Fetal therapy: ethical, legal and medical considerations

Operative techniques

Fetal therapy: ethical, legal and medical considerations

D. T. Y. Liu and The-Hung Bui

Our ability to detect fetal abnormalities has increased substantially over the last 2 decades. Radiology, occasionally still used for diagnosis of skeletal abnormalities, has been largely superseded by the safety, ease of application and flexibility of ultrasound scanning. An experienced sonographer with a sophisticated machine can delineate structural abnormalities which when categorised act as phenotypic markers of chromosomal aberration or malformation syndromes. Invasive procedures for prenatal diagnosis have also undergone rapid evolution. Amniocentesis for biochemical analysis of liquor amnii or cytoculture of amniocytes for karyotyping was followed by placentacentesis to obtain fetal blood to exclude haemoglobinopathies such as thalassaemia and sickle cell disease.’ Fetoscopy, which allowed direct visualisation of the mid-trimester fetus added precision to gain access to fetal blood or tissue.2 This sizeable instrument is 2.2-3 mm in diameter hence post procedural leakage of amniotic fluid and an associated fetal loss rate of approximately 5’K3 Once sophisticated sonography became available less traumatic access to pure fetal blood was obtained by needle placement to the umbilical cord, the hepatic vein and, less satisfactorily, the fetal heart.4 In the second trimester rapid (results available in 24-48 h) karyotyping by transabdominal chorion villus sampling can be performed.5*6 This same tissue can be collected for prenatal diagnosis in the first trimester.‘** Both the abdominal and transcervical routes are shown to be safe and acceptable techniques for villus sampling at this stage.’ This is currently David. T. Y. Liu, Department

of Obstetrics and Gynaecology, City Hospital, Nottingham, UK, The-Hung Bui, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden Current Obsrerrics 0 1994 Longmm

and Gynaecology

GroupLtd

(1994) 4, 160-165

still the only procedure which provides a reliable diagnosis within the first 12 weeks of pregnancy. Chorionic villi has also been shown to be ideally suited for recombinant DNA analysis and enzymatic studies. The ability to achieve early diagnosis is a significant step towards the potential for fetal therapy. Besides safer and more expedient resolution if pregnancy is not continued, first trimester diagnosis provides time for counselling to determine if therapy is feasible or indeed appropriate. Furthermore any proposed innovative fetal therapy is reliant upon an early answer to utilise the embryological advantage offered by immunological tolerance before 14-16 weeks of gestation.‘2*‘3 Once effective prenatal diagnostic procedures become established the same evolutionary steps in medical concepts for postnatal life can be expected for the fetus with a correctable congenital defect. First, make the diagnosis, then treat if that is feasible and reasonably safe. The fetus, now more than ever, is demanding recognition to be treated as an individual - as a patient in its own right. This status is enhanced by the fast expanding industry of molecular biology. Polymerase chain reaction and in situ hybridization technology can enhance the speed and accuracy of diagnosis. Isolation of the genetic basis of inheritable defects followed by cloning of the defective genes opened the way to examining the controversial question of somatic gene therapy.14 Treatment of the fetus before birth excites because of the challenge it poses. This challenge captivates the imagination of the medical profession and the media. In the last decade however, our enthusiasm has been tempered by consideration of medical advances, by increased understanding of patho160

FETAL THERAPY: ETHICAL, LEGAL AND MEDICAL CONSIDERATIONS

physiology of the disease process and the often belated but vital dictates of societal and medico-legal adjudication. Who and when to treat

Most fetal therapy is still experimental. Before embarking on any treatment programme the criteria for intervention should be appreciated. The statements below reflect good medical practice and is a distillation of the lessons from the past decade. 1. Diagnosis should be established as early as possible to alleviate anxiety and to allow time to consider management options. Early diagnosis allowing early intervention can avert progressive deterioration in certain fetal abnormalities such as inherited metabolic disorders. Another good example is fetal obstructive uropathy where expedient placement of a shunt protects functional renal parenchyma. 2. Referral should be to a centre where a multidisciplinary team is available. Pivotal in this team is an obstetrician involved in prenatal diagnostic procedures and fetal therapy. Other members of this team such as a paediatric surgeon or nephrologist can be co-opted when appropriate for support and advice. Of necessity this referral centre must have neonatal intensive care facilities backed by committed neonatologists. 3. The couple with an affected baby must be fully informed of the consequence of the fetal condition. Information must be couched in language which the couple can appreciate. Clinical geneticists and support groups can all contribute to ensure the decision by the couple is based on comprehensive knowledge of the fetal condition. In the pre-viable fetus termination of pregnancy is an option. Risks and benefits of any intervention must be clearly explained. Great care must be taken not to over emphasize the benefits bearing in mind the experimental nature of many of the intended procedures and treatments. The fundamental tenent of medical practice is do no harm and to prevent harm. Hysterotomy to gain access to the fetus subjects the mother to considerable risk and can jeopardise her future pregnancies hence is seldom justified for an indeterminant outcome. Whilst it is reasonable to intervene to avert irreparable fetal damage, delivery of a damaged fetus able only to eke out a poor quality of life cannot be considered good medical practice. 4. Animal models are often used to substantiate innovative fetal therapy. Results from animal studies must however be assessed critically since not all can be extrapolated for clinical usage. The sheep uterus can be incised and repaired without provoking preterm labour.

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This is not the case with the human or subhuman primate uterus. 5. When the situation permits an attempt should be made to achieve fetal maturity ~ the mature fetus is a much better candidate for anaesthesia and surgery. After 32 weeks fetal lung maturity is likely hence it is best to consider delivery of the fetus to enable definitive treatment rather than subject mother and baby to risky intricate inutero procedures. The difficult balance between the obstetrician’s anxiety for the fetus and the neonatologist’s preference for fetal maturity is best achieved by close collaboration to optimise outcome. 6 No department can command comprehensive expertise in the range of fetal problems. Consultative dialogue between centres is encouraged to promote exchange of views to keep up-to-date and learn from each other’s experience. Insertion of a ventriculo-amniotic shunt to drain hydrocephalus need not be difficult but corporate experience of the last decade suggests this procedure is seldom justified.15 Likewise fetal bladder urinary electrolytes have been proposed as useful guides for a vesico-amniotic shunt until it was realised that their value need not reflect the functional integrity of both kidneys.lh Ethics and medico-legal

issues

Once the fetus is given the status of a patient in its own right, this recognition immediately demands consideration of many challenging ethical and legal issues. Before the point of viability usually defined as 24 weeks gestation, the mother’s wishes are paramount and the fetus has no legal right to be carried to term. When an inherited abnormality or fetal malformation is diagnosed, therapeutic abortion is the prerogative of the mother where this facility is available and acceptable. If abortion is not considered acceptable or appropriate then the mother has an obligation to ensure that her child should be delivered with as little damage as possible. Of necessity intrauterine surgical therapies will invade the body of the mother and subject her to a degree of risk. Once the decision is made that pregnancy should continue, the fetus demands the right that its mother and the medical profession involved in its care must try and prevent further damage. On the other hand it is equally important not to subject the fetus to an unacceptable risk of unnecessary injury. Violation of these obligations expose the mother and the medical carers to liabilities of being negligent for failing to care for the welfare of the fetus if the baby dies after birth or lives but is badly damaged because no attempt was made to salvage. All parties involved may also court charges of homicide or child abuse. These same statements are equally applicable to the viable fetus with a non-lethal condition.

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The need for counselling of the parents to ensure comprehensive appreciation of the fetal problem cannot be over-emphasized. In the pre-viable fetus knowledge of the patho-physiology of the fetal malformation is essential. Continued obstruction of the urinary tract will lead to progressive damage of remaining healthy renal tissue. Early intervention is thus appropriate. Alternatively a sizeable simple exomphalocele detected in early pregnancy may look much less threatening at delivery. Abortion of a karyotypically normal fetus with only this isolated malformation may not be reasonable. For therapies of proven value counselling is less demanding. The onus is on the mother to accept some degree of risk even if her bodily integrity is breached to achieve a welcome end for her child. Intrauterine fetal therapies, however, have not been subjected to the rigors of clinical trials. Although the fully informed mother can consent to experimental inutero fetal therapy, there is no legal nor moral compunction for her to accept any procedure which is not established. In the eyes of the law no dominant approach concept is available for intrauterine fetal treatment. Before the question of tort in this aspect of therapy is considered, the following should be addressed. The fetus and intrauterine therapy After 24 weeks of pregnancy, the definition for fetal viability, detection of any fetal abnormality raises questions of the severity of the problem, whether the condition will deteriorate and if it is lethal before or after birth. For trisomy 13 and trisomy 18 or anencephalics the decision is relatively simple since therapy is not available and survival is not likely. The argument is less secure when confronted with trisomy 21, Turner’s syndrome (X0) or Klinefelter (XXY) fetuses. The potential for fetal therapy will invariably conflict with the question of wholesale abortion when fetal conditions are considered treatable. Issues of wrongful life, of causing more harm, must all be balanced against the threat of being considered negligent if a relatively simple, low risk attempt is not made to benefit the fetus. Couples, medical professionals and intrauterine fetal therapy Potential for fetal therapy will give hope to couples with an affected treatable much wanted offspring. The medical profession is obliged to raise the issue of therapy once the media or medical fraternity introduce its possibility. This possibility will, however, immediately pose dilemmas when the context of counselling is addressed. Over the last decade knowledge of the pathophysiology and outcome of many malformations is only beginning to filter through with consensus experience. Statements used during counselling can only be honest accounts which

reflects contemporary knowledge. Even if the outcome is adverse and the fetus may not have benefitted by the intervention, a course of action can be justified and is defensible if each step of the decision process is thought through, discussed fully and executed in good faith to achieve benefit. Medical practice is not an exact science. This is particularly pertinent in fetal therapy where the experimental nature of this emergent subspecialty of necessity means intended outcome may not be realised after intervention. Couples exercise the right to refuse experimental fetal therapy. In light of above discussion, overenthusiastic voluntary recruitment into risky programmes which leaves the mother scarred for dubious fetal benefit must be restrained, despite any perceived glamour. Experimentation is a prerequisite to medical progress but risk framing must be appropriate. Here again there is room for debate. How does one quantify risk, what are our yard sticks? What is acceptable risk for the mother? We all could accept that the risk to the mother associated with insertion of needles as in amniocentesis, insertion of shunts or even fetoscopy is not excessive. We perform Caesarean section to expedite delivery of a compromised fetus. In this latter example the balance is between life or threat of death and damage of the fetus. Subjecting the mother to the risk of surgery for known beneficial outcome can be defended. On the other hand hysterotomy for access to the fetus cannot be easily justified unless substantial fetal benefit is assured. Society and intrauterine fetal therapy In the pre-viable fetus or, more specifically, in the viable fetus where the malformation can be simply remedied despite uncertain outcome, can society impose or resort to use of law to protect the fetus? Because the mother’s body must be invaded for access to the fetus the question of infringement of the mother’s integrity becomes an issue. Imposing a risk no more than that of an amniocentesis finds support. To flex legal muscles to enforce Caesarean section for a normal baby is not the same when the law is recruited to impose therapy which is experimental and where the outcome is at best guarded or unknown. Within the context of the National Health Service there is compliance to absorb care requirements by the child after it is born. Incurred damage or partial resolution of the fetal problem may result in the need for costly and protracted medical support for the rest of the child’s life. This phase of the therapeutic programme must be clearly discussed if the cost of subsequent care rests within the presage of the parents. Fetal therapy - the contemporary picture The need for careful judicious counselling before intrauterine fetal therapy should not be a constraint

FETAL THERAPY: ETHICAL. LEGAL AND MEDICAL CONSIDERATIONS

to develop this promising area of medical advance. Although inutero balloon angioplasty has attracted recent media attention,17 attempts to treat the fetus before birth are not new concepts. In 1963 Liley pioneered invasive inutero therapy when he performed intra-peritoneal transfusion for a Rhesus affected fetus.” Once the conceptual barrier against access to the fetus is overcome there followed 3 decades of innovative experiments to devise ways and means to treat the fetus before birth.

Transplacental

medical fetal therapy

Most substances can cross the placenta in varying amounts by pinocytosis, active transport or gradient diffusion. Adaptations of this concept for clinical utility are exemplified in prescription of antibiotics such as spiramycin for treatment of toxoplasmosis.” Fetal hydrops resulting from fetal cardiac arrythymia such as supraventricular tachycardia can be treated successfully by giving the mother Digoxin or Verapamil.” Dexamethasone given to the mother will enhance maturation of Type II alveolocytes and reduce the incidence of respiratory distress syndrome in preterm births. 21 Less emphasized however, is a similar beneficial effect with beta sympathomimetics and the anti-phosphodiesterase aminophyline - the latter through potentiation of intracellular increase in cyclic adenosine monophosphate ( AMP).22 Barbiturates have been used to induce fetal liver enzymes to reduce postnatal fetal bilirubin concentrations. Also advocated but of less proven value is administration of gamma globulin for alloimmune thrombocytopenia.23 Treatment of the female fetus with 21-hydroxylase deficiency congenital adrenal hyperplasia is a cogent example of transplacental medical intrauterine therapy. 24 Dexamethasone prescribed as early as pregnancy is known will suppress the adrenal glands in affected female fetuses and prevent masculinization. Likewise, fetuses affected by biotin-responsive multiple carboxylase deficiency or the B12 responsive form of methylmalonic acidemia can benefit by giving the mother either biotin or B12 vitamins in the antenatal period.2s.2h As our understanding of abnormalities of mineral metabolism and vitamin responsive genetic errors of metabolism increase so does the potential for medical inutero therapy.

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Manipulation of amnioticfiuid When there is severe oligohydraminos physiological solutions can be introduced into the uterine cavity to allow better ultrasound examination of the fetus.“7 This procedure may also be considered to assist lung development in the first half of pregnancy. The need for repetition of this exercise however, carries the risk of inducing miscarriage. In the feto-fetal transfusion syndrome repeated drainage of the polyhydramnios sac is advocated as a possible therapeutic option. The rationale is to adjust the haemodynamic balance thus correcting the oligohydramnios to promote growth of the affected poorly developed fetus.‘* The amniotic fluid is swallowed by the fetus. Supplementation of the fetal nutrient by additions into the amniotic fluid is potentially feasible. This inutero fetal oral route of therapy has to date been little explored. It is readily conceivable that this approach may receive more attention in the near future.

Transfusion of blood products Iso-immunization with the Rhesus factor but more rarely with other factors such as ABO and Kell can lead to fetal anaemia, hydrops fetalis and inutero death. Likewise, parvovirus infection can cause a transient pancytopenia again with resultant hydrops and possible fetal death. Intraperitoneal transfusion of blood to treat Rhesus affected fetuses removed the conceptual barriers to direct access of the fetus. Although intraperitoneal transfusion remains a useful alternative because of its ready access, nowadays blood is usually transfused through the umbilical cord or the hepatic vein to achieve more precise control4 Where iso-immunization is the cause of the fetal anaemia repeated transfusion is required until safe delivery is assured. For parvovirus infection, expectant management or at times one or two transfusions may be all that is required to avoid fetal demise.” Allo-immune thrombocytopenia is analogous to Rhesus iso-immunization. Maternal antibodies cross the placenta to destroy platelets in the fetus with resultant risk of fetal bleeding. Intermittent transfusion of platelets until safe delivery is advocated as an avenue of treatment2”

Progenitor haemopoietic cell transplantation Low risk minimally invasive inutero fetal therapy

Introduction of needles, trocars or fine scopes through the mother’s abdomen into the uterine cavity is the current principle surgical approach for access to the fetus. These procedures are performed under ultrasound guidance and can broadly be grouped as discussed below.

Before the 14th, and certainly before the 12th, week of gestation the fetal immunological system is not yet mature. Transplantation of haemopoietic cells at this stage will be accepted as self without risk of rejection. Furthermore, cells extracted from first trimester fetuses will be less likely to mount a graft against host reaction. In the second half of the first trimester progenitor haemopoietic cells in the fetal

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liver are in the process of seeding the bone marrow - the site of adult haemopoiesis. This phase of enhanced bone marrow receptivity is an added theoretical advantage for the concept of haemopoietic stem cell transplantation. The haemoglobinopathies, such as thalassaemia A, thalassaemia B, sickle cell disease and many metabolic disorders can potentially benefit by transplantation with haemopoietic stem cells3’ Experimental work with animals and the subhuman primate substantiate the feasibility of stem cell transplantation by demonstration that haemopoietic chimeras can be created.31 Haempoietic progenitor stem cells from fetal liver have been transplanted into the human fetus to successfully treat severe combined immunodeficiency syndromes.32 Many pertinent questions such as the optimum number of stem cells required, the quality of cells used and the best gestation for transplantation will need to be answered. The stage is however, set for further exploration of this exciting field of research.33 Inutero drainage and shunting procedures

Drainage of a hydrocephalus or any large collection of fluid such as ascites to facilitate delivery is easily achieved. Where fluid is likely to reaccumulate repeated aspiration will be necessary. In this circumstance it would seem logical to consider introduction of a drain or a shunt to encourage continuous escape of the fluid into the amniotic cavity. Various designs of shunts are available commercially. Shunting of the thorax (thoraco-amniotic shunt) of the abdomen (peritoneal-amniotic shunt) and bladder (vesicoamniotic shunt) are currently the three most rewarding situations where this form of therapy can be considered. Insertion of a thoraco-amniotic shunt relieves pressure on the developing fetal lungs and reduces the risk of pulmonary hypoplasia.34 For a similar reason drainage of ascites can benefit fetal growth and development. Since many fetal structural defects are associated with chromosomal abnormalities it is mandatory to ensure karyotyping is performed before considering surgery. Likewise it is important to exclude other associated abnormalities before intervention is discussed. Experimental fetal surgery

Heroic attempts at fetal salvage often attract media attentions, such as inutero cardiac catheterisation to dilate outlet obstruction. Hysterotomy to allow direct access for fetal thoracotomy to repair diaphragmatic hernias have also been attempted.35 Outcome from all these experiments are however, guarded. Conclusion

At first the developing fetus merely aroused curiosity in obstetricians. This curiosity led to application of

technological advances to examine and monitor its welfare. The inevitable consequence of increased knowledge about the fetus is attempts to treat some of the detected abnormalities. The above dissertation illustrates the medical, legal and moral ramifications once the fetus demands recognition as an entity in its own right. Once the fetus adopts this role it loses the sanctity of seclusion. There are many advances in the subspecialties of infertility, gynaecology and oncology. The final domain and next exciting frontier for perinatologists is inutero therapy for the fetus. References 1. Kan YW, Valenti C, Giudotti R et al. Fetal blood sampling

in utero. Lancet 1974; i: 79-80 2. Rodeck CH, Campbell S. Sampling pure fetal blood by fetoscopy in second trimester of pregnancy. BMJ 1978; 2: 728-730 3. International Fetoscopy Group. The status of fetoscopy and fetal tissue sampling. Prenatal Diagn 1984; 4: 79-81 4. Nicolini U, Rodeck CH. Fetal blood and tissue sampling. In: Brock DJH, Rodeck CH, Ferguson-Smith MA, eds. Prenatal diagnosis and screening, Edinburgh: Churchill Livingstone, 1992; 39-51 5. Nicolaides KH, Soothill PW, Rodeck CH et al. Why confine chorionic villi (placental) biopsy to the first trimester? Lancet 1986; i: 543-544 6. Pijpers L, Jahoda MGJ, Reuss A et al. Transabdominal chorionic villus sampling in the second and third trimester of pregnancy to determine fetal karyotype. BMJ 1988; 297: 822-823 I. Chorion villus sampling, Liu DTY, Symonds EM, Golbus MS, eds. London: Chapman and Hall Medical, 1987 8. A practical guide to chorion villus sampling. ed. Liu DTY, Oxford: Oxford Medical Publications, 1991 9. Jackson LG, Zachary JM, Fowler SE et al. A randomised comparison of transcervical and transabdominal chorionic villus sampling. The New Eng J Med 1992; 327: 594-8 10. Phillips III JA, Vnencak-Jones CL. Molecular genetic techniques for prenatal diagnosis. In: Milunski A, ed. Genetic disorders and the fetus. Diagnosis, prevention, and treatment, 3E. Baltimore: The John Hopkins University Press, 1992; 257-301 11. Besley GTN. Enzyme analysis. In: Brock DJH, Rodeck CH, Ferguson-Smith MA, eds. Prenatal diagnosis and screening, Edinburgh: Churchill Livingstone, 1992; 127-145 12. Flake AW, Harrison MR, Adzick NS et al. Transplantation of fetal haematopoietic stem cells in utero: the creation of haematoooietic chimeras. Science 1986: 233: 766-778 13. Royo C,‘Touraine JL, De Bouteiller 0: Ontogeny of T lymphocyte differentiation in the human fetus: acquisition of phenotype and function. Thymus 1987; 10: 57-73 14. Vega MA. Prospects for homologous recombination in human gene therapy. Hum Genet 1991; 87: 245-253 15. Manning FA. The fetus with ventriculomegaly: the fetal surgery registry. In: Harrison MR, Golbus MS, Filly RA, eds. The unborn patient. Prenatal diagnosis and treatment, 2E. Philadelphia: WB Saunders Company, 1990; 448-452 16. Nicolini U, Fisk NM, Beacham J, Rodeck CH. Fetal urinary biochemistry. An index of renal maturation and dysfunction. Br J Obstet Gvnaecol 1992: 99: 46-50 17. Maxwell D. Ailan L, Tynan MJ. Balloon dilatation of the aortic valves in the fetus: a report of the two cases. Br Heart J 1991; 65: 256-258 18. Liley AW. Intrauterine transfusion of fetus in haemolytic disease. Br Med J 1963; 2: 1107-1109 19. Stray-Pedersen B. Toxoplasmosis in pregnancy. Baillieres Clin Obstet Gynaecol 1993; 7: 107-137 20. Sagot P, David A, Yvinec M. Intrauterine treatment of thyroid goitres. Fetal Diagn Ther 1991; 6: 28-33 21. Crowley P. Promoting pulmonary maturation. In: Chalmers I, Enkin M, Keirse MJNC, eds. Effective care in pregnancy and childbirth, Vol 1. Oxford: Oxford University Press, 1989; 7466764

FETAL THERAPY: ETHICAL, LEGAL AND MEDICAL CONSIDERATIONS 22. Liu DTY, Melville HAH, Measday B. Premature labour parameters for comparison employing methyl-xanthing therapy. Aust NZ J Obstet Gynaecol. 1975; 15: 145-149 23. Kaplan C, Morel-Kopp MC, Daffos F et al. Fetal and neonatal alloimmune thrombocytopenia: current trends in diagnosis and therapy. Transfus Med 1992; 2: 265-271 24. Forest MG, Betuel H, David M. Prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update 88 of the French multicentre study. Endocrin Res 1989; 15: 277-301 25. Roth KS, Yang W, Allan L et al. Prenatal administration of biotin in biotin responsive multiple carboxylase deficiency. Ped Res 1982, 16: 126-129 26. Rosenblatt DS, Cooper BA, Schumtz SM et al. Prenatal B12 therapy of a fetus with methylcobolamin deficiency. Lancet 1985; (i): 1127-l 129 21. Gembruch G. Hansmann M. Artificial instillation of amniotic fluid a new technique for the diagnostic evaluation of cases of oligohydramnios. Prenatal Diagn 1988; 8: 33-45 28. Elliott JP, Urig MA, Clewell WH, et al. Aggressive therapeutic amniocentesis for treatment of twin-twin transfusion syndrome. Obstet Gynecol 1991; 77: 537-540

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29. Berry PJ, Gray ES, Porter HJ, et al. Parvovirus infection of the human fetus and newborn. Sem Dian Path01 1992; 9: 4-12 30. Farah SB, Simpson TJ, Golbus MS. Hemopoietic stem cell for the treatment of genetic diseases. Clin Obstet Gynecol 1986; 29: 543-550 31. O’Reilly RJ, Pollack MS, Kapoor N. Fetal liver transplantation in man and animals. In: Gale RG, ed. Recent advances in bone marrow transplantation. New York: Alan R. Liss, 1983; 799-830 32. Touraine JL, Raudrant D, Rebaud A et al. In utero transplantation of stem cells in humans: immunological aspects and clinical follow-up of patients. Bone Marrow Transplant 1992; 9: 121-126 33. Diukman R, Golbus MS. In utero stem cells therapy. J Reprod Med 1992; 37: 515-520 34. Thompson PJ, Greenough A, Nicolaides KH. Respiratory function in infancy following pleuro-amniotic shunting. Fetal Diagn Ther 1993; 8: 79--83 35. Lorenz HP, Adzick NS, Harrison MR. Open human fetal surgery. .4dv Sug 1993; 26: 259-273