Preventive Genetics—Holistic Healthcare1

The ancient Indian medical system of Ayruveda is the epitome of preventive aspect of healthcare. The definition of health according to this system is given by the following verse from Sushruta (ancient Indian sage).

It means when all three Doshas (proximate principles), Agni (metabolic driving forces), all seven Dhatu (body tissues) and Malakriya (body waste disposal systems) are evenly balanced and when Atma (soul), Indriyas (body organs) and the Manas (mind) are happy and contended then one is said to be healthy. This is the most positive and encompassing definition.

It is true that our Genetic blue print is beyond our control and comprehensively regulates the development, functioning of human body in health and disease at all stages of life. Contrary to belief, our Genetic Destiny is not totally preordained!

By implementing multispecialty, holistic, preventive approach at all stages of life we can make a lot of difference in incidence of genetic disorders, their severity, the chances of survival, quality of life of our patients and their families. Community health planners are becoming well aware about these facts and a new specialty of Preventive Genetics is emerging rapidly to tackle these problems.

Importance of genetic disorders in clinical practice is seen in Table 1.1.

The exact incidence of various categories of genetic disorders is not known, Table 1.2 shows the incidence of these disorders from a very large study by Baird et al, 1988.²

The incidence of genetic disorders in India was found to be 2.3 percent in a study by IC Verma.³

Important components of such a program should include:

Requirements of a good screening program are shown in Table 1.3.

Developing countries like India face some major problems in setting-up of genetic screening programs like very large population, lack of awareness, late antenatal registration. Genetic screening is not mandatory even in high risk pregnancies. Cost factor is very important as 40 percent deliveries are conducted in public sector, where totally free services are provided. The meager funds are not adequate to cover even higher priorities like malnutrition, prematurity, infectious diseases hence priority for such screening programs is quite low. On the other hand 60 percent deliveries are conducted by private sector, which is self-funded by the patients as insurance coverage is still very low, due to lack of awareness and high costs the acceptance of screening tests is still quite low. All the same screening programs like NTD, Down’s syndrome, thalassemia/sickle cell disorders have become quite popular in urban and semi-urban areas. Though neonatal metabolic screening program has not yet been that well- accepted. The author’s center was one of the first clinic to set-up second trimester screening for Down’s syndrome in Mumbai city almost a decade back. Limitations of genetic screening programs are low positive predictive value, false positivity, confusing risk assessment, need for confirmatory tests and ethical issues which make the implementation of these screening programs quite challenging.

History of genetic disorders like thalassemia, hemophilia, muscular dystrophy, etc. will immediately prompt the clinician to advice appropriate screening tests to both partners so as to advice them about risk of recurrence, specific tests for prenatal diagnosis and management.

Although most of the conceptions with chromosomal defects are lost during antenatal stage, 0.6-0.8 percent of live born show chromosomal defects. Of these 0.4 percent is severe defects diagnosable at birth while 0.3 percent can be more subtle and have effect on child bearing. It is essential to have appropriate cytogenetic tests to be done in such individuals and counsel them accordingly.⁴

Blood group testing is now universally done in antenatal period but it should be done routinely at premarital stage itself. As it will give timely information in discordant couples so that necessary preventive measures can be taken up.

Certain cancers are caused by specific defective genes like BRCA-1 gene which is responsible for breast cancers. Cancers of breast, ovaries, colon and prostate are known to occur in families with presence of such abnormal genes. Some of the genetic disorders are more prone to cancers like leukemia in Down’s syndrome babies, Fanconi anemia while gonadal malignancies are more likely in undescended testes and residual gonads in Turner’s syndrome.

Consanguinity should be investigated and proper counseling offered about the increased risk of genetic diseases. The problem of consanguinity is quite common particularly in Muslims and certain ethnic communities in southern states in India.

Certain genetic disorders and concurrent pregnancy can have mutually deleterious effects. Increased risk of thrombophlebitis, embolic episodes is seen during pregnancy and childbirth in homocystinuria.⁵ Ehler-Danlos syndrome and Marfan’s syndrome have higher risk of aortic/vascular rupture and uterine rupture during pregnancy and childbirth.⁶ Sickle cell, epilepsy, SLE and myotonic muscular dystrophy and untreated maternal phenylketonuria increase risk of pregnancy losses, birth defects considerably. Hence proper control of these prior to conception and close monitoring of maternal and fetal health all through the pregnancy is essential.

Many of the maternal medical disorders like diabetes mellitus, thyroid disorders, epileptic convulsions, psychotic disorders and autoimmune disorders pose a risk of genetic/birth defects, hence proper control of these with use of safer therapeutic options should be achieved prior to planning a pregnancy. It has been shown that strict metabolic control of diabetes prior to conception reduced the risk of congenital malformations in the fetus was 0.8 percent as compared to 7.55 when the metabolic control achieved after completion of 8th week.⁷

Environmental factors like illicit drugs, smoking, alcohol, exposure to excessive heat and occupational exposure to potential teratogens should be curtailed where ever possible.

Prophylactic immunization against rubella, hepatitis-B, E and screening for potentially teratogenic maternal infections like TORCH group, HIV-AIDS and other sexually transmitted infections is equally important prior to conception.

Pre and periconception supplementation of folic acid, zinc will go a long way in NTD, facial clefting and certain inborn errors of metabolism prophylaxis as well as to reduce risk of pregnancy losses from miscarriages. 11For maximum benefit the supplementation should be started a menstrual cycle before couple stops contraception and continues till 16-18 weeks of conception. Low dose aspirin prophylaxis is of some benefit in autoimmune disorders like SLE, APL syndrome, unexplained IUGR/still births and higher risk for PIH. Low dose glucocorticoids have been also used for indications like SLE, APL syndrome, unexplained pregnancy wastages with variable results.

Postconception stage is the time when majority of women present themselves to the obstetrician. Early enrollment, preferably as soon as pregnancy is diagnosed, is essential as it gives the clinician adequate time to do various screening tests and offer appropriate diagnostics tests and management options.

The emphasis in antenatal screening has been to develop earlier, more reliable, cost effective and safer screening tests so as to cover maximum low risk population to identify the high risk sub-group. As a result diagnostic testing like fetal tissue sampling and confirmatory tests (which are potentially harmful, labor intensive and expensive) can be offered to a smaller sub-population with maximum pick-up of affected fetuses.

With improvement in the resolution of USG equipment and intensive training of operators, 10-14 week scan by abdominal and vaginal route has become the first anomaly scan. Apart from confirming the viability of the pregnancy, almost 70-80 percent of major structural anomalies can be picked up at this scan. This gives enough time to the clinician to perform any confirmatory tests, offer counseling and start antenatal therapy (where ever feasible) at an early stage. In cases with lethal anomalies an easier and more private option of first trimester can be offered.

Use of serum markers for screening for NTD and Down’s syndrome started with the advent of Triple Test in early 1980s. Age as screening parameter is not enough as it can pick-up only one-third of Down’s babies. To bring forward the screening in the first trimester attempts were started and two molecules, viz. free beta hCG and PAPP-A were used by Nicolaides and his group in 1995. Together they had detection rate of ~60 percent at 5 percent false positive. With combination of maternal age, nuchal translucency and these two serum markers the detection rate jumped to almost 90 percent.⁹ To achieve this spectacular success nuchal translucency measurement has to be accurately done on a high resolution scanner by a trained operator and software for risk assessment has to be used as well. With additional USG markers of nasal bone and Doppler flow studies of ductus venosus the detection rate can be further improved. The author 13set-up combined first trimester screening program in Mumbai city in 2002 analysis of first 300 tests showed a detection rate of 85 percent at 5 percent false positivity. Out of these 22 cases were screen positive. After post-test counseling 18 underwent fetal tissue sampling and karyotyping, 10 had normal karyotype, while 8 showed aneuploidy.¹⁰ To improve the detection rate sequential screening of 11-14 weeks combined testing followed by a Quadruple Test at 16 to 18 weeks has been tried with some improvements (DR 92%).

Chorion villous sampling for confirmation in screen positive cases has emerged as the logical choice. The chorionic tissue is suitable for cytogenetic tests, DNA testing as well as metabolic studies. Though amniocentesis is the most commonly performed prenatal diagnostic procedure CVS has the advantage of early and rapid diagnosis in first trimester thus reducing anxiety, keeping the pregnancy private and also to offer the safer first trimester termination option. To achieve the high safety and success of CVS it is essential to have properly trained operator with experience of at least 300-400 tests and should be well versed in embryology and first trimester USG. Good resolution ultrasound machines also makes the procedure quick and safe. Major clinical experiences in first trimester CVS is shown in Table 1.5.

Doubt about the safety of CVS was raised after the cluster of severe Limb Reduction Defect anomalies (LRD) reported by Firth et al in 1991. WHO statement based on the complete follow-up of 76476 cases by the WHO-CVS registry did not show any increased risk of LRD following CVS performed by well experienced operators and performed only after eighth completed week of pregnancy. The risk of bleeding, feto-maternal hemorrhage, infection and pregnancy loss is more than amniocentesis but due to it’s advantage of early diagnosis the test is becoming more popular.¹⁷

Basic requirements of a worthwhile screening program are shown in Table 1.6.

There is no screening program that meets these criteria fully, but NTD screening by combined maternal screening and Ultrasonography comes fairly close. Maternal serum screening for Down’s and NTD was introduced in seventies. Initially double, then triple and quadruple tests were offered to patients. After introduction of first trimester maternal serum screening with/without NT measurements first and second trimester combined screening was offered to improve the detection rate and reduce the need for the interventional tests. The efficacy of various screening tests is shown in following graph (Fig. 1.1).

Although maternal serum screening for NTD and Down’s syndrome should be offered to all women at 16-18 weeks, we in developing country like India face some vexing problem in prenatal screening for NTD and Down’s syndrome. Significant percentage of women deliver at home and do not receive comprehensive antenatal care, the time of enrollment is also late (mostly by 5-7th month) thus missing the chance for such screening. In Mumbai city 40 percent deliveries take place in public sector hospitals at almost free of charge, due to resource limitations such screening can not be provided. Remaining 60 percent deliveries take place in private nursing homes and hospitals most of these are paid for by patients 15themselves, which adds to the cost.

16Anomaly scan at 18-20 weeks is vital as it should be able to pick-up most of the structural anomalies, except some of the anomalies like renal, musculoskeletal and growth-related defects which appear later. Study of various ultrasonography markers associated with chromosomal anomalies like nuchal thickness, duodenal atresia, choroid plexus cysts, etc. is equally vital to pick-up the high risk cases and offer prenatal diagnostic testing to them. In view of this some workers are shifting the anomaly scan to 22 weeks.

Amniocentesis is the most prevalent test and is considered as a gold standard. Genetic amniocentesis is conventionally done between 15-24 weeks of pregnancy. The amniotic fluid is tested for chromosomal evaluation by study of cultured/uncultured amniocytes (conventional karyotyping, FISH/QF-PCR), study of single gene disorders by DNA diagnostic tests and evaluating errors of metabolism by study of supernatant fluid or amniocytes. Fetal involvement in maternal infections can be verified by DNA testing, immunological work-up. The clinical safety and success of amniocentesis depends upon: (1) experience of the operator performing the procedure, (2) characteristics of the amniotic fluid (blood staining/discolored fluid) (3) direct ultrasonography supervision and (4) indication for the procedure.²⁰ The clinical efficacy of this test performed in over 500 cases last year by our center was success rate of 99.6 percent and pregnancy loss rate of 0.4 percent. The efficacy of the laboratory testing was over 99 percent with failure to grow AF culture in less than 1 percent.²¹

Fetal blood sampling for prenatal diagnosis is most likely to be done for rapid fetal karyotyping, evaluation of fetal hematological disorders and fetal infections, DNA diagnosis. Therapeutic procedures like intrauterine transfusions, drug therapy and stem cell transfer are also performed through cordocentesis. Direct ultrasound-guided cord blood sampling is the most commonly preferred technique. Safety of the procedure is acceptable with uncorrected pregnancy loss rate of 1.6 percent in a large collaborative data 17from 14 North American centers.²² In a similar multicentric study by the author, 1216 cordocentesis were evaluated from seven centers in India with success rate of 93.2 percent and uncorrected pregnancy loss of 2.3 percent.¹⁶

The extension of transabdominal CVS in second and third trimester is a very convenient, safe alternative to amniocentesis and fetal blood sampling particularly as an alternative to early amniocentesis, when patient presents late or an anomaly diagnosed beyond 26 weeks or when amniocentesis or cordocentesis is confounded by unfavorable conditions like severe oligohydramnios.^23,24 We have also been using late CVS in second and third trimesters as an alternative to fetal blood sampling and amniocentesis with gratifying results.

The whole exercise is worth as it gives the woman range of options like intrauterine therapy, postnatal therapy, medical termination (when ever feasible and possible) and plan the place, time and mode of delivery so as to give best chance to the high risk fetus. We have been conducting a Multispecialty Fetal Medicine Consultancy Services in Mumbai for last three years. We have managed over 350 high risk pregnancies with good results.²⁶

Management of IUGR is far from satisfactory, particularly when ever it is idiopathic. In spite of many claims there is no effective treatment for such cases. Early diagnosis and amelioration of causative pathology, improving maternal nutrition (especially preconceptional stage onwards), and close monitoring of high risk cases by a team approach so as to decide the optimum time, place and mode of delivery yield best results. These fetuses require close neonatal and long term follow-up so as to manage various problems in a preventive manner.

In case of sad outcomes like termination of an affected pregnancy, stillbirths/neonatal death it is utmost important for the treating physicians to put across the need for confirmatory tests like postmortem, genetic/metabolic tests in a sympathetic but firm manner. The couple and the family are in a state of grief and shock and are unable to grasp the importance of such studies from future preconception counseling and evaluation. Properly conducted studies like these can be very valuable for confirmation of 21antenatal diagnosis, risk assessment, preconception evaluation and appropriate tests to be done in future pregnancies. Imaging modalities like MRI can be used in cases where the request, for postmortem is refused to get better idea about the details of structural anomalies diagnosed antenataly.

Of course such testing has it’s own ethical dilemmas like confidentiality of the client versus right of relatives to know the lab results, misuse of such information by third parties like insurers, employees governments with discrimination against the individual and prolonged period of anxiety when there is no clinical disease as yet.

It will take a shift in the mind set of general population and medical and paramedical workers and a concerted, multispecialty approach spanning all streams and branches of medicine and other related faculties that will yield the desired results. The spectacular advances in the fields of 22biotechnology, genetic engineering and pharmacogenetics are double-edged weapons and should be handled in a responsible and far sighted manner to avoid problems of eugenics, discrimination, ethical and religious insensitivity. The clash of maternal and fetal interests will also pose significant problems requiring adroit handling.

In spite of all these problems it is necessary for all of us to move ahead in making preventive genetics as an essential part of. The rewards will be worth the efforts healthcare.