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A Review of Ethical Issues Involved in Premature Birth

Gerri R. Baer and Robert M. Nelson1

Morning rounds on any day in any academic neonatal intensive care unit (NICU) are likely to involve some reference to an ethical dilemma. Many ethical questions have been defined in the area of premature birth, and many more will arise. Advances in medical technology have allowed neonatologists to provide premature infants mechanical ventilation, intravenous nutrition, and artificial surfactant, but prevention of major complications of prematurity remains elusive. It also appears that a threshold of viability has been reached, before which neonatal technology is of no benefit.

In this paper, we provide a review of the literature describing ethical issues related to premature birth. We focused our initial literature searches on empirical studies and added judicial decisions, commentaries, and ethical analyses to complement the data. There are many ethical issues related to prematurity for which there are no empirical data, and we have commented accordingly.

We first present the literature on decision making, which is one of the most frequently addressed areas in neonatal ethics. We discuss the two main frameworks for decision making in the neonatal period, describe several high-profile court cases, and present the difficulties with achieving informed

1

G. R. Baer, Department of Pediatrics, The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia. R. M. Nelson, Department of Pediatrics and Department of Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia.



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Preterm Birth: Causes, Consequences, and Prevention C A Review of Ethical Issues Involved in Premature Birth Gerri R. Baer and Robert M. Nelson1 Morning rounds on any day in any academic neonatal intensive care unit (NICU) are likely to involve some reference to an ethical dilemma. Many ethical questions have been defined in the area of premature birth, and many more will arise. Advances in medical technology have allowed neonatologists to provide premature infants mechanical ventilation, intravenous nutrition, and artificial surfactant, but prevention of major complications of prematurity remains elusive. It also appears that a threshold of viability has been reached, before which neonatal technology is of no benefit. In this paper, we provide a review of the literature describing ethical issues related to premature birth. We focused our initial literature searches on empirical studies and added judicial decisions, commentaries, and ethical analyses to complement the data. There are many ethical issues related to prematurity for which there are no empirical data, and we have commented accordingly. We first present the literature on decision making, which is one of the most frequently addressed areas in neonatal ethics. We discuss the two main frameworks for decision making in the neonatal period, describe several high-profile court cases, and present the difficulties with achieving informed 1 G. R. Baer, Department of Pediatrics, The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia. R. M. Nelson, Department of Pediatrics and Department of Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia.

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Preterm Birth: Causes, Consequences, and Prevention consent. Next, we review approaches to conflicts between the autonomy of the pregnant woman and her obligations of beneficence toward the fetus. We then present the current attitudes and practices with respect to the limits of viability. Next, we present the literature related to ethical issues in end-of-life care, including the practice of withholding or withdrawing life-sustaining medical treatments, pain control and palliative care, the concept of futility, and the differences in end-of-life practices between U.S. physicians and physicians in some parts of Europe. We then examine the literature concerning the economic and social implications of premature birth. Finally, we comment on the inclusion of pregnant women, fetuses, and neonates in research. ETHICAL ASPECTS OF DECISION MAKING The predominant ethical paradigm for decision making about the early stages of reproduction (i.e., preventing pregnancy, becoming pregnant, deciding to stay pregnant, and engaging in activities that may help or harm a fetus) focuses on the autonomy of the woman. A transition occurs in midpregnancy, wherein the emphasis on a woman’s autonomy is weakened in favor of balancing fetal and maternal “best interests.” For some, this shift may be viewed as occurring when either the choice or the opportunity for termination of the pregnancy has passed. This time of transition during pregnancy from a previable to a viable fetus (i.e., 23 to 25 weeks of gestation) can also be viewed as an ethical (and perhaps legal) transition from an individual autonomy-based model of decision making to a negotiated beneficence-based model of decision making. This view, although useful, is perhaps an oversimplification, as fetal interests are often important factors early in pregnancy and maternal autonomy remains influential during the late stages of pregnancy. The paradigm (in the United States and most Western countries) for proxy decision making for infants and children focuses on a child’s “best interest,” with the parents or guardians generally viewed as the primary surrogate decision makers for their infants. However, health care professionals play an important role in determining what actions are, in fact, in a child’s best interest, leading to a more complex “negotiated” decision-making process. Ethical dilemmas may arise when parents and the medical professionals caring for their infants disagree on the best course of action. Empirical Data Concerning Proxy Decision Making Parents largely believe that they do and should take primary responsibility for decisions concerning the limitation or withdrawal of life-sustaining medical treatment (LSMT) from their critically ill infants. The majority

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Preterm Birth: Causes, Consequences, and Prevention of health care professionals believe that parents should not be solely responsible, but also that physicians often make the “final” decision in actuality. The dramatic difference in perceptions may reflect a complex process of shared decision making by use of a “negotiated” model of best interest. We first present data on parental perceptions, followed by data on health care professionals’ perceptions and studies that have combined both groups. Most of the following data were collected outside the United States and thus may not reflect the attitudes of families and the practices of physicians in the United States. Semistructured interviews of parents of infants in NICUs were performed in Scotland by a research team led by Hazel McHaffie. Parents were interviewed about whether any discussion of limitation of their infants’ LSMT had occurred. The interviews revealed that 56 percent of the parents thought that they had taken the responsibility for decision making, with three-quarters of those believing that it had been their decision alone and one-quarter believing that the decision had been made in conjunction with the infant’s doctors. Eighty-three percent of parents believed that the correct person(s) had made the decision. The authors concluded that parents desire involvement in decision making (1). An international study group interviewed the parents of surviving very low birth weight (VLBW) infants to examine their perceptions of perinatal counseling and decision making at nine centers in Pacific Rim countries and two centers in San Francisco, California. The majority of subjects were the parents of survivors, as cultural taboos prevented interviewing the parents of deceased infants in most countries. In all countries, more than 90 percent of the parents believed that the physician’s opinion was important in decisions regarding resuscitation status. A large majority of the parents in all countries (93 to 100 percent) considered the physician’s opinion in decisions regarding resuscitation status. In all locations except Melbourne, Australia, the majority of parents (75 to 86 percent) perceived that there was joint decision making between the physician and the parents. In Melbourne, three-quarters of the parents perceived that the physician made the decision alone. A majority of parents at all sites (62 to 95 percent) preferred the model of joint decision making. In the assessment of antenatal counseling, a majority of the parents at all centers (65 to 90 percent) believed that they understood their infant’s prognosis after antenatal counseling. More than three-quarters of all parents thought that the sequelae of their infants’ illnesses were better than they had expected. The authors concluded that parents across the Australasian countries make decisions similarly, with importance placed on physician and partner input. They also concluded that parents prefer a joint decision-making approach and believe that it often happens. Finally, parental assessment of the adequacy of antenatal counseling was found to differ by center and by topic (2).

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Preterm Birth: Causes, Consequences, and Prevention In contrast to many studies showing parental preference for joint decision making, a qualitative interview study from Norway revealed that most parents believed that the physician should be the one to make the final decision on an “end-of-life” question but that the decision should be made with parental involvement. Families emphasized health care professionals’ experience and knowledge, the parents’ incapability to make a rational decision, and the parents’ need to be taken seriously and listened to (3). The Scottish research team also performed surveys of health care professionals concerning decision making in the NICU. Analysis of those data revealed that only 3 percent of physicians and 6 percent of nurses believe that parents should make the ultimate decision to withhold or withdraw LSMT. Rather, parents should be involved but should not be solely responsible for decision making (4). A recent survey of New England neonatologists sought to describe current practices of delivery room decision making and prenatal consultation at the border of viability. Given a hypothetical scenario of impending delivery of a 23.5- to 24.5-week preterm infant of appropriate weight for gestational age, more than three-quarters of neonatologists believed that they and the parents should make the final decision together. However, only 40 percent of the neonatologists believed that both parties actually made the final decision. Half the neonatologists reported that they made these decisions alone, in reality. Regarding their role in perinatal consultations with parents, 58 percent of the neonatologists believed that their primary role in discussing resuscitation strategies with parents was providing factual information, in contrast to the 40 percent who believed that their primary role was assisting the parents in weighing the risks and the benefits of their resuscitation options. Predictors of shared decision making were believing that the primary role of the neonatologist was to assist parents in weighing their options (odds ratio [OR] = 4.1, p = 0.004) and being in practice >10 years (OR = 3.6, p = 0.004). The authors concluded that neonatologists should continue to incorporate parental preferences and should improve communication about long-term outcomes and quality-of-life issues with families to comply with American Academy of Pediatrics (AAP) recommendations on perinatal consultation (5). In a Canadian survey of parents of extremely low birth weight (ELBW) survivors, neonatologists, and neonatal nurses, nearly all parents and more than three-quarters of the health care professionals either agreed or strongly agreed that the parents should have the final word regarding the initiation or the limitation of treatment. In contradiction to that finding, the health care professionals also agreed or strongly agreed nearly 100 percent of the time that doctors should make the final decision. Parents agreed or strongly agreed 50 to 75 percent of the time that doctors should make the final decision. The authors concluded that the physicians polled believed that

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Preterm Birth: Causes, Consequences, and Prevention they should have more of a role in decision making than the parents wanted to allow them (6). A comparative case-based qualitative study of decision making was conducted in NICUs in both France and the United States. Over a 2-year period, the investigators interviewed 60 clinicians and 71 parents, as well as conducted a chart review of end-of-life cases. The investigators concluded that the autonomy that parents are thought to have in the United States is not true autonomy, citing findings that the clinicians decide when to broach issues and decision points, that withdrawal is offered only on severely moribund infants who are certain to die, and that neonatologists do not ask parents’ permission to continue treatment; rather, they ask parents’ permission only to discontinue treatment (7). The “Best Interests” Standard and Decision Making The model of collaborative decision making is endorsed by numerous sets of professional guidelines. Many authors have acknowledged that although a collaborative model with emphasis on parental autonomy and values is ideal, it remains difficult to achieve. There is an imbalance of knowledge, control, and expertise in favor of medical professionals, who at times may have a different assessment of an infant’s “best interest.” In her commentary on decision making and parental autonomy, McHaffie made the case that parental autonomy was impossible. She argued that (a) physicians may present facts along with guidance toward the recommended medical option; (b) an imbalance of power exists between parent and physician; (c) parents rely on the medical team for facts, and the physician may include or exclude information in an effort to persuade the parents to choose his or her professional recommendation; and (d) physicians may not offer certain options unless they are convinced that the options were the appropriate course of treatment, thus weighting the balance of power in the relationship toward the physician (4). A group of prominent North American neonatologists, pediatricians, and intensive care physicians convened to review questions regarding decision making at the end of life in ELBW infants. The results of their discussions were published in 1994. Questions were asked regarding the withdrawal of a burdensome treatment in several cases of infants with chronic disease. These physicians concluded that “parents, in consultation with a physician who has provided ongoing care to the child, are in the best position to make the difficult decision to discontinue support.” These discussions also shed light on ethical dilemmas, such as the fact that parents’ options for withdrawing life-sustaining treatments are subject to their “physicians’ practice styles and moral values.” The group concluded that “phy-

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Preterm Birth: Causes, Consequences, and Prevention sicians should be careful to separate their personal views … from current medical, legal, and moral standards of care for such children” (8). The AAP Committee on Fetus and Newborn published guidelines in The Initiation or Withdrawal of Treatment for High-Risk Newborns and recommended an active role for parents in decision making. However, they state, “physicians should not be forced to undertreat or overtreat an infant if, in their best medical judgment, the treatment is not in compliance with the standard of care for that infant” (9). Leuthner, in a commentary on the four AAP policy statements related to decision making for premature and/or critically ill newborns, argued that the most appropriate model of “best interest” is a “negotiated” model. That model strongly incorporates parental values as well as the objective medical facts and acknowledges that the moral values of the physician should be respected (10). Loretta Kopelman, a bioethicist who has written extensively about ethical issues in prematurity, recently proposed a negative version of the Best Interests Standard, which applies to incompetent individuals of all ages and (1) instructs decision makers to decide what act(s) [is] in the incompetent individual’s immediate and long-term interests and maximize his or her net benefits and minimize net burdens, setting that act(s) as a prima facie duty; (2) presupposes a consensus among reasonable and informed persons of good will about what choices for the incompetent individual are, all things considered, not unacceptable; and (3) determines the scope of the Best Interests Standard in terms of the scope of established moral or legal duties to incompetent individuals” (11). She defended this version of “best interests,” as it allows parents to make choices within ranges of options that are acceptable to “reasonable and informed people of good will and fulfill basic duties.” Use of this standard “requires what is reasonable” and “makes room for individualized and compassionate choices that may reflect somewhat different values” (11). Parental Informed Consent: Legal Precedents Ethically, physicians have a duty to inform the parents and potential parents of newborns about resuscitation procedures and potential outcomes for their preterm infants as well as to obtain their consent (either implicit or explicit) to proceed with resuscitation and treatment. The process of informing is inherently flawed by the uncertainty of predicting outcomes and is often flawed by the urgency and tension of the potential parents’ situation. The question of whether physicians require parental consent to resuscitate premature infants has been addressed in several high-profile court cases.

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Preterm Birth: Causes, Consequences, and Prevention Although the 1994 State v. Messenger case in Michigan supported the right of a parent to refuse LSMT for a 25-week-gestation infant, the more recent Miller v. HCA (Texas, 2003) and Montalvo (Wisconsin, 2002) cases have restricted the parents’ role in resuscitation decisions of an ELBW infant. The Miller case held that a physician was not bound by the prior expressed wishes of the parent since the infant could not be evaluated prior to birth. Although the Miller infant was resuscitated, the court decision does not compel resuscitation of ELBW infants but allows for professional judgment about “warranted medical treatment.” State v. Messenger (1994) in Michigan affirmed the right of an infant’s father to refuse treatment for his child who was born at 25 weeks of gestation. The Messenger infant was resuscitated against the expressed wishes of his parents. Once in the NICU, the infant’s father, a physician, asked to be alone with his son and disconnected the ventilator so that the infant would expire. Dr. Messenger was charged with manslaughter and tried in a criminal court, where he was acquitted by a jury (12). The problem of achieving informed consent for resuscitation of premature infants was brought to public attention by the case of Miller v. HCA (which was decided in 2003). Sidney Miller was born in 1990, at 23 weeks of gestation and with a body weight of 615 grams. Prior to delivery, the Miller parents had told their obstetrician and the neonatologist that they wanted no heroic measures performed to resuscitate the infant. A hospital administrator incorrectly informed the medical team that the hospital had a policy of resuscitating every infant born weighing at least 500 grams. The neonatologist at the delivery noted that the infant had a heartbeat and cried spontaneously, so he intubated her and began artificial ventilation. At several days of life, Sidney suffered a brain hemorrhage and now lives severely mentally and physically impaired. The Millers sued the hospital for battery and negligence for treating the infant without consent. Initially, the family was awarded $60 million by a jury, but the judgment was overturned by the Texas Court of Appeals. Citing the Texas Natural Death Act, the court ruled that parents could withhold treatment only if their child’s medical condition was terminal. In the subsequent appeal to the Texas Supreme Court, it was decided that parental consent was not required for resuscitation, during the “emergent circumstances” of preterm birth. “Sidney could only be properly evaluated when she was born. Any decision … made before Sidney’s birth … would necessarily be based on speculation.” Although “best practice is to obtain parental consent before birth to make an evaluation and render ‘warranted medical treatment,’” the Court declined “to impose liability [for battery or negligence] … solely for providing life-sustaining treatment under emergent circumstances to a new-born infant without that consent” (13). It should be noted that the absence of a parental right to refuse resusci-

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Preterm Birth: Causes, Consequences, and Prevention tation does not imply that a physician is obligated to resuscitate. A physician should still make a professional judgment as to whether resuscitation is medically warranted. Empirical Data Regarding Informed Consent Concerns about the challenge of obtaining informed consent for neonatal resuscitation are reinforced by evidence that health care professionals incorrectly estimate survival and disability rates for ELBW infants. Achieving informed consent for procedures and research may also be problematic. One study has shown that parents have difficulty recalling crucial content communicated during the consent process for research. Underestimating survival of preterm infants may also lead to inappropriate obstetrical decision making. The difficulty in ensuring accurate prenatal counseling was demonstrated in a study from Vermont, which tested health care professionals’ estimates of survival before and after an intervention to educate them on current survival data. Obstetricians, neonatologists, nurses, and nurse practitioners were found to underestimate survival rates and overestimate major disability rates for premature infants at various gestational ages. Physicians and nurses underestimated the rates of survival at 23 to 28 weeks gestation, and nurse practitioners underestimated the rates of survival at 23 to 27 weeks gestation. For example, physicians’ mean estimate of the rate of survival at 25 weeks gestation (prior to the study intervention) was ~50 percent, although the actual survival rate was closer to 75 percent. Physicians and nurses overestimated disability rates at <26 weeks of gestation, and nurse practitioners overestimated disability rates at <28 weeks gestation. For example, nurse practitioners’ mean estimate of major disability at 25 weeks gestation was ~65 percent, whereas the actual disability rate was ~30 percent. The inaccuracy of health professionals’ estimations of survival and disability rates decreased after an educational intervention, but the inaccuracies did not completely disappear. The authors concluded that improved education of health care professionals is needed to ensure accurate counseling for families (14). Obstetricians and family practice physicians who performed deliveries were surveyed in Alabama in 1992 regarding the perceived rates of survival and obstetric practices between 23 and 36 weeks gestation. The respondents significantly underestimated the rates of survival and freedom from handicap for all gestational ages. The respondents reported that they would transfer pregnant women to a perinatal center for management at a mean of 23 weeks gestation, and most would administer steroids for fetal lung maturity at a median earliest gestational age of 25 weeks. However, only half of the respondents would have performed a delivery by cesarean section for

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Preterm Birth: Causes, Consequences, and Prevention fetal distress at 25 weeks gestation, which raised concerns for the authors that underestimation of the rates of survival and survival free of handicap was leading to inappropriate obstetric care. When compared with the authors’ study that estimated rates of survival and that had been conducted 10 years earlier, estimates of survival had improved, but perinatal management had not changed adequately to reflect the improved rates of survival (15). The validity of informed consent obtained in the neonatal period was examined by Ballard et al. In telephone or face-to-face interviews of parents who had consented to enroll their neonates in the NEOPAIN trial, the investigators found that 8 percent of parents had no recollection of the study at all. Of the parents who recalled the study, about two-thirds recalled the purpose of the study. Ninety-five percent of parents who recalled that their infants had entered the study could verbalize potential benefits, but only 5 percent could recall one or more risks. The time interval between the time that they signed the consent and the study interviews did not affect understanding of the NEOPAIN study’s purpose, risks, benefits, or voluntary nature. Mothers were more likely than fathers to recall the purpose and benefits of the study, and administration of magnesium sulfate had no effect on the mother’s recall. When stringent criteria of informed consent were used (understanding of the purpose, benefits, and risks of the study; understanding the voluntary nature of the study; and freedom from coercion), only 3 percent of the parents met the criteria for giving informed consent. The authors were concerned that the provision of informed consent by parents of ill neonates is not achievable in the current model. They suggested modifications to the process, including emphasis of the presence of risks and an interactive consent process that includes plenty of time for the parents to ask questions (16). ETHICAL TENSIONS DURING PREGNANCY: BALANCING THE INTERESTS OF THE PREGNANT WOMAN AND HER FETUS Over the past 2 to 3 decades, multiple paradigms have been proposed for the discussion and resolution of so-called maternal-fetal conflicts. Some authors have proposed that maternal autonomy should be the dominant concern in decision making, whereas others have established the fetus as a patient who should be treated according to the principles of beneficence. A number of cases of court-ordered interventions for pregnant women have received publicity, but these cases are rare. The tension between maternal autonomy and fetal best interest may be seen in decisions about the mode and the location of delivery. For example, a pregnant woman may decide against delivery by cesarean section in the case of fetal distress, yet ask that all resuscitative measures be used after delivery.

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Preterm Birth: Causes, Consequences, and Prevention In the past 20 years, Chervenak, an obstetrician-gynecologist, and McCullough, an ethicist, have written extensively on the approach to maternal-fetal conflicts. They start with the concept of the fetus as a patient. They do not argue that the fetus is a person with the rights of personhood but argue that the fetus is a patient who should be managed according to beneficence principles. In an often-cited paper from 1985, they defined the ethical obligations of the parties involved in ethical conflict as the maternal autonomy-based obligations of the physician, the maternal beneficence-based obligations of the physician, the fetal beneficence-based obligations of the mother, and the fetal beneficence-based obligations of the physician. When maternal autonomy and fetal beneficence came into conflict, they recommended persuasion of the pregnant woman to undergo treatment to benefit the fetus and stated that coercion or court intervention may sometimes be justifiable on a moral basis (17). In 1993 they published “An Ethical Justification for Emergency, Coerced Cesarean Delivery,” which allowed coerced delivery by cesarean section if the procedure was likely to prevent morbidity or mortality to the infant, there was no physical resistance from the woman, and there was no time to obtain a court order (18). In 1990, the American Medical Association suggested guidelines for consideration of justifiable court-ordered interventions for pregnant women, including stipulations that the intervention must pose minimal risk to the woman’s health, involve minimal invasion of her bodily integrity, and have a high probability of preventing substantial, irreversible fetal harm (19). The American College of Obstetricians and Gynecologists (ACOG) has published several statements on the matter of coerced or court-ordered intervention during pregnancy. In 2004, ACOG published an ethics handbook that stated that in cases of maternal refusal of treatment, intervention by courts against the pregnant woman’s wishes is “rarely if ever acceptable.” The paper recommended examining the barriers to health-promoting behavior, addressing the social and cultural contexts of the woman’s decisions, and recognizing the fallibility of medical knowledge (20). In 2005 ACOG published a committee opinion, “Maternal Decision Making, Ethics, and the Law.” In the opinion, the Committee on Ethics strongly opposes coercive and punitive legal approaches to pregnant women. The committee argued that (a) coercive and punitive actions violate the entitlement of competent adults to informed consent, (b) court orders for intervention neglect the fact that there are limitations to medical knowledge and prediction of outcomes, (c) coercive and punitive policies have a detrimental effect on prenatal care and the physician-patient relationship, (d) “coercive and punitive policies unjustly single out the most vulnerable women,” and (e) these policies create the potential to criminalize otherwise legal behavior by pregnant women. The committee recommended that “in the absence of extraordinary circumstances … judicial authority should

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Preterm Birth: Causes, Consequences, and Prevention not be used to implement treatment regimens … for such actions violate the pregnant woman’s autonomy” (21). Lisa Harris, in an essay in Obstetrics and Gynecology, proposed new methods for framing and solving maternal-fetal conflicts. Framing maternal-fetal conflict as the “conflict between clinicians’ moral obligations, not maternal and fetal rights,” has worked best in the obstetrics literature, and Harris defined the ethical dilemmas in this way. She argued that the limitations of using principles to frame these dilemmas are that the principles are “difficult to use when negotiating moral dilemmas between intimates”; that life particularities, such as social class, race, politics, and religion, must also be considered when judging ethical dilemmas; and that principle-based ethics “neglects the broad social and political arrangements in which clinical care occurs,” citing difficulties with the hierarchy of power that exists between physician and patient, particularly in cases of sex, race, and class inequality. Finally, she suggested that an alternative model for addressing perinatal ethical dilemmas would include attention to understanding the pregnant woman within the context of her social network and community, addressing the clinicians’ standpoint and ethical judgment, and recognizing that the generation of a diversity of opinions may help to deal with issues of race and sex inequalities (22). Brain Death in Pregnant Women with Periviable Fetuses Although brain death in pregnant women with periviable fetuses has been and continues to be of interest to the media (and some ethicists), it is of little ethical value in illuminating decisions about premature infants. The pregnant woman who is now dead has no “interests” (other than perhaps the respectful disposition of her body, although the principle of “respect for the dead” is grounded in the moral obligations of the living rather than a right of the once living who survives death), and thus, there is no conflict between the now-dead pregnant woman and the still living fetus. These cases usually reflect conflict within the family or confusion about “brain death” (as in the headline “Brain Dead Pregnant Woman Dies”). Veatch defined the two potential ways to view these cases as (a) the pregnant woman is alive but terminally ill; therefore, continued treatment would be appropriate; or (b) the pregnant woman is newly dead, in which case the legal and ethical justifications for continued support are more difficult; but with no argument among family members, the life of the brain dead pregnant woman might be maintained if the fetus is near viability. Decisions under these circumstances hinge on states’ definition of death and any prior expressed wishes of the now dead pregnant woman and/or her surrogate decision makers (23). In a review of 10 cases of extended somatic support for pregnant women

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Preterm Birth: Causes, Consequences, and Prevention Empirical Data Concerning Access to Perinatal Care In a population-based cohort study done in South Carolina (from 1993 to 1995), total birth weight-adjusted mortality rates were significantly higher in Level I and II perinatal centers than in Level III centers (as many as 267 deaths per 1,000 births in Level I centers down to 146 deaths per 1,000 births in Level III centers [p < 0.05]). There was a trend toward lower mortality rates among VLBW infants born in Level III centers, although the numbers for some subgroups were too small for the trend to reach statistical significance (85). In a population-based cohort study in Georgia (from 1994 to 1996), it was determined that 77 percent of VLBW infants were born at Level III or IV centers, 9.8 percent were born at Level II+ hospitals, and 13.1 percent were born at centers with other levels. The neonatal mortality rate, after adjustment for birth weight, correlated with the level of the perinatal center, with the lowest rate found for infants born at Level III centers (127.8/ 1,000 births) and the highest rate found for infants born at Level II centers (276.2/1,000 births). (Mortality rates were higher for infants born at Level IV hospitals [181.8/1,000 births] than at Level III centers because of the nature of the patient population.) The authors concluded that the highest mortality rates were at the centers with the lowest levels of care, even after consideration of the differences in the populations delivering at hospitals with various levels of care (86). In a Swedish population-based cohort study, infants born at between 24 and 27 weeks (from 1992 to 1998) had increased mortality rates at general hospitals (32 percent) compared with those at university hospitals (23 percent). There was no difference in mortality rates for infants born at between 28 and 31 weeks gestation when the rates were compared by hospital type. The authors concluded that extremely preterm infants born at general hospitals suffered a substantially increased mortality rate. They question whether additional centralization may improve survival (87). In a retrospective Australian review of outcomes for infants with necrotizing enterocolitis, infants cared for in centers with neonatal surgical facilities had neither improved survival nor improved outcomes such as LOS, resection for strictures, days on total parenteral nutrition (TPN), or mortality compared with the survival rates and outcomes for infants who were cared for in centers without neonatal surgical facilities. The study was confounded by factors that included the differential administration of antenatal steroids to the two groups. The authors concluded that the management of infants with necrotizing enterocolitis in centers without surgical capabilities was not associated with increases in morbidity or mortality (88). One study conducted in the 1980s examined differences in the incidence of LBW or perinatal mortality between populations residing in met-

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Preterm Birth: Causes, Consequences, and Prevention ropolitan and nonmetropolitan areas in the United States. By using data from the National Linked Birth Death Data Set obtained between 1985 and 1987, it was found that at the national level, residence in a nonmetropolitan area was not associated with a higher risk of LBW or neonatal mortality, although the risks of postneonatal mortality and the late onset of prenatal care were slightly higher. The authors concluded that “non-metropolitan residence is not a strong risk factor for low birth weight outcome and neonatal mortality in the United States.” The study was limited by its inability to assess other morbidities and by the fact that the data were collected in the mid-1980s, after which time major changes in clinical practice and mortality have occurred (89). Race and Ethnicity and Access to Medical Care Insidious racism or ethnic prejudice on the part of obstetricians or neonatologists may affect access to proper treatments. In a population-based retrospective cohort of women delivering singletons in the United States between 1989 and 2000, it appeared that preterm birth rates were declining among African American women (18.5 percent in 1989 versus 16.2 percent in 2000), although they were still substantially higher than the preterm birth rates among white women (9.4 percent in 2000). The numbers of medically indicated preterm births rose among both African American and white women, although they rose to a much higher degree among white women (an increase of 32 percent for African American women and an increase of 55 percent for white women). The authors concluded that the increase in preterm birth rates among white women was largely due to an increase in medically indicated preterm birth, whereas in African American women the preterm birth rate declined because of decreased rates of preterm rupture of membranes and spontaneous preterm birth. The authors raised concerns about the racial differences in obstetric interventions (90). Distributive Justice and the Care of Preterm Infants Ethical concerns about the distributive justice of caring for premature infants in light of the incidence of prematurity in high-risk populations of low socioeconomic status may be overstated, as the epidemiology of prematurity is changing. Rates of premature birth remain excessive in African American women, adolescents, and women of low socioeconomic status. Thus, there remain differences in perinatal outcomes between women of high and low socioeconomic status, and in particular, there are significantly poorer perinatal outcomes for African American women in the United States. However, preterm birth rates may be increasing among women of high socioeconomic status as they delay childbearing and use ARTs to con-

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Preterm Birth: Causes, Consequences, and Prevention ceive. As a result, the proportion of premature infants born to mothers of higher socioeconomic status may be rising. Some data have raised the concern that infants conceived by the use of ART are more likely to be born premature or of low birth weight. Achieving access to high-quality prenatal and obstetric care for all women, regardless of socioeconomic status, race, or ethnicity, would help the realization of justice for pregnant women and neonates. In a population-based study of birth outcomes in North Carolina (1993 to 1997), it was found that Hispanic and white women had similar rates of infant mortality, low birth weight, and prematurity but that African American women had significantly higher rates of all adverse outcomes. In that study, Hispanic women had less education than African American women but had prenatal care patterns similar to those of African American women. Hispanic women also had significantly lower rates of daily tobacco use than white or African American women. The authors could not explain why, despite similar rates of use of prenatal care use, Hispanic women had significantly better birth outcomes than African American women. They did suggest that health behaviors such as smoking may be an important difference with respect to birth outcomes (91). In an observational study from Arizona, adolescents had a greater incidence of delivering LBW infants, with 2 percent of their deliveries being VLBW, whereas the rate was 1.1 percent among women at least 19 years old (p = 0.002) (92). In a large population-based study in New Zealand spanning the years from 1980 to 1999, it was found that the overall rates of premature births rose from 4.3 to 5.9 percent; however, the largest increase was among families living in the least-deprived areas (a 71.9 percent increase, from 3.2 to 5.5 percent). The authors concluded that preterm births were still on the rise, potentially because of changes in ultrasound dating techniques, changes in the definition of viability, decreased numbers of stillbirths, and increased rates of assisted conception. They also concluded that the social gradient in preterm birth had disappeared, with possible reasons including changes in maternal age and parity and women’s participation in the workforce (93). ETHICAL ISSUES IN PERINATAL AND NEONATAL RESEARCH The ethical conduct of clinical research involving children was recently reviewed by the Institute of Medicine in a report published in 2004 (94). Overall, the regulations (referred to as Subpart D) and the associated ethical framework are appropriate for research involving premature infants. Although the topic is not unique to neonatology, several themes have been the subject of investigation and commentary in the context of neonatal research. These include (a) the prospect of direct benefit to an infant from

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Preterm Birth: Causes, Consequences, and Prevention being included in the research, apart from any direct benefit from the research intervention (95, 96); (b) the documented prevalence of the “off-label” use of medications and the need for evidence-based medicine (97, 98); and (c) the need for alternative approaches to the retrieval of informed consent for neonatal research (16, 99–101). These topics are not reviewed in this appendix. Specific questions arise, however, in two main areas: (a) the applicability of Subpart B at the threshold for viability and (b) the ability of adolescent pregnant women to consent to research. These two areas are discussed in more detail below. Applicability of Subpart B: Additional Protections for Pregnant Women, Human Fetuses, and Neonates Involved in Research Subpart B “applies to all research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates” (102). Definitions “Nonviable neonate means a neonate after delivery that, although living, is not viable.” “Viable, as it pertains to the neonate, means being able, after delivery, to survive (given the benefit of available medical therapy) to the point of independently maintaining heartbeat and respiration” (102). Research Involving Pregnant Women and Neonates Pregnant women or fetuses may be involved in research if all of the conditions that are listed in §46.204 are met. Consistent with the research protections found in Subpart A and applicable to all human research subjects, there should be sufficient preclinical and clinical data to assess “potential risks to pregnant women and fetuses.” Absent the prospect of direct benefit for either the pregnant woman or the fetus, the risk to the fetus must be minimal and the knowledge to be obtained must be important and unobtainable by any other means. The definition of minimal risk is found in Subpart A: “Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” “If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained in accord with the informed consent provisions of subpart A of this part, except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the

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Preterm Birth: Causes, Consequences, and Prevention pregnancy resulted from rape or incest.” Otherwise, the consent of the pregnant woman is sufficient. “For children as defined in §46.402(a) who are pregnant, assent and permission are obtained in accord with the provisions of subpart D of this part.” Children are defined as “persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.” There must be an independent assessment of the viability of the neonate. In addition, “individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy.” Neonates of uncertain viability and nonviable neonates may be involved in research (§46.205) if the following conditions are met: Neonates of uncertain viability may not be involved in research unless the research holds out the prospect of enhancing the probability of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective, or the purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research. If neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent’s legally authorized representative can be obtained. After delivery a nonviable neonate may not be involved in research covered by this subpart unless all of the following additional conditions are met: (a) vital functions of the neonate will not be artificially maintained; (b) the research will not terminate the heartbeat or respiration of the neonate; (c) there will be no added risk to the neonate resulting from the research; (d) the purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and (e) the legally effective informed consent of both parents of the neonate is obtained (unless either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, or the consent of the father need not be obtained if the pregnancy resulted from rape or incest). The consent of a legally authorized representative of either or both of the parents of a nonviable neonate will not suffice. A neonate, after delivery, that has been determined to be viable may be included in research only to the extent permitted by and in accord with the requirements of subparts A and D of this part. Research Involving Pregnant Adolescents Although the National Commission intended that the state consent laws for the treatment of minors apply in the research setting, this has been a point of contention and debate. For example, in adopting Subpart D, the

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Preterm Birth: Causes, Consequences, and Prevention Food and Drug Administration specifically did not adopt the waiver of parental permission found in 45 CFR 46.408(c) (103). “Section 46.408(c) of DHHS [U.S. Department of Health and Human Services] subpart D allows an IRB [institutional review board] to determine that a research protocol is designed for conditions or for a subject population for which the permission of parents or guardians is not a reasonable requirement to protect the subjects.” This section has often been used by institutional review boards to waive the requirement for parental permission for research involving adolescents, provided that the research involved procedures that the adolescent could consent to under applicable state law. Although most states include marriage as a condition that results in the emancipation of an adolescent from parental control, only two states (New Jersey and Wisconsin) mention pregnancy or previous birth. The ability to independently consent for research participation as an “expanded” view of emancipation may be reasonable, but this has not been addressed explicitly in state laws (104). State laws usually contain provisions for a minor to consent to health care (so-called mature minor statutes), with pregnancy often included as a qualifying condition. In addition, states allow a minor to consent to treatments for specific disorders or conditions such as sexually transmitted diseases, family planning, and alcohol or drug abuse. However, the applicability of these statutes to the research setting is far from clear (104). REFERENCES 1. McHaffie HE, Lyon AJ, Hume R. Deciding on treatment limitation for neonates: the parents’ perspective. European Journal of Pediatrics 2001;160:339–344. 2. Partridge JC, Martinez AM, Nishida H, et al. International comparison of care for very low birth weight infants: parents’ perceptions of counseling and decision-making. Pediatrics 2005;116(2):e263–e271. 3. Brinchmann B. What matters to the parents? A qualitative study of parents’ experiences with life-and-death decisions concerning their premature infants. Nursing Ethics 2002;9(4):388–404. 4. McHaffie HE, Laing IA, Parker M, McMillan J. Deciding for imperilled newborns: medical authority or parental autonomy? Journal of Medical Ethics 2001;27:104–109. 5. Bastek TK, Richardson DK, Zupancic JAF, Burns JP. Prenatal consultation practices at the border of viability: a regional survey. Pediatrics 2005;116(2):407–413. 6. Streiner DL, Saigal S, Burrows E, Stoskopf B, Rosenbaum P. Attitudes of parents and health care professionals toward active treatment of extremely premature infants. Pediatrics 2001;108(1):152–157. 7. Orfali K. Parental role in medical decision-making: fact or fiction? A comparative study of ethical dilemmas in French and American neonatal intensive care units. Social Science & Medicine 2004;58(10):2009–2022. 8. Lantos JD, Tyson JE, Allen A, et al. Withholding and withdrawing life sustaining treatment in neonatal intensive care: issues for the 1990s. Archives of Disease in Childhood: Fetal and Neonatal Edition 1994;71(3):F218–F223.

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Preterm Birth: Causes, Consequences, and Prevention 94. Field MJ, Behrman RE, eds. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press; 2004. 95. Lantos JD. The “inclusion benefit” in clinical trials. Journal of Pediatrics 1999; 134(2):130–131. 96. Silverman WA. Disclosing the “inclusion benefit.” Journal of Perinatology 2002; 22(4):261–262. 97. Choonara I, Conroy S. Unlicensed and off-label drug use in children: implications for safety. Drug Safety 2002;25(1):1–5. 98. Turner S, Nunn AJ, Fielding K, Choonara I. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatrica 1999; 88(9):965–968. 99. Tyson JE, Knudson PL. Views of neonatologists and parents on consent for clinical trials. Lancet 2000;356(9247):2026–2067. 100. Manning DJ. Presumed consent in emergency neonatal research. Journal of Medical Ethics 2000;26(4):249–253. 101. Rogers CG, Tyson JE, Kennedy KA, Broyles RS, Hickman JF. Conventional consent with opting in versus simplified consent with opting out: an exploratory trial for studies that do not increase patient risk. Journal of Pediatrics 1998;132(4):606–611. 102. U.S. Department of Health and Human Services. 45 CFR Part 46: Protection of Human Subjects. Federal Register 2001;66(219):56775–56780. 103. Food and Drug Administration. Additional safeguards for children in clinical investigations of FDA-regulated products. Federal Register 2001;66(79):20589–20600. 104. Campbell AT. State regulation of medical research with children and adolescents: an overview and analysis. In: Field MJ, Behrman RE, eds. Ethical Conduct of Clinical Research Involving Children. Washington, DC: National Academies Press; 2004:320–387.