==== Front Ann Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 2379343110.5144/0256-4947.2013.273asm-3-273Original ArticleRisk factors for congenital hypothyroidism in Egypt: results of a population case-control study (2003–2010) Abdelmoktader Ahmed Mahmoud From the Fayoum Faculty of Medicine, Department of Pediatrics, Fayoum, EgyptCorrespondence: Prof. Ahmed Mahmoud Abdelmoktader, Fayoum Faculty of Medicine, Department of Pediatrics, Fayoum 12345, Egypt, T: 00201001802142, F: 0020846300587, abdelmoktader2006@yahoo.comMay-Jun 2013 33 3 273 276 Copyright © 2013, Annals of Saudi Medicine2013This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.BACKGROUND AND OBJECTIVES Although the prevention of the neuropsychological consequences of congenital hypothyroidism (CH) through the use of replacement therapy represents an important public health success, knowledge about the modifiable risk factors could reduce the number of infants affected by this disease. This study was carried out to identify risk factors for CH at Fayoum Governorate, Egypt. DESIGN AND SETTINGS This was a population-based case-control study, which started in 2003 and was carried out for 8 years through Fayoum center of the Egyptian Ministry of Health and Population screening program for CH. METHODS This study was a population-based case-control study carried out by using national project for CH. One control was enrolled for each new CH infant; 320 cases and 320 controls were enrolled in 8 years. Maternal and neonatal influences were investigated. RESULTS A statistically significant association of CH was observed with birth defects, female gender, gestational age >40 weeks, and gestational diabetes. An increased risk for CH was detected in twins by a multivariate analysis. CONCLUSION Our results suggest a multifactorial origin of CH in which genetic (high frequency of additional malformations) and environmental factors (especially maternal diabetes) play a role in the development of the disease. ==== Body Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency at birth. CH is most commonly caused by a problem with thyroid gland development (dysgenesis) or a disorder of thyroid hormone biosynthesis (dyshormonogenesis); these disorders result in primary hypothyroidism.1 CH is one of the most common preventable causes of mental retardation. The worldwide incidence is approximately 1:2,000 to 1:4,000 newborns.2 Kurinczuk3 reported that the approximate incidence rate is 1 in 3,400 births; girls had more than twice the risk than boys. The authors also observed a U-shaped curve in incidence rates with birth weight and with gestational age (37 or 41 weeks of gestation). Approximately 10% of affected newborns had another birth defect, which is approximately twice the frequency of birth defects among the general population. Emanuel et al reported an increased risk of subclinical hypothyroidism during pregnancy in a group of women with gestational diabetes.4 Screening programs for CH, which have been extensively implemented in developed countries, provide the opportunity to investigate the etiology and the pathogenesis of CH.5 In Egypt, the overall incidence of CH was 1:2,020 live births in 2005.6 The Egyptian Ministry of Health and Population started to implement the screening program for CH in 2000 in 5 governorates, and by the end of 2003, all 27 Governorates were covered.7 As the occurrence of genetic mutations has been observed only in a small proportion of the patients, the etiology of CH due to thyroid dysgenesis is still largely unknown. Hence, it is clear that the investigation of modifiable risk factors for CH is important because of the potential to prevent CH.8 The results of a population-based case-control study are presented in this paper. Maternal and neonatal exposure was investigated with the aim of identifying the most important risk factors for CH at Fayoum Governorate, Egypt. METHODS The study enrolment started in 2003 and was carried out for 8 years. Only recently, the diagnosed cases of CH screened by the selected center were included in the study. The screening test for CH was performed on dried blood spots. Thyroid-stimulating hormone (TSH) and thyroxine (T4) were measured. The positive results of the first screening test were then confirmed by serum TSH, T4, and free T4. Infants with normalized TSH between screening and recall were not included in the sample. One control was enrolled for each new CH case. This control was the first infant recorded in the same Health office where the new CH case was recorded. Cases and controls included in the study were residents of the same region. Parents were interviewed and gave their informed consent for participation in the study. The reproductive and medical history of mothers was recorded, including gestational diabetes to assess the effect of these factors during pregnancy. Neonatal features of cases and controls were collected directly from medical records. The study protocol was approved by the institutional ethics committee (Fayoum Faculty of Medicine ethics committee). Statistical analysis Analyses by two-by-two contingency tables were performed to estimate the association between CH and possible risk factors. Continuous variables were categorized according to biological considerations or conventional cut-off points. Matched crude ORs were estimated by the Mantel–Haenszel method. The Mantel–Haenszel summary χ2 test was used to test the significance of the matched ORs. A conditional logistic regression was performed to evaluate the adjusted effect of the considered variables on the risk of being a CH case. RESULTS During the 8 years of the study, 320 cases and 320 controls were enrolled and were considered for statistical analysis. Results are summarized in Tables 1, 2, and 3. The mother’s age at delivery was slightly higher in the CH cases than in the controls (28 [8.8%] vs. 13 [4%]; age at delivery ≥40 years). No differences in risk factors related to pregnancy (parity, previous spontaneous abortion) were observed between the 2 groups. With regard to neonatal risk factors, the frequency of females was significantly higher in the CH infants than in the controls “P=.01.” Also, an advanced gestational age was significantly associated with CH. In fact, 113 (35.3%) of CH infants were born after 40 weeks of gestation as compared to 51 (15.9%) of the controls “P=.01.” Overall, no statistically significant difference was found in the birth weight between the cases and controls. With regard to the other neonatal features, a higher frequency of twinning was observed among cases compared to controls (5.1% vs. 0.7%, P<.01). In the multivariate analysis, 4 neonatal features were significantly associated with the birth of a CH infant: female gender (OR=2.0, 95% CI: 1.2–3.3), twinning (OR=12.2, 95% CI: 2.4–62.3), additional birth defects (OR=7.5, 95% CI: 2.9–19.0), and gestational age >40 weeks (OR=3.0, 95% CI: 1.8–5.1). DISCUSSION Our study confirmed the already known higher prevalence of CH among females than males.9–12 In fact, in this case-control study, a 2-fold higher risk of permanent CH was estimated in females than in males. However, it is still unclear why females were more susceptible to developing CH. In our study, a significant association was observed between prolonged gestational age (≥41 weeks) and CH. Some authors had suggested that infants with CH had a tendency to a prolonged gestation.13,14 With regard to the other neonatal risk factors, our results showed that twins had a high risk for CH. However, further investigations were needed to understand the causal association between twinning and CH. As expected,15–17 a high frequency of malformations had been observed among cases with CH 45 (14.3%) while a frequency similar to that expected in the general population was found in the control group 7 (2.1%). Although the association of congenital birth defects and CH had already been well documented, the inclusion of that variable in the multivariate model allowed an adjusted estimate of the relative risk for other factors, such as twins pregnancy,18,19 related to both CH and malformations. Our results reported an increased risk of CH with gestational diabetes. These results were also consistent with those obtained by other authors in an experimental model;20 it was reported in this report that maternal diabetes in pregnancy negatively affects the fetal thyroid hormone status in pregnant rats with streptozotocin-induced diabetes mellitus. The causal relationship between diabetes in pregnancy and CH is not clear. However, it is well known that maternal diabetes affects embryonic development, leading to increased morbidity in the offspring.14 In addition to the inherent limitations of this type of study, we used a sample of convenience from Fayoum Governorate, a technique that may have limited the generalizability of our findings. To help overcome this limitation, we selected our participants via a population-based case-control study to reduce the selection bias from the sample. Fortunately, the demographics of our sample were similar to the overall population of Egyptian mothers.7 In conclusion, our results suggest that genetic (high frequency of malformations) and environmental factors (especially maternal diabetes) play a role in the development of CH at Fayoum Governorate, Egypt Acknowledgments The author thanks Dr. Fakhery Farag and Dr. Ahmed Yaseen, pediatricians of Fayoum Insurance Hospital, for data supplementation. The author also thanks Dr. Yaseen’s wife for linguistic revision. Table 1 The selected demographic characteristics, consanguinity, and pregnancy history of CH cases compared to their matched controls. Characteristic Cases (n=320) Controls (n=320) P n % n % Sociodemographic factors Mother’s age  ≤25 years 42 13.12 144 45  25–39 years 250 78.12 163 50.93 .09a  ≥40 years 28 8.75 13 4.06 Consanguinity Pregnancy 10 3.12 20 6.25 .99  First pregnancy 182 56.87 118 36.87 .78  Previous abortion 71 22.18 51 15.93 .61 Gestational diabetes 16 5 4 1.24 <.01 CH: Congenital hypothyroidism. a Overall χ2 test. Table 2 The neonatal characteristics of CH cases compared to their matched controls. Neonatal characteristics Cases (n=320) Controls (n=320) P n % n % Female gender 201 62.8 154 48.12 <.01 Gestational age (weeks) ≤37 23 7.18 15 4.68 37–40 184 57.50 254 79.37 ≥41 113 35.31 51 15.93 <.01a Birth weight (grams) ≤2500 21 6.56 17 5.31 2500–3500 196 61.25 196 61.12 3500–4500 98 30.62 104 32.50 ≥4500 5 1.56 3 0.93 .20a Twins 16 5 2 0.62 <.01 Additional birth defects 45 14.06 7 2.18 <.01 a Overall χ2 test Table 3 The OR for CH estimated by the conditional logistic regression. Risk factors Cases (n=320) OR Controls (n=320) 95% CIs Female gender Mother’s age (years) 2.0 1.2–3.3  ≤25 1.7 0.96–3.4  ≥40 1.6 0.6–4.6 Gestational age (weeks)  ≤37 1.4 0.5–3.9  ≥40 3.0 1.8–5.1 Twins pregnancy 12.2 2.4–62.3 Additional birth defects 7.5 2.9–19.0 CH: Congenital hypothyroidism. ==== Refs REFERENCES 1 Gaudino R Garel C Czernichow P Leger J Proportion of various types of thyroid disorders among newborns with congenital hypothyroidism and normally located gland: a regional cohort study Clin Endocrinol (Oxf) 2005 62 4 444 8 15807875 2 Rastogi MV LaFranchi SH Congenital hypothyroidism Orphanet J Rare Dis 2010 5 17 20537182 3 Kurinczuk JJ Bower C Lewis B Byrne G Congenital hypothyroidism in Western Australia 1981–1998 J Paediatr Child Health 2002 38 2 187 91 12031004 4 Medda E Olivieri A Stazi MA Grandolfo ME Fazzini C Baserga M Risk factors for congenital hypothyroidism: results of a population case-control study (1997–2003) Eur J Endocrinol 2005 153 765 73 16322381 5 Grüters A Biebermann H Krude H Neonatal thyroid disorders Horm Res 2003 59 24 9 12566717 6 El-Zanaty F Way A Egypt demographic and health statistics Egyptian National Population Council Cairo, Egypt 2006 7 Ministry of Health, Cairo, Egypt Demographic and Health Surveys 2009 8 Park SM Clifton-Bligh RJ Betts P Chatterjee VK Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor Clin Endocrinol (Oxf) 2004 60 220 7 14725684 9 Sobel EH Saenger P Hypothyroidism in the newborn Pediatr Rev 1989 11 15 20 2664746 10 Waller DK Anderson JL Lorey F Cunningham GC Risk factors for congenital hypothyroidism: an investigation of infant’s birth weight, ethnicity, and gender in California, 1990–1998 Teratology 2000 62 36 41 10861631 11 Law WY Bradley DM Lazarus JH John R Gregory JW Congenital hypothyroidism in Wales (1982–1993): demographic features, clinical presentation and effects on early neurodevelopment Clin Endocrinoln (Oxf) 1998 48 201 7 12 Sun G Xu Zm Liang JF Lin L Tang DX Twelve-year prevalence of common neonatal congenital malformations in Zhejiang Province, China World J Pediatr 2011 7 331 6 22015725 13 Parazzini F Cortinovis I Bortolus R Fedele L Decarli A Weight at birth by gestational age in Italy Hum Reprod 1995 10 1862 3 8582998 14 Nold JL Georgieff MK Infants of diabetic mothers Pediatr Clin North Am 2004 51 619 37 15157588 15 Sorcini M Fazzini C Olivieri A Grandolfo ME Medda E Stazi MA Neonatal screening in congenital hypothyroidism in Italy. 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