clinical & basic research SQU Med J, April 2010, Vol. 10, Iss. 1, pp. 23-30, Epub. 17th Apr 10 Submitted 21st Oct 2009 Revision Req. 12th Dec 09, Revision Recd. 21st Jan 10 Accepted 16th Feb 10 1Eye & Ear Health Care, Department of Non-communicable Diseases Control, Directorate General of Health Affairs, Ministry of Health, Oman; 2Department of Maternal & Child Health Care, Ministry of Health, Oman To whom correspondence should be addressed. Email: rajshpp@omantel.net.om حدوث وحتديد العيوب اخِللِْقيّة وقصور اإلنزيم لدى املواليد األحياء يف سلطنة ُعمان مراجعة السجل الوطين لعام 2005م راجيف خانديكار، يا�شمني جعفر ال�رقة هذه اخِلْلِقّية. الت�ش�هات حاالت ت�شجيل ببدء الطف�لة رعاية بربنامج ممثلة 2003 عام يف ال�شحة وزارة �رسعت الهدف: امللخ�ص: عام 2005م. بال�شجل وامل�شجلة ُعمان ب�شلطنة االأحياء امل�اليد بني اخِلْلِقّية الت�ش�هات ذوي االأطفال لدى ااِلْخِتطار َع�اِمِل مقدار ت�شتعر�س الطريقة: قام االأطباء املخت�ش�ن بطب االأطفال وطب حديثي ال�الدة بفح�س االأطفال ذوي العي�ب اخِلْلِقّية الذين مت ت�شجيلهم والتبليغ عنهم اإما اأثناء فح�شهم عند ال�الدة اأو يف خالل ال�شنة االأوىل من العمر اأثناء ترددهم للعيادات.مت اإجراء الفح��شات ال�رسيرية واملختربية والت�ش�ير . قبل الفح��شات مت كتابة التفا�شيل ال�شخ�شية، ن�ع الت�ش�هات اخِلْلِقيّة باالإ�شافة اإىل ا�شتخدام الت�شنيف الدويل َ�اِتيِّ ال�شعاعي والَتْخطيط الَت�شْ لالأمرا�س - ICD-10 ( 10 ( مع َع�اِمِل اِْخِتطار خمتارة. مت ح�شاب معدالت االإ�شابة بالن�شبة املئ�ية.النتيجة: كان معدل االإ�شابة ال�شن�ية يف �شلطنة ُعمان %2.53 )فرتة ثقة 95 : 2.68-2.38 (. كان لدى الذك�ر اِْخِتطار اأعلى بالت�ش�هات اخللقية من االإناث. )اْخِتطاٌر ِن�ْشِبّي = 2.0 (. التباين املناطقي كان معتدا اإح�شائيا اأي�شا ) مربع كاي = 363 (. كان معدل االإ�شابة بفقر الدم نتيجة ا�شطرابات االإنزميات %1.4. اأما ت�ش�هات اجلهاز الب�يل-التنا�شلي واليدين والقدمني ومتالزمة داون فكانت مُتّثل العي�ب الت�رسيحية الرئي�شية. كان الزواج لدي االأقارب )اْخِتطاٌر ِن�ْشِبّي = 0.85( وانخفا�س ال�زن عند ال�الدة ) )اْخِتطاٌر ِن�ْشِبّي = 0.28 ( مرتبطني �شلبيا مع الت�ش�هات اخِلْلِقّية. كان االْخِتطاٌر الِن�ْشِبّي )1.89( واالأم. االأب من كل عمر ارتباطا.بني جند مل اأطفالهن. عند عالية اخِلْلِقّية الت�ش�هات اأن تبني حيث اأ�شب�عا 37< يلدن الل�اتي االأمهات لدى اخلال�صة: يعترب ال�شجل ال�طني للت�ش�هات اخِلْلِقّية اأداة هامة للتقييم. اإن َع�اِمِل ااِلْخِتطار الناجتة عن الع�امل ال�راثية واملكت�شبة ميكن اأن ت�ؤثر على معدل العي�ب اخِلْلِقّية ون�عيتها يف �شلطنة ُعمان. مفتاح الكلمات: الت�ش�هات اخِللقية، العي�ب اخِللقية، �شلطنة ُعمان. abstract: Objectives: In 2003, the Omani Ministry of Health Child Health Care Program initiated a national Birth Defects (BD) Register. This paper reviews the magnitude and risk factors of birth defects in children born and registered in 2005 using data from the BD Register. Methods: Pediatricians and neonatologists examined children with BDs found either during screening at birth or when attending clinics in their first year of their life. Clinical examination, laboratory, sonographic and radiological investigations were carried out. A pre-tested form was used to note personal details, type of birth defect including International Classification of Diseases-10 (ICD-10) codes of BD and selected risk factors. The incidence rates per 100 live births were calculated. Results: The annual incidence of BD in Oman was 2.53% (95% CI 2.38–2.68). Males had a significantly higher risk of BD than females (relative risk (RR) = 2.0). The regional variation of BD was also significant (χ 2 = 363). The incidence of anaemia due to enzyme disorders was 1.4%. BD of urogenital organs, hands and feet and Down’s syndrome were the main types of anatomical defects. Consanguinity among parents (RR = 0.85) and low birth weight (RR = 0.28) was negatively associated to birth defects. Mothers giving birth at gestational age of <37 weeks (RR = 1.89) had a higher risk of having children with BD. Maternal and paternal age were not associated to BD. Conclusion: The national Register for BD is an important evaluation tool. Both genetic and acquired risk factors seem to affect BD rates and types in Oman. Keywords: Birth defects; Congenital anomalies; Oman. Incidence and Determinants of Birth Defects and Enzyme Deficiencies among Live Births in Oman A review of the 2005 National Register *Rajiv Khandekar,1 Yasmin Jaffer2 clinical & basic research Incidence and Determinants of Birth Defects and Enzyme Deficiencies among Live Births in Oman A review of the 2005 National Register 24 | SQU Medical Journal, April 2010, Volume 10, Issue 1 The United Nation’s Millennium Developmental Goal-4 to reduce child mortality by two-thirds from 1990 levels by 2015 will not be met unless the mortality from birth defects and preterm birth is recognised and addressed.1 Worldwide, the prevalence rates of all genetic birth defects combined range from a high of 82/1,000 live births in low-income regions to a low of 39.7/1,000 live births in high- income regions.2 Countries like Oman, which has undergone rapid socioeconomic development, are currently undergoing epidemiological transition. Communicable disease rates are declining, but chronic and non-communicable diseases are on the rise.3 The magnitude of genetic disorders is high in Omani children and it is likely to increase unless known risk factors like consanguinity, better survival of preterm babies due to improved child health care, and limited acceptance of therapeutic abortions are addressed.4 The Maternal and Child Health Care Program as well as the programme for controlling genetic disorders in Oman has recognised this health problem and included it in 6th Five Year Health Plan.5 A national BD Register was started in 2003 with BD defined as physical abnormalities or enzyme deficiency, mainly glucose-6-phosphate dehydrogenase deficiency (G6PD). Paediatricians provide the information for the Register and its programme managers improved its quality of Register in the initial years. The authors analysed the national BD Register for 2005 to estimate the incidence of BDs for live births and their epidemiological determinants. On this basis, public health related recommendations were proposed. Methods This was a review of the national BD Register. The Ethical and Research Committee of the Ministry of Health gave permission for the study. Paediatricians and neonatologists at ten regional hospitals were our study investigators. All babies born in the year 2005 in Oman were our total study population. Children with BDs, found either during screening at birth or when attending clinics in their first year of their life, were our specific study population. Those identified with anatomical deformities were registered after detailed clinical examination. Blood tests were performed for children suspected to suffer from genetic blood disorders. Children with BDs also underwent radiological and sonographic evaluation to identify any other anomalies in addition to the principal defect. Personal information like date of birth, sex, area of residence, tribe, mother’s age at birth, father’s age, order of birth, birth weight, gestational age on birth, status of child in the first year of life (alive or dead), medical history and degree of consanguinity among parents were noted on a standardised pre-tested form. The principal BD as per the International Classification of Diseases-10 (ICD-10) code was also noted. All the children with Down’s syndrome had their condition confirmed by laboratory tests. The children were managed by paediatric services either in regional hospitals or with the help of a paediatric surgeon Advances in Knowledge 1. This review provides a profile of infants with birth defects (BD) as reported in the Oman BD Register 2. The incidence of different BD in relation to live births for 2005. 3. Down’s syndrome and anomalies of extremities were common in Oman. 4. To meet international standards, the Register should include BDs of aborted fetuses. 5. The current methodology of including enzyme deficiencies as BDs, although important for Oman, is not as per the international database on BD. 6. Incidence of BD in Oman in this study could be underestimated. Application to Patient Care 1. Countries experiencing a significant decline in the infant mortality rate due to less communicable and nutrition-related diseases still have to face the burden of genetic and birth defect related problems in infants. 2. Knowledge of the magnitude of the BD problem, the profile of birth defects and risk factors will enable the child health care programme of a country improve its implementation and planning. 3. The prevalence of BDs in Oman in 2005 was 2.53% (95% CI 2.38–2.68). Males, children with low birth weight, and residents of specific regions were significantly associated with BDs in children. 4. A well maintained national BD register is an important tool for global and national efforts to address this problem. Rajiv Khandekar and Yasmin Jaffer Clinical and Basic Research | 25 at tertiary hospitals. If treatment was possible, but facilities were not available within the country, the child’s treatment, in a reputed centre abroad, was paid for by the Omani government. The BD Register was initiated in the year 2002. The first year was the pilot phase to strengthen the registration system. From 2003, a national data collection system was implemented by the national Health Information Management System (HIMS). The Department of Mother and Child Health (MCH) of the Ministry of Health (MoH) liaised with regions to monitor and follow the registration of children with BD. Neonatologists and other specialists like paediatric ophthalmologists, ear, nose and throat surgeons, cardiologists, etc, in regional and wilayat (district) MoH hospitals reported information on BD. The attending physician of the institution where such a child was first reported was labelled as the reporting person. As information in the Register was based on identity of the parent health institution, duplications were avoided. The national supervisor for MCH followed through with the attending physicians to ensure the completion of all relevant information in the BD Register. The data on live births, children with low birth weights (< 2.5 kg) and the proportion of twin births, to determine plurality, was provided by the Department of Health Information and Statistics.6 The proportion of preterm babies in general population was 9.4% in a study in Saudi Arabia.7 We took it as reference for calculating preterm babies in the cohort of live births in 2005 in Oman. The regional health information officers computed the data from the pre-tested forms by using Epi Info™ 6 software (Center for Disease Control, USA).The statistician of the Oman Ministry of Health’s (MoH) Maternal & Child Health Care (MCH) Department compiled the national Register. After ensuring completion of information, univariate analysis was carried out using the parametric method and the Statistical Package for Social Studies (SPSS, Version 12). Frequencies and incidence of BDs nationally and of regional subgroups were calculated per 100 live births. The risk of BD was compared to the children born without BD in 2005 in Oman by calculating relative risk, 95% confidence intervals (CI) and P values (set at (< 0.05). The identities of children with BD and their parents were de-linked from information on risk factors of BD and only the principal investigator had access to this information. The results of this study were shared with regional paediatricians and the staff of the programme for the control of genetic diseases. Policies for strengthening the BD Register and the care of children with BD were then proposed to the members of the national Mother and Child Health Care Committee. Results The BD Register of Oman had 1,393 children registered in 2005. Of them, 1,065 (76.5%) children were born in 2005. Fifty-seven (4.02%) children with BD died in the first year of life. The characteristics of children with BD were compared to all the Omani children born in 2005 [Table 1]. Five children with BD had undetermined gender on clinical examination. The incidence of BDs was calculated for different epidemiological variables. Live births were used as the denominator to calculate the incidence of BD. Data on the birth cohort, number of children with BD, incidence per 100 live births, the relative risk, their 95% CI and the P values are given in Table 2. The incidence of BD in Oman during 2005 Table 1: Characteristics of the children born in 2005 and children with birth defects in Oman Children born in 2005 Children with birth defects # % # % Gender Male Female Undetermined Missing 21,264 20,801 - - 50.6 49.4 - - 582 288 5 190 54.6 27.0 0.5 17.8 region Muscat Dhofar Dhakhiliya North Sharqiya South Sharqiya North Batinah South Batinah Dhahira Musandam Al Wusta 9,861 4,115 5,727 3,466 4,088 6,856 3,778 3,578 436 160 23.4 9.8 13.6 8.2 9.7 16.3 9.0 8.5 1.0 0.4 184 66 338 40 105 190 78 41 21 2 17.3 6.2 31.7 3.8 9.9 17.8 7.3 3.8 2.0 0.2 Total 42,065 100 1,065 100 Incidence and Determinants of Birth Defects and Enzyme Deficiencies among Live Births in Oman A review of the 2005 National Register 26 | SQU Medical Journal, April 2010, Volume 10, Issue 1 was 2.53 per 100 live births and was significantly higher in boys compared to girls. (RR = 1.98 (95% CI 1.72–2.27), P = <0.001). The regional variation of reporting BD in children was significant. The Dhakhiliya region had significantly higher BD rates (5.90 per 100 live births; 95% CI 5.29–6.51), whereas the North Sharqiya and Dhahira regions had lower incidences of BD (1.15/100 live births). The types of BDs as per the ICD-10 codes with incidence per 100 live births are given in Table 3. Of the 1,065 children with BD, 589 (55.3%) had anaemia due to G6PD enzyme disorders. Deformities of hands and feet were noted in 106 children with an incidence of 0.25 per 100 live births. The rate of BDs was compared among the different subgroups of children born in 2005; the frequencies, relative risks, 95% CI and P values are given in Table 4. We did not find a significant association between maternal age at birth and the presence of BD. The information on other variables was missing for nearly half of the participants. Discussion This is the first attempt at national level in Oman to review the profile of children with BD. The infant mortality rate (IMR) in Oman of 10.28/1,000 live births is now mainly due to non-communicable diseases. The high rate of hospital deliveries in Oman, together with a nearly 100% immunisation rate of children against infectious diseases (including rubella) as well as free access to high standard, regional neonatal and child health care services have resulted in a marked decline in deaths due to avoidable conditions.8 Unfortunately, risk factors for genetic disorders such as the high rate of diabetes in women,9 consanguineous marriage practices, 10 limited therapeutic abortions and mothers of older age are still present in Oman. In such a situation, knowledge of the incidence of BDs and their risk factors is crucial in order to formulate future prevention and intervention policies. In 2005, the overall incidence of BD in Oman was 2.53% (95% CI 2.38–2.68), but a study in one of the regions of Oman showed a BD prevalence of 2.46%.11 The rate in Oman was more than that reported in Iran (1.01%),12 Kuwait (1.25%)13 Bangladesh (2.3%)14 and the UAE (0.79%).15 It is worth noting that, in spite of variations in all these studies, the populations were all of Muslim religion. Apart from Bangladesh, the other study areas were in Middle Eastern countries, where the health services are accessible and of a high standard. Therapeutic abortion is also not widely accepted in these countries. Despite the similarities among these countries the differences in the rates cannot be explained. Perhaps the high incidence of diabetes in the >20 population in Oman and diabetes in mothers being a known risk factor of BD, could be a logical explanation for the higher incidence of BD in our study.16,17,18 Further studies of specific BDs in Oman are recommended to explain the reason for the higher incidence of BD in Oman compared to neighbouring countries. However, Oman has the following factors which militate against the higher incidence of BDs found in this study: 1) only 0.5% prevalence of smoking among females;19 2) a religious taboo on the consumption of alcohol and controls on its availability; 3) low incidence of malnourishment and folic acid provision to females during antenatal period points at a lower risk of central nervous system congenital malformation;20 4) universal immunisation against rubella,21 and 5) controlled prescription of medicines with teratogenic properties. The incidence of BD was significantly higher in males compared to females in our study. This was also reported in Iran and in a study by Cui et Table 2: Incidence of Birth Defect (BD) per 100 live births in Oman in 2005. Variant Live births No. with BD % of BD 95% CI Gender* Male Female 21,264 20,801 799 390 2.74 1.38 2.52–2.96 1.23–1.54 region** Muscat Dhofar Dhakhiliya N. Sharqiya S. Sharqiya N. Batinah S. Batinah Dhahira Musundam Wousta 9,861 4,115 5,727 3,466 4,088 6,856 3,778 3,578 436 160 184 66 339 40 105 190 78 41 21 2 1.87 1.60 5.90 1.15 2.57 2.77 2.06 1.15 4.82 1.25 1.60–2.13 1.22–1.99 5.29–6.51 0.80–1.51 2.08–3.05 2.38–3.16 1.61–2.52 0.80–1.49 2.81–6.83 -0.47 -2.97 Legend: RR = relative risk; *Validity: RR = 1.98, 95% CI = 1.72 – 2.27, P value = <0.001; **Validity: χ 2 = 363, 95% CI : Df =8, P value = <0.001 Rajiv Khandekar and Yasmin Jaffer Clinical and Basic Research | 27 al.12, 22 A study of opposite sex twins suggested that males had a 29% higher risk of BD compared to their sisters.23 A study with a large sample showed that a higher percentage of males was noted with obstructive cardiac defects while females were more likely to have all types of neural tube defects.24 Folic acid supplementation and high take-up rates of antenatal care in Oman may have resulted in a lower incidence of neural tube defects and less females with BD of these types. The regional variation in BD was marked in Oman. Different tribes in different regions could explain this variation. Regional variation was noted in the prevalence of congenital heart defects in a study done in Saudi Arabia.20 A maternal age of more than 25 years was associated with BDs in the United Arab Emirates.15 In our study also, younger mothers had children with BD. In contrast, mothers of >35 years of age had a significantly higher risk of having children with autism and heart defects BD.25, 26 In another study in Oman, older aged mothers had a significant risk of giving birth to children with Down’s syndrome.27 We cannot explain the reason for this negative association in the present study. We did not include stillborn and naturally aborted preterm infants when calculating the incidence and risk factor in our study. Multi-system genetic disorders could be higher in the group that died prematurely. Perhaps this could be the reason of the observed non- association in our study. The influence of paternal age (>35 years) was associated with a higher incidence of Down’s syndrome.28 Factors related to the father’s occupation also have been attributed to incidence of BD.29 In our study, we did not find such an association. Information on the father’s age was missing for 29 children and these fathers are more likely to be in the >45 years age group. If we review the risk of BD on this assumption, then paternal age was a significant risk factor for BD in Oman. Low birth weight and preterm babies are known risk factors for BD.13, 15, 30 Surprisingly, low birth weight was negatively associated to BD in our study. The non-inclusion of stillbirths with BD might be the reason for such an association. The risk of BD has been noted in twin and multiple pregnancies especially those arising from artificial reproductive techniques.31 Since there was no information on weight and plurality for a large number of children in our cohort, the association of BD with birth weight and plurality should be viewed with caution. Given the fact that there were only seven pairs of twin children, we did not calculate the risk of BD to plurality. It should be noted that BD could be the reason for preterm deliveries and low birth weight of infants. Consanguinity has been documented as a risk factor for many congenital anomalies.32, 33 However, in our study, it was not found to be a risk factor for BD. Since we excluded still births and aborted fetuses, we may have found less multi-syndromic congenital anomalies with a strong genetic link. In addition, small and close-knit communities, such as the Kabila tribe in Oman, could have a long history of consanguinity; however, given better education Table 3: Birth Defect (BD) by type in Oman in 2005 (42,065 live births in 2005) Children with BD Incidence of BD 95% Confidence Interval Type of BD Anaemia due to enzyme disorders Deformities of hand & feet Urogenital anomalies Anomalies of skull & spine Anomalies of heart & great vessels Down’s syndrome Musculoskeletal anomalies Cleft palate/lip Anomalies of alimentary canal Malformations of eye & ear Respiratory anomalies Other 589 106 80 41 41 32 23 21 21 19 6 86 1.40 0.25 0.19 0.10 0.10 0.08 0.05 0.05 0.05 0.05 0.01 0.20 1.29–1.51 0.20–0.30 0.15–0.23 0.07–0.13 0.07–0.13 0.05–0.10 0.03–0.08 0.03–0.07 0.03–0.07 0.02–0.07 0.00–0.03 0.16–0.25 oman 1,065 2.53 2.38–2.68 Incidence and Determinants of Birth Defects and Enzyme Deficiencies among Live Births in Oman A review of the 2005 National Register 28 | SQU Medical Journal, April 2010, Volume 10, Issue 1 in the younger generation, consanguinity, a known risk factor for BD, may now be less than in the past. Migration to urban areas and the growth of the nuclear family has also been postulated to dilute the role of consanguinity and that could be the reason for the observed association of consanguinity with BD in our study. 34 Anaemia due to G6PD enzyme disorders was the main reported BD in Oman. This agreed with earlier observations in Oman.35, 36 There were a significant number of BDs of the urogenital system, Down’s Syndrome children and deformities of the hands and feet in our study. Further studies with a larger sample of these BDs are recommended. The surveillance for BD in different countries as reported by International Center for Birth Defect Surveillance and Research (ICBDSR) suggested that rate of Down’s syndrome in our study matched that of Cuba and Italy. However, it was lower than USA, Canada and France.37 Inclusion of BD among aborted fetuses in other countries could be the reason for the higher rate compared to our study. In these countries, the registration included BD among aborted fetus and paid special attention to factors during pregnancy associated to BD. In Oman, the BD Register included genetic blood disorders and excluded aborted fetuses therefore comparison of rates should be done with great caution. As this study was a retrospective Register review, loss of data or incomplete data was an inherent limitation. In spite of communicating with regional programme managers to complete the Register as well as using indirect indicators from other sources like the child health registers at primary health institutions and records of infant deaths at regional hospitals, we still had missing information that could have introduced bias into our study especially while reviewing the association of risk factors to BD. Our study suggested that the incidence of BD in surviving infants was high. The Maternal and Child Health Program should emphasise the Table 4: Risk factors for Birth Defects (BD) risk factor Live births Children with BD RR 95% Confidence Interval P value Mother’s age < 35 years ≥ 35 years Missing 36,122 5,929 874 128 13 0.89 - - 0.77– .07 - - 0.25 - - Father’s age < 45 years ≥ 45 years Missing 37,981 4,084 1,217 147 29 1.11 - - 0.95–1.29 - - 0.19 - - History of consanguinity in parents Yes No 23,683 18,382 555 510 0.85 0.75–0.96 0.007 Birth weight < 2.5 kg ≥ 2.5 kg Missing 3,470 38,595 114 350 601 0.28 - - 0.23–0.35 - - < 0.0001 - - Gestational age at birth < 37 weeks ≥ 37 weeks Missing 3,954 38,111 77 371 617 1.98 1.55–2.53 < 0.001 Plurality Single birth Multiple births Missing 41,689 376 - 457 7 601 1.70 - - 0.81–3.56 - - 0.20 - - Rajiv Khandekar and Yasmin Jaffer Clinical and Basic Research | 29 need for improved quality of registration in order to ensure complete records. Both genetic and acquired factors seem to interact and result in a high incidence of BD in Oman. The health services at regional level should be well equipped to identify and manage children with BD. Some of the children with BD, even after successful management, will need long term follow-up and rehabilitation. Hence prevention, care and rehabilitation should be an integral component of the BD control programme. Further studies of important BDs and their risk factors would enable the programme to formulate a preventive and rehabilitative approach for each of them. a c k n o w l e d g e m e n t s We would like to thank Mr Hamoud S Al-Gabri, Health Information Officer and Ms Flor Deliza of the Ministry of Health’s Maternal and Child Health Program for their help in interpreting the data related to maternal and child health care linked to the national Register for BD in Oman. We also acknowledge the contribution of health professionals in regions especially the paediatricians and neonatologists who examined the children with BDs. We thank Dr. Anna Rajab of the Genetics Unit at the Royal Hospital, Muscat, Oman, for advice in writing part of the discussion section. The cooperation and commitment of parents and relatives of children with BD are highly appreciated. The preliminary results of this study were presented in 1st National Conference of Birth Defects held in Muscat, Oman, in 2007. References 1. Martines J, Paul VK, Bhutta ZA, Koblinsky M, Soucat A, Walker N, et al. Neonatal survival: a call for action. Lancet 2005; 365:1189–97. 2. Christianson A, Howeson CP, Modell B. Executive Summary, Global report on Birth Defects. White Plains, New York: March of Dimes Birth Defects Foundation, 2006. pp. 2–8. 3. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 2001; 104:2746–53. 4. Al-Riyami A, Ebrahim GJ. Genetic Blood Disorders Survey in the Sultanate of Oman. J Trop Pediatr 2003; 49:1–20. 5. Ministry of Health, Sultanate of Oman. Birth defect Domain in 7th Five Year Health Plan. Muscat: International Printing Press. pp. 197–204, 6. Ministry of Health, Sultanate of Oman. Annual Health Report year 2005, Muscat: Ministry of Health. pp: 8/11–8/15. 7. Arafa MA, Alkhouly A, Youssef ME. Influence of inter-pregnancy interval on preterm delivery. Paediatr Perinat Epidemiol 2004; 18:248–52. 8. Sulaiman AJ, Al-Riyami A, Farid S, Ebrahim GJ. Oman Family Health Survey 1995. J Trop Pediatr 2001; 47:1–33. 9. Sawardekar KP. Profile of major congenital malformations at Nizwa Hospital, Oman: 10-year review. J Paediatr Child Health 2005; 41:323–30. 10. Golalipour MJ, Ahmadpour-Kacho M, Vakili MA. Congenital malformations at a referral hospital in Gorgan, Islamic Republic of Iran. East Mediterr Health J 2005; 11:707–15. 11. Madi SA, Al-Naggar RL, Al-Awadi SA, Bastaki LA. Profile of major congenital malformations in neonates in Al-Jahra region of Kuwait. East Mediterr Health J 2005; 11:700–6. 12. Khanum S, Noor K, Kawser CA. Studies on congenital abnormalities and related risk factors. Mymensingh Med J 2004; 13:177–80. 13. Cui W, Ma CX, Tang Y, Chang V, Rao PV, Ariet M, et al. Sex differences in birth defects: a study of opposite-sex twins. Birth Defects Res A Clin Mol Teratol 2005; 73:876–80. 14. Sharpe PB, Chan A, Haan EA, Hiller JE. Maternal diabetes and congenital anomalies in South Australia 1986-2000: a population-based cohort study. Birth Defects Res A Clin Mol Teratol 2005; 73:605–11. 15. Al-Lawati JA, Mohammed AJ. Diabetes in Oman: Comparison of 1997American diabetes association classification of diabetes mellitus with 1985 WHO classification. Ann Saudi Med 2000; 20:12–5. 16. Al Riyami AA, Afifi M. Smoking in Oman: prevalence and characteristics of smokers. East Mediterr Health J 2004; 10:600–9. 17. Gao LJ, Zhao ZT, Li D, Jiang BF, Hao FR. A case- control study on the risk factors of central nervous system congenital malformations. Zhonghua Liu Xing Bing Xue Za Zhi 2004; 25:794–8. 18. Cutts FT, Robertson SE, Diaz-Ortega JL, Samuel R. Control of rubella and congenital rubella syndrome (CRS) in developing countries, Part 1: Burden of disease from CRS. Bull World Health Organ 1997; 75:55–68. 19. Al Hosani H, Salah M, Abu-Zeid H, Farag HM, Saade D. The National Congenital Anomalies Register in the United Arab Emirates. East Mediterr Health J 2005; 11:690–9. 20. Lisi A, Botto LD, Rittler M, Castilla E, Bianca S, Bianchi F, et al. Sex and congenital malformations: an Incidence and Determinants of Birth Defects and Enzyme Deficiencies among Live Births in Oman A review of the 2005 National Register 30 | SQU Medical Journal, April 2010, Volume 10, Issue 1 international perspective. Am J Med Genet A 2005; 134:49–57. 21. Greer W, Sandridge AL, Al-Menieir M, Al Rowais A. Geographical distribution of congenital heart defects in Saudi Arabia. Ann Saudi Med 2005; 25:63–9. 22. Maimburg RD, Vaeth M. Perinatal risk factors and infantile autism. Acta Psychiatr Scand 2006; 114:257–64. 23. Reefhuis J, Honein MA. Maternal age and non- chromosomal birth defects, Atlanta, 1968-2000: teenager or thirty-something, who is at risk? Birth Defects Res A Clin Mol Teratol 2004; 70:572–9. 24. Rajab A, Neitzel H, Näthe J, Goud M, Al-Harrasi S, Khandekar R, et al. Down syndrome in Oman. Epidemiol Molecul Studies (in press) 25. Chia SE, Shi LM, Chan OY, Chew SK, Foong BH. A population-based study on the association between parental occupations and some common birth defects in Singapore (1994-1998). J Occup Environ Med 2004; 46:916–23. 26. Salt A, D’Amore A, Ahluwalia J, Seward A, Kaptoge S, Halliday S, et al. Outcome at 2 years for very low birth weight infants in a geographical population: risk factors, cost, and impact of congenital anomalies. Early Hum Dev 2006; 82:125–33. 27. Hellmann O, Bentov Y. Congenital malformations in children born after IVF. Harefuah 2005; 144:852–8, 910. 28. Ramegowda S, Ramachandra NB. Parental consanguinity increases congenital heart diseases in South India. Ann Hum Biol 2006; 33:519–28. 29. Donbak L. Consanguinity in Kahramanmaras city, Turkey, and its medical impact. Saudi Med J 2004; 25:1991–4. 30. Bittles AH. Endogamy, consanguinity and community genetics. J Genet 2002; 81:91–8. 31. Al-Riyami A, Ebrahim GJ. Genetic Blood Disorders Survey in the Sultanate of Oman. J Trop Pediatr 2003; 49:i1–20. 32. Rajab AG, Patton MA, Modell B. Study of hemoglobinopathies in Oman through a national register. Saudi Med J 2000; 21:1168–72. 33. Rajab A, Patton M. A study of consanguinity in the Sultanate of Oman. Annals of Hum Biology 2000; 3:321-326. 34. Mathew M, Machado L, Al-Ghabshi R, Al-Haddabi R. Fetal macrosomia. Risk factor and outcome. Saudi Med J 2005 Jan; 26:96-100. 35. Mathew M, Saquib S, Rizvi SG. Polyhydramnios. Risk factors and outcome. Saudi Med J 2008 Feb; 29:256-60. 36. Ghosh S, Feingold E, Dey SK. Etiology of Down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am J Med Genet A 2009; 149:1415–20. 37. International Center on Birth Defects and Research (ICBDSR). Table 6 in collaborative research projects. In: Annual report for 2007 with Data for 2005. ICBDSR, Rome: Italy, 2007. p. 13. From http://www. icbdsr.org/filebank/documents/ar2005/Report2007. pdf Accessed January 2010.