Comprehensive Newborn Screening Program: ARAMCO Experience, The National Need and Recommendations

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1 Originial Articles Comprehensive Newborn Screening Program: ARAMCO Experience, The National Need and Recommendations Yousef K. Abu-Osba, MD; Ahmad Mallouh, MD; Mouhamed Salamah, MD; Richard Hann, MD; Amin Thalji, MD; Jahed Hamdan, MD; Abed Alrahman Sa'di, MD From the Departments of Pediatrics (Dr. Abu-Osba), King Faisal Specialist Hospital and Research Centre, Riyadh, and the Department of Pediatrics and Pathology (Drs. Mallouh, Salamah, Hann, Thalji, Hamdan, Sa'di), Dhahran Health Center, Dhahran. Address reprint requests and correspondence to Dr. Abu-Osba: Neonatology/Perinatology Section, Department of Pediatrics (MBC 58), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Accepted for publication 8 July Comprehensive screening programs for congenital diseases of newborn infants are lacking at a national or regional level. A comprehensive newborn screening program modified to the needs and resources available was established in ARAMCO Dhahran Health Center. This program includes screening for congenital hypothyroidism, phenylketonuria, abnormal hemoglobins, glucose-6-phosphate dehydrogenase deficiency, and blood group incompatibilities. Several problems were encountered during the operation which required several modifications of the program. The organization and procedures of the program are described. Since the program was started in 1980, more than 70,000 newborn infants have been screened. Valuable epidemiological data have been collected and necessary information for direct clinical use was obtained. A national program to screen all neonates in the Kingdom of Saudi Arabia is achievable and urgently needed. Recommendations based on ARAMCO experience are given. YK Abu-Osba, A Mallouh, M Salamah, R Hann, A Thalji, J Hamdan, AA Sa'di, Comprehensive Newborn Screening Program: Aramco Experience, The National Need and Recommendations. 1992; 12(3): Screening programs for congenital diseases of newborn infants have been in effect for several decades in some countries. More than 30 diseases can be screened for in the neonatal period, and this list is growing [1 6]. Developing countries lack newborn screening programs for various reasons. But which diseases should be screened for and what is the priority? A major obstacle is lack of knowledge of the accurate incidence and the natural history of such diseases in the developing countries including Saudi Arabia. Sickle cell disease is a good example in which the clinical history varies in different geographical areas [7 15]. In newborn infants and children, an increased incidence of sepsis and serious infections in association with glucose-6-phosphate dehydrogenase deficiency and abnormal hemoglobins has been documented [16 19]. Peculiar clinical presentation and the incidence of hemoglobin H disease in the neonatal period has been described in Saudi Arab infants [20]. Health care has greatly improved in the last decades in the Kingdom. Now is the time to put effort into the campaign of controlling and preventing some potentially disastrous genetic diseases. Such comprehensive screening programs are lacking at the national or regional level, although a screening program for congenital hypothyroidism has been started by the Ministry of Health. The cost/benefit effectiveness of neonatal screening has been established. Regionalization, automation and testing a single specimen for several defects simultaneously will decrease the cost in a comprehensive genetic screening program even further. Several problems and obstacles face the establishment of a newborn screening program for the whole Kingdom. These can be summarized in the following: manpower, technical expertise, time of sample collection, confirmation, treatment and follow-up, and appropriate funds to run the program. The following options are available to establish a mass screening program for the Kingdom: affiliation

2 with an established program which is costly and time consuming, or establishing/designating a central laboratory in every region which is more cost effective with less delays in diagnosis. ARAMCO Newborn Screening Program Experience Arabian American Oil Company (ARAMCO) Medical Organization provides the medical care for 50 to 60,000 employees and their dependents in several health care facilities and a major referral hospital (Dhahran Health Center). ARAMCO established the first comprehensive neonatal screening program in the Kingdom in October 1980 [21]. This program includes screening for congenital hypothyroidism, phenylketonuria, abnormal hemoglobins, glucose-6-phosphate dehydrogenase, and blood group incompatibilities. The total number of newborn infants born in ARAMCO medical care facilities ranges between 6,000 to 8,000 deliveries per year. More than 70,000 newborn infants have been screened so far in this program which is the largest and most comprehensive in the country. ARAMCO employees come from more than 32 countries. More than 90% of the newborn infants are Saudi Arabs whose families come from the whole country from Najran to Dammam. The personnel computer files are coded for the family original residence and nationality thus facilitating the analysis of the results. Organization and Procedures of ARAMCO NSP Blood Sample Collection Midwives or physicians attending deliveries collect blood samples from the cord and laboratory technicians or nurses collect venous capillary blood samples according to standard procedures from babies who were delivered in hospital or at home, respectively. Both cord blood and capillary or venous samples are suitable for testing for blood group incompatibility, abnormal hemoglobins, G-6-PD and congenital hypothyroidism. Heel stick sample on a filter paper after 48-hours feeding or at the time of discharge from the hospital were collected for PKU. Infants born at home were tested during hospitalization or their first visit to the clinic. Sample Processing All blood samples were labelled and transported to Dhahran Medical Laboratory where all tests were performed. A copy of the results was distributed to each of the medical records of the outpatient file, screening physician and the coordinator of screening program. All results were entered in a specially designed computer program for analysis. Subsequently, all results were available in a computer terminal in all ARAMCO clinics which provide direct and easy access to the results. Laboratory Methods G-6-PD deficiency in red blood cells was tested as described by Beutler and Mitchell [22]. Total serum thyroxine was determined by radioimmunoassay using a comercially available kit (Tetra-Tab RIA), Nuclear- Medical Laboratories, Inc., Dallas, Texas, USA. Thyroid stimulating hormone was measured by radioimmunoassay for all infants with cord blood thyroxine value of two standard deviations below the mean for all the tests performed. Abnormal hemoglobins were tested for by screening hemoglobin electrophoresis and quantitative confirmatory tests were utilized to verify hemoglobin migrating in the same area as S, C, H, and Bart's. Blood typing was done by the slide and tube procedures. Phenylketonuria was tested for by Guthrie method [23]. Quality control for all tests was performed. Coordination of Patient Care A manual was developed defining the goals, policies, procedures, methods, treatment and follow-up, personnel responsibilities and quality control (available at King Faisal Specialist Hospital and Research Centre Medical Library) [24]. The primary responsibility was carried out by a designated physician in every medical care facility. A hematologist, endocrinologist, and a developmental pediatrician were available for consultation and follow-up. A coordinator for the entire screening program had the following responsibilities: (1) reviews the newborn screening program policies and procedures and revises them if necessary, (2) performs statistical analysis of the results, (3) provides guidance to the physicians and nurses with regard to the program, (4) initiates a quality assurance program, (5) maintains the newborn screening program manual; reviewing, revising and updating.

3 Results of ARAMCO NSP Since the ARAMCO newborn screening program was started in 1980 more than 70,000 newborn infants have been screened. The following is an overview of the preliminary analysis of the first 35,000 infants. Abnormal Hemoglobins The incidence of all abnormal hemoglobins (Abn Hb) in Saudi Arab neonates varied significantly from one original family residence to another (Table 1). In Urn Al-Hamam, it was as high as 62.8%, in Abha as low as 6.7%, and Riyadh 12.5%. Sickle cell hemoglobin (Hb S) incidence for all Saudi Arab neonates screened was 14.4% and ranged from 0.8% in Najran to 26.4% in Al-Qudayh. Hb S was present in association with various other hemoglobins, sickle cell disease was present in 1.37% and sickle cell trait in 13.1% of all infants (Figure 1). Bart's hemoglobin (Hb B) incidence in all infants screened was 17.8%, ranging between 4.7% in Najran to 36.3% in Al- Awwamiyah, Hb B was present in association with various other hemoglobins, incidence of alpha thalassemia syndromes was 17.3% and probable beta thalassemia 0.5% (Figure 2). Some rare hemoglobins such as Hb C and Hb E were also found (Figure 3). Table 1. Incidence of all abnormal hemoglobins in Saudi Arab neonates. Abnormal Location Total Number screened hemoglobin (%) Hofuf 3, Gatif 2, Um Al-Hamam Safwa 1, Abqaiq Bilad Ghamid Abha Zahran Jizan Yanbu Jiddah Baljurashi Hayil Khamis Mushayt Najran Results of non-saudi Arabs from various nationalities also showed variable incidences of abnormal hemoglobins (Table 2). Although the number screened from these countries was small; sickle cell and Bart's hemoglobins were found in neonates from Jordan, Lebanon, Egypt, Pakistan and Sudan. Hemoglobin E was found in neonates from Pakistan and Egypt. It is of interest to observe the high incidence of hemoglobin F in neonates from Pakistan (3.79%) only. Blood Groups The pattern of blood groups was different in the Saudi Arab newborn infants from that of white Americans and all other nationalities as a group (Figure 4). G-6-PD Deficiency G-6-PD deficiency was present in 24% of all the males and in 12% of all the females, ranged from 1.26% in Abha, 2.59% in Riyadh and 11.59% in Bilad Ghamid to 43.8% in Al-Qudayh (Figure 5). G-6-PD deficiency was also present in neonates from other countries: Jordan 1%, Pakistan 1.2%, Sudan 1.3% and Philippines 1.8%.

4 Congenital Hypothyroidism Cord blood T 4 was 10.3 ± 2.2 mcg/dl (X ± SD) in the Saudi Arab neonates which was not significantly different from other nationalities (Table 3). The incidence of congenital hypothyroidism was approximately 1/3500 live newborn, similar to what has been reported in literature [25,26]. In infants with congenital hypothyroidism T 4 values were 4.3 ± 1.4 mcg/dl (X ± SD), and TSH 278 ± mciu/dl. Clinical presentation, treatment and long term follow up are under preparation. No cases of PKU were discovered through the screening program. Details of the analysis for the various villages and cities and the nationalities screened are available at King Faisal Specialist Hospital and Research Centre Medical Library [27]. Details of the analysis for various problems are under preparation. Figure 1. Hemoglobins associated with sickle cell hemoglobin in Saudi Arab neonates. Figure 2. Hemoglobins associated with Bart's hemoglobin in Saudi Arab neonates. Figure 3. Hemoglobins associated with hemoglobin C in Saudi Arab neonates.

5 Figure 4. Blood groups in newborn infants from various countries. Figure 5. Incidence of glucose-6-phosphatase dehydrogenase deficiency in Saudi Arab neonates. Table 2. Umbilical cord blood screening hemoglobin electrophoresis of neonates of Middle Eastern countries other than Saudi Arabia. Jordan Lebanon Egypt Pakistan Sudan Hb No. (%) No. (%) No. (%) No. (%) No. (%) FA FAS FACE FAB FS F FAE FADG Total Table 3. Umbilical cord blood T 4 values for various nationalities. Nationality Umbilical cord blood T 4 (mcg/dl) Mean SD Minimum Maximum Saudi Arabia USA Jordan Lebanon Egypt India Pakistan Sudan

6 Discussion A comprehensive newborn screening program modified to the needs and resources available was established in ARAMCO Dhahran Health Center. Several problems were encountered during the investigation which required modifications to the program. Since the program was started in 1980, more than 70,000 newborn infants have been screened. Valuable epidemiological data have been collected and necessary information for direct clinical use obtained. A comprehensive national program to screen all neonates in the Kingdom of Saudi Arabia is achievable and urgently needed. Screening for congenital hypothyroidism, which was started by the Ministry of Health, is an important step in the right direction, but other congenital problems such as hemoglobinopathies and G-6-PD deficiency is equally important. The fast and dynamic internal immigration and mixing of the population make it inaccurate to extrapolate the results of any small scale screening program in a particular geographical area to the community at large. The plans for a comprehensive national screening program should take into consideration the multiple health care systems present in the Kingdom, and wide scatter of the population. This national program can be subdivided into smaller regional programs according to the geographical distribution of the population and/or according to the various health care organizations. Due to the limited number of human resources and problems related to technology transfer and the cost of establishing such programs, a joint plan among the various medical health organizations in the Kingdom can be adopted and modified according to the circumstances and needs of each organization. Such a plan will define the program's objectives, procedures, operational plans, quality assurance, statistical analysis and evaluation. A central laboratory affiliated with one of the universities or Ministry of Health to perform the sophisticated confirmatory tests for all the Kingdom should serve as a reference central laboratory. A computerized program for entering the data, reporting and analysis will serve in obtaining accurate epidemiological statistics and rapid reporting, treatment and follow-up. Acknowledment We thank Prof. RDG Milner for his critical review of the manuscript. References 1. American Academy of Pediatrics, American Thyroid Association. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1987;80: Task Force on genetic screening. The pediatrician and genetic screening (every pediatrician a geneticist). Pediatrics 1976;58: World Health Organization working group. Hereditary anemias, genetic bases, clinical features, diagnosis and treatment. Bull WHO 1982;60: Hsia YE, Wolf B. Inherited Metabolic Disorder. In: Avery G, ed. Neonatology Pathophysiology and Management of the Newborn, ed 2. Philadelphia: JB Lippincott, 1981; Grover R, Wethers D, Shahidi S, et al. Evaluation of the expanded newborn screening program in New York city. Pediatrics 1978;761; Schneider RG, Hightower B, Hosty TS, et al. Abnormal hemoglobins in a quarter million people. Blood 1976;48: El-Hazmi MAF. Sickle cell anaemia patients and sickle cell trait cases in Saudi Arabia (letter). Saudi Med J 1989;10: Mallouh A, Talab Y. Bone and joint infection in patients with sickle cell disease. J Pediatr Orthop 1985;5: Mallouh AA, Salamah MM. Pattern of bacterial infections in homozygous sickle cell disease. AJDC 1985;139: El-Mouzan MI, Al-Awamy BH. Al-Torki MT, Niazi GA. Variability of sickle cell disease in the Eastern Province of Saudi Arabia. J Pediatr 1989; Serjeant GR. The challenge of sickle cell disease in Saudi Arabia. Ann Saudi Med 1990;10: Perrine RP, John P, Pembrey M, Perrine S. Sickle cell disease in Saudi Arabia in early childhood. Arch Dis Child 1981;56: El-Hazmi MAF, Al-Faleh FZ, Warsy AS. Plasma uric acid, urea and creatinine in sickle cell disease. Saudi Med J 1989;10: Weatherall DJ. Some aspects of the hemoglobinopathies of particular relevance to Saudi Arabia and other parts of the Middle East. Saudi Med J 1988;9:

7 15. Abu-Osba YK, Mallouh M, Salamah M. Incidence of hemoglobinopathies in newborn infants from various villages in Saudi Arabia. Proceedings of the 2nd International Conference "Fetal and Neonatal Physiological Measurements". Oxford, United Kingdom, 1984; Abu-Osba YK, Mallouh A, Hann R. Increased incidence of sepsis in glucose-6-phosphate dehydrogenase deficient newborns. J Pediatr 1989;114: Mallouh AA, Abu-Osba YK. Bacterial infections in children with glucose-6-phosphate dehydrogenase deficiency. J Pediatr 1987;6: Abu-Osba YK, Mallouh AA, Hann RW, Tolley S. Pattern of and risk factors for neonatal sepsis in Saudi Arab newborn. J Obstet Gynaecol 1989;10(suppl 1):S Abu-Osba YK, Mallouh A, Hann R, et al. Pattern and risk of sepsis in infants with abnormal haemoglobins. Proceedings of the Second International Conference of Veterinary Perinatology in conjunction with Summer Meeting of the Neonatology Society, St. John's College, Cambridege 1990; Abu-Osba YK, Mallouh A, Hann R. Haemoglobin H disease in the newborn: presentation and management. Proceedings of the Fourth Annual Paediatric Symposium. Riyadh, Saudi Arabia 1989: Abu-Osba YK, Thalji AA, Mallouh A, et al. Comprehensive screening program for the newborn infant; importance, problems and feasibility. Proceedings of the Sixth Saudi Medical Meeting, Jeddah, 1981; Beutler E, Mitchell M. Special modifications of the fluorescent screening method for glucose-6-phosphate dehydrogenase deficiency. Blood 1968;32: Guthrie R. Organization of a regional newborn screening laboratory. In: Bickle H, Guthrie R, Hammersen G, eds. Neonatal screening for inborn errors of metabolism. New York, Berlin: Springer Verlag, 1980; Abu-Osba YK. Newborn Screening Program: Organization, policies and procedures. Ararnco Medical Organization, Dhahran Health Center, Dhahran, Saudi Arabia, Abu-Osba YK, Mathew PM, Hann RW, et al. Hypothyroxinemia in the Saudi Arab premature infants. Proceedings of General Pediatric Annual Symposium, Al-Khobar, Saudi Arabia, Mathew PM, Abu-Osba YK, Shamma JH, et al. Congenital hypothyroidism at Aramco. The Fifth Jordanian Medical Conference: recent advances in Medicine and Surgery, Amman, Jordan 1987: Abu-Osba YK, Mallouh A, Salamah M, et al. Aramco newborn screening program for blood incompatabilities, hemoglobinopathies, G-6-PD deficiency, PKU and congenital hypothyroidism: preliminary results of 35,000 newborn infants screened from Aramco Medical Organization, Dhahran Health Center, Dhahran, Saudi Arabia, 1987.