REP ORT MATERNAL SCREENING FOR FOETAL ABNORMALITY assessment assessment HEALTH TECHNOLOGY ASSESSMENT UNIT MEDICAL DEVELOPMENT DIVISION health MINISTRY OF HEALTH MALAYSIA MOH/PAK/59.03(TR) 1 MEMBERS OF EXPERT COMMITTEE Dr Zaridah Shafie Obstetric & Gynecology Consultant Kangar Hospital Dr Zulkfili Mohd Kassim Pakar Perunding O & G Hospital Kuala Terengganu Dr Mohd Rouse Abd Majid Obstetric & Gynecology Consultant Sg Petani Hospital Dr Neoh Siew Hong Pediatric Consultant Taiping Hospital Dr Rosnah Sutan Jabatan Kesihatan Bersekutu National University of Malaysia Prof Jamiyah Hassan Faculty of Medicine University Malaya Project Coordinators Dr S Sivalal Deputy Director Health Technology Assessment Unit Ministry of Health Malaysia Dr Rusilawati Jaudin Principal Assistant Director Health Technology Assessment Unit Ministry of Health Malaysia Ms Sin Lian Thye Nursing Sister Health Technology Assessment Unit Ministry of Health Malaysia 2 EXECUTIVE SUMMARY INTRODUCTION Congenital malformations are structural or anatomical defects that are present at birth, resulting from influences acting on the developing embryo in early pregnancy. Some congenital malformations are potentially preventable; however, they remain major causes of early death, hospitalization of infants and young children and significant long-term physical and developmental disabilities. Screening and early detection of Downs Syndrome and other chromosomal anomalies in-utero provides several benefits like the opportunity to inform parents and counseling on the likelihood of delivery of an affected baby. This would allow them subsequently to make an informed decision about whether to continue with the pregnancy or alternatively undergo selective therapeutic abortion to avoid the birth of a disabled baby. The other potential benefits of maternal screening and early diagnosis include preparing the parents psychologically for the delivery of a handicapped baby, enabling doctors to better prepare for the delivery and care of baby, and also avoidance of unnecessary caesarian section in cases with lethal chromosomal abnormality. In addition, maternal screening can also identify foetuses with open neural tube defects. OBJECTIVE The objective of this assessment is to determine the effectiveness, safety, cost implications, ethical, legal and social implications of maternal screening for foetal abnormality of the following conditions: Downs Syndrome, Neural Tube Defects and Thalassaemia. RESULTS (1) Downs Syndrome A literature review found that screening using triple serum markers during the second trimester combined with ultrasound to date gestation, increased the detection rate of Downs Syndrome compared to the use of the last menstrual period, so as to avoid performing amniocentesis and chorionic villi sampling (CVS). Ultrasound is used as a secondary tool if serum marker results are positive. It also found that thickened nuchal fold visualized by ultrasound in the second trimester is not a practical screening tool for decisions on offering amniocentesis. However screening using serum markers followed by invasive prenatal diagnosis by amniocentesis or CVS has to be carried out with caution. It was also found that a screening programme is more cost effective than caring for Downs Syndrome children. There are serious ethical and religious issues in screening of maternal serum. It can be concluded that there is sufficient evidence to support the use of triple serum markers combined with ultrasound in second trimester, but there are major ethical and religious issues especially among the Muslim population. 3 (2) Neural Tube Defects There is evidence that the use of maternal serum alpha- fetoprotein and ultrasound is effective to detect neural tube defects. However, there is insufficient evidence to support the use of other modalities of screening. It was found that amniocentesis might cause spontaneous abortion. A screening programme showed cost benefits. However, there are major ethical and religious issues especially among the Muslim population. (3) Thalassaemia A literature review found that screening tests like MCV/Red cell indices; Hemoglobin A2 estimation, Hb electrophoresis using high performance liquid chromatography or isoelectric focusing; DNA mutation analysis; polymerase chain reaction and other modalities like anti-zeta antibody test are the effective modalities for screening for thalassaemia, However, again there are major ethical and religious issues especially among the Muslim population. RECOMMENDATION Due to the ethical and religious issues surrounding prenatal screening, invasive diagnostic procedures and termination of pregnancies, a national programme of routine antenatal maternal serum screening for Downs Syndrome, neural tube defects and Thalassaemia is not recommended. However, screening should be made available to women who request for the test. 4 1. BACKGROUND Congenital malformations are structural or anatomical defects that are present at birth, resulting from influences acting on the developing embryo in early pregnancy. Some congenital malformations are potentially preventable; however, they remain major causes of early death, hospitalization of infants and young children and significant long-term physical and developmental disabilities. There is a lack of local data on birth defects. A study in Hospital Kuala Lumpur in 1996 on 15 535 estimated the incidence of major birth defects to be 0.91%. A subsequent study at University Hospital, Kuala Lumpur in 1970 on 1404 live births found an incidence of 4.7%. A similar study of 14 123 live births in Hospital Alor Setar from 1984-1987 revealed 1.53% birth defects. More recent aggregated national data indicated that 17.9% of stillbirths and neonatal deaths were as a result of lethal congenital malformations. National data on hospital discharges over 1996-1998 indicated that incidence of spina bifida and hydrocephalus ranged from 5.12% (1996), 5.83% (1997) to 5.5.%(1998) of all congenital abnormalities. In 1999, there were 225 cases of neural tube defects out of the 1055 lethal congenital malformations (unpublished data). 2. INTRODUCTION Currently in Malaysia, routine antenatal care includes the identification of risk factors, health and laboratory screening and counselling. Basic laboratory screening encompasses screening for syphilis, Human Immuno-deficiency Virus, rhesus factor, and Malaria (in endemic areas only). Patients with bad obstetric history such as consecutive miscarriages, perinatal death and abnormal babies are undergo further investigations like Glucose Tolerance Test, LE cell, TORCHES and others based on the related identified risk factors. Ultrasound screening during pregnancy is also carried out at some centers. Maternal serum screening is used to screen pregnant mothers for foetuses with chromosomal abnormalities like Down’s Syndrome and other rare disorders like trisomy 18 and open neural tube defects. Screening and early detection of Down’s syndrome and other chromosomal anomalies in-utero provides several benefits. It provides an opportunity to inform parents and provide them with counseling on the likelihood of delivering an affected baby. This would allow them subsequently to make an informed decision about whether to continue with the pregnancy or undergo selective therapeutic abortion to avoid the birth of a disabled baby. Mothers who are screened positive undergo an invasive prenatal diagnostic procedure like amniocentesis or chorionic villus biopsy to confirm or exclude chromosomal abnormality. The other potential benefits of maternal serum screening and early diagnosis include preparing the parents psychologically for the delivery of their baby who has a handicap, enabling doctors to better prepare for the delivery and care of the baby and avoidance of unnecessary caesarian section in cases with a lethal chromosomal abnormality like trisomy 18. It is also able to avoid late fetal loss in those with a lethal chromosomal 5 abnormality. In addition, maternal serum screening can also identify fetuses with open neural tube defects. While currently there is no national maternal serum screening programme in Malaysia, some pregnant mothers obtain screening as part of their obstetric care in the private sector, on a fee-for-service basis. It is also important to note that selective abortion of abnormal fetuses, unless lethal, is not legal in Malaysia. 3. OBJECTIVE To determine the effectiveness, safety, and cost, ethical, legal and social implications of maternal screening for fetus abnormality of the following conditions: Down’s Syndrome, Neural Tube Defect and Thalassemias. 4. METHODOLOGY Each condition has been assessed separately so that the methodology is elaborated under individual condition. DOWN’S SYNDROME 1. INTRODUCTION Down’s syndrome (Down syndrome in the United State), also known as Trisomy 21, is a congenital syndrome caused by all or part of trisomy chromosome 21, resulting in mental retardation and other abnormalities. Down’s children have a characteristic appearance where the head may be smaller than normal (microcephaly) and abnormally shaped. Other facial features include a flattened nose, protruding tongue, and upward slanting eyes. The inner corner of the eyes may have a rounded fold of skin (epicanthal fold) rather than coming to a point. The hands are short and broad with short fingers and often have a single crease in the palm. Retardation of normal growth and development is typical and most affected children never reach average adult height. They usually have