Maternal Obezitenin Anne-Bebek Sağlığına Etkileri: Sistematik Derleme ve Meta-Analiz

Yıl 2023, , 305 - 330, 31.05.2023

Döndü Kurnaz , Zekiye Karaçam

https://doi.org/10.46237/amusbfd.1224641

Cited By: 3

Öz

Amaç: Bu çalışma, birincil çalışmalara dayalı olarak, maternal obezitenin anne-bebek sağlığına etkilerinin belirlemesi amacı ile yapılmıştır.
Yöntem: Sistematik derleme ve meta-analiz niteliğinde olan bu çalışmada, PRISMA kontrol listeleri kullanılmıştır. Çalışma için taramalar Eylül-Ekim 2021 tarihlerinde yapılmış ve Aralık 2022’de güncellenmiştir. Taramalar, PubMed, MEDLINE, theCochrane Library, EBSCO, Web of Science, Ulusal Tez MerkeziveDergiPark arama motorlarından yapılmıştır. Taramalarda obesity* AND (pregnancy*OR “babieshealth” OR “maternalHealth” OR management) kelime ve kelime grupları kullanılmıştır. Araştırmaların metodolojik kalitesi, JoannaBriggsInstitute tarafından geliştirilen “Kritik Değerlendirme Kontrol Listeleri” ile değerlendirilmiştir. Veriler meta-analiz yöntemleri ile sentez edilmiştir.
Bulgular: Çalışmaya 2013-2022 yıllarında yayımlanmış 38araştırma dahil edilmiştir. Araştırmaların toplam örneklem hacmi 784265’tir. Yapılan meta-analizlerde maternal obezitenin istatistiksel olarak anlamlı bir şekilde, gestasyonel diyabet oluşumunu 4.09 kat (z=12.07, p<0.00001), gebelikte hipertansiyonu 4.83 kat (z=11.25, p<0.00001) ve preeklampsiyi ise3.34 kat (z=37.91, p<0,00001) arttırdığı saptanmıştır. Ayrıca maternal obezitenin sezaryen doğum, doğumda indüksiyon kullanımı, bebeğin doğum ağırlığı, preterm doğum, gebelik ayına göre iri bebek, makrozomi ve postpartum kanama gelişme olasılığını istatistiksel olarak anlamlı bir şekilde arttırdığı, spontan vajinal doğum vegebelik ayına göre küçük bebek olasılığını azalttığı saptanmıştır.
Sonuç: Bu çalışmada, maternal obezitenin anne-bebek sağlığı ile ilgili birçok parametrede olumsuz sonuçları olduğu sonucuna ulaşılmıştır. Kadınların gebeliğe normal kilo ile başlamalarının ve gebelik sürecinde maternal obezitenin yönetiminin sağlanması, anne-bebek sağlığının gelişimine katkıda bulunulabilir

Anahtar Kelimeler

Anne sağlığı, Bebek sağlığı, Gebelik, Maternal obezite

Destekleyen Kurum

Destekleyen bir kurum bulunmamaktadır

Effects of Maternal Obesity on Maternal-Infant Health: Systematic Review and Meta-Analysis

Öz

Objective: This study was conducted with the aim of determining the effects of maternalobesity on mother-infant healthbased on primary studies.
Method: This study was made following the PRISMA Statement. Scans were performed between September and October 2021 and updated in December 2022. Searc hes were made from the PubMed, National Thesis Centre, DergiPark, MEDLINE, Cochrane Library and EBSCO searchengines. Themethodologicalquality of studieswasevaluatedwith Critical Evaluation Checklists, developedby Joanna Briggs Institute Data were synthesized using meta-analysis methods.
Results: For this study, the results of 38 studies published in 2013-2022 were compiled. The total sample size of the studies is 784265. In the meta-analyses, it was found that maternal obesity in creased the risk of developing gestational diabetes 4.09 times (z=12.07, p<0.00001), hypertension during pregnancy 4.83 times (z=11.25, p<0.00001), and preeclampsia 3.34 times (z=37.91, p<0.00001) in a statistically significant way. Inaddition, it was found that cesarean, section increased the probability of birth induction, birth weight, preterm birth, large baby for gestational age, macrosomia, postpartum hemorrhage, and statistically significantly decreased the probability of spontaneous vaginal delivery and small baby for gestational age.
Conclusion: In this study, it was revealed that maternal obesity has negative consequences in many parameters related to mother-infant health. Ensuring that women start pregnancy with a normal weight and management of maternal obesity during pregnancy can contribute to the development of mother-infant health.

Anahtar Kelimeler

Maternal health, Infant health, Pregnancy, Maternal obesity

Kaynakça

• 1. World Health Organization. Obesity. (2022). https://www.who.int/health-topics/obesity#tab=tab_1. (Erişim: 25 Şubat 2022).
• 2. Organization for Economic Co-operation and Development, (2017). Obesity Update 2017. Organization for Economic Co-operationand Development. https://www.oecd.org/els/health-systems/Obesity-Up. (Erişim: 24 Temmuz 2021).
• 3. Dolin, C. D., &Kominiarek, M. A. (2018). Pregnancy in women with obesity. Obstet Gyneco Clin North Am, 45(2), 217–232.
• 4. World Health Organization. Obesity. (2020). https://gateway.euro.who.int/en/indicators/h2020_9-obesity/. (Erişim: 24 Temmuz 2021).
• 5. Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü. (2019). 2018 Türkiye Nüfus ve Sağlık Araştırması (TNSA), Temel Bulgular. Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü, T.C. Cumhurbaşkanlığı Strateji ve Bütçe Başkanlığı ve TÜBİTAK, Ankara, Türkiye.
• 6. Dutton, H., Borengasser, S. J., Gaudet, L. M., Barbour, L. A., & Keely, E. J. (2018). Obesity in pregnancy. MednClin North Am, 102(1), 87-106.
• 7. Kutchi, I., Chellammal, P., & Akila, A. (2020). Maternal obesity and pregnancy outcome: in perspective of new Asian Indian Guidelines. Am J Obstet Gynecol, 70(2):138-144.
• 8. Cattane, N., Räikkönen, K., Anniverno, R., Mencacci, C., Riva, M. A., Pariante, C. M., et al. (2020). Depression, obesity and their comorbidity during pregnancy: effects on the offspring’s mental and physical health. Mol Psychiatry, 26(2), 462-481.
• 9. Godoy, A., Nascimento, S., & Surita, F. (2015). A systematic review and meta-analysis of gestational weight gain recommendations and related outcomes in Brazil. Clinics, 70(11), 758-764.
• 10. Marchi, J., Berg, M., Dencker, A., Olander, E. K., & Begley, C. (2015). Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews. Obes Rev, 16(8), 621-638.
• 11. Resmi Gazete. Sağlık meslek mensupları ile sağlık hizmetlerinde çalışan diğer meslek mensuplarının iş ve görev tanımlarına dair yönetmelik. Resmî Gazete Tarih: 22.05.2014, Sayı: 29007. (Erişim: 24 Temmuz 2021).
• 12. Khadilkar, S. S. (2019). Obesity in pregnancy: Obstetrician’ s obstacle. Journal Obstet Gynecology India, 69 (3), 197-202.
• 13. Adamo, K. B., Ferraro, Z. M., Goldfield, G., Keely, E., Stacey, D., Hadjiyannakis, S., et al. (2013). The maternal obesity management (MOM) Trial protocol: A lifestyle intervention during pregnancy to minimize downstream obesity. Contemp Clin Trials, 35(1), 87–96.
• 14. Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., et al. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 372, n71.
• 15. Moola, S., Munn, Z., Tufanaru, C., Aromataris, E., Sears, K., Sfetcu, R., et al. (2017). Checklist for analytical crosssectional studies. Joanna Briggs Inst. 2017; Rev. Man. 6. AvaiableFrom: https://doi.org/10.17221/96/2009- CJGPB.
• 16. JBI. Data Extraction Forms. Retrieved May, 2022, from: https://jbi-global- wiki.refined.site/space/MANUAL/4687700
• 17. Bardak, Ö. (2020). Obez ve obez olmayan miad gebelerde d vitamini eksikliğinin gebelik sonuçlarına etkisi (Yayınlanmamış Uzmanlık Tezi). T.C. Sağlık Bilimleri Üniversitesi Konya Eğitim ve Araştırma Hastanesi Kadın Hastalıkları ve Doğum Kliniği, Konya.
• 18. Özgül, S. & Taşpınar, A. (2019). Maternal obezitenin anne ve yenidoğan sağlığına etkisi. Aydın. Adnan Menderes Üniversitesi Sağlık Bilimleri Fakültesi Dergisi, 3(3),178-189.
• 19. Saucedo, M., Esteves-Pereira, A. P., Pencolé, L., Rigouzzo, A., Proust, A., Deneux-Tharaux, C. (2020). Understanding maternal mortality in women with obesity and the role of care they receive: a national case- control study. Int J Obes, 45(1),258-265.
• 20. Aksoy, A. N. (2018). Term gebelerde vücut kitle indeksinin maternal ve fetal kan akım parametreleri üzerine olan etkisinin araştırılması. (Yayınlanmamış Yüksek Lisans Tezi). Atatürk Üniversitesi Sağlık Bilimleri Enstitüsü, Erzurum.
• 21. Alfadhli, E. M. (2021). Maternal obesity influences birth weight more than gestational diabetes. BMC Pregnancy Childbirth, 21(1),111.
• 22. Angali, K. A., Azhdari, M., Cheraghi, M., Shahri, P., Salmanzadeh, S., & Borazjani, F. (2020). The Association between pre-pregnancy BMI, gestational weight gain and pregnancy outcomes: A retrospective cohort study in Ahvaz, Iran. Research Square, 1-15.
• 23. Berglund, S. K., García-Valdés, L., Torres-Espinola, F. J., Segura, M. T., Martínez-Zaldívar, C., Campoy, C. et al. (2016). Maternal, fetal and perinatal alterations associated with obesity, overweight and gestational diabetes: an observational cohort study (PREOBE). BMC Public Health, 16(1),207.
• 24. Bogaerts, A. F. L., Devlieger, R., Nuyts, E., Witters, I., Gyselaers, W., Guelinckx, I., et al. (2013). Anxiety and depressed mood in obese pregnant women: A prospective controlled cohort study. Obesity Facts, 6(2), 152- 164.
• 25. Boudet-Berquier, J., Salanave, B., Desenclos, J. C., & Castetbon, K. (2017). Sociodemographic factors and pregnancy Outcomes associated with prepregnancy obesity: effect modification of parity in the nationwide Epifane birth-cohort. BMC Pregnancy and Childbirth, 17(1),273-286.
• 26. Gaillard, R., Voerman, E., Santos, S., Inskip, H., Amiano, P., Barros, H., et al. (2019). Association of gestational weight gain with adverse maternal and ınfant outcomes. JAMA, 321(17), 1702.
• 27. Lauth, C., Huet, J., Dolley, P., Thibon, P., & Dreyfus, M. (2020). Maternalobesity in prolonged pregnancy: Labor, mode of delivery, maternal and fetal outcomes. GynecoObstet Hum Reprod, 50(1), 101909.
• 28. Masturzo, B., Franzè, V., Germano, C., Attini, R., Gennarelli, G., Lezo, A., et al. (2019). Risk of adverse pregnancy Outcomes by pre-pregnancy Body Mass Index among Italian population: a retrospective population-based cohort study on 27,807 deliveries. Arch Gynecol Obsteti. 299(4), 983-991.
• 29. Madi, S., Garcia, R., Souza, V., Rombaldi, R., Araújo, B., &Madi, J. (2017). Effect of obesity on gestational and perinatal outcomes. Rev Bras Gineco Obstet, 39(07), 330-336.
• 30. McPherson, J. A., Smid M. C., Smiley, S,. & Stamilio, D. M. (2016). Association of maternal obesity with child cerebral palsyor death. Am J Perinato, 34(06), 563-567.
• 31. Melchor, I., Burgos, J., del Campo, A., Aiartzaguena, A., Gutiérrez, J., & Melchor, J. C. (2019). Effect of maternal obesity on pregnancy outcomes in women delivering singleton babies: a historical cohort study. J PerinatMed, 47(6),625-630.
• 32. Mina, T. H., Denison, F. C., Forbes, S., Stirrat, L. I., Norman, J. E., & Reynolds, R. M. (2015). Associations of moodsymptomswithante- and postnatal weightchange in obesepregnancyare not mediatedbycortisol. PsycholMed, 45(15), 3133-3146.
• 33. Mitanchez, D., Jacqueminet, S., Nizard, J., Tanguy, M. L., Ciangura, C., Lacorte, J. M., et al. (2017). Effect of maternalobesity on birthweightand neonatal fatmass: A prospectiveclinicaltrial. PLOS ONE, 12(7), e0181307.
• 34. Ramonienė, G., Maleckienė, L., Nadišauskienė, R. J., Bartusevičienė, E., Railaitė, D. R., Mačiulevičienė, R., et al. (2017). Maternal obesity and obstetric outcomes in a tertiaryreferral center. Medicina, 53(2), 109-113.
• 35. Sun, Y., Shen, Z., Zhan, Y., Wang, Y., Ma, S., Zhang, S., et al. (2020). Effects of pre-pregnancy body mass indexandgestationalweightgain on maternaland infant complications. BMC Pregnancy Childbirth, 20(1),390.
• 36. Vinturache, A. E., McDonald, S., Slater, D., & Tough, S. (2015). Perinatal outcomes of maternal over weight and obesity in terminfants: a population-based cohort study in Canada. SciRep, 5(1).
• 37. Wei, Y. M., Yang, H. X., Zhu, W. W., Liu, X. Y., Meng, W. Y., Wang, Y. Q., et al. (2015). Risk of adverse pregnancy outcomes stratified for pre-pregnancy body mass index. Matern Fetal Neonatal Med, 1,5. 2205-2209.
• 38. Ata, K. (2014). Gebelik öncesi obezitenin anne ve bebek sağlığı üzerine etkilerinin belirlenmesi. (Yayınlanmamış Yüksek Lisans Tezi). İstanbul Üniversitesi Sağlık Bilimleri Enstitüsü, İstanbul.
• 39. Bhavadharini, B., Anjana, R. M., Deepa, M., Jayashree, G., Nrutya, S., Shobana M., et al. (2017). Gestational weight gain and pregnancy outcomes in relationto Body Mass İndex in Asian Indian Women. Indian J EndocrinolMetab, 21(4),588-593.
• 40. Blomberg, M. (2014). Maternal Body Mass Index and risk of obstetric anal sphincter ınjury. BiomedResInt, 1,8.
• 41. Ceylan, S. (2016). Obez ve normal kilolu olan annelerin erken dönemde emzirme öz yeterliliği ile emzirme başarılarının karşılaştırılması. (Yayınlanmamış Yüksek Lisans Tezi). Yıldırım Beyazıt Üniversitesi Sağlık Bilimleri Enstitüsü, Ankara.
• 42. Eltayeb, R. A., & Khalifa, A. A. (2021). Impact of maternal Body Mass Index on maternal and neonatal outcomes among sudanese women. Cureus, 13(9), 18365.
• 43. Enomoto, K., Aoki, S., Toma, R., Fujiwara, K., Sakamaki, K., & Hirahara, F. (2016). Pregnancy outcomes based on pre-pregnancy Body Mass Index in japanese women. PLOS ONE, 11(6), e0157081.
• 44. Hjertberg, L., Uustal, E., Pihl, S., & Blomberg, M. (2018). Maternal Body Mass Index and anovaginal distance in active phase of term labor. Biomed ResInt, 1,6.
• 45. Jones, A. D., Zhao, G., Jiang, Y., Zhou, M., Xu, G., Kaciroti, N., et al. (2016). Maternal obesity during pregnancy is negative lyas sociated with maternal and neonatal ironstatus. Eur J Clin Nutr, 70(8), 918-924.
• 46. Koçak, N., Ersoy, S., & Pala, E. (2022). The effects of pregnant obesity in newborn. Med Records, 4(2),123- 127.
• 47. Kumpulainen, S. M., Girchenko, P., Lahti-Pulkkinen, M., Reynolds, R. M., Tuovinen, S., Pesonen, A. K., et al. (2017). Maternal early pregnancy obesity and depressive symptoms during and after pregnancy. Psychol Med,48(14),2353-2363.
• 48. Kundu, S., Kaukemueller, L., VonKaisenberg, C., Hillemanns, P., Soergel, P., Kuehnle, E., et al. (2019). Influence of maternal BMI and maternal weight gain during pregnancy on maternal and perinatal outcome - A retrospective data analysis of pregnancies during 2004 and 2014. Int J Womens Health Wellness, 5,95.
• 49. Li, N., Liu, E., Guo, J., Pan, L., Li, B., Wang, P., et al. (2013). Maternal prepregnancy Body Mass Index and gestational weight gain on pregnancy outcomes. PLoS ONE, 8(12), e82310.
• 50. Minsart, A. F., Buekens, P., De Spiegelaere, M., &Englert, Y. (2013). Neonatal outcomes in obese mothers: a population-based analysis. BMC Pregnancy Childbirth, 11(13),36.
• 51. Oteng-Ntim, E., Kopeika, J., Seed, P., Wandiembe, S., & Doyle, P. (2013). Impact of obesity on pregnancy outcome in different ethnic groups: Calculating population attributable fractions. PLoS ONE, 8(1), e53749.
• 52. Racz, S., Hantosi, E., Marton, S., Toth, K., Ruzsa, D., Halvax, L., et al. (2016). Impact of maternal obesity on the fetal electrocardiogram during labor. Fetal Neonatal Med, 29(22), 3712-3716.
• 53. Sadıkhacıoğlu, F. (2019). Maternal obezitenin doğum ve doğum sonu dönemde kadın sağlığına etkileri. (Yayınlanmamış Yüksek Lisans Tezi). Marmara Üniversitesi Sağlık Bilimleri Enstitüsü, İstanbul.
• 54. Tanaka, T., Ashihara, K., Nakamura, M., Kanda, T., Fujita, D., Yamashita, Y., et al. (2014). Associations between the pre-pregnancy body massindex and gestational weight gain with pregnancy outcomes in Japanese women. J Obstet Gynaecol Res, 40(5), 1296-1303.
• 55. Chen, C., Chen, H. S., & Hsu, H. C. (2020). Maternal prepregnancy Body Mass Index, gestationalweigestasyonel hipertansiyon gain, and risk of adverse perinatal outcomes in Taiwan: A population-based birth cohort study. Int J Enviro ResPublic Health, 17(4), 1221.
• 56. Grieger, J. A., Hutchesson, M. J., Cooray, S. D., Bahri Khomami, M., Zaman, S., Segan, L., et al. (2021). A review of maternal overwei gestasyonel hipertansiyon and obesity and it simpact on cardiometabolic outcomes during pregnancy and postpartum. Ther Adv Reprod Health, 15,1-16.
• 57. Johnsson, I.W., Lindberger, E., Ahlsson, F., Jan Gustafsson, J., & Lundgren, M.E. (2022). Relation of maternal birth wei gestasyonel hipertansiyon with early pregnancy obesity, gestational diabetes, and offspring macrosomia. J Dev OrigHealthDis, 13(5):650-655.
• 58. Fallatah, A.M., Babatin, H. M., Nassibi, K. M., Banweer, M. K., Mohammad N. Fayoumi, M. N., & Oraif, A. M. (2019). Maternal and neonatal outcomes among obese pregnant women in King Abdulaziz University Hospital: A retrospective single-center medical record review. MedArch, 73(6), 425-432.
• 59. Magann, E. F., Doherty, D. A., Sandlin, A. T., Chauhan, S. P., & Morrison, J. C. (2013). The effects of an increasing gradient of maternal obesity on pregnancy outcomes. Aust N Z J ObstetGynaecol, 53(3), 250-257.
• 60. Onubi, O. J., Marais, D., Aucott, L., Okonofua, F., & Poobalan, A. S. (2015). Maternal obesity in Africa: a systematic review and meta-analysis. J Public Health, 38(3), 218–231.
• 61. Hadley, E. E., Discacciati, A., Costantine, M. M., Munn, M. B., Pacheco, L. D., Saade, G. R., et al. (2017). Maternal obesity is associated with chorio amnionitis and earlierindicated preterm delivery among expectantly managed women with preterm prematüre rupture of membranes. J Matern Fetal Neonatal Med, 32(2):271-278.
• 62. Tan, J., Qi, Y. N., He, G. L., Yang, H. M., Zhang, G. T., Zou, K., et al. (2018). Association between maternal wei gestasyonel hipertansiyon ındicators and ıron deficiencyanemia during pregnancy. ChinMed J, 131(21), 2566-2574.
• 63. Johns, E. C., Hill, E. A., Williams, S., Sabil, A., Riha, R.L., Denison, F.C., et al. (2022). High prevalence of obstructives leep apnea in pregnant women with class III obesity: a prospective cohort study. J ClinlSleepMed, 18(2),423-432.
• 64. Bourjeily, G., Danilack, V. A., Bublitz, M. H., Lipkind, H., Muri, J., Caldwell, D., et al. (2017). Obstructive sleep apnea in pregnancy is associatedwith adverse maternal outcomes: a national cohort. Sleep Med, 38, 50-57.
• 65. Pires, G. N., Benedetto, L., Cortese, R., Gozal, D., Gulia, K. K., Kumar, V. M., et al. (2020). Effects of sleep modulation during pregnancy in the mother and off spring: Evidences from preclinical research. Sleep Res, 30(3),13135.
• 66. Institute of Medicine, (2009). WeiGestasyonel hipertansiyon gain during pregnancy: reexamining the guidelines. Washington, D.C: The national academies press. 2009. Institute of Medicine. https://pubmed.ncbi.nlm.nih. gov/20669500/.
• 67. Denison, F., Aedla, N., Keag, O., Hor, K., Reynolds, R., & Milne, A. (2018). Care of women with obesity in pregnancy. BJOG, 72, 62-106.
• 68. Hill, B., Skouteris, H., Boyle, J. A., Bailey, C., Walker, R., Thangaratinam, S., et al. (2020). Health in preconception, pregnancy and postpartum global alliance: International network pregnancy priorities for the prevention of maternal obesity and related pregnancy and long-term complications. J of Clin Med, 9(3), 822.
• 69. Araji, S., Griffin, A., Dixon, L., Spencer, S., Peavie, C., & Wallace, K. (2020). An overview of maternal anxiety during pregnancy and the post-partum period. J Mental Health Clin Psycho, 4(4), 47-56.
• 70. Sawyer, K. M., Zunszain, P. A., Dazzan, P., & Pariante, C. M. (2019). Inter generational transmission of depression: Clinical observations and molecular mechanisms. Mol Psychiatry, 24(8):1157-1177.
• 71. Hu, H., Feng, P., Yu, Q., Zhu, W., Xu, H,.Wu, D., et al. (2022). Themediating role of gestationaldiabetesmellitus in theassociations of maternalprepregnancy body massindexwith neonatal birthwei Gestasyonel hipertansiyon. J Diabetes, 14(1), 26-33.
• 72. Su, W., Chen, Y., Huang, P., Shi, X., Yan, F., Chen, Z., et al. (2019). Effects of Prepregnancy Body Mass Index, weigestasyonel hipertansiyon gain and gestational diabetes mellitus on pregnancy outcomes: A population-based study in xiamen, China, 2011–2018. Ann NutrMetab, 75(1),31-38.
• 73. Haque, R., Keramat, S. A., Rahman, S. M., Mustafa, M. U. R., & Alam, K. (2021). Association of maternal obesity with fetal and neonatal death: Evidencefrom South and South-East Asiancountries. PlosOne, 2 (9), 16.
• 74. Turner, D., Monthé-Drèze, C., Cherkerzian, S., Gregory, K., & Sen, S. (2019). Maternal obesity and cesarean section delivery: additional risk factors for neonatal hypoglycemia? J Perinat, 39, 1057-1064.
• 75. Masters, H., Housley, E., Van Hook, J., & DeFranco, E. (2018). Maternal obesity ıs an ındependent risk factor for ıntensive care unit admission during delivery hospitalization. Am Journal Perinatol, 35(14):1423-1428.
• 76. Achike, M., & Akpınar, Elçi, M. (2021). The role of maternal prepregnancy Body Mass Index in breastfeeding outcomes: A systematic review. Breastfeed Med, 16(9),678-686.
• 77. Hauff, L. E., Leonard, S. A., & Rasmussen, K. M. (2014). Associations of maternal obesity and psycho-social factors with breastfeeding intention, initiation, andduration. 99(3), 524–534.