Association of the maternal diabetes mellitus with cleft lip and palate in offspring: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

FENG Rong ¹ ,  ZENG Yan ² , CUI Xinping ¹ , ZHOU Qian ³ , SONG Bin ⁴

1. North Sichuan Medical College, Nanchong 637000, P. R. China;
2. Department of Pediatrics, People's Hospital of Deyang City, Deyang 618000, P. R. China;
3. Southwest Medical University, Luzhou 646000, P. R. China;
4. Department of Nephrology, People's Hospital of Deyang City, Deyang 618000, P. R. China;

Corresponding author：

ZENG Yan, Email: drzengyan@126.com

Keywords：

Diabetes mellitus; Offspring; Cleft lip and palate; Meta-analysis

DOI：

10.7507/1672-2531.202411012

Video：

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Objective To systematically review the associations of maternal diabetes mellitus with cleft lip and palate in offspring. Methods The PubMed, EMbase, Cochrane Library, Web of Science, CNKI, VIP and WanFang Data databases were electronically searched to collect the observational studies on the association of maternal diabetes mellitus with cleft lip and palate in offspring from inception to June, 2024. Two reviewers independently screened literature, extracted data and assessed the risk of bias of the included studies. Meta-analysis was then performed by using Stata 17.0 and RevMan 5.4 software. Results A total of 34 studies involving 2 556 911 participants were included. The results of meta-analysis showed that maternal pregestational diabetes mellitus was associated with an increased risk of cleft lip and palate in offspring (OR=1.91, 95%CI 1.59 to 2.30, P<0.01). Maternal type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) were also associated with an increased risk of cleft lip and palate in offspring(T1DM: OR=2.28, 95%CI 1.65 to 2.30, P<0.01; T2DM: OR=1.87, 95%CI 1.10 to 3.19, P<0.01). There was no correlation between maternal gestational diabetes mellitus and cleft lip and palate in offspring. Conclusion Current evidence shows that maternal pregestational diabetes mellitus was associated with an increased incidence of cleft lip and palate in offspring. Due to the limited quality and quantity of the included studies, more high quality studies are needed to verify the above conclusion.

1.	Babai A, Irving M. Orofacial clefts: genetics of cleft lip and palate. Genes (Basel), 2023, 14(8): 1603.
2.	胡淼, 邢丽英, 张丽姿, 等. 唇腭裂病因研究进展. 中华产科急救电子杂志, 2024, 13(1): 60-63.
3.	Liu XL, Zahrt DM, Simms MD. An interprofessional team approach to the differential diagnosis of children with language disorders. Pediatr Clin North Am, 2018, 65(1): 73-90.
4.	周新丽, 陈仁吉, 张文婧. 非综合征型唇腭裂语言障碍研究进展. 北京口腔医学, 2023, 31(2): 150-152.
5.	Gritli-Linde A. The etiopathogenesis of cleft lip and cleft palate: usefulness and caveats of mouse models. Curr Top Dev Biol, 2008, 84: 37-138.
6.	Spilson SV, Kim HJ, Chung KC. Association between maternal diabetes mellitus and newborn oral cleft. Ann Plast Surg, 2001, 47(5): 477-481.
7.	Correa A, Gilboa SM, Besser LM, et al. Diabetes mellitus and birth defects. Am J Obstet Gynecol, 2008, 199(3): 237.e1-9.
8.	Stott-Miller M, Heike CL, Kratz M, et al. Increased risk of orofacial clefts associated with maternal obesity: case-control study and Monte Carlo-based bias analysis. Paediatr Perinat Epidemiol, 2010, 24(5): 502-512.
9.	Chen LJ, Chiu CH, Huang JY, et al. Maternal diabetes mellitus and birth defects in Taiwan: a 5-year nationwide population-based cohort study. J Chin Med Assoc, 2023, 86(6): 589-595.
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): 603-605.
11.	Rostom A, Dube C, Cranney A, et al. Celiac disease. Rockville (MD): Agency for Healthcare Research and Quality (US), 2004.
12.	Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
13.	Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF. Maternal diabetes: the risk for specific birth defects. Eur J Epidemiol, 1992, 8(4): 503-508.
14.	Janssen PA, Rothman I, Schwartz SM. Congenital malformations in newborns of women with established and gestational diabetes in Washington State, 1984-91. Paediatr Perinat Epidemiol, 1996, 10(1): 52-63.
15.	Martínez-Frías ML, Bermejo E, Rodríguez-Pinilla E, et al. Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers. Am J Med Genet, 1998, 78(2): 140-145.
16.	Sharpe PB, Chan A, Haan EA, et al. Maternal diabetes and congenital anomalies in South Australia 1986-2000: a population-based cohort study. Birth Defects Res A Clin Mol Teratol, 2005, 73(9): 605-611.
17.	Nielsen GL, Nørgard B, Puho E, et al. Risk of specific congenital abnormalities in offspring of women with diabetes. Diabet Med, 2005, 22(6): 693-696.
18.	Bánhidy F, Acs N, Puhó EH, et al. Congenital abnormalities in the offspring of pregnant women with type 1, type 2 and gestational diabetes mellitus: a population-based case-control study. Congenit Anom (Kyoto), 2010, 50(2): 115-121.
19.	Garne E, Loane M, Dolk H, et al. Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol, 2012, 94(3): 134-140.
20.	Vinceti M, Malagoli C, Rothman KJ, et al. Risk of birth defects associated with maternal pregestational diabetes. Eur J Epidemiol, 2014, 29(6): 411-418.
21.	Liu S, Rouleau J, León JA, et al. Impact of pre-pregnancy diabetes mellitus on congenital anomalies, Canada, 2002-2012. Health Promot Chronic Dis Prev Can, 2015, 35(5): 79-84.
22.	Agha MM, Glazier RH, Moineddin R, et al. Congenital abnormalities in newborns of women with pregestational diabetes: a time-trend analysis, 1994 to 2009. Birth Defects Res A Clin Mol Teratol, 2016, 106(10): 831-839.
23.	Jenkins MM, Reefhuis J, Herring AH, et al. Impact of sample collection participation on the validity of estimated measures of association in the national birth defects prevention study when assessing gene-environment interactions. Genet Epidemiol, 2017, 41(8): 834-843.
24.	Yang GR, Dye TD, Li D. Effects of pre-gestational diabetes mellitus and gestational diabetes mellitus on macrosomia and birth defects in upstate New York. Diabetes Res Clin Pract, 2019, 155: 107811.
25.	Tinker SC, Gilboa SM, Moore CA, et al. Specific birth defects in pregnancies of women with diabetes: national birth defects prevention study, 1997-2011. Am J Obstet Gynecol, 2020, 222(2): 176. e1-176. e11.
26.	Wu Y, Liu B, Sun Y, et al. Association of maternal prepregnancy diabetes and gestational diabetes mellitus with congenital anomalies of the newborn. Diabetes Care, 2020, 43(12): 2983-2990.
27.	Schraw JM, Langlois PH, Lupo PJ. Comprehensive assessment of the associations between maternal diabetes and structural birth defects in offspring: a phenome-wide association study. Ann Epidemiol, 2021, 53: 14-20. e8.
28.	Heydari MH, Sadeghian A, Khadivi G, et al. Prevalence, trend, and associated risk factors for cleft lip with/without cleft palate: a national study on live births from 2016 to 2021. BMC Oral Health, 2024, 24(1): 36.
29.	Chang TI, Horal M, Jain SK, et al. Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia, 2003, 46(4): 538-545.
30.	Negrato CA, Marques PR, Leite HB, et al. Glycemic and nonglycemic mechanisms of congenital malformations in hyperglycemic pregnancies: a narrative review. Arch Endocrinol Metab, 2022, 66(6): 908-918.
31.	Loeken MR. Mechanisms of congenital malformations in pregnancies with pre-existing diabetes. Curr Diab Rep, 2020, 20(10): 54.
32.	Goulding M, Sterrer S, Fleming J, et al. Analysis of the Pax-3 gene in the mouse mutant splotch. Genomics, 1993, 17(2): 355-363.
33.	Morgan SC, Lee HY, Relaix F, et al. Cardiac outflow tract septation failure in Pax3-deficient embryos is due to p53-dependent regulation of migrating cardiac neural crest. Mech Dev, 2008, 125(9-10): 757-767.
34.	Ji Y, Garland MA, Sun B, et al. Cellular and developmental basis of orofacial clefts. Birth Defects Res, 2020, 112(19): 1558-1587.
35.	Eidem I, Stene LC, Henriksen T, et al. Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999-2004. Acta Obstet Gynecol Scand, 2010, 89(11): 1403-1411.
36.	Kozma A, Radoi V, Ursu R, et al. Gestational diabetes mellitus and the development of cleft lip/palate in newborns. Acta Endocrinol (Buchar), 2019, 5(1): 118-122.
37.	Sabbagh HJ, Baghlaf KK, Jamalellail HMH, et al. Environmental tobacco smoke exposure and non-syndromic orofacial cleft: Systematic review and meta-analysis. Tob Induc Dis, 2023, 21: 76.
38.	Mossey PA, Little J, Munger RG, et al. Cleft lip and palate. Lancet, 2009, 374(9703): 1773-1785.

1. Babai A, Irving M. Orofacial clefts: genetics of cleft lip and palate. Genes (Basel), 2023, 14(8): 1603.
2. 胡淼, 邢丽英, 张丽姿, 等. 唇腭裂病因研究进展. 中华产科急救电子杂志, 2024, 13(1): 60-63.
3. Liu XL, Zahrt DM, Simms MD. An interprofessional team approach to the differential diagnosis of children with language disorders. Pediatr Clin North Am, 2018, 65(1): 73-90.
4. 周新丽, 陈仁吉, 张文婧. 非综合征型唇腭裂语言障碍研究进展. 北京口腔医学, 2023, 31(2): 150-152.
5. Gritli-Linde A. The etiopathogenesis of cleft lip and cleft palate: usefulness and caveats of mouse models. Curr Top Dev Biol, 2008, 84: 37-138.
6. Spilson SV, Kim HJ, Chung KC. Association between maternal diabetes mellitus and newborn oral cleft. Ann Plast Surg, 2001, 47(5): 477-481.
7. Correa A, Gilboa SM, Besser LM, et al. Diabetes mellitus and birth defects. Am J Obstet Gynecol, 2008, 199(3): 237.e1-9.
8. Stott-Miller M, Heike CL, Kratz M, et al. Increased risk of orofacial clefts associated with maternal obesity: case-control study and Monte Carlo-based bias analysis. Paediatr Perinat Epidemiol, 2010, 24(5): 502-512.
9. Chen LJ, Chiu CH, Huang JY, et al. Maternal diabetes mellitus and birth defects in Taiwan: a 5-year nationwide population-based cohort study. J Chin Med Assoc, 2023, 86(6): 589-595.
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): 603-605.
11. Rostom A, Dube C, Cranney A, et al. Celiac disease. Rockville (MD): Agency for Healthcare Research and Quality (US), 2004.
12. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
13. Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF. Maternal diabetes: the risk for specific birth defects. Eur J Epidemiol, 1992, 8(4): 503-508.
14. Janssen PA, Rothman I, Schwartz SM. Congenital malformations in newborns of women with established and gestational diabetes in Washington State, 1984-91. Paediatr Perinat Epidemiol, 1996, 10(1): 52-63.
15. Martínez-Frías ML, Bermejo E, Rodríguez-Pinilla E, et al. Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers. Am J Med Genet, 1998, 78(2): 140-145.
16. Sharpe PB, Chan A, Haan EA, et al. Maternal diabetes and congenital anomalies in South Australia 1986-2000: a population-based cohort study. Birth Defects Res A Clin Mol Teratol, 2005, 73(9): 605-611.
17. Nielsen GL, Nørgard B, Puho E, et al. Risk of specific congenital abnormalities in offspring of women with diabetes. Diabet Med, 2005, 22(6): 693-696.
18. Bánhidy F, Acs N, Puhó EH, et al. Congenital abnormalities in the offspring of pregnant women with type 1, type 2 and gestational diabetes mellitus: a population-based case-control study. Congenit Anom (Kyoto), 2010, 50(2): 115-121.
19. Garne E, Loane M, Dolk H, et al. Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol, 2012, 94(3): 134-140.
20. Vinceti M, Malagoli C, Rothman KJ, et al. Risk of birth defects associated with maternal pregestational diabetes. Eur J Epidemiol, 2014, 29(6): 411-418.
21. Liu S, Rouleau J, León JA, et al. Impact of pre-pregnancy diabetes mellitus on congenital anomalies, Canada, 2002-2012. Health Promot Chronic Dis Prev Can, 2015, 35(5): 79-84.
22. Agha MM, Glazier RH, Moineddin R, et al. Congenital abnormalities in newborns of women with pregestational diabetes: a time-trend analysis, 1994 to 2009. Birth Defects Res A Clin Mol Teratol, 2016, 106(10): 831-839.
23. Jenkins MM, Reefhuis J, Herring AH, et al. Impact of sample collection participation on the validity of estimated measures of association in the national birth defects prevention study when assessing gene-environment interactions. Genet Epidemiol, 2017, 41(8): 834-843.
24. Yang GR, Dye TD, Li D. Effects of pre-gestational diabetes mellitus and gestational diabetes mellitus on macrosomia and birth defects in upstate New York. Diabetes Res Clin Pract, 2019, 155: 107811.
25. Tinker SC, Gilboa SM, Moore CA, et al. Specific birth defects in pregnancies of women with diabetes: national birth defects prevention study, 1997-2011. Am J Obstet Gynecol, 2020, 222(2): 176. e1-176. e11.
26. Wu Y, Liu B, Sun Y, et al. Association of maternal prepregnancy diabetes and gestational diabetes mellitus with congenital anomalies of the newborn. Diabetes Care, 2020, 43(12): 2983-2990.
27. Schraw JM, Langlois PH, Lupo PJ. Comprehensive assessment of the associations between maternal diabetes and structural birth defects in offspring: a phenome-wide association study. Ann Epidemiol, 2021, 53: 14-20. e8.
28. Heydari MH, Sadeghian A, Khadivi G, et al. Prevalence, trend, and associated risk factors for cleft lip with/without cleft palate: a national study on live births from 2016 to 2021. BMC Oral Health, 2024, 24(1): 36.
29. Chang TI, Horal M, Jain SK, et al. Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia, 2003, 46(4): 538-545.
30. Negrato CA, Marques PR, Leite HB, et al. Glycemic and nonglycemic mechanisms of congenital malformations in hyperglycemic pregnancies: a narrative review. Arch Endocrinol Metab, 2022, 66(6): 908-918.
31. Loeken MR. Mechanisms of congenital malformations in pregnancies with pre-existing diabetes. Curr Diab Rep, 2020, 20(10): 54.
32. Goulding M, Sterrer S, Fleming J, et al. Analysis of the Pax-3 gene in the mouse mutant splotch. Genomics, 1993, 17(2): 355-363.
33. Morgan SC, Lee HY, Relaix F, et al. Cardiac outflow tract septation failure in Pax3-deficient embryos is due to p53-dependent regulation of migrating cardiac neural crest. Mech Dev, 2008, 125(9-10): 757-767.
34. Ji Y, Garland MA, Sun B, et al. Cellular and developmental basis of orofacial clefts. Birth Defects Res, 2020, 112(19): 1558-1587.
35. Eidem I, Stene LC, Henriksen T, et al. Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999-2004. Acta Obstet Gynecol Scand, 2010, 89(11): 1403-1411.
36. Kozma A, Radoi V, Ursu R, et al. Gestational diabetes mellitus and the development of cleft lip/palate in newborns. Acta Endocrinol (Buchar), 2019, 5(1): 118-122.
37. Sabbagh HJ, Baghlaf KK, Jamalellail HMH, et al. Environmental tobacco smoke exposure and non-syndromic orofacial cleft: Systematic review and meta-analysis. Tob Induc Dis, 2023, 21: 76.
38. Mossey PA, Little J, Munger RG, et al. Cleft lip and palate. Lancet, 2009, 374(9703): 1773-1785.

Chinese Journal of Evidence-Based Medicine

Latest ArticlesAssociation of the maternal diabetes mellitus with cleft lip and palate in offspring: a meta-analysis

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