Review Article
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Ethical Issues in Fetal Diagnosis and Treatment Conor L. McMann1
Brian S. Carter, MD2,3
John D. Lantos, MD2,3
1 Vanderbilt University, Nashville, Tennessee 2 Bioethics Center, Children’s Mercy Hospital, Kansas City, Missouri 3 Department of Pediatrics, University of Missouri-Kansas City, Kansas
Address for correspondence Brian S. Carter, MD, Children’s Mercy Bioethics Center, 2401 Gillham Road, Kansas City, MO 64108 (e-mail: [email protected]).
City, Missouri
Abstract Keywords
► fetal medicine ► ethics ► congenital heart disease ► meningomyelocele
Fetal diagnosis has raised ethical issues since it was first developed in the 1940s and 1950s. Two controversial issues have predominated. First, when the techniques for prenatal diagnosis were invasive techniques, they created risks to the pregnant women. Second, prenatal diagnosis led to either prenatal treatment, which also generally had some risks to the pregnant woman, or to abortion, which has always been ethically controversial. In this article, we will review the history of ethical controversy over fetal diagnosis and discuss how they presage today’s controversies.
Fetal diagnosis has raised ethical issues since it was first developed in the 1940s and 1950s. Two controversial issues have predominated. First, when the techniques for prenatal diagnosis were invasive techniques, they created risks to the pregnant women. Second, prenatal diagnosis led to either prenatal treatment, which also generally had some risks to the pregnant woman, or to abortion, which has always been ethically controversial. In this article, we will review the history of ethical controversy over fetal diagnosis and discuss how they presage today’s controversies.
A Brief History of Fetal Diagnosis in an Ethical Context The first disease to be diagnosed prenatally was erythroblastosis fetalis (EBF). In 1950, Bevis used amniocentesis to monitor the severity of disease in pregnancies affected by EBF by measuring bilirubin levels in amniotic fluid. A higher level of bilirubin indicated more severe hemolytic disease. This was used to predict which fetuses had such severe EBF that they were likely to die in utero.1 For the sickest fetuses, it was sometimes possible to induce delivery early. But it was a delicate balance. There were no neonatal intensive care units and no way to provide treatment for fetuses born with respiratory distress as a result of their prematurity. So, the doctors had to decide when and if the complications of
received October 15, 2013 accepted after revision November 27, 2013 published online February 10, 2014
premature birth would be less than the complications of ongoing hemolytic disease. These were the first medical tests that allowed diagnosis of disease in the fetus. They gave rise to discussions about when a treatment—induced delivery—ought to be provided even though it might be risky for the pregnant woman and lead to the death of the newborn. In 1963, Liley proposed to treat severe intrauterine EBF by giving a blood transfusion to the fetus in utero. This, he predicted, would ameliorate the effects of hemolysis and would allow the fetus to survive for a few more days or weeks in the womb and increase the chances of survival after birth. It was a daring proposal. Nobody had ever treated a fetus before. There were no ultrasound machines or catheters small enough to actually cannulate the veins of a fetus. Having earlier accidently entered the peritoneal cavity of a fetus while performing an amniocentesis, Liley proposed to inject the blood not into a vein or even the bone marrow (as would be done for a newborn in those days), but instead to inject it directly into the peritoneal cavity of the fetus and hope that the blood cells would be absorbed. The idea came to him from a visitor to Auckland, New Zealand who had experience with intraperitoneal transfusion for children with sickle cell anemia in Nigeria. It was Liley’s opinion that “transfusion in utero appeared the logical procedure for these very severely affected babies early in the third trimester, and intraperitoneal transfusion seemed the simplest technique.”2
Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1364190. ISSN 0735-1631.
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It worked. With amniocentesis and intrauterine transfusion, it became clear that at least some prenatal interventions would demand tradeoffs between the potential benefits to the fetus and the potential risks to the pregnant woman. Because such interventions had never been done before, doctors could not really quantify the risks or the benefits. Liley acknowledged that he could not know whether the fetus would have died without treatment. He could not know when he undertook the procedure whether it would help or harm the fetus. Such uncertainties plague all clinical innovation but are particularly complex when the research subject is a newborn or fetus and cannot consent. These problems were recognized in Liley’s time as they are today. The editors of the British Medical Journal wrote an editorial to accompany Liley’s original case report in which they noted, “The procedures involved bear so many hazards to mother and foetus that they can clearly have only a limited application.”3 Fetal diagnosis entered a new era in 1957 when Lejeune et al discovered that Down syndrome was caused by a chromosomal abnormality, Trisomy 21.4 Lejeune had hoped that this would lead to therapies for Down syndrome. Instead, in combination with amniocentesis, it led to the possibility of fetal diagnosis and the termination of pregnancy. These two early forays into fetal diagnosis raised ethical issues that continue to this day. When is fetal intervention appropriate because the benefits to the fetus outweigh the risks to both fetus and pregnant woman? When is fetal intervention possible? What sorts of fetal diagnoses justify abortion? Over the past half century, these ethical controversies have continued and grown more complex. With regard to fetal therapy, the questions have focused on the appropriateness of doing risky procedures to the pregnant woman for the uncertain possibility of benefit to her fetus. With regard to abortion, the questions have been both the fundamental questions about the ethics of abortion in any situation but also the more focused questions about what sorts of fetal anomalies justify an abortion. The ethical issues raised by the two sets of questions overlap. They both focus on the implications of particular fetal diagnosis for the future quality of life of the child. Both raise unique issues that arise from the unique moral status of the pregnant woman. She alone, of all patients, makes decisions about her own medical care that are also decisions about the medical care, the prognosis, and even the possibility of survival of another being. To analyze the ethical implications of technological advances in fetal diagnosis and treatment over the last 50 years, we will examine two conditions—meningomyelocele (MMC) and hypoplastic left heart syndrome (HLHS)—which have been the focus of many advances in this field. These are both conditions that can, today, be diagnosed prenatally. MMC is a condition for which a preventive prenatal treatment has been partially effective. They are both conditions in which prenatal diagnosis leads to choices about fetal therapy, abortion, or continued pregnancy. If pregnancy is continued, then both conditions lead to neonatal situations in which doctors and parents may decide whether to opt for life-prolonging treatment or palliative care. By analyzing these two situaAmerican Journal of Perinatology
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tions, we hope to shed light on dilemmas in conditions that are less common, less well-defined, but that raise similar issues after prenatal diagnosis.
Meningomyelocele Epidemiology MMC is the most common severe central nervous system birth disorder.5 The most recent estimates of birth prevalence in the United States is 3.4 cases per 10,000 live births, or approximately 1,200 to 1,500 new cases of MMC per year.6 In the recent decades, the birth prevalence of MMC has been changing both because of the introduction of folate supplementation and because of improvements in fetal diagnosis. Thus, the statistics on prevalence of MMC reflect both the natural occurrence of this defect and the effects of medical interventions. Approximately, two-thirds of pregnant women who receive an early diagnosis of fetal MMC elect to terminate the pregnancy.7 Thus, the prevalence of MMC in fetuses is likely at least twice as high as the birth prevalence.
Natural History of Meningomyelocele MMC is caused by the failure of caudal neurulation during the 4th week of gestation.8 This leads to several secondary complications. Chiari II malformations occur in nearly 100% of infants with MMC and can cause hindbrain herniation, brain stem compression, and brain stem irregularities. The malformation can also cause hydrocephalus. Approximately 80% of MMC patients require ventriculoperitoneal (VP) shunting. The damage to the spinal cord inherent in MMC almost always results in paralysis and sensory changes below the level of the MMC lesion. Talipes equinovarus (club foot) is also common in MMC patients, as are hip dysplasia, and bowel or bladder dysfunction.9 Approximately 14% of infants born with MMC die within the first 5 years of life. Mortality rates are twice that high for patients with increased brain stem dysfunction due to the Arnold–Chiari malformation.10 Aside from purely physical symptoms, patients with MMC, on average, score lower on intelligence tests and more frequently have learning disabilities. Surprisingly, there is little data on long-term life expectancy for MMC patients.11,12 Longevity has been steadily increasing for several decades. A large majority of patients born after 1975 survive at least into their 30s, though even this cohort lacks documentation of true life expectancy due its relatively young age at present. There are no comprehensive and contemporary studies of overall life-expectancy in this disease, especially taking into account increasing longevity.
Prevention and Treatment There have been three approaches to prevent the morbidity and mortality of MMC: prenatal folate supplementation, maternal–fetal surgery, and postnatal repair of the spinal lesion.
Folate Supplementation In 1980, Smithells et al suggested that periconceptional supplementation with multivitamins could reduce the risk
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of MMC.13 In the following decades, many studies, both experimental and observational,14 identified folic acid as a key vitamin and demonstrated that folate intake around the period of conception could significantly reduce the prevalence of MMC.15 Whereas the mechanism is not known, current hypotheses suggests that MMC and other neural tube defects may be caused either by a folate deficiency or an abnormal metabolic pathway that requires folate.16 Folate supplementation was one of the major public health successes of the 20th century.17
Prenatal Diagnosis Prenatal diagnosis of MMC has evolved over the last four decades. In the 1970s, doctors began testing amniotic fluid alpha fetoprotein (AFP) levels in pregnant women as a screening test for MMC.18 Elevated-AFP levels indicate an increased risk of MMC. They also, however, indicate a higher risk for many other disorders. Thus, AFP screening was found to not be specific or conclusive for MMC.19 There were also problems with false-negative values for both amniotic fluid and, more recently, maternal serum AFP levels. Overall, AFP alone allowed detection rates of 65 to 83% of pregnancies in which the fetus had MMC.20 Fetal ultrasound was introduced as a technique to diagnose fetal MMC in 1975.21 Ultrasound screenings are now standard and can diagnose most cases of fetal MMC in the first trimester.22 The severity of the defect can now be analyzed based on ultrafast magnetic resonance images which can be used to assess leg movement, level of spinal defect, level of hindbrain herniation, and the presence of other anomalies in fetuses with MMC.23
Postdiagnosis Decisions Most newborns with MMC survive. Decisions about interventions after a fetal diagnosis focus mostly on the child’s anticipated quality of life. Until recently, there were three options following such a diagnosis: (1) voluntary termination of pregnancy; (2) postnatal palliative care; or (3) postnatal surgery as indicated. In the 1970s, some doctors advocated palliative care for newborns with the most severe cases of MMC. Lorber, Stark, and others reported their experiences with scoring systems that rated illness severity in newborns with MMC.24–26 These proposals were controversial, both because of questions about the validity of the prognostic scoring systems and questions about the morality of allowing any baby to die of a nonlethal condition for which life-saving treatment was available and effective.27 These controversies became the focus of a national controversy in the early 1980s when the federal government issued regulations prohibiting the foregoing of life-sustaining treatment in newborns with congenital anomalies.28 These regulations allowed anonymous reporting of suspected medical neglect. Such reports triggered real-time federal investigations of the clinical treatment (or nontreatment) of individual newborns who were the subject of such reports. One such case was a newborn with MMC who was born on Long Island and became known as Baby Jane Doe. Her parents
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chose not to authorize surgery to repair her MMC and hydrocephalus, but, instead, to provide “conservative” treatment that consisted of antibiotics and sterile coverings for her spinal lesion. The legal battle eventually reached the United States Supreme Court which struck down the federal regulations.29 Although this supreme court decision overturned one particular federal initiative to change the paradigm for decisions, the national discussion led to an apparent shift in attitudes and practices. Since the mid-1980s, there have been no reports of protocols to predominantly provide palliative care or to postpone surgery for newborns with MMC. Thus, in the 1980s and 1990s, there were, for all practical purposes, only two choices after a prenatal diagnosis of MMC— termination of pregnancy or postnatal surgery—that changed with the development of in utero maternal–fetal surgery.
Recent Developments—Maternal–Fetal Surgery Since 1997, some women have been offered the option of in utero, maternal–fetal surgery to attempt to repair the spinal lesion after a prenatal diagnosis of MMC [29].30 In the late 1990s and early 2000s, such surgery was developed in a few tertiary care centers. Several preliminary clinical studies (most of which used historical controls) suggested that the in utero surgery could resolve hindbrain herniation, increase extremity function, decrease the likelihood of the infant needing a VP shunt, decrease instance of talipes, facilitate ventricular recovery, and perhaps improve cognitive function.31–33, Such surgery was complex and risky. Surgery needed to be performed late in the second trimester. In some cases, it led to premature labor and the birth of an extremely premature newborn, oligohydramnios, or uteroplacental problems. It was unclear whether outcomes were, in fact, better for the newborns born after such surgery. The debates mirrored those that took place over intrauterine transfusion for EBF decades before. The key question was whether, and for whom, the risks outweighed the benefits. As a result of the ongoing controversy about the indication for and outcomes of the maternal–fetal surgery, three leading centers proposed a prospective randomized-controlled trial. The trial was complicated to carry out, both technically and ethically.
Maternal–Fetal Surgery for Meningomyelocele As a result of the ongoing controversy about the indication for and outcomes of the maternal–fetal surgery for MMC, three leading centers proposed a prospective randomized-controlled trial. Between 2003 and 2010, the Children’s Hospital of Philadelphia, Vanderbilt University Medical Center, and the University of California at San Francisco Medical Center conducted a study called the Management of Myelomeningocele Study (MOMS). The MOMS was a prospective, randomized trial designed to determine whether maternal–fetal surgery improved outcomes. There were two primary outcomes: the first outcome, at 12 months, was a composite of fetal or neonatal death or the need for a VP shunt. The second primary outcome, at 30 months, was a composite score of the Mental Development Index of the Bayley Scales of Infant American Journal of Perinatology
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Development II and the child’s motor function, with adjustment for lesion level. The study also analyzed whether such surgery led to increased preterm birth or increased obstetrical complications for the pregnant woman.34 Comparing the two groups with regard to a composite outcome of fetal or neonatal death, or the need for placement of a VP shunt by the age of 12 months, newborns in the treatment arm did better than those in the control arm (68 vs. 98%; relative risk, 0.70; 97.7% confidence interval [CI], 0.58– 0.84; p < 0.001). With regard to neurodevelopmental, outcome at the age of 30 months, newborns in the treatment arm also did better. Most strikingly, newborns in the maternal– fetal surgery arm were twice as likely as newborns in the control arm to be walking independently (42 vs. 21%, p ¼ 0.01). Prenatal surgery, however, was risky for mothers as it included a hysterotomy obligating them to future cesarean deliveries. In addition, study mothers had associated increased risks for preterm delivery, uterine dehiscence at delivery, and placental abruption.
The New Ethics of Prenatal Decision Making The results of the MOMS will inevitably change the way doctors and patients think about the decisions they face after a prenatal diagnosis. The results of the MOMS suggest that, at least in situations similar to those in the study, maternal–fetal surgery is clearly in the interest of the fetus. They also show that such surgery clearly increases risks for the pregnant woman. The question is whether and how fetal interests (and the related interests of the child that the fetus has the potential to become) should be weighed against the interests of the pregnant woman. Chervenak and McCullough present an ethical analysis of this situation by analyzing whether the fetus should be considered a patient.35 In their opinion, the fetus should be considered a patient once it is viable, that is, after the 24th week of gestation. Before that, they argue, the decision should be based entirely on what is best for the pregnant woman. But they add a complicated caveat. If the woman is planning on carrying the pregnancy to term, then even a previable fetus should be considered a patient. Under these conditions, Chervenak and McCullough claim a physician “has beneficence-based obligations” to protect the life and health of the MMC fetus. Thus, the doctor would have to give equal weight to the prospective mother and fetus as patients. Most other authors who have analyzed the ethics of this situation prioritize the health and the autonomy of the pregnant woman more than they do any ascribed rights of the fetus as patient. They worry that the woman’s health and her rights might be compromised out of concern for fetal benefit. van Lith et al asserts that “a fetus is not a patient in the real sense…[and] it would be unethical if a care provider, without the woman’s informed consent, promoted the interests of the fetus over those of the woman.”36 These two views illustrate different ways of balancing the interests of the pregnant woman and those of the fetus. Often, doctors do not have to choose one over the other. Instead, it is common for the well-informed pregnant women to choose to take the risks of maternal–fetal surgery in hopes that such American Journal of Perinatology
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surgery will be of benefit to her fetus. In such situations, presumably, she has decided that the potential benefits to her fetus outweigh the potential risks to herself. In such circumstances, clarity about maternal risks is crucial. Although the procedure was being offered as part of a research protocol, the informed consent process was rigorous and comprehensive. In addition, the eligibility criteria were strict and strictly observed. A similar screening and consent process should occur even if the surgery is being offered outside of a research protocol. The MOMS allows some risks to be precisely quantified for women who have similar risk factors as those women who were eligible for the trial. It is likely, however, that maternal–fetal surgery will now be offered to women with additional risk factors. For example, the MOMS excluded obese women (those with a body mass index, BMI, >35 kg/m2), whose risks may be higher. Furthermore, the total number of subjects in the MOMS was small enough that rare complications might not have occurred. For example, there are no recorded instances of maternal death from the MMC maternal–fetal surgery. The problem of generalizing research results from strictly conducted clinical trials to populations of patients who were not included in those trials is not unique to fetal surgery. If other centers start offering such surgery, or if it is offered to women who do not meet the strict eligibility criteria that were used in MOMS, the outcomes may be different. The effects of in utero surgery on future reproductive health are similarly difficult to quantify. Two follow-up studies of women who underwent maternal–fetal surgery found negligible detriment to future reproductive ability and suggested that the hysterotomy required for the surgery posed little more risk than an ordinary cesarean section.37 As more women undergo maternal–fetal surgery, more data on its long-term risks will accrue. Continued collection of follow-up data and continued analysis of long-term risks is essential. The matter of surgical timing is another key ethical issue. In the MOMS, surgery was done when the fetus was between 20 and 25 weeks of gestation. However, animal studies and human experience have suggested that if the surgery were initiated earlier, there could be more extensive prevention of complications due to MMC. The danger in this, of course, is the risk of prematurity. Proceeding too early could injure the fetus, cause intrauterine fetal death, or delivery before viability. Again, as with expanded eligibility criteria, further study is essential to determine whether the outcomes that were achieved in MOMS can be replicated. Clearly, the MOMS was just a first step. Further research will need to focus on developing less invasive surgical techniques. Adzick suggests that such techniques “may not only minimize preterm labor and delivery, but may also permit prenatal coverage of the lesion much earlier in gestation.”38 Attempting to find a safer, less invasive method of MMC maternal–fetal surgery would raise many of the same sorts of ethical issues as the attempts to develop the present surgery. We will only know if these techniques are better by studying them. But studying them will require some people to be willing to undergo an unstudied innovative treatment rather
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Hypoplastic Left Heart Syndrome
published data on longer-term outcomes or life expectancy. However, survival after postnatal surgery rates have been documented to stabilize after the first year,55 and therefore, those that survive surgical intervention fairly consistently survive into adulthood.
Prenatal Diagnosis
HLHS offers another example of the ways in by which improved prenatal diagnosis is changing the ways that clinicians think about diseases of the fetus and the newborn. As with MMC, HLHS illustrates the complex ways in which a fetal diagnosis may influence the decision-making process in obstetrics as well as neonatology.
The measurement of nuchal translucency on a first trimester ultrasound allows the identification of fetuses at high risk for congenital heart disease.56,57 Detailed second trimester fetal echocardiography can identify most fetuses with HLHS.58 Nevertheless, about 30 to 40% of newborns with HLHS have not been identified prenatally.59,60
Epidemiology
Prenatal Testing and Prognosis
HLHS is a congenital heart defect that comprises from 2 to 9% of cardiac disorders in newborns [35]. It occurs in approximately 0.2% of live births in the United States. Thus, there approximately 1,000 new cases per year.39 Two factors—intrauterine fetal demise and termination of pregnancy—complicate the interpretation of these statistics about birth prevalence. The risk of stillbirth in HLHS has been reported as between 1.7 and 12.5%, the wide range resulting from different study methodologies.40,41 The percentage of women who choose termination of pregnancy after a prenatal diagnosis of HLHS has been estimated to be anywhere from 2042 to 87%.43 The rate of termination varies between countries, between different medical centers, and is higher when the diagnosis is made earlier in pregnancy and when other congenital defects are present.44
There has been debate over the utility of prenatal diagnosis for HLHS. Before 2001, several studies found no correlation between prenatal diagnosis of HLHS and survival.61 In 2001, Tworetzky et al and Mahle et al62 showed that newborns who were diagnosed prenatally had a significantly increased rate of survival and better neurological outcomes compared with postnatally diagnosed newborns. Tworetzky et al suggested that prenatal diagnosis allowed delivery at a tertiary care center where newborns received immediate treatment—thus avoiding hypoxemia, acidemia, and other complications. Others have suggested that increased survival after prenatal diagnosis results from the fact that prenatal diagnosis allows the identification of fetuses with other congenital anomalies. If women choose to terminate their pregnancies in these circumstances, then the newborns who are born with HLHS have fewer other anomalies. That might lead to increased survival. This is supported by the observation that the infants in the Tworetzky study had a significantly lower incidence of presurgical complications. Prospective parents of HLHS fetuses report being happier, better adjusted, and more at peace with their decisions following a prenatal diagnosis.63 This could be because of the increased time for education, planning, and decision making that comes with a prenatal diagnosis.
Physiology In HLHS, the left ventricle, ascending aorta, aortic, and mitral valves do not develop properly.45 With no medical intervention, the ductus closes quickly after birth, leading to limited systemic blood flow, and resulting in death if no intervention is taken. In addition to this cardiopulmonary pathology, newborns with HLHS frequently have other anomalies. Many have abnormal brain development, behavior problems, and learning disabilities.46 Physical and neurodevelopmental complications of the condition are thought to be somewhat independent of the heart malformation itself.47–49 Before 1980, there was no treatment for HLHS and it was uniformly fatal. In the early 1980s, two treatments were developed. Norwood developed a three-stage reconstructive operation, while other doctors proposed neonatal heart transplantation.50 There is controversy about how to assess overall survival rates for HLHS. Some studies report overall survival after prenatal diagnosis.51,52 This measure includes cases in which a choice was made for termination of pregnancy. Others include outcomes for live-born newborns. This measure includes cases in which a choice was made to forego surgery.53 Still other studies report outcomes only among newborns who had surgery to correct the defect.54 Survival rates range from 20 to 30% for all fetuses diagnosed prenatally to 80 to 90% for newborns who undergo surgery. There is still no
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Prospects—Maternal–Fetal Surgery There are no studies evaluating open maternal–fetal surgery for HLHS. Some investigators have attempted percutaneous prenatal atrial septal stent placement for evolving HLHS.64 To date, these have not been successful.65
Postdiagnosis Decisions After a prenatal diagnosis of HLHS, there are five possible choices: (1) termination of pregnancy; (2) in utero intervention; (3) postnatal heart transplantation; (4) postnatal staged palliative repair; or (5) postnatal palliative care. Different doctors recommend different choices. There is even disagreement about whether all of these choices should be offered.66 However, the availability of prenatal diagnosis, coupled with easy access to information on the internet, makes the discussion of all choices necessary. As long as termination of pregnancy is legal, doctors have an obligation to inform pregnant women of this option. American Journal of Perinatology
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than the current standard treatment. Investigators will have to decide which patients are eligible and will have to carefully collect data that will allow them to evaluate this innovative approach against the protocols used in the MOMS.
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Prenatal counseling should include information about the diagnosis and the prognosis. Postnatal decisions are more complicated. Clearly, parents need to be informed of the availability of treatment. They also need to be informed that decisions must be made relatively quickly. As surgical outcomes after staged-repair improve, transplantation is becoming an increasingly rare option. Choosing a three-stage reconstruction means choosing a long and burdensome course of treatment that involves frequent, lengthy hospitalizations, as well as substantial postoperative pain and anxiety.
Ethics of Postdiagnostic Decision Making The central ethical debate today among experts in HLHS is about whether or not parents should still be offered the option of palliative care. Wernovsky proposes that the modern prognosis for HLHS patients is so good that it is clearly in the newborn’s best interest to have surgery.67 He compares HLHS to other congenital defects with similar or worse survival rates, such as heterotaxia and pulmonary atresia, for which palliative care is generally not considered an option. He views palliative care as unethical in a situation in which 5-year survival rates are well over 50%. Kon, by contrast, argues that palliative care should continue to be offered.68 He bases this argument on both the burdens of treatment to the child and the neurocognitive and physical complications associated with staged-surgical repair. He has surveyed neonatologists, neonatal nurses, cardiologists, and cardiac surgeons and shown that many of these health professionals would choose palliative care for their own newborn with HLHS.69,70 Over the last 30 years, the trend in pediatric ethics and health law with regard to decisions about foregoing lifesustaining treatment has been to restrict the situations in which such decisions are permitted. It used to be common— and permissible—for parents to refuse cancer chemotherapy, surgery for newborns with Down syndrome and congenital anomalies, and surgery for newborns with severe MMC. In those situations, surveys showed—as they do now for HLHS— that many doctors thought that is was acceptable to choose palliative care rather than life-prolonging treatment. Over the last three decades, however, pediatricians, bioethicists, and judges have come to see many of these decisions are inappropriate because they are not in the child’s interests and because they are they are based on inaccurate views of the quality of life experienced by children with disabilities.71 HLHS seems different, however, in important ways. Surgery for newborns with Down syndrome and operable congenital anomalies is, generally, a single operation. The burden of treatment is much lower than in surgery for HLHS and the prognosis for survival is better. Cancer chemotherapy for acute lymphocytic leukemia is a long and burdensome treatment. However, the chances for cure are very high—and children who are cured no longer have cancer. In HLHS, the treatment is burdensome, long-term survival rates are below 90%, and the survivors are not cured. Instead, they have a lifelong chronic disease. In fact, most surgeons who operate on newborns with HLHS describe the operation as “palliative,” American Journal of Perinatology
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rather than “curative.” In these circumstances, the choice of palliative care remains an ethically defensible choice.
Meningomyelocele and Hypoplastic Left Heart Syndrome: A Comparison MMC and HLHS exemplify many of the issues in the advancing field of fetal and neonatal medicine. In both, early prenatal diagnosis allows for carefully considered and well-developed prenatal and postnatal treatment strategies. When confronted with a prenatal diagnosis of either disease, many women choose to terminate pregnancy. In both situations, there is controversy about the appropriateness of neonatal palliative care. MMC and HLHS additionally belong to a small category of defects for which maternal–fetal surgery is being investigated. They are thus laboratories for investigating the issues that arise when obstetricians and maternal–fetal medicine specialists must balance potential benefits to the fetus against potential harms to the pregnant woman. Both HLHS and MMC present with a wide range of illness severity and associated anomalies. These lead to differences in prognosis. In such situations, decisions must be individualized to reflect the individual circumstances. There is no single right choice for all newborns with HLHS or all newborns with MMC. There are also interesting differences between MMC and HLHS. In MMC, there is preventive treatment (folate) and an effective form of maternal–fetal surgery. In MMC, neonatal palliative care has largely been abandoned as a practice. This may reflect the ease of first trimester prenatal diagnosis and the availability of abortion. MMC and HLHS are relatively common among prenatally diagnosable conditions. The issues that arise in decisionmaking for fetuses with these conditions also arise in conditions that are far less common. Soon, noninvasive prenatal genetic diagnosis will be available for thousands of conditions that have never been diagnosed prenatally before. The lessons learned from MMC and HLHS will shape the discussion about how doctors and parents should respond to information from such prenatal diagnosis. For the foreseeable future, however, it seems likely that the dominant feature of many prenatal diagnoses will be one of significant uncertainty about prognosis. In such situations, doctors have an ethical obligation to understand and communicate not only the level of uncertainty but also the full range of options available to them. They have an additional ethical obligation to collect careful data on outcomes to inform future discussions. We can discuss MMC and HLHS now because some doctors have been meticulous in studying outcomes and publishing their results. Unfortunely, there are also many centers dabbling in “fetal medicine” without studying outcomes or publishing results. There are very few long-term outcome studies, even for HLHS and MMC. There are even fewer for many other conditions. To best serve pregnant women and babies, fetal medicine centers must cooperate in research on interventions and carefully study both short-term and long-term outcomes.
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23 Glastonbury CM, Kennedy AM. Ultrafast MRI of the fetus. Australas
Radiol 2002;46(1):22–32 24 Lorber J. Results of treatment of myelomeningocele. An analysis of
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Petersen OB, Mosdal C. Decreased incidence of myelomeningocele at birth: effect of folic acid recommendations or prenatal diagnostics? Childs Nerv Syst 2011;27(11):1951–1955 Au KS, Ashley-Koch A, Northrup H. Epidemiologic and genetic aspects of spina bifida and other neural tube defects. Dev Disabil Res Rev 2010;16(1):6–15 Johnson CY, Honein MA, Dana Flanders W, Howards PP, Oakley GP Jr, Rasmussen SA. Pregnancy termination following prenatal diagnosis of anencephaly or spina bifida: a systematic review of the literature. Birth Defects Res A Clin Mol Teratol 2012;94(11): 857–86310.1002/bdra.23086 Kaufman BA. Neural tube defects. Pediatr Clin North Am 2004; 51(2):389–419 Guille JT, Sarwark JF, Sherk HH, Kumar SJ. Congenital and developmental deformities of the spine in children with myelomeningocele. J Am Acad Orthop Surg 2006;14(5):294–302 Adzick NS. Fetal surgery for spina bifida: past, present, future. Semin Pediatr Surg 2013;22(1):10–17 Davis BE, Daley CM, Shurtleff DB, et al. Long-term survival of individuals with myelomeningocele. Pediatr Neurosurg 2005; 41(4):186–191 Dillon CM, Davis BE, Duguay S, Seidel KD, Shurtleff DB. Longevity of patients born with myelomeningocele. Eur J Pediatr Surg 2000;10 (Suppl 1):33–34 Smithells RW, Sheppard S, Schorah CJ, et al. Possible prevention of neural-tube defects by periconceptional vitamin supplementation. Lancet 1980;1(8164):339–340 De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 2007; 357(2):135–142 Berry RJ, Li Z, Erickson JD, et al; Collaborative Project for Neural Tube Defect Prevention. Prevention of neural-tube defects with folic acid in China. China-U.S. N Engl J Med 1999;341(20): 1485–1490 Dias MS. Neurosurgical management of myelomeningocele (spina bifida). Pediatr Rev 2005;26(2):50–60, discussion 50–60 Morris JK, Wald NJ. Quantifying the decline in the birth prevalence of neural tube defects in England and Wales. J Med Screen 1999; 6(4):182–185 Macri JN, Weiss RR. Prenatal serum alpha-fetoprotein screening for neural tube defects. Obstet Gynecol 1982;59(5):633–639 Cameron M, Moran P. Prenatal screening and diagnosis of neural tube defects. Prenat Diagn 2009;29(4):402–411 Brock DJ, Scrimgeour JB, Steven J, Barron L, Watt M. Maternal plasma alpha-fetoprotein screening for fetal neural tube defects. Br J Obstet Gynaecol 1978;85(8):575–581 Campbell S, Pryse-Davies J, Coltart TM, Seller MJ, Singer JD. Ultrasound in the diagnosis of spina bifida. Lancet 1975;1(7915):1065–1068 Ben-Sira L, Garel C, Malinger G, Constantini S. Prenatal diagnosis of spinal dysraphism. Childs Nerv Syst 2013;29(9):1541–1552
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524 unselected cases, with special reference to possible selection for treatment. Dev Med Child Neurol 1971;13(3):279–303 Stark GD, Drummond M. Results of selective early operation in myelomeningocele. Arch Dis Child 1973;48(9):676–683 Lorber J. Spina bifida cystica. Results of treatment of 270 consecutive cases with criteria for selection for the future. Arch Dis Child 1972;47(256):854–873 Freeman JM. Early management and decision making for the treatment of myelomeningocele: a critique. Pediatrics 1984; 73(4):564–566 Kopelman LM. Are the 21-year-old Baby Doe rules misunderstood or mistaken? Pediatrics 2005;115(3):797–802 Annas GJ. Checkmating the Baby Doe regulations. Hastings Cent Rep 1986;16(4):29–31 Meuli M, Moehrlen U. Fetal surgery for myelomeningocele: a critical appraisal. Eur J Pediatr Surg 2013;23(2):103–109 Sutton LN, Adzick NS, Bilaniuk LT, Johnson MP, Crombleholme TM, Flake AW. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 1999;282(19):1826–1831 Bruner JP, Tulipan N, Paschall RL, et al. Fetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 1999;282(19):1819–1825 Johnson MP, Sutton LN, Rintoul N, et al. Fetal myelomeningocele repair: short-term clinical outcomes. Am J Obstet Gynecol 2003; 189(2):482–487 Adzick NS, Thom EA, Spong CY, et al; MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011;364(11):993–1004 Chervenak FA, McCullough LB. Ethics of maternal-fetal surgery. Semin Fetal Neonatal Med 2007;12(6):426–431 van Lith JM, Johnson MP, Wilson RD. Current controversies in prenatal diagnosis 3: fetal surgery after MOMS: is fetal therapy better than neonatal? Prenat Diagn 2013;33(1):13–16 Wilson RD, Lemerand K, Johnson MP, et al. Reproductive outcomes in subsequent pregnancies after a pregnancy complicated by open maternal-fetal surgery (1996–2007). Am J Obstet Gynecol 2010; 203(3):209.e1–209.e6 Adzick NS. Fetal surgery for spina bifida: past, present, future. Semin Pediatr Surg 2013;22(1):10–17 Canfield MA, Honein MA, Yuskiv N, et al. National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001. Birth Defects Res A Clin Mol Teratol 2006;76(11):747–756 Allen RH, Benson CB, Haug LW. Pregnancy outcome of fetuses with a diagnosis of hypoplastic left ventricle on prenatal sonography. J Ultrasound Med 2005;24(9):1199–1203 Verheijen PM, Lisowski LA, Plantinga RF, et al. Prenatal diagnosis of the fetus with hypoplastic left heart syndrome management and outcome. Herz 2003;28(3):250–256 Prsa M, Holly CD, Carnevale FA, Justino H, Rohlicek CV. Attitudes and practices of cardiologists and surgeons who manage HLHS. Pediatrics 2010;125(3):e625–e630 10.1542/peds.2009-1678 Germanakis I, Sifakis S. The impact of fetal echocardiography on the prevalence of liveborn congenital heart disease. Pediatr Cardiol 2006;27(4):465–472 Murtuza B, Elliott MJ. Changing attitudes to the management of hypoplastic left heart syndrome: a European perspective. Cardiol Young 2011;21(Suppl 2):148–158 Byrne PJ, Murphy A. Informed consent and hypoplastic left heart syndrome. Acta Paediatr 2005;94(9):1171–1175 Goldberg CS, Gomez CA. Hypoplastic left heart syndrome: new developments and current controversies. Semin Neonatol 2003; 8(6):461–468
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We should not have to rely on single-center studies or case reports. Good ethics starts with good facts. Good facts come from good science. Good science regarding rare diseases can only come from cooperation among tertiary care centers.
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47 Hinton RB, Andelfinger G, Sekar P, et al. Prenatal head growth and
59 Acherman RJ, Evans WN, Luna CF, et al. Prenatal detection of
white matter injury in hypoplastic left heart syndrome. Pediatr Res 2008;64(4):364–369 Licht DJ, Shera DM, Clancy RR, et al. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg 2009;137(3):529–536, discussion 536–537 Clouchoux C, du Plessis AJ, Bouyssi-Kobar M, et al. Delayed Cortical Development in Fetuses with Complex Congenital Heart Disease. Cereb Cortex 2012 Goldberg CS, Gomez CA. Hypoplastic left heart syndrome: new developments and current controversies. Semin Neonatol 2003; 8(6):461–468 Axt-Fliedner R, Enzensberger C, Fass N, et al. Fetal diagnosis of hypoplastic left heart, associations and outcomes in the current era. Ultraschall Med 2012;33(7):E51–E56 Tibballs J, Cantwell-Bartl A. Outcomes of management decisions by parents for their infants with hypoplastic left heart syndrome born with and without a prenatal diagnosis. J Paediatr Child Health 2008;44(6):321–324 Fortuna RS, Ruzmetov M, Geiss DM. Outcomes of the modified Norwood procedure: hypoplastic left heart syndrome versus other single-ventricle malformations. Pediatr Cardiol 2013 [Epub ahead of print] Newburger JW, Sleeper LA, Bellinger DC, et al; Pediatric Heart Network Investigators. Early developmental outcome in children with hypoplastic left heart syndrome and related anomalies: the single ventricle reconstruction trial. Circulation 2012;125(17): 2081–2091 McGuirk SP, Griselli M, Stumper OF, et al. Staged surgical management of hypoplastic left heart syndrome: a single institution 12. year experience. Heart 2006;92(3):364–370 Atzei A, Gajewska K, Huggon IC, Allan L, Nicolaides KH. Relationship between nuchal translucency thickness and prevalence of major cardiac defects in fetuses with normal karyotype. Ultrasound Obstet Gynecol 2005;26(2):154–157 Rasiah SV, Publicover M, Ewer AK, Khan KS, Kilby MD, Zamora J. A systematic review of the accuracy of first-trimester ultrasound examination for detecting major congenital heart disease. Ultrasound Obstet Gynecol 2006;28(1):110–116 Israel SW, Roofe LR, Saville BR, Walsh WF. Improvement in antenatal diagnosis of critical congenital heart disease implications for postnatal care and screening. Fetal Diagn Ther 2011; 30(3):180–183
congenital heart disease in southern Nevada: the need for universal fetal cardiac evaluation. J Ultrasound Med 2007;26(12): 1715–1719, quiz 1720–1721 Barron DJ, Kilby MD, Davies B, Wright JG, Jones TJ, Brawn WJ. Hypoplastic left heart syndrome. Lancet 2009;374(9689): 551–564 Tworetzky W, McElhinney DB, Reddy VM, Brook MM, Hanley FL, Silverman NH. Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation 2001;103(9): 1269–1273 Mahle WT, Clancy RR, McGaurn SP, Goin JE, Clark BJ. Impact of prenatal diagnosis on survival and early neurologic morbidity in neonates with the hypoplastic left heart syndrome. Pediatrics 2001;107(6):1277–1282 Sklansky M, Tang A, Levy D, et al. Maternal psychological impact of fetal echocardiography. J Am Soc Echocardiogr 2002;15(2): 159–166 Chaturvedi RR, Ryan G, Seed M, van Arsdell G, Jaeggi ET. Fetal stenting of the atrial septum: technique and initial results in cardiac lesions with left atrial hypertension. Int J Cardiol 2013; 168(3):2029–2036 McElhinney DB, Tworetzky W, Lock JE. Current status of fetal cardiac intervention. Circulation 2010;121(10):1256–1263 Vandvik IH, Førde R. Ethical issues in parental decision-making. An interview study of mothers of children with hypoplastic left heart syndrome. Acta Paediatr 2000;89(9):1129–1133 Wernovsky G. The paradigm shift toward surgical intervention for neonates with hypoplastic left heart syndrome. Arch Pediatr Adolesc Med 2008;162(9):849–854 Kon AA. Healthcare providers must offer palliative treatment to parents of neonates with hypoplastic left heart syndrome. Arch Pediatr Adolesc Med 2008;162(9):844–848 Prsa M, Holly CD, Carnevale FA, Justino H, Rohlicek CV. Attitudes and practices of cardiologists and surgeons who manage HLHS. Pediatrics 2010;125(3):e625–e630 Kon AA, Prsa M, Rohlicek CV. Choices doctors would make if their infant had hypoplastic left heart syndrome: comparison of survey data from 1999 and 2007. Pediatr Cardiol 2013;34(2): 348–353 Payot A, Barrington KJ. The quality of life of young children and infants with chronic medical problems: review of the literature. Curr Probl Pediatr Adolesc Health Care 2011;41(4):91–101
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Ethical Issues in Fetal Diagnosis and Treatment Conor L. McMann1
Brian S. Carter, MD2,3
John D. Lantos, MD2,3
1 Vanderbilt University, Nashville, Tennessee 2 Bioethics Center, Children’s Mercy Hospital, Kansas City, Missouri 3 Department of Pediatrics, University of Missouri-Kansas City, Kansas
Address for correspondence Brian S. Carter, MD, Children’s Mercy Bioethics Center, 2401 Gillham Road, Kansas City, MO 64108 (e-mail: [email protected]).
City, Missouri
Abstract Keywords
► fetal medicine ► ethics ► congenital heart disease ► meningomyelocele
Fetal diagnosis has raised ethical issues since it was first developed in the 1940s and 1950s. Two controversial issues have predominated. First, when the techniques for prenatal diagnosis were invasive techniques, they created risks to the pregnant women. Second, prenatal diagnosis led to either prenatal treatment, which also generally had some risks to the pregnant woman, or to abortion, which has always been ethically controversial. In this article, we will review the history of ethical controversy over fetal diagnosis and discuss how they presage today’s controversies.
Fetal diagnosis has raised ethical issues since it was first developed in the 1940s and 1950s. Two controversial issues have predominated. First, when the techniques for prenatal diagnosis were invasive techniques, they created risks to the pregnant women. Second, prenatal diagnosis led to either prenatal treatment, which also generally had some risks to the pregnant woman, or to abortion, which has always been ethically controversial. In this article, we will review the history of ethical controversy over fetal diagnosis and discuss how they presage today’s controversies.
A Brief History of Fetal Diagnosis in an Ethical Context The first disease to be diagnosed prenatally was erythroblastosis fetalis (EBF). In 1950, Bevis used amniocentesis to monitor the severity of disease in pregnancies affected by EBF by measuring bilirubin levels in amniotic fluid. A higher level of bilirubin indicated more severe hemolytic disease. This was used to predict which fetuses had such severe EBF that they were likely to die in utero.1 For the sickest fetuses, it was sometimes possible to induce delivery early. But it was a delicate balance. There were no neonatal intensive care units and no way to provide treatment for fetuses born with respiratory distress as a result of their prematurity. So, the doctors had to decide when and if the complications of
received October 15, 2013 accepted after revision November 27, 2013 published online February 10, 2014
premature birth would be less than the complications of ongoing hemolytic disease. These were the first medical tests that allowed diagnosis of disease in the fetus. They gave rise to discussions about when a treatment—induced delivery—ought to be provided even though it might be risky for the pregnant woman and lead to the death of the newborn. In 1963, Liley proposed to treat severe intrauterine EBF by giving a blood transfusion to the fetus in utero. This, he predicted, would ameliorate the effects of hemolysis and would allow the fetus to survive for a few more days or weeks in the womb and increase the chances of survival after birth. It was a daring proposal. Nobody had ever treated a fetus before. There were no ultrasound machines or catheters small enough to actually cannulate the veins of a fetus. Having earlier accidently entered the peritoneal cavity of a fetus while performing an amniocentesis, Liley proposed to inject the blood not into a vein or even the bone marrow (as would be done for a newborn in those days), but instead to inject it directly into the peritoneal cavity of the fetus and hope that the blood cells would be absorbed. The idea came to him from a visitor to Auckland, New Zealand who had experience with intraperitoneal transfusion for children with sickle cell anemia in Nigeria. It was Liley’s opinion that “transfusion in utero appeared the logical procedure for these very severely affected babies early in the third trimester, and intraperitoneal transfusion seemed the simplest technique.”2
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DOI http://dx.doi.org/ 10.1055/s-0033-1364190. ISSN 0735-1631.
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It worked. With amniocentesis and intrauterine transfusion, it became clear that at least some prenatal interventions would demand tradeoffs between the potential benefits to the fetus and the potential risks to the pregnant woman. Because such interventions had never been done before, doctors could not really quantify the risks or the benefits. Liley acknowledged that he could not know whether the fetus would have died without treatment. He could not know when he undertook the procedure whether it would help or harm the fetus. Such uncertainties plague all clinical innovation but are particularly complex when the research subject is a newborn or fetus and cannot consent. These problems were recognized in Liley’s time as they are today. The editors of the British Medical Journal wrote an editorial to accompany Liley’s original case report in which they noted, “The procedures involved bear so many hazards to mother and foetus that they can clearly have only a limited application.”3 Fetal diagnosis entered a new era in 1957 when Lejeune et al discovered that Down syndrome was caused by a chromosomal abnormality, Trisomy 21.4 Lejeune had hoped that this would lead to therapies for Down syndrome. Instead, in combination with amniocentesis, it led to the possibility of fetal diagnosis and the termination of pregnancy. These two early forays into fetal diagnosis raised ethical issues that continue to this day. When is fetal intervention appropriate because the benefits to the fetus outweigh the risks to both fetus and pregnant woman? When is fetal intervention possible? What sorts of fetal diagnoses justify abortion? Over the past half century, these ethical controversies have continued and grown more complex. With regard to fetal therapy, the questions have focused on the appropriateness of doing risky procedures to the pregnant woman for the uncertain possibility of benefit to her fetus. With regard to abortion, the questions have been both the fundamental questions about the ethics of abortion in any situation but also the more focused questions about what sorts of fetal anomalies justify an abortion. The ethical issues raised by the two sets of questions overlap. They both focus on the implications of particular fetal diagnosis for the future quality of life of the child. Both raise unique issues that arise from the unique moral status of the pregnant woman. She alone, of all patients, makes decisions about her own medical care that are also decisions about the medical care, the prognosis, and even the possibility of survival of another being. To analyze the ethical implications of technological advances in fetal diagnosis and treatment over the last 50 years, we will examine two conditions—meningomyelocele (MMC) and hypoplastic left heart syndrome (HLHS)—which have been the focus of many advances in this field. These are both conditions that can, today, be diagnosed prenatally. MMC is a condition for which a preventive prenatal treatment has been partially effective. They are both conditions in which prenatal diagnosis leads to choices about fetal therapy, abortion, or continued pregnancy. If pregnancy is continued, then both conditions lead to neonatal situations in which doctors and parents may decide whether to opt for life-prolonging treatment or palliative care. By analyzing these two situaAmerican Journal of Perinatology
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tions, we hope to shed light on dilemmas in conditions that are less common, less well-defined, but that raise similar issues after prenatal diagnosis.
Meningomyelocele Epidemiology MMC is the most common severe central nervous system birth disorder.5 The most recent estimates of birth prevalence in the United States is 3.4 cases per 10,000 live births, or approximately 1,200 to 1,500 new cases of MMC per year.6 In the recent decades, the birth prevalence of MMC has been changing both because of the introduction of folate supplementation and because of improvements in fetal diagnosis. Thus, the statistics on prevalence of MMC reflect both the natural occurrence of this defect and the effects of medical interventions. Approximately, two-thirds of pregnant women who receive an early diagnosis of fetal MMC elect to terminate the pregnancy.7 Thus, the prevalence of MMC in fetuses is likely at least twice as high as the birth prevalence.
Natural History of Meningomyelocele MMC is caused by the failure of caudal neurulation during the 4th week of gestation.8 This leads to several secondary complications. Chiari II malformations occur in nearly 100% of infants with MMC and can cause hindbrain herniation, brain stem compression, and brain stem irregularities. The malformation can also cause hydrocephalus. Approximately 80% of MMC patients require ventriculoperitoneal (VP) shunting. The damage to the spinal cord inherent in MMC almost always results in paralysis and sensory changes below the level of the MMC lesion. Talipes equinovarus (club foot) is also common in MMC patients, as are hip dysplasia, and bowel or bladder dysfunction.9 Approximately 14% of infants born with MMC die within the first 5 years of life. Mortality rates are twice that high for patients with increased brain stem dysfunction due to the Arnold–Chiari malformation.10 Aside from purely physical symptoms, patients with MMC, on average, score lower on intelligence tests and more frequently have learning disabilities. Surprisingly, there is little data on long-term life expectancy for MMC patients.11,12 Longevity has been steadily increasing for several decades. A large majority of patients born after 1975 survive at least into their 30s, though even this cohort lacks documentation of true life expectancy due its relatively young age at present. There are no comprehensive and contemporary studies of overall life-expectancy in this disease, especially taking into account increasing longevity.
Prevention and Treatment There have been three approaches to prevent the morbidity and mortality of MMC: prenatal folate supplementation, maternal–fetal surgery, and postnatal repair of the spinal lesion.
Folate Supplementation In 1980, Smithells et al suggested that periconceptional supplementation with multivitamins could reduce the risk
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of MMC.13 In the following decades, many studies, both experimental and observational,14 identified folic acid as a key vitamin and demonstrated that folate intake around the period of conception could significantly reduce the prevalence of MMC.15 Whereas the mechanism is not known, current hypotheses suggests that MMC and other neural tube defects may be caused either by a folate deficiency or an abnormal metabolic pathway that requires folate.16 Folate supplementation was one of the major public health successes of the 20th century.17
Prenatal Diagnosis Prenatal diagnosis of MMC has evolved over the last four decades. In the 1970s, doctors began testing amniotic fluid alpha fetoprotein (AFP) levels in pregnant women as a screening test for MMC.18 Elevated-AFP levels indicate an increased risk of MMC. They also, however, indicate a higher risk for many other disorders. Thus, AFP screening was found to not be specific or conclusive for MMC.19 There were also problems with false-negative values for both amniotic fluid and, more recently, maternal serum AFP levels. Overall, AFP alone allowed detection rates of 65 to 83% of pregnancies in which the fetus had MMC.20 Fetal ultrasound was introduced as a technique to diagnose fetal MMC in 1975.21 Ultrasound screenings are now standard and can diagnose most cases of fetal MMC in the first trimester.22 The severity of the defect can now be analyzed based on ultrafast magnetic resonance images which can be used to assess leg movement, level of spinal defect, level of hindbrain herniation, and the presence of other anomalies in fetuses with MMC.23
Postdiagnosis Decisions Most newborns with MMC survive. Decisions about interventions after a fetal diagnosis focus mostly on the child’s anticipated quality of life. Until recently, there were three options following such a diagnosis: (1) voluntary termination of pregnancy; (2) postnatal palliative care; or (3) postnatal surgery as indicated. In the 1970s, some doctors advocated palliative care for newborns with the most severe cases of MMC. Lorber, Stark, and others reported their experiences with scoring systems that rated illness severity in newborns with MMC.24–26 These proposals were controversial, both because of questions about the validity of the prognostic scoring systems and questions about the morality of allowing any baby to die of a nonlethal condition for which life-saving treatment was available and effective.27 These controversies became the focus of a national controversy in the early 1980s when the federal government issued regulations prohibiting the foregoing of life-sustaining treatment in newborns with congenital anomalies.28 These regulations allowed anonymous reporting of suspected medical neglect. Such reports triggered real-time federal investigations of the clinical treatment (or nontreatment) of individual newborns who were the subject of such reports. One such case was a newborn with MMC who was born on Long Island and became known as Baby Jane Doe. Her parents
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chose not to authorize surgery to repair her MMC and hydrocephalus, but, instead, to provide “conservative” treatment that consisted of antibiotics and sterile coverings for her spinal lesion. The legal battle eventually reached the United States Supreme Court which struck down the federal regulations.29 Although this supreme court decision overturned one particular federal initiative to change the paradigm for decisions, the national discussion led to an apparent shift in attitudes and practices. Since the mid-1980s, there have been no reports of protocols to predominantly provide palliative care or to postpone surgery for newborns with MMC. Thus, in the 1980s and 1990s, there were, for all practical purposes, only two choices after a prenatal diagnosis of MMC— termination of pregnancy or postnatal surgery—that changed with the development of in utero maternal–fetal surgery.
Recent Developments—Maternal–Fetal Surgery Since 1997, some women have been offered the option of in utero, maternal–fetal surgery to attempt to repair the spinal lesion after a prenatal diagnosis of MMC [29].30 In the late 1990s and early 2000s, such surgery was developed in a few tertiary care centers. Several preliminary clinical studies (most of which used historical controls) suggested that the in utero surgery could resolve hindbrain herniation, increase extremity function, decrease the likelihood of the infant needing a VP shunt, decrease instance of talipes, facilitate ventricular recovery, and perhaps improve cognitive function.31–33, Such surgery was complex and risky. Surgery needed to be performed late in the second trimester. In some cases, it led to premature labor and the birth of an extremely premature newborn, oligohydramnios, or uteroplacental problems. It was unclear whether outcomes were, in fact, better for the newborns born after such surgery. The debates mirrored those that took place over intrauterine transfusion for EBF decades before. The key question was whether, and for whom, the risks outweighed the benefits. As a result of the ongoing controversy about the indication for and outcomes of the maternal–fetal surgery, three leading centers proposed a prospective randomized-controlled trial. The trial was complicated to carry out, both technically and ethically.
Maternal–Fetal Surgery for Meningomyelocele As a result of the ongoing controversy about the indication for and outcomes of the maternal–fetal surgery for MMC, three leading centers proposed a prospective randomized-controlled trial. Between 2003 and 2010, the Children’s Hospital of Philadelphia, Vanderbilt University Medical Center, and the University of California at San Francisco Medical Center conducted a study called the Management of Myelomeningocele Study (MOMS). The MOMS was a prospective, randomized trial designed to determine whether maternal–fetal surgery improved outcomes. There were two primary outcomes: the first outcome, at 12 months, was a composite of fetal or neonatal death or the need for a VP shunt. The second primary outcome, at 30 months, was a composite score of the Mental Development Index of the Bayley Scales of Infant American Journal of Perinatology
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Development II and the child’s motor function, with adjustment for lesion level. The study also analyzed whether such surgery led to increased preterm birth or increased obstetrical complications for the pregnant woman.34 Comparing the two groups with regard to a composite outcome of fetal or neonatal death, or the need for placement of a VP shunt by the age of 12 months, newborns in the treatment arm did better than those in the control arm (68 vs. 98%; relative risk, 0.70; 97.7% confidence interval [CI], 0.58– 0.84; p < 0.001). With regard to neurodevelopmental, outcome at the age of 30 months, newborns in the treatment arm also did better. Most strikingly, newborns in the maternal– fetal surgery arm were twice as likely as newborns in the control arm to be walking independently (42 vs. 21%, p ¼ 0.01). Prenatal surgery, however, was risky for mothers as it included a hysterotomy obligating them to future cesarean deliveries. In addition, study mothers had associated increased risks for preterm delivery, uterine dehiscence at delivery, and placental abruption.
The New Ethics of Prenatal Decision Making The results of the MOMS will inevitably change the way doctors and patients think about the decisions they face after a prenatal diagnosis. The results of the MOMS suggest that, at least in situations similar to those in the study, maternal–fetal surgery is clearly in the interest of the fetus. They also show that such surgery clearly increases risks for the pregnant woman. The question is whether and how fetal interests (and the related interests of the child that the fetus has the potential to become) should be weighed against the interests of the pregnant woman. Chervenak and McCullough present an ethical analysis of this situation by analyzing whether the fetus should be considered a patient.35 In their opinion, the fetus should be considered a patient once it is viable, that is, after the 24th week of gestation. Before that, they argue, the decision should be based entirely on what is best for the pregnant woman. But they add a complicated caveat. If the woman is planning on carrying the pregnancy to term, then even a previable fetus should be considered a patient. Under these conditions, Chervenak and McCullough claim a physician “has beneficence-based obligations” to protect the life and health of the MMC fetus. Thus, the doctor would have to give equal weight to the prospective mother and fetus as patients. Most other authors who have analyzed the ethics of this situation prioritize the health and the autonomy of the pregnant woman more than they do any ascribed rights of the fetus as patient. They worry that the woman’s health and her rights might be compromised out of concern for fetal benefit. van Lith et al asserts that “a fetus is not a patient in the real sense…[and] it would be unethical if a care provider, without the woman’s informed consent, promoted the interests of the fetus over those of the woman.”36 These two views illustrate different ways of balancing the interests of the pregnant woman and those of the fetus. Often, doctors do not have to choose one over the other. Instead, it is common for the well-informed pregnant women to choose to take the risks of maternal–fetal surgery in hopes that such American Journal of Perinatology
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surgery will be of benefit to her fetus. In such situations, presumably, she has decided that the potential benefits to her fetus outweigh the potential risks to herself. In such circumstances, clarity about maternal risks is crucial. Although the procedure was being offered as part of a research protocol, the informed consent process was rigorous and comprehensive. In addition, the eligibility criteria were strict and strictly observed. A similar screening and consent process should occur even if the surgery is being offered outside of a research protocol. The MOMS allows some risks to be precisely quantified for women who have similar risk factors as those women who were eligible for the trial. It is likely, however, that maternal–fetal surgery will now be offered to women with additional risk factors. For example, the MOMS excluded obese women (those with a body mass index, BMI, >35 kg/m2), whose risks may be higher. Furthermore, the total number of subjects in the MOMS was small enough that rare complications might not have occurred. For example, there are no recorded instances of maternal death from the MMC maternal–fetal surgery. The problem of generalizing research results from strictly conducted clinical trials to populations of patients who were not included in those trials is not unique to fetal surgery. If other centers start offering such surgery, or if it is offered to women who do not meet the strict eligibility criteria that were used in MOMS, the outcomes may be different. The effects of in utero surgery on future reproductive health are similarly difficult to quantify. Two follow-up studies of women who underwent maternal–fetal surgery found negligible detriment to future reproductive ability and suggested that the hysterotomy required for the surgery posed little more risk than an ordinary cesarean section.37 As more women undergo maternal–fetal surgery, more data on its long-term risks will accrue. Continued collection of follow-up data and continued analysis of long-term risks is essential. The matter of surgical timing is another key ethical issue. In the MOMS, surgery was done when the fetus was between 20 and 25 weeks of gestation. However, animal studies and human experience have suggested that if the surgery were initiated earlier, there could be more extensive prevention of complications due to MMC. The danger in this, of course, is the risk of prematurity. Proceeding too early could injure the fetus, cause intrauterine fetal death, or delivery before viability. Again, as with expanded eligibility criteria, further study is essential to determine whether the outcomes that were achieved in MOMS can be replicated. Clearly, the MOMS was just a first step. Further research will need to focus on developing less invasive surgical techniques. Adzick suggests that such techniques “may not only minimize preterm labor and delivery, but may also permit prenatal coverage of the lesion much earlier in gestation.”38 Attempting to find a safer, less invasive method of MMC maternal–fetal surgery would raise many of the same sorts of ethical issues as the attempts to develop the present surgery. We will only know if these techniques are better by studying them. But studying them will require some people to be willing to undergo an unstudied innovative treatment rather
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Hypoplastic Left Heart Syndrome
published data on longer-term outcomes or life expectancy. However, survival after postnatal surgery rates have been documented to stabilize after the first year,55 and therefore, those that survive surgical intervention fairly consistently survive into adulthood.
Prenatal Diagnosis
HLHS offers another example of the ways in by which improved prenatal diagnosis is changing the ways that clinicians think about diseases of the fetus and the newborn. As with MMC, HLHS illustrates the complex ways in which a fetal diagnosis may influence the decision-making process in obstetrics as well as neonatology.
The measurement of nuchal translucency on a first trimester ultrasound allows the identification of fetuses at high risk for congenital heart disease.56,57 Detailed second trimester fetal echocardiography can identify most fetuses with HLHS.58 Nevertheless, about 30 to 40% of newborns with HLHS have not been identified prenatally.59,60
Epidemiology
Prenatal Testing and Prognosis
HLHS is a congenital heart defect that comprises from 2 to 9% of cardiac disorders in newborns [35]. It occurs in approximately 0.2% of live births in the United States. Thus, there approximately 1,000 new cases per year.39 Two factors—intrauterine fetal demise and termination of pregnancy—complicate the interpretation of these statistics about birth prevalence. The risk of stillbirth in HLHS has been reported as between 1.7 and 12.5%, the wide range resulting from different study methodologies.40,41 The percentage of women who choose termination of pregnancy after a prenatal diagnosis of HLHS has been estimated to be anywhere from 2042 to 87%.43 The rate of termination varies between countries, between different medical centers, and is higher when the diagnosis is made earlier in pregnancy and when other congenital defects are present.44
There has been debate over the utility of prenatal diagnosis for HLHS. Before 2001, several studies found no correlation between prenatal diagnosis of HLHS and survival.61 In 2001, Tworetzky et al and Mahle et al62 showed that newborns who were diagnosed prenatally had a significantly increased rate of survival and better neurological outcomes compared with postnatally diagnosed newborns. Tworetzky et al suggested that prenatal diagnosis allowed delivery at a tertiary care center where newborns received immediate treatment—thus avoiding hypoxemia, acidemia, and other complications. Others have suggested that increased survival after prenatal diagnosis results from the fact that prenatal diagnosis allows the identification of fetuses with other congenital anomalies. If women choose to terminate their pregnancies in these circumstances, then the newborns who are born with HLHS have fewer other anomalies. That might lead to increased survival. This is supported by the observation that the infants in the Tworetzky study had a significantly lower incidence of presurgical complications. Prospective parents of HLHS fetuses report being happier, better adjusted, and more at peace with their decisions following a prenatal diagnosis.63 This could be because of the increased time for education, planning, and decision making that comes with a prenatal diagnosis.
Physiology In HLHS, the left ventricle, ascending aorta, aortic, and mitral valves do not develop properly.45 With no medical intervention, the ductus closes quickly after birth, leading to limited systemic blood flow, and resulting in death if no intervention is taken. In addition to this cardiopulmonary pathology, newborns with HLHS frequently have other anomalies. Many have abnormal brain development, behavior problems, and learning disabilities.46 Physical and neurodevelopmental complications of the condition are thought to be somewhat independent of the heart malformation itself.47–49 Before 1980, there was no treatment for HLHS and it was uniformly fatal. In the early 1980s, two treatments were developed. Norwood developed a three-stage reconstructive operation, while other doctors proposed neonatal heart transplantation.50 There is controversy about how to assess overall survival rates for HLHS. Some studies report overall survival after prenatal diagnosis.51,52 This measure includes cases in which a choice was made for termination of pregnancy. Others include outcomes for live-born newborns. This measure includes cases in which a choice was made to forego surgery.53 Still other studies report outcomes only among newborns who had surgery to correct the defect.54 Survival rates range from 20 to 30% for all fetuses diagnosed prenatally to 80 to 90% for newborns who undergo surgery. There is still no
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Prospects—Maternal–Fetal Surgery There are no studies evaluating open maternal–fetal surgery for HLHS. Some investigators have attempted percutaneous prenatal atrial septal stent placement for evolving HLHS.64 To date, these have not been successful.65
Postdiagnosis Decisions After a prenatal diagnosis of HLHS, there are five possible choices: (1) termination of pregnancy; (2) in utero intervention; (3) postnatal heart transplantation; (4) postnatal staged palliative repair; or (5) postnatal palliative care. Different doctors recommend different choices. There is even disagreement about whether all of these choices should be offered.66 However, the availability of prenatal diagnosis, coupled with easy access to information on the internet, makes the discussion of all choices necessary. As long as termination of pregnancy is legal, doctors have an obligation to inform pregnant women of this option. American Journal of Perinatology
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than the current standard treatment. Investigators will have to decide which patients are eligible and will have to carefully collect data that will allow them to evaluate this innovative approach against the protocols used in the MOMS.
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Prenatal counseling should include information about the diagnosis and the prognosis. Postnatal decisions are more complicated. Clearly, parents need to be informed of the availability of treatment. They also need to be informed that decisions must be made relatively quickly. As surgical outcomes after staged-repair improve, transplantation is becoming an increasingly rare option. Choosing a three-stage reconstruction means choosing a long and burdensome course of treatment that involves frequent, lengthy hospitalizations, as well as substantial postoperative pain and anxiety.
Ethics of Postdiagnostic Decision Making The central ethical debate today among experts in HLHS is about whether or not parents should still be offered the option of palliative care. Wernovsky proposes that the modern prognosis for HLHS patients is so good that it is clearly in the newborn’s best interest to have surgery.67 He compares HLHS to other congenital defects with similar or worse survival rates, such as heterotaxia and pulmonary atresia, for which palliative care is generally not considered an option. He views palliative care as unethical in a situation in which 5-year survival rates are well over 50%. Kon, by contrast, argues that palliative care should continue to be offered.68 He bases this argument on both the burdens of treatment to the child and the neurocognitive and physical complications associated with staged-surgical repair. He has surveyed neonatologists, neonatal nurses, cardiologists, and cardiac surgeons and shown that many of these health professionals would choose palliative care for their own newborn with HLHS.69,70 Over the last 30 years, the trend in pediatric ethics and health law with regard to decisions about foregoing lifesustaining treatment has been to restrict the situations in which such decisions are permitted. It used to be common— and permissible—for parents to refuse cancer chemotherapy, surgery for newborns with Down syndrome and congenital anomalies, and surgery for newborns with severe MMC. In those situations, surveys showed—as they do now for HLHS— that many doctors thought that is was acceptable to choose palliative care rather than life-prolonging treatment. Over the last three decades, however, pediatricians, bioethicists, and judges have come to see many of these decisions are inappropriate because they are not in the child’s interests and because they are they are based on inaccurate views of the quality of life experienced by children with disabilities.71 HLHS seems different, however, in important ways. Surgery for newborns with Down syndrome and operable congenital anomalies is, generally, a single operation. The burden of treatment is much lower than in surgery for HLHS and the prognosis for survival is better. Cancer chemotherapy for acute lymphocytic leukemia is a long and burdensome treatment. However, the chances for cure are very high—and children who are cured no longer have cancer. In HLHS, the treatment is burdensome, long-term survival rates are below 90%, and the survivors are not cured. Instead, they have a lifelong chronic disease. In fact, most surgeons who operate on newborns with HLHS describe the operation as “palliative,” American Journal of Perinatology
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rather than “curative.” In these circumstances, the choice of palliative care remains an ethically defensible choice.
Meningomyelocele and Hypoplastic Left Heart Syndrome: A Comparison MMC and HLHS exemplify many of the issues in the advancing field of fetal and neonatal medicine. In both, early prenatal diagnosis allows for carefully considered and well-developed prenatal and postnatal treatment strategies. When confronted with a prenatal diagnosis of either disease, many women choose to terminate pregnancy. In both situations, there is controversy about the appropriateness of neonatal palliative care. MMC and HLHS additionally belong to a small category of defects for which maternal–fetal surgery is being investigated. They are thus laboratories for investigating the issues that arise when obstetricians and maternal–fetal medicine specialists must balance potential benefits to the fetus against potential harms to the pregnant woman. Both HLHS and MMC present with a wide range of illness severity and associated anomalies. These lead to differences in prognosis. In such situations, decisions must be individualized to reflect the individual circumstances. There is no single right choice for all newborns with HLHS or all newborns with MMC. There are also interesting differences between MMC and HLHS. In MMC, there is preventive treatment (folate) and an effective form of maternal–fetal surgery. In MMC, neonatal palliative care has largely been abandoned as a practice. This may reflect the ease of first trimester prenatal diagnosis and the availability of abortion. MMC and HLHS are relatively common among prenatally diagnosable conditions. The issues that arise in decisionmaking for fetuses with these conditions also arise in conditions that are far less common. Soon, noninvasive prenatal genetic diagnosis will be available for thousands of conditions that have never been diagnosed prenatally before. The lessons learned from MMC and HLHS will shape the discussion about how doctors and parents should respond to information from such prenatal diagnosis. For the foreseeable future, however, it seems likely that the dominant feature of many prenatal diagnoses will be one of significant uncertainty about prognosis. In such situations, doctors have an ethical obligation to understand and communicate not only the level of uncertainty but also the full range of options available to them. They have an additional ethical obligation to collect careful data on outcomes to inform future discussions. We can discuss MMC and HLHS now because some doctors have been meticulous in studying outcomes and publishing their results. Unfortunely, there are also many centers dabbling in “fetal medicine” without studying outcomes or publishing results. There are very few long-term outcome studies, even for HLHS and MMC. There are even fewer for many other conditions. To best serve pregnant women and babies, fetal medicine centers must cooperate in research on interventions and carefully study both short-term and long-term outcomes.
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We should not have to rely on single-center studies or case reports. Good ethics starts with good facts. Good facts come from good science. Good science regarding rare diseases can only come from cooperation among tertiary care centers.
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congenital heart disease in southern Nevada: the need for universal fetal cardiac evaluation. J Ultrasound Med 2007;26(12): 1715–1719, quiz 1720–1721 Barron DJ, Kilby MD, Davies B, Wright JG, Jones TJ, Brawn WJ. Hypoplastic left heart syndrome. Lancet 2009;374(9689): 551–564 Tworetzky W, McElhinney DB, Reddy VM, Brook MM, Hanley FL, Silverman NH. Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation 2001;103(9): 1269–1273 Mahle WT, Clancy RR, McGaurn SP, Goin JE, Clark BJ. Impact of prenatal diagnosis on survival and early neurologic morbidity in neonates with the hypoplastic left heart syndrome. Pediatrics 2001;107(6):1277–1282 Sklansky M, Tang A, Levy D, et al. Maternal psychological impact of fetal echocardiography. J Am Soc Echocardiogr 2002;15(2): 159–166 Chaturvedi RR, Ryan G, Seed M, van Arsdell G, Jaeggi ET. Fetal stenting of the atrial septum: technique and initial results in cardiac lesions with left atrial hypertension. Int J Cardiol 2013; 168(3):2029–2036 McElhinney DB, Tworetzky W, Lock JE. Current status of fetal cardiac intervention. Circulation 2010;121(10):1256–1263 Vandvik IH, Førde R. Ethical issues in parental decision-making. An interview study of mothers of children with hypoplastic left heart syndrome. Acta Paediatr 2000;89(9):1129–1133 Wernovsky G. The paradigm shift toward surgical intervention for neonates with hypoplastic left heart syndrome. Arch Pediatr Adolesc Med 2008;162(9):849–854 Kon AA. Healthcare providers must offer palliative treatment to parents of neonates with hypoplastic left heart syndrome. Arch Pediatr Adolesc Med 2008;162(9):844–848 Prsa M, Holly CD, Carnevale FA, Justino H, Rohlicek CV. Attitudes and practices of cardiologists and surgeons who manage HLHS. Pediatrics 2010;125(3):e625–e630 Kon AA, Prsa M, Rohlicek CV. Choices doctors would make if their infant had hypoplastic left heart syndrome: comparison of survey data from 1999 and 2007. Pediatr Cardiol 2013;34(2): 348–353 Payot A, Barrington KJ. The quality of life of young children and infants with chronic medical problems: review of the literature. Curr Probl Pediatr Adolesc Health Care 2011;41(4):91–101
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