Association between second trimester maternal hypothyroidism and congenital heart diseases in fetuses: a retrospective study

Öz

Aim: This study aimed to investigate the association between second-trimester maternal hypothyroidism and congenital heart diseases (CHDs) in fetuses. Material and Methods: This retrospective study was conducted at Obstetrics and Pediatrics Training and Research Hospital between June 2022 and December 2024. The patient group comprised mothers of children diagnosed with major CHDs, while the control group included mothers of children without CHDs or with minor anomalies not requiring intervention. Maternal thyroid status was determined by second-trimester TSH levels: >4.0 mIU/mL was classified as hypothyroid, while 0.2–4.0 mIU/mL was considered euthyroid. Statistical analyses, including ROC analysis, regression analysis, Chi-square test, Fisher's exact test, and Mann-Whitney U test, were performed using SPSS 25, with p < 0.05 considered significant. Results: The median TSH level was significantly higher in the CHD group compared to controls (p = 0.002). Logistic regression analysis revealed that each unit increase in maternal TSH levels increased the risk of fetal CHD by 1.47 times (95% CI: 1.212–1.792, p < 0.001). ROC analysis determined an optimal TSH cutoff of 1.795 mIU/mL (AUC = 0.627; sensitivity: 59.6%, specificity: 59.4%). While differences in CHD subgroups were observed, including conotruncal and valvular defects, these did not reach statistical significance (p > 0.05). Conclusion: The study suggests a potential association between maternal hypothyroidism and fetal CHD.

Anahtar Kelimeler

• Maternal hypothyroidism
• congenital heart disease
• fetal echocardiography
• thyroid function
• second trimester.

Destekleyen Kurum

The authors received no financial support for the research and/or authorship of this article.

Etik Beyan

The study was approved by the Institutional Ethics Review Board for Clinical Research of Giresun Education and Research Hospital Ethics Committee (approval date: 25.12.2024; approval number: 2024/02). Written informed consent was obtained from the patients prior to inclusion in the study.

Maternal hipotiroidi ile fetal konjenital kalp hastalıkları arasındaki ilişki: retrospektif bir çalışma

Öz

Amaç: Bu çalışma, ikinci trimesterdeki maternal hipotiroidi ile fetal konjenital kalp hastalıkları (KKH) arasındaki ilişkiyi araştırmayı amaçladı. Gereç ve Yöntemler: Bu retrospektif çalışma, Haziran 2022 ile Aralık 2024 tarihleri arasında Kadın Doğum ve Çocuk Hastalıkları Eğitim ve Araştırma Hastanesi'nde gerçekleştirildi. Hasta grubu, majör konjenital kalp hastalığı tanısı alan çocukların annelerinden oluşurken, kontrol grubu KKH olmayan veya müdahale gerektirmeyen minör anomalilere sahip çocukların annelerini içeriyordu. Annelerin tiroid durumu, ikinci trimesterde ölçülen TSH seviyelerine göre belirlendi: >4,0 mIU/mL hipotiroid, 0,2–4,0 mIU/mL ötiroid olarak kabul edildi. İstatistiksel analizler arasında ROC analizi, regresyon analizi, Ki-kare testi, Fisher'ın kesin testi ve Mann-Whitney U testi yer almakta olup, tüm analizler SPSS 25 kullanılarak gerçekleştirildi ve p < 0,05 anlamlı kabul edildi. Bulgular: Medyan TSH seviyesi, KKH grubunda kontrol grubuna göre anlamlı derecede daha yüksek bulundu (p = 0,002). Lojistik regresyon analizinde, maternal TSH seviyelerindeki her bir birimlik artışın fetal KKH riskini 1,47 kat artırdığı tespit edildi (95% CI: 1,212–1,792, p < 0,001). ROC analizi, TSH için optimal eşik değerini 1,795 mIU/mL olarak belirledi (AUC = 0,627; duyarlılık: %59,6, özgüllük: %59,4). Konotrunkal ve valvüler defektler gibi KKH alt gruplarında farklılıklar gözlenmiş olsa da, bu farklar istatistiksel anlamlılığa ulaşmadı (p > 0,05). Sonuç: Çalışma, maternal hipotiroidizm ile fetal KKH arasında potansiyel bir ilişki olabileceğini göstermektedir.

Anahtar Kelimeler

• Maternal hipotiroidizm
• konjenital kalp hastalığı
• fetal ekokardiyografi
• tiroid fonksiyonu
• ikinci trimester

Kaynakça

1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890-900.
2. Kula S, Cevik A, Olguntürk FR, Tunaoğlu FS, Oğuz AD, Ilhan MN. Distribution of congenital heart disease in Turkey. Turk J Med Sci 2011; 41: 889-893.
3. Botto LD. Epidemiology and prevention of congenital heart defects. Cong Heart Dis Karger Publishers 2015: 28-45.
4. Gilboa SM, Salemi JL, Nembhard WN, Fixler DE, Correa A. Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006. Circulation 2010; 122: 2254-63.
5. Petrini J, Damus K, Johnston RB. An overview of infant mortality and birth defects in the United States. Teratology 1997; 56: 8-10.
6. Petrini J, Damus K, Russell R, Poschman K, Davidoff MJ, Mattison D. Contribution of birth defects to infant mortality in the United States. Teratology 2002; 66: S3-S6.
7. Yang Q, Khoury MJ, Mannino D. Trends and patterns of mortality associated with birth defects and genetic diseases in the United States, 1979–1992: An analysis of multiple‐cause mortality data. Gen Epidemiol 1997; 14: 493-505.
8. Atiq M. Early Diagnosis of Congenital Heart Disease Improves Outcome. LNJPC 2020; 2: 39-42.

9. Sun R, Liu M, Lu L, Zheng Y, Zhang P. Congenital heart disease: causes, diagnosis, symptoms, and treatments. Cell Biochem Biophys 2015; 72: 857-60.
10. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 2017; 27: 315-89.
11. van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M et al. Significance of (sub) clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update 2011; 17: 605-19.
12. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549-55.
13. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002; 12: 63-8.
14. Sahu MT, Das V, Mittal S, Agarwal A, Sahu M. Overt and subclinical thyroid dysfunction among Indian pregnant women and its effect on maternal and fetal outcome. Arch Gynecol Obstet 2010; 281: 215-20.
15. León G, Murcia M, Rebagliato M, Álvarez-Pedrerol M, Castilla AM, Basterrechea M et al. Maternal thyroid dysfunction during gestation, preterm delivery, and birthweight. The Infancia y Medio Ambiente Cohort, Spain. Paediatr Perinat Epidemiol 2015; 29: 113-22.
16. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21: 1081-125.
17. Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol 1993; 81: 349-53.
18. Liu S, Joseph KS, Lisonkova S, Rouleau J, Van den Hof M, Sauve R et al. Association between maternal chronic conditions and congenital heart defects: a population-based cohort study. Circulation 2013; 128: 583-9.
19. Dong J, Peng T, Li M-Q, Xie F, Wu J-N. Association between Maternal Thyroxine and Risk of Fetal Congenital Heart Defects: A Hospital‐Based Cohort Study. Int J Endocrinol 2022; 2022(1): 3859388.
20. Zhang Y, Zhang L, Zhao W, Li N, Chen G, Ge J et al. Cardiac structural and functional remodeling in the fetuses associated with maternal hypothyroidism during pregnancy. Matern Fetal Neonatal Med 2023; 36: 2203796.
21. Browne ML, Rasmussen SA, Hoyt AT, Waller DK, Druschel CM, Caton AR et al. Maternal thyroid disease, thyroid medication use, and selected birth defects in the National Birth Defects Prevention Study. Birth Defects Res A Clin Mol Teratol 2009; 85: 621-8.
22. Ghanbari M, Ghasemi A. Maternal hypothyroidism: An overview of current experimental models. Life Sci 2017; 187: 1-8.
23. Gupta P, Jain M, Verma V, Gupta NK. The study of prevalence and pattern of thyroid disorder in pregnant women: a prospective study. Cureus 2021; 13(7).
24. Ezzeddine D, Ezzeddine D, Hamadi C, et al. Prevalence and correlation of hypothyroidism with pregnancy outcomes among Lebanese women. J Endocr Soc 2017; 1: 415-22.
25. Sohail R, Yasmin H, Tasneem N, Khanum Z, Sachdeve PS, Pal SA et al. The Prevalence of Subclinical Hypothyroidism During Early Pregnancy in Pakistan: A Cross-Sectional Study. Cureus 2021; 13: e20316.
26. Turunen S, Vääräsmäki M, Männistö T, Hartikainen AL, Lahesmaa-Korpinen AM, Gissler M et al. Pregnancy and Perinatal Outcome Among Hypothyroid Mothers: A Population-Based Cohort Study. Thyroid 2019; 29: 135-41.
27. Mittag J, Lyons DJ, Sällström J, Vujovic M, Dudazy-Gralla S, Warner A et al. Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions. J Clin Invest 2013; 123: 509-16.
28. Abdul Ahad FA, Maria Murtaza, Midhat E Zahra Naqvi, Mehnaz Atiq. Cardiac involvement in fetuses of mothers with hypothyroidism. Res Med Sci Rev 2024; 2: 1929-35.
29. Grattan MJ, Thomas DS, Hornberger LK, Hamilton RM, Midodzi WK, Vohra S. Maternal hypothyroidism may be associated with CHD in offspring. Cardiol Young 2015; 25: 1247-53.
30. Miao M, Liu H, Yuan W, Madsen N, Yu Y, László KD et al. Association of Maternal Hypothyroidism With Cardiovascular Diseases in the Offspring. Front Endocrinol (Lausanne) 2021; 12: 739629.