Executive Summary of the Workshop on the Border of Viability
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《小儿科》
Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Department of Pediatrics, St Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania
ABSTRACT
One of the most complex areas in perinatal-neonatal medicine remains the care of the mother delivering a newborn infant at the border of viability, referred to as "periviable" gestation. To address the knowledge gaps that preclude optimal, evidence-based care in this critical field of perinatal medicine, the National Institute of Child Health and Human Development organized a workshop in March 2004. This article provides a summary of the discussions, focusing on major knowledge gaps and prioritized suggestions for studies in this area.
Key Words: prematurity fetal death cerebral palsy neonatal resuscitation intensive care ethics
The care of women with pregnancy complications at gestations considered near the "border of viability" involves a complex set of medical, emotional, and social challenges for health care professionals and for the concerned families of patients.1 Because there is no uniformly accepted definition for the term "border of viability," we use the term "periviable" to refer to the fetus at 20 to 26 weeks of gestational age, when brief pregnancy prolongation can alter dramatically the potential for survival and long-term complications. Care practices have varied widely in this critical area of perinatal-neonatal medicine. Few randomized, controlled trials have been conducted to identify optimal approaches to the care of women and infants at periviable gestations, and no guidelines help clinicians formulate uniform treatment plans.
To address these issues, the Pregnancy and Perinatology Branch of the National Institute of Child Health and Human Development sponsored a workshop titled "Border of Viability" in March 2004. The participating expert panel reviewed the existing literature and discussed challenges facing the health care team in providing prenatal, perinatal, and neonatal management for infants born at the threshold of viability, in light of the current statistics on short-term survival rates and long-term sequelae. The panel reviewed gaps in knowledge and variations in current management practice and formulated research priorities to rectify the gaps and to facilitate development of uniform practice guidelines in the future. This article provides a summary of those discussions.
OBSTETRIC CARE AT PERIVIABLE GESTATIONS
When the need for periviable delivery is considered, obstetric care requires a critical evaluation of the medical conditions of both the mother and the fetus. Under certain circumstances (eg, clinically evident intrauterine infection), delivery is necessary to reduce both maternal and fetal/neonatal morbidity. In other circumstances, the need for expeditious delivery may be less clear or the needs of the mother and fetus may conflict. In the absence of an acute indication for delivery, estimates of maternal, fetal, and neonatal risks with efforts to conserve the pregnancy must be weighed against the risks of perinatal death and long-term sequelae with expeditious delivery. Efforts to continue the pregnancy to allow additional fetal growth and maturation may occur in a potentially "hostile" intrauterine environment. A crucial step in estimating newborn risk in the periviable period is accurate assessment of gestational age and fetal growth. Regarding maternal and fetal risks of continued pregnancy, there is a need to understand the impact of the maternal or fetal condition necessitating consideration of delivery and the consequences of continued pregnancy in such a circumstance.
The dilemma for obstetricians can be seen in the following example. For a pregnant woman presenting at a reported gestation of 23 weeks with signs of hypertension, a 2-week prolongation of pregnancy may benefit her fetus, because survival rates after periviable birth improve from 20% to 35% at 23 weeks to 50% to 70% at 25 weeks.2 If the gestational age assignment is inaccurate and the pregnancy is only 21 weeks at presentation, then pregnancy prolongation of 2 weeks can increase potential survival rates from 0% to 20% to 35%, with a significant risk of serious long-term morbidity among survivors. A 25-week gestation with a growth-restricted, 23-week-sized fetus may also demonstrate significantly improved survival rates with a 2-week delay in delivery, but with increased potential for fetal loss. If the mother has mild chronic hypertension, then conservative management is often well tolerated. For a mother with new-onset acute hypertension associated with severe preeclampsia, however, attempts to prolong the pregnancy place the mother at increased risk of complications, including acute hypertensive crisis, stroke and myocardial ischemia, eclampsia and hemolysis/elevated liver enzymes/low platelets syndrome, and renal failure, among other serious complications. In this situation, therefore, accurate assessments of the gestational age and fetal growth, techniques to predict fetal reserve serially and accurately, a better understanding of the effects of prolonged exposure to uteroplacental dysfunction in the periviable period, and markers to better distinguish those who can be successfully treated conservatively for extended periods from those who cannot, in the setting of hypertension, are needed.
ACCURACY OF GESTATIONAL AGE ASSESSMENTS
Unfortunately, even after decades of significant advances in obstetrics, the accuracy of estimating gestational age in mid-pregnancy remains far from satisfactory. Although there are established criteria for gestational age assessments based on the date of the last menstrual period and ultrasound studies, the margins of error for these methods remain relatively large, because of random errors in the range of the windows of fertility and conception and variations in fetal growth in the second and third trimesters. Even an apparently small margin of error of 1 to 2 weeks in estimated gestational age at mid-gestation can affect therapeutic decisions dramatically, in opposite directions, because survival rates improve tremendously with each advancing week of gestation beyond 23 weeks. In addition to the gestational age assessment, another knowledge gap is in the ability to determine why some infants appear to be physiologically more mature than others at identical gestational ages, as exemplified by female infants, whose lung function is superior, on average, to that of male infants of the same gestational age.
PERINATAL COUNSELING AND THERAPY
Because of the lack of randomized controlled trials, most obstetric decisions involving the care of women with pregnancy complications in the late second trimester and early third trimester have been empirical, based on small case series, expert opinion, and practice experiences. Such experiences and opinions often cannot be generalized. Although the "best available" information should be offered to patients with these complications, an appraisal of the limitations of the available information is appropriate. Health care professionals planning to counsel such women in labor should also have accurate current information regarding infant survival rates and long-term sequelae after periviable birth, with evidence-based data. The information provided should include national statistics, integrated with local experience regarding outcomes related to specific disorders (eg, outcomes of pregnancies complicated by fetal abdominal wall defects and surgery to treat such defects), where possible.
It is well established that therapies such as prenatal corticosteroid therapy for fetal lung maturation3 among women with preterm labor and antibiotic treatment for pregnancy prolongation with premature rupture of the membranes4 are beneficial when used for pregnancies with preterm delivery. However, the value of these therapies has not been fully studied among women at risk for delivery between 20 and 24 weeks of gestation. Furthermore, the optimal mode of delivery (vaginal versus cesarean) for the fetus and the mother in the periviable period is not known. Scientists planning future randomized, controlled trials in these areas might wish to consider the baseline data from early observational trials describing such interventions and outcomes. Other specific aspects of knowledge gaps regarding the care of fetus and newborn at periviable gestations are listed in Table 1.
NEONATAL RESUSCITATION AND CARDIOPULMONARY MANAGEMENT
There is little specific information to guide resuscitation of a periviable infant in the delivery room. For instance, we do not know what concentration of oxygen is optimal. Nor do we know what means of mechanical intervention provides optimal lung expansion and transpulmonary gas exchange while minimizing the risk of chronic lung disease. In this regard, the value of continuous positive airway pressure begun in the delivery room has yet to be studied. Furthermore, management strategies for periviable infants in the intensive care nursery remain empirical, especially with regard to the dose and appropriate frequency of exogenous surfactant therapy and the methods of ideal ventilatory support (eg, high frequency, conventional, assist control, or volume guarantee). Studies are needed to establish the optimal range for the safe effective use of supplemental oxygen with assisted ventilation. This is critically needed, because too-low concentrations might lead to hypoxic injury and too-high concentrations to retinopathy of prematurity and chronic lung disease. Periviable infants are often cared for with equipment designed for larger infants. It may be that optimal treatment requires specific equipment of appropriate size and design to accommodate the specific needs of this population.
The impact of preterm birth on the cardiovascular system is not well studied. The status of the ductus arteriosus and changes in pulmonary blood flow may affect both the cardiac and pulmonary systems. Routine use of prophylactic or therapeutic indomethacin treatment for early patent ductus arteriosus closure remains controversial. Similarly, myocardial function among periviable infants has not been well studied. Studies are needed urgently to define normal boundaries of systemic blood pressure, mechanisms that control changes in blood pressure, and effects on cerebral blood flow. Effects of medications on the cardiopulmonary system are not well delineated. The short-term and long-term effects of apnea are unclear. Long-term cardiopulmonary outcomes in early childhood and adulthood for the tiniest survivors remain a significant issue.
FLUID, NUTRITION, AND MEDICATION SUPPORT
Fluid management of periviable infants remains a major challenge. Extreme skin immaturity, high rates of insensible water loss, and cardiovascular instability all add to the complexity of fluid management among periviable infants. Therefore, optimal fluid and electrolyte management remains unclear. Some issues include high versus low fluid intake (200–300 vs 60–90 mL/kg per day), time and mode of treatment of patent ductus arteriosus, fluid management in relation to patent ductus arteriosus, regulation of the enzyme Na+/K+-ATPase, effects of electrolyte abnormalities (hyponatremia and calcium abnormalities) and glucose abnormalities on neurodevelopmental outcomes, and optimization of parenteral nutrition, with supplementation of trace elements, micronutrients, and vitamins. The best strategy for providing environmental support, including optimal temperature and humidity, has not been well established for this population.
Breakdown of skin integrity and infection continue be vexing problems among periviable infants, particularly during the first and second weeks of life and among infants supported with high environmental humidity. However, the best methods to prevent the loss of skin integrity, especially with its roles in heat loss, fluid loss, and prevention of infection, remain undetermined. Although the skin is the largest organ in the body, its function in the neonatal period has not been well studied. Studies are needed to understand the developmental maturation of the skin, with respect to gestational age, in relation to fluid and electrolyte exchange functions, the maintenance of skin integrity and immunologic functions, and the best measures to support proper skin growth.
Providing appropriate nutritional support for periviable infants remains a major challenge. Scientific evidence is lacking to guide optimal parenteral and enteral administration of protein, fat, and carbohydrates and the appropriate caloric balance in the early neonatal period for infants born at periviable gestations. Enteral feeding strategies for this group have not been well evaluated. The effects of reflux and antireflux medications on short- and long-term outcomes among periviable infants are unknown.
The maturation of the gastrointestinal tract and its role in immunity are emerging areas of research. Necrotizing enterocolitis continues to be a significant problem in the NICU. The definition of ideal growth for periviable infants remains unclear. How fast should an infant grow Should treatment aim to achieve maintenance of intrauterine growth rates What are the long-term effects of variations in growth and growth rates What is the impact of growth on brain growth These questions must be addressed. Similarly, the composition of breast milk from mothers who deliver periviable infants and breast milk's role in improving outcomes remain to be elucidated. At the present time, we use normative information for growth parameters such as length, weight, and head circumference based on data for full-term infants; for assessment of growth, however, we need data for extremely low birth weight infants. It is unclear whether information from intrauterine fetal growth or infants born at periviable gestations should be used. The effects of early and late interventions to promote optimal growth and their long-term outcomes need to be studied.
The study of drugs and the effects of maternal drugs on periviable infants is a large scientific gap. Similarly, data are not available on the pharmacokinetic features, doses, and metabolism of common drugs used for newborn infants, such as antibiotics, inotropic agents, and analgesics.
NEONATAL INFECTIONS
Both early- and late-onset infections occur very commonly among infants born in the periviable period. Diagnosis of blood culture-proven sepsis for such infants is often difficult, because their small blood volume precludes drawing large samples for culture. However, infants who are diagnosed with "presumptive or rule-out sepsis," defined as being treated with antibiotics for 5 days, even in the absence of positive blood cultures, are at risk for much worse long-term neurodevelopmental outcomes than are those without such diagnoses. Despite the widespread use of antibiotics in the treatment of proven or presumed sepsis, there is a paucity of information about the short-term and long-term safety of antibiotic therapy for periviable infants. It is unclear to what extent the illness or the treatments lead to adverse outcomes.
Other concurrent conditions and treatments may alter the course of neonatal sepsis or may themselves be altered by sepsis. Some of these conditions include respiratory distress syndrome, intraventricular hemorrhage, periventricular leukomalacia, chronic lung disease, and corticosteroid treatment. Similarly, the effects of nutrition and growth on immune function and the development of sepsis, possible racial and ethnic differences in responses to infections, and the overall relationships of these factors to antecedent chorioamnionitis remain to be studied.
NEUROLOGIC ISSUES
The high frequency of severe long-term neurologic sequelae after periviable birth remains an important challenge. More studies are needed to understand the biological basis for injury to the developing brain and mitigators of such damage. In this regard, elucidation of the role of cytokines as inflammatory mediators and neuroprotective factors may provide insights.
The effects of oxygenation (both hypoxia and hyperoxia and relative amounts of oxygen supplementation), iron treatment (transfusions and supplementation), and carbon dioxide levels on the brain, optimization of oxygen levels, and the effects of bilirubin on periviable brain development need to be studied. Although indomethacin prophylaxis has been shown to be effective in reducing grades III and IV intraventricular hemorrhage,5 there is no long-term benefit from such therapy.6 The specific value of indomethacin among periviable infants is unclear.
The effects of maternal thyroid status and the endocrinologic effects of early placental withdrawal on the periviable fetus are unknown. Influences of the micro- and macroenvironment on the brain and the developing nervous system before delivery and in the NICU are not well studied. The factors that might affect optimal growth and development of the brain in the ex utero environment, compared with the in utero environment, have yet to be elucidated.
Treatments directed against complications in a certain organ system may produce adverse effects in the same or other organ systems. For instance, glucocorticoid therapy to facilitate the weaning of infants from mechanical ventilation can have dramatic effects on the pulmonary system; however, long-term follow-up studies revealed a dose-dependent increase in the risk of cerebral palsy among surviving infants exposed to corticosteroid therapy postnatally, as well as acute changes in growth in this population.7
MULTIPLE GESTATIONS
Special populations of periviable infants pose unique challenges. With the advent of assisted reproductive technology, the rates of twin and high-order multiple gestations have increased. These pregnancies are represented disproportionately among preterm and early preterm births. Evidence-based management guidelines with respect to prenatal, periviable, neonatal, and long-term therapies would be extremely helpful for these groups of infants.
NEONATAL FOLLOW-UP MONITORING
In assessments of the long-term outcomes of periviable infants, we are confronted with such fundamental questions as the following. What is normal What are normal development and growth How long should an infant be given a "corrected" score (based on gestational age) on a given test Reports of outcomes must include information regarding birth weight, gestational age, mode of delivery, prenatal glucocorticoid therapy, and population-based data with clearly defined numerators and denominators. Suggestions for realistic denominators for assessment of perinatal outcomes related to periviable birth have included all women delivering periviable infants, live-born infants undergoing aggressive resuscitative efforts, and only infants admitted to the NICU. Each may be appropriate, depending on the specific evaluation being addressed. Attrition rates in follow-up periods for population-based studies need to be minimized, so that estimates are accurate.
Many additional questions need to be answered. What are the correct evaluation tools for follow-up monitoring Are we using the correct testing venues and instruments Neonatal follow-up monitoring for children up to 3 years of age has included Bayley developmental assessments traditionally. What are the functional (as opposed to numerically scored) outcomes Children may have problems but may be able to perform activities of daily living without much difficulty. Conversely, some children may be severely impaired, resulting in tremendous burdens for parents and caregivers. How do psychiatric, behavioral, and attention issues affect follow-up assessments These issues occur at somewhat older ages (school age). How has chronic illness affected follow-up assessments Do available resources and access to care affect outcomes Prediction of outcomes based on clinical complications and clinical courses can be performed in population-based studies, but each child may not fit the model for these types of predictions.
BRIDGING BASIC AND CLINICAL SCIENCE
There are gaps in basic and translational research, including placentation and placental pathologic processes, the effects of oxygen and carbon dioxide on developing organ systems, and the effects of drugs on cells and tissues. All of these are extremely relevant to the care of this population. Cellular and animal studies are necessary to define normal and abnormal development more clearly.
ETHICS IN THE PERIVIABLE PERIOD
Ethical dilemmas continue to confront clinicians in decision-making. Medical care, therapy, and interventions in the periviable period are based largely on extrapolation of information from infants born at greater gestational ages. Often clinicians are faced with very difficult medical decisions regarding escalation, limitation, and withdrawal of therapy. However, because of the many unknown factors, offering palliative care on a routine basis is not considered appropriate. Decisions must be made on a case-by-case basis, and this is truly an art in medicine. Decisions must be made in consultation with parents during the crisis of a threatened or imminent periviable delivery; this is difficult because of gaps in knowledge. Because of these gaps, there are many approaches, none of which has been evaluated rigorously in this population.
PREDICTION AND PREVENTION OF PERIVIABLE BIRTH
Finally, although considerable effort is needed to understand more completely and to guide optimal treatment of a mother with complications leading to periviable birth and also to maximize the infant outcome once periviable birth occurs, there is a critical need to develop predictive tools and preventative strategies for periviable birth that will allow us to avoid the end-stage clinical situation in which the mother and fetus are at direct risk and delivery may be inevitable. Because preterm birth is multifactorial in nature, because markers for preterm birth near term may not be appropriate for periviable birth, and because periviable birth is itself a relatively uncommon complication, affecting <2% to 3% of the population, traditional models of prediction and prevention may not be appropriate for periviable births. Decidual inflammation and infection play increasing roles in preterm birth with decreasing gestational age. In addition, abnormal placentation and uteroplacental dysfunction may play important roles in periviable births. A better understanding of the proximate causes and antecedent risk factors for periviable birth is needed. Early pregnancy markers that are predictive of periviable birth in low- and high-risk groups must be identified. Once this is accomplished, prospective studies evaluating focused interventions directed at specific groups may yield improved pregnancy outcomes. Among women at risk for periviable birth, in some cases the paradigm may need to be shifted from preterm birth prevention to pregnancy prolongation and optimization of the timing of delivery to maximize neonatal outcomes.
CONCLUSIONS
The participants recognized that there are many gaps in knowledge that need to be clarified in the care of the mother and fetus at risk for periviable birth and the newborn infant after periviable birth. Studies are needed to provide evidence-based information that can assist clinicians regarding the complex biological issues, societal implications, and parental expectations surrounding periviable birth. Studies should also evaluate the effects of incomplete knowledge in this area on management decisions. Attention should be devoted to determining the short-term and long-term outcomes related to periviable births and the benefits and burdens of such births for society. A special note was made that, although we should not hesitate to develop hospice-like care for terminally ill periviable infants, we should not forget the continued need to develop medical care and support for handicapped infants who are born at periviable gestations and survive into adulthood.
ACKNOWLEDGMENTS
The following invited scientists participated in the conference: Marilee Allen, Johns Hopkins University (Baltimore, MD); Garland Anderson, University of Texas (Galveston, TX); Eduardo Bancalari, University of Miami (Miami, FL); Stephen Baumgaurt, State University of New York (Stony Brook, NY); Anita Catlin, Sonoma (Napa, CA); Maureen Hack, Case Western Reserve University (Cleveland, OH); William Hay, University of Colorado (Denver, CO); Brian Mercer, Case Western Reserve University (Cleveland, OH); Nigel Paneth, University of Michigan (Ann Arbor, MI); Jeff Perlman, Cornell University (New York, NY); Barbara Stoll, Emory University (Atlanta, GA) (presented by Jon Tyson, University of Texas [Houston, TX]); and Jon Tyson, University of Texas (Houston, TX), and Katherine Wenstrom, University of Alabama (Birmingham, AL). Moderators: Maria Delivoria-Papadopolous, Drexel University College of Medicine (Philadelphia, PA); Jerold Lucey, University of Vermont (Burlington, VT); Sheldon Korones, University of Tennessee (Memphis, TN); Jon Tyson, University of Texas (Houston, TX); and Betty Vohr, Brown University (Providence, RI).
FOOTNOTES
Accepted Sep 13, 2004.
No conflict of interest declared.
REFERENCES
MacDonald H, American Academy of Pediatrics, Committee on the Fetus and the Newborn. Perinatal care at the threshold of viability. Pediatrics. 2002;110 :1024 –1027
NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. Effects of corticosteroids for fetal maturation on perinatal outcomes. JAMA. 1995;273 :413 –418
Mercer BM, Miodovnik M, Thurnau GR, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes: National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. JAMA. 1997;278 :989 –995
Ment LR, Oh W, Ehrenkranz RA, et al. Low dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics. 1994;93 :543 –550
Ment LR, Vohr B, Allan W, et al. Outcome of children in the Indomethacin Intraventricular Hemorrhage Prevention Trial. Pediatrics. 2000;105 :485 –491
O'Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics. 1999;104 :15 –21(Rosemary D. Higgins, MD, )
Department of Pediatrics, St Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania
ABSTRACT
One of the most complex areas in perinatal-neonatal medicine remains the care of the mother delivering a newborn infant at the border of viability, referred to as "periviable" gestation. To address the knowledge gaps that preclude optimal, evidence-based care in this critical field of perinatal medicine, the National Institute of Child Health and Human Development organized a workshop in March 2004. This article provides a summary of the discussions, focusing on major knowledge gaps and prioritized suggestions for studies in this area.
Key Words: prematurity fetal death cerebral palsy neonatal resuscitation intensive care ethics
The care of women with pregnancy complications at gestations considered near the "border of viability" involves a complex set of medical, emotional, and social challenges for health care professionals and for the concerned families of patients.1 Because there is no uniformly accepted definition for the term "border of viability," we use the term "periviable" to refer to the fetus at 20 to 26 weeks of gestational age, when brief pregnancy prolongation can alter dramatically the potential for survival and long-term complications. Care practices have varied widely in this critical area of perinatal-neonatal medicine. Few randomized, controlled trials have been conducted to identify optimal approaches to the care of women and infants at periviable gestations, and no guidelines help clinicians formulate uniform treatment plans.
To address these issues, the Pregnancy and Perinatology Branch of the National Institute of Child Health and Human Development sponsored a workshop titled "Border of Viability" in March 2004. The participating expert panel reviewed the existing literature and discussed challenges facing the health care team in providing prenatal, perinatal, and neonatal management for infants born at the threshold of viability, in light of the current statistics on short-term survival rates and long-term sequelae. The panel reviewed gaps in knowledge and variations in current management practice and formulated research priorities to rectify the gaps and to facilitate development of uniform practice guidelines in the future. This article provides a summary of those discussions.
OBSTETRIC CARE AT PERIVIABLE GESTATIONS
When the need for periviable delivery is considered, obstetric care requires a critical evaluation of the medical conditions of both the mother and the fetus. Under certain circumstances (eg, clinically evident intrauterine infection), delivery is necessary to reduce both maternal and fetal/neonatal morbidity. In other circumstances, the need for expeditious delivery may be less clear or the needs of the mother and fetus may conflict. In the absence of an acute indication for delivery, estimates of maternal, fetal, and neonatal risks with efforts to conserve the pregnancy must be weighed against the risks of perinatal death and long-term sequelae with expeditious delivery. Efforts to continue the pregnancy to allow additional fetal growth and maturation may occur in a potentially "hostile" intrauterine environment. A crucial step in estimating newborn risk in the periviable period is accurate assessment of gestational age and fetal growth. Regarding maternal and fetal risks of continued pregnancy, there is a need to understand the impact of the maternal or fetal condition necessitating consideration of delivery and the consequences of continued pregnancy in such a circumstance.
The dilemma for obstetricians can be seen in the following example. For a pregnant woman presenting at a reported gestation of 23 weeks with signs of hypertension, a 2-week prolongation of pregnancy may benefit her fetus, because survival rates after periviable birth improve from 20% to 35% at 23 weeks to 50% to 70% at 25 weeks.2 If the gestational age assignment is inaccurate and the pregnancy is only 21 weeks at presentation, then pregnancy prolongation of 2 weeks can increase potential survival rates from 0% to 20% to 35%, with a significant risk of serious long-term morbidity among survivors. A 25-week gestation with a growth-restricted, 23-week-sized fetus may also demonstrate significantly improved survival rates with a 2-week delay in delivery, but with increased potential for fetal loss. If the mother has mild chronic hypertension, then conservative management is often well tolerated. For a mother with new-onset acute hypertension associated with severe preeclampsia, however, attempts to prolong the pregnancy place the mother at increased risk of complications, including acute hypertensive crisis, stroke and myocardial ischemia, eclampsia and hemolysis/elevated liver enzymes/low platelets syndrome, and renal failure, among other serious complications. In this situation, therefore, accurate assessments of the gestational age and fetal growth, techniques to predict fetal reserve serially and accurately, a better understanding of the effects of prolonged exposure to uteroplacental dysfunction in the periviable period, and markers to better distinguish those who can be successfully treated conservatively for extended periods from those who cannot, in the setting of hypertension, are needed.
ACCURACY OF GESTATIONAL AGE ASSESSMENTS
Unfortunately, even after decades of significant advances in obstetrics, the accuracy of estimating gestational age in mid-pregnancy remains far from satisfactory. Although there are established criteria for gestational age assessments based on the date of the last menstrual period and ultrasound studies, the margins of error for these methods remain relatively large, because of random errors in the range of the windows of fertility and conception and variations in fetal growth in the second and third trimesters. Even an apparently small margin of error of 1 to 2 weeks in estimated gestational age at mid-gestation can affect therapeutic decisions dramatically, in opposite directions, because survival rates improve tremendously with each advancing week of gestation beyond 23 weeks. In addition to the gestational age assessment, another knowledge gap is in the ability to determine why some infants appear to be physiologically more mature than others at identical gestational ages, as exemplified by female infants, whose lung function is superior, on average, to that of male infants of the same gestational age.
PERINATAL COUNSELING AND THERAPY
Because of the lack of randomized controlled trials, most obstetric decisions involving the care of women with pregnancy complications in the late second trimester and early third trimester have been empirical, based on small case series, expert opinion, and practice experiences. Such experiences and opinions often cannot be generalized. Although the "best available" information should be offered to patients with these complications, an appraisal of the limitations of the available information is appropriate. Health care professionals planning to counsel such women in labor should also have accurate current information regarding infant survival rates and long-term sequelae after periviable birth, with evidence-based data. The information provided should include national statistics, integrated with local experience regarding outcomes related to specific disorders (eg, outcomes of pregnancies complicated by fetal abdominal wall defects and surgery to treat such defects), where possible.
It is well established that therapies such as prenatal corticosteroid therapy for fetal lung maturation3 among women with preterm labor and antibiotic treatment for pregnancy prolongation with premature rupture of the membranes4 are beneficial when used for pregnancies with preterm delivery. However, the value of these therapies has not been fully studied among women at risk for delivery between 20 and 24 weeks of gestation. Furthermore, the optimal mode of delivery (vaginal versus cesarean) for the fetus and the mother in the periviable period is not known. Scientists planning future randomized, controlled trials in these areas might wish to consider the baseline data from early observational trials describing such interventions and outcomes. Other specific aspects of knowledge gaps regarding the care of fetus and newborn at periviable gestations are listed in Table 1.
NEONATAL RESUSCITATION AND CARDIOPULMONARY MANAGEMENT
There is little specific information to guide resuscitation of a periviable infant in the delivery room. For instance, we do not know what concentration of oxygen is optimal. Nor do we know what means of mechanical intervention provides optimal lung expansion and transpulmonary gas exchange while minimizing the risk of chronic lung disease. In this regard, the value of continuous positive airway pressure begun in the delivery room has yet to be studied. Furthermore, management strategies for periviable infants in the intensive care nursery remain empirical, especially with regard to the dose and appropriate frequency of exogenous surfactant therapy and the methods of ideal ventilatory support (eg, high frequency, conventional, assist control, or volume guarantee). Studies are needed to establish the optimal range for the safe effective use of supplemental oxygen with assisted ventilation. This is critically needed, because too-low concentrations might lead to hypoxic injury and too-high concentrations to retinopathy of prematurity and chronic lung disease. Periviable infants are often cared for with equipment designed for larger infants. It may be that optimal treatment requires specific equipment of appropriate size and design to accommodate the specific needs of this population.
The impact of preterm birth on the cardiovascular system is not well studied. The status of the ductus arteriosus and changes in pulmonary blood flow may affect both the cardiac and pulmonary systems. Routine use of prophylactic or therapeutic indomethacin treatment for early patent ductus arteriosus closure remains controversial. Similarly, myocardial function among periviable infants has not been well studied. Studies are needed urgently to define normal boundaries of systemic blood pressure, mechanisms that control changes in blood pressure, and effects on cerebral blood flow. Effects of medications on the cardiopulmonary system are not well delineated. The short-term and long-term effects of apnea are unclear. Long-term cardiopulmonary outcomes in early childhood and adulthood for the tiniest survivors remain a significant issue.
FLUID, NUTRITION, AND MEDICATION SUPPORT
Fluid management of periviable infants remains a major challenge. Extreme skin immaturity, high rates of insensible water loss, and cardiovascular instability all add to the complexity of fluid management among periviable infants. Therefore, optimal fluid and electrolyte management remains unclear. Some issues include high versus low fluid intake (200–300 vs 60–90 mL/kg per day), time and mode of treatment of patent ductus arteriosus, fluid management in relation to patent ductus arteriosus, regulation of the enzyme Na+/K+-ATPase, effects of electrolyte abnormalities (hyponatremia and calcium abnormalities) and glucose abnormalities on neurodevelopmental outcomes, and optimization of parenteral nutrition, with supplementation of trace elements, micronutrients, and vitamins. The best strategy for providing environmental support, including optimal temperature and humidity, has not been well established for this population.
Breakdown of skin integrity and infection continue be vexing problems among periviable infants, particularly during the first and second weeks of life and among infants supported with high environmental humidity. However, the best methods to prevent the loss of skin integrity, especially with its roles in heat loss, fluid loss, and prevention of infection, remain undetermined. Although the skin is the largest organ in the body, its function in the neonatal period has not been well studied. Studies are needed to understand the developmental maturation of the skin, with respect to gestational age, in relation to fluid and electrolyte exchange functions, the maintenance of skin integrity and immunologic functions, and the best measures to support proper skin growth.
Providing appropriate nutritional support for periviable infants remains a major challenge. Scientific evidence is lacking to guide optimal parenteral and enteral administration of protein, fat, and carbohydrates and the appropriate caloric balance in the early neonatal period for infants born at periviable gestations. Enteral feeding strategies for this group have not been well evaluated. The effects of reflux and antireflux medications on short- and long-term outcomes among periviable infants are unknown.
The maturation of the gastrointestinal tract and its role in immunity are emerging areas of research. Necrotizing enterocolitis continues to be a significant problem in the NICU. The definition of ideal growth for periviable infants remains unclear. How fast should an infant grow Should treatment aim to achieve maintenance of intrauterine growth rates What are the long-term effects of variations in growth and growth rates What is the impact of growth on brain growth These questions must be addressed. Similarly, the composition of breast milk from mothers who deliver periviable infants and breast milk's role in improving outcomes remain to be elucidated. At the present time, we use normative information for growth parameters such as length, weight, and head circumference based on data for full-term infants; for assessment of growth, however, we need data for extremely low birth weight infants. It is unclear whether information from intrauterine fetal growth or infants born at periviable gestations should be used. The effects of early and late interventions to promote optimal growth and their long-term outcomes need to be studied.
The study of drugs and the effects of maternal drugs on periviable infants is a large scientific gap. Similarly, data are not available on the pharmacokinetic features, doses, and metabolism of common drugs used for newborn infants, such as antibiotics, inotropic agents, and analgesics.
NEONATAL INFECTIONS
Both early- and late-onset infections occur very commonly among infants born in the periviable period. Diagnosis of blood culture-proven sepsis for such infants is often difficult, because their small blood volume precludes drawing large samples for culture. However, infants who are diagnosed with "presumptive or rule-out sepsis," defined as being treated with antibiotics for 5 days, even in the absence of positive blood cultures, are at risk for much worse long-term neurodevelopmental outcomes than are those without such diagnoses. Despite the widespread use of antibiotics in the treatment of proven or presumed sepsis, there is a paucity of information about the short-term and long-term safety of antibiotic therapy for periviable infants. It is unclear to what extent the illness or the treatments lead to adverse outcomes.
Other concurrent conditions and treatments may alter the course of neonatal sepsis or may themselves be altered by sepsis. Some of these conditions include respiratory distress syndrome, intraventricular hemorrhage, periventricular leukomalacia, chronic lung disease, and corticosteroid treatment. Similarly, the effects of nutrition and growth on immune function and the development of sepsis, possible racial and ethnic differences in responses to infections, and the overall relationships of these factors to antecedent chorioamnionitis remain to be studied.
NEUROLOGIC ISSUES
The high frequency of severe long-term neurologic sequelae after periviable birth remains an important challenge. More studies are needed to understand the biological basis for injury to the developing brain and mitigators of such damage. In this regard, elucidation of the role of cytokines as inflammatory mediators and neuroprotective factors may provide insights.
The effects of oxygenation (both hypoxia and hyperoxia and relative amounts of oxygen supplementation), iron treatment (transfusions and supplementation), and carbon dioxide levels on the brain, optimization of oxygen levels, and the effects of bilirubin on periviable brain development need to be studied. Although indomethacin prophylaxis has been shown to be effective in reducing grades III and IV intraventricular hemorrhage,5 there is no long-term benefit from such therapy.6 The specific value of indomethacin among periviable infants is unclear.
The effects of maternal thyroid status and the endocrinologic effects of early placental withdrawal on the periviable fetus are unknown. Influences of the micro- and macroenvironment on the brain and the developing nervous system before delivery and in the NICU are not well studied. The factors that might affect optimal growth and development of the brain in the ex utero environment, compared with the in utero environment, have yet to be elucidated.
Treatments directed against complications in a certain organ system may produce adverse effects in the same or other organ systems. For instance, glucocorticoid therapy to facilitate the weaning of infants from mechanical ventilation can have dramatic effects on the pulmonary system; however, long-term follow-up studies revealed a dose-dependent increase in the risk of cerebral palsy among surviving infants exposed to corticosteroid therapy postnatally, as well as acute changes in growth in this population.7
MULTIPLE GESTATIONS
Special populations of periviable infants pose unique challenges. With the advent of assisted reproductive technology, the rates of twin and high-order multiple gestations have increased. These pregnancies are represented disproportionately among preterm and early preterm births. Evidence-based management guidelines with respect to prenatal, periviable, neonatal, and long-term therapies would be extremely helpful for these groups of infants.
NEONATAL FOLLOW-UP MONITORING
In assessments of the long-term outcomes of periviable infants, we are confronted with such fundamental questions as the following. What is normal What are normal development and growth How long should an infant be given a "corrected" score (based on gestational age) on a given test Reports of outcomes must include information regarding birth weight, gestational age, mode of delivery, prenatal glucocorticoid therapy, and population-based data with clearly defined numerators and denominators. Suggestions for realistic denominators for assessment of perinatal outcomes related to periviable birth have included all women delivering periviable infants, live-born infants undergoing aggressive resuscitative efforts, and only infants admitted to the NICU. Each may be appropriate, depending on the specific evaluation being addressed. Attrition rates in follow-up periods for population-based studies need to be minimized, so that estimates are accurate.
Many additional questions need to be answered. What are the correct evaluation tools for follow-up monitoring Are we using the correct testing venues and instruments Neonatal follow-up monitoring for children up to 3 years of age has included Bayley developmental assessments traditionally. What are the functional (as opposed to numerically scored) outcomes Children may have problems but may be able to perform activities of daily living without much difficulty. Conversely, some children may be severely impaired, resulting in tremendous burdens for parents and caregivers. How do psychiatric, behavioral, and attention issues affect follow-up assessments These issues occur at somewhat older ages (school age). How has chronic illness affected follow-up assessments Do available resources and access to care affect outcomes Prediction of outcomes based on clinical complications and clinical courses can be performed in population-based studies, but each child may not fit the model for these types of predictions.
BRIDGING BASIC AND CLINICAL SCIENCE
There are gaps in basic and translational research, including placentation and placental pathologic processes, the effects of oxygen and carbon dioxide on developing organ systems, and the effects of drugs on cells and tissues. All of these are extremely relevant to the care of this population. Cellular and animal studies are necessary to define normal and abnormal development more clearly.
ETHICS IN THE PERIVIABLE PERIOD
Ethical dilemmas continue to confront clinicians in decision-making. Medical care, therapy, and interventions in the periviable period are based largely on extrapolation of information from infants born at greater gestational ages. Often clinicians are faced with very difficult medical decisions regarding escalation, limitation, and withdrawal of therapy. However, because of the many unknown factors, offering palliative care on a routine basis is not considered appropriate. Decisions must be made on a case-by-case basis, and this is truly an art in medicine. Decisions must be made in consultation with parents during the crisis of a threatened or imminent periviable delivery; this is difficult because of gaps in knowledge. Because of these gaps, there are many approaches, none of which has been evaluated rigorously in this population.
PREDICTION AND PREVENTION OF PERIVIABLE BIRTH
Finally, although considerable effort is needed to understand more completely and to guide optimal treatment of a mother with complications leading to periviable birth and also to maximize the infant outcome once periviable birth occurs, there is a critical need to develop predictive tools and preventative strategies for periviable birth that will allow us to avoid the end-stage clinical situation in which the mother and fetus are at direct risk and delivery may be inevitable. Because preterm birth is multifactorial in nature, because markers for preterm birth near term may not be appropriate for periviable birth, and because periviable birth is itself a relatively uncommon complication, affecting <2% to 3% of the population, traditional models of prediction and prevention may not be appropriate for periviable births. Decidual inflammation and infection play increasing roles in preterm birth with decreasing gestational age. In addition, abnormal placentation and uteroplacental dysfunction may play important roles in periviable births. A better understanding of the proximate causes and antecedent risk factors for periviable birth is needed. Early pregnancy markers that are predictive of periviable birth in low- and high-risk groups must be identified. Once this is accomplished, prospective studies evaluating focused interventions directed at specific groups may yield improved pregnancy outcomes. Among women at risk for periviable birth, in some cases the paradigm may need to be shifted from preterm birth prevention to pregnancy prolongation and optimization of the timing of delivery to maximize neonatal outcomes.
CONCLUSIONS
The participants recognized that there are many gaps in knowledge that need to be clarified in the care of the mother and fetus at risk for periviable birth and the newborn infant after periviable birth. Studies are needed to provide evidence-based information that can assist clinicians regarding the complex biological issues, societal implications, and parental expectations surrounding periviable birth. Studies should also evaluate the effects of incomplete knowledge in this area on management decisions. Attention should be devoted to determining the short-term and long-term outcomes related to periviable births and the benefits and burdens of such births for society. A special note was made that, although we should not hesitate to develop hospice-like care for terminally ill periviable infants, we should not forget the continued need to develop medical care and support for handicapped infants who are born at periviable gestations and survive into adulthood.
ACKNOWLEDGMENTS
The following invited scientists participated in the conference: Marilee Allen, Johns Hopkins University (Baltimore, MD); Garland Anderson, University of Texas (Galveston, TX); Eduardo Bancalari, University of Miami (Miami, FL); Stephen Baumgaurt, State University of New York (Stony Brook, NY); Anita Catlin, Sonoma (Napa, CA); Maureen Hack, Case Western Reserve University (Cleveland, OH); William Hay, University of Colorado (Denver, CO); Brian Mercer, Case Western Reserve University (Cleveland, OH); Nigel Paneth, University of Michigan (Ann Arbor, MI); Jeff Perlman, Cornell University (New York, NY); Barbara Stoll, Emory University (Atlanta, GA) (presented by Jon Tyson, University of Texas [Houston, TX]); and Jon Tyson, University of Texas (Houston, TX), and Katherine Wenstrom, University of Alabama (Birmingham, AL). Moderators: Maria Delivoria-Papadopolous, Drexel University College of Medicine (Philadelphia, PA); Jerold Lucey, University of Vermont (Burlington, VT); Sheldon Korones, University of Tennessee (Memphis, TN); Jon Tyson, University of Texas (Houston, TX); and Betty Vohr, Brown University (Providence, RI).
FOOTNOTES
Accepted Sep 13, 2004.
No conflict of interest declared.
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