882 ART cycles. Bjog. 2019; 126(2):280\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLand J. How should we report on perinatal outcome? Human reproduction (Oxford, England). 2006; 21(10):2638\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC Pediatr. 2003; 3:6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStamnes Koepp U, Frost Andersen L, Dahl-Joergensen K, Stigum H, Nass O, Nystad W. Maternal pre-pregnant body mass index, maternal weight change and offspring birthweight. Acta obstetricia et gynecologica Scandinavica. 2012; 91(2):243\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update. 2019; 25(1):2\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSha T, Yin X, Cheng W, Massey IY. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis. Fertil Steril. 2018; 109(2):330 \u0026ndash; 42.e9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoung LE, Sinclair KD, Wilmut I. Large offspring syndrome in cattle and sheep. Rev Reprod. 1998; 3(3):155\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNelissen EC, Van Montfoort AP, Coonen E, Derhaag JG, Geraedts JP, Smits LJ, et al. Further evidence that culture media affect perinatal outcome: findings after transfer of fresh and cryopreserved embryos. Hum Reprod. 2012; 27(7):1966\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVergouw CG, Kostelijk EH, Doejaaren E, Hompes PG, Lambalk CB, Schats R. The influence of the type of embryo culture medium on neonatal birthweight after single embryo transfer in IVF. Hum Reprod. 2012; 27(9):2619\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS G, T F, E A, D H, G G, Z D, et al. Factors associated with low birthweight among newborns delivered at public health facilities of Nekemte town, West Ethiopia: a case control study. BMC pregnancy and childbirth. 2019; 19(1):220.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM H, NK K, HG T. Long-term developmental outcomes of low birth weight infants. The Future of children. 1995; 5(1):176\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA L, E T, K M, E W, Y K, M O. Growth in high risk infants \u0026lt; 1500 g birthweight during the first 5 weeks. Early human development. 2008; 84(10):645\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams T, Drake A. Preterm birth in evolutionary context: a predictive adaptive response? Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2019; 374(1770):20180121.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKalra SK, Ratcliffe SJ, Barnhart KT, Coutifaris C. Extended embryo culture and an increased risk of preterm delivery. Obstet Gynecol. 2012; 120(1):69\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG C, E P. The world of twins: an update. The journal of maternal-fetal \u0026amp; neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2010:59\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBabatunde OA, Adebamowo SN, Ajayi IO, Adebamowo CA. Neurodevelopmental Outcomes of Twins Compared With Singleton Children: A Systematic Review. Twin Res Hum Genet. 2018; 21(2):136\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePiro E, Schierz IAM, Serra G, Puccio G, Giuffr\u0026egrave; M, Corsello G. Growth patterns and associated risk factors of congenital malformations in twins. Ital J Pediatr. 2020; 46(1):73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBranum A, Schoendorf K. The effect of birth weight discordance on twin neonatal mortality. Obstetrics and gynecology. 2003; 101(3):570\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnston J, Gusmano MK, Patrizio P. Preterm births, multiples, and fertility treatment: recommendations for changes to policy and clinical practices. Fertil Steril. 2014; 102(1):36\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZaninovic N, Zhan Q, Clarke R, Ye Z, Malmsten J, Rosenwaks Z. Perinatal outcome using time-lapse system and reduced oxygen culture in IVF patients. Fertility and Sterility. 2015; 104(3)\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1: \u003c/strong\u003eDescription of included studies in the meta-analysis\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy and year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePeriod of enrollment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTLI group,\u0026nbsp;\u003c/strong\u003e \u003cstrong\u003elive births\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSI group,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003elive births\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eType of ART\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eEmbryo stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eNeontatal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eoutcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eQuality score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eKovacs \u003cem\u003eet al\u003c/em\u003e.\u003c/p\u003e\n \u003cp\u003e(2019)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHungary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOct 2012 to Apr 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh: 34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh: 26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIVF/ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD3/Blastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eage \u0026lt;36 years\u003c/p\u003e\n \u003cp\u003e1st/2nd cycle\u003c/p\u003e\n \u003cp\u003eautologous oocyte use\u003c/p\u003e\n \u003cp\u003enormal ovarian reserve\u003c/p\u003e\n \u003cp\u003eeSET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eadvanced stage endometriosis polycystic ovary syndrome\u003c/p\u003e\n \u003cp\u003esurgical sperm extraction\u003c/p\u003e\n \u003cp\u003ePGD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ebirthweight\u003c/p\u003e\n \u003cp\u003elow birthweight (\u0026lt;2500g)\u003c/p\u003e\n \u003cp\u003every low birthweight(\u0026lt;1500g)\u003c/p\u003e\n \u003cp\u003egestational age (GA) at delivery\u003c/p\u003e\n \u003cp\u003epreterm delivery(\u0026lt;37w)\u003c/p\u003e\n \u003cp\u003every preterm delivery(\u0026lt;32w)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003eInsua \u003cem\u003eet al\u003c/em\u003e.\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(2017)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOct 2012 to Apr 2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh: 216\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh: 162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD3/Blastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge 20-38 years\u003c/p\u003e\n \u003cp\u003e1st/2nd cycle\u003c/p\u003e\n \u003cp\u003eBMI 18-25kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003esevere male factor\u003c/p\u003e\n \u003cp\u003ehydrosalpinx\u003c/p\u003e\n \u003cp\u003eacquired or congenital uterine abnormalities\u003c/p\u003e\n \u003cp\u003eendocrinopathies\u003c/p\u003e\n \u003cp\u003erecurrent pregnancy losses\u003c/p\u003e\n \u003cp\u003eendometriosis\u003c/p\u003e\n \u003cp\u003elow-responder patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBirthweight\u003c/p\u003e\n \u003cp\u003elow birthweight (\u0026lt;2500g)\u003c/p\u003e\n \u003cp\u003every low birthweight(\u0026lt;1500g)\u003c/p\u003e\n \u003cp\u003egestational age (GA) at delivery\u003c/p\u003e\n \u003cp\u003epreterm delivery(\u0026lt;37w)\u003c/p\u003e\n \u003cp\u003eMalformations\u003c/p\u003e\n \u003cp\u003eNeonatal height\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eZaninovic\u003cem\u003e\u0026nbsp;et al\u003c/em\u003e.\u003c/p\u003e\n \u003cp\u003e(2015)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eThe USA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRetrospective cohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2012 to May 2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh: 947\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh: 714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIVF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNot mentioned\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFrozen ET and PGD/S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMalformations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e*****\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMascarenhas \u003cem\u003eet al\u003c/em\u003e.\u003c/p\u003e\n \u003cp\u003e(2018)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eThe UK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRetrospective cohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eJan 2014 to Oct 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh: 341\u003c/p\u003e\n \u003cp\u003eFrozen: 150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh: 252 Frozen: 132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIVF/ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD3/Blastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNot mentioned\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNot mentioned\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBirthweight\u003c/p\u003e\n \u003cp\u003elow birthweight (\u0026lt;2500g)\u003c/p\u003e\n \u003cp\u003every low birthweight(\u0026lt;1500g)\u003c/p\u003e\n \u003cp\u003egestational age (GA) at delivery\u003c/p\u003e\n \u003cp\u003epreterm delivery(\u0026lt;37w)\u003c/p\u003e\n \u003cp\u003every preterm delivery(\u0026lt;32w)\u0026nbsp;Macrosomia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e*******\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBingxin \u003cem\u003eet al.\u0026nbsp;\u003c/em\u003e(2021)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRetrospective cohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eJanuary 2016 to December 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh:\u0026nbsp;1875\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFresh:\u0026nbsp;1445\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIVF/ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD3/Blastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSI group were selected to match the ages and oocytes of the\u003cbr\u003e\u0026nbsp;TLI group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNot mentioned\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBirthweight\u003c/p\u003e\n \u003cp\u003elow birthweight (\u0026lt;2500g)\u003c/p\u003e\n \u003cp\u003every low birthweight(\u0026lt;1500g)\u003c/p\u003e\n \u003cp\u003egestational age (GA) at delivery\u003c/p\u003e\n \u003cp\u003epreterm delivery(\u0026lt;37w)\u003c/p\u003e\n \u003cp\u003every preterm delivery(\u0026lt;32w) Macrosomia (\u0026ge;4000g)\u003c/p\u003e\n \u003cp\u003eSex ratio\u003c/p\u003e\n \u003cp\u003eMalformations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e*******\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":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"neonatal outcomes, singleton pregnancy, systematic review and meta-analysis, standard incubator, time-lapse incubation systems","lastPublishedDoi":"10.21203/rs.3.rs-1637133/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1637133/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e To date, time-lapse incubation system (TLI) is widely used in assisted reproductive laboratory for continuously embryo observe and selection. But only few randomized controlled trials (RCT) have been published that evaluated the safety of TLI, especially the neonatal outcomes. We conducted a systematic review and meta-analyses to evaluate the neonatal outcomes between TLI and standard incubators (SI).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cem\u003e \u003c/em\u003eA literature search up to October 2021 was carried out to search for clinical trials from electronic databases comparing TLI versus SI on neonatal outcomes. The summary measures were reported as odds ratio (OR) with 95% confidence-interval (CI).\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003cem\u003e \u003c/em\u003e\u003c/strong\u003eA total of 5905 live-born infants were included from fresh embryos transfer cycles. Only singleton pregnancies were analyzed, no statistical differences were found with respect to gestational weeks at delivery (Mean difference=0.09; 95%CI, -0.18 to 0.35; I\u003csup\u003e2\u003c/sup\u003e=33%; \u003cem\u003eP\u003c/em\u003e=0.52), preterm births (\u0026lt;37weeks) (OR=0.98; 95%CI 0.78 to 1.24; I\u003csup\u003e2\u003c/sup\u003e=0%; \u003cem\u003eP\u003c/em\u003e=0.86), and early preterm birth (\u0026lt;32 weeks) (OR=0.41; 95%CI, 0.11 to 1.50; I\u003csup\u003e2\u003c/sup\u003e=50%; \u003cem\u003eP\u003c/em\u003e=0.18). Besides, no statistical significances were also observed in TLI group on birth weight (Mean difference=71.61; 95%CI, -30.55 to 173.77; I\u003csup\u003e2\u003c/sup\u003e=62%; \u003cem\u003eP\u003c/em\u003e=0.17), low birth weight rate (\u0026lt;2,500g) (OR=0.85; 95%CI, 0.64 to 1.13; I\u003csup\u003e2\u003c/sup\u003e=0%; \u003cem\u003eP\u003c/em\u003e=0.26), very low birth weight rate (\u0026lt;1,500g) (OR=0.58; 95%CI, 0.17 to 1.96; I\u003csup\u003e2\u003c/sup\u003e=50%; \u003cem\u003eP\u003c/em\u003e=0.38), and macrosomia rate (≥4,000g) (OR=1.11; 95%CI, 0.84 to 1.47; I\u003csup\u003e2\u003c/sup\u003e=0%; \u003cem\u003eP\u003c/em\u003e=0.48). Moreover, incidences of malformations of babies delivered from TLI and SI groups were also similar (OR=1.19; 95%CI, 0.66 to 2.14; I\u003csup\u003e2\u003c/sup\u003e=0%; \u003cem\u003eP\u003c/em\u003e=0.56). And finally, sex ratio analysis still showed no differences between the two groups (OR=2.16; 95%CI, 0.53 to 8.81; I\u003csup\u003e2\u003c/sup\u003e=96%; \u003cem\u003eP\u003c/em\u003e=0.28).\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe strategy of culturing embryo in time-lapse incubation systems would not increase adverse risks of neonatal outcomes comparing to SI. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e PROSPERO (2018: CRD42020186807)\u003c/p\u003e","manuscriptTitle":"The safety of time-lapse incubation system for embryo culture in assisted reproductive laboratory: A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-31 18:05:32","doi":"10.21203/rs.3.rs-1637133/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":"18c3e5c8-05e4-4b36-8165-890b66d42371","owner":[],"postedDate":"May 31st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-09-07T07:29:51+00:00","versionOfRecord":[],"versionCreatedAt":"2022-05-31 18:05:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1637133","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1637133","identity":"rs-1637133","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}