With the advent of routine early ultrasonography, the gestational age is fairly well established on admission to the obstetrics unit for the vast majority of women presenting with premature labor, premature rupture of the membranes, or other problems diagnosed in the second trimester of pregnancy. Such patients need to be immediately placed in the charge of a specialist in maternal-fetal medicine (MFM) in order to coordinate the evaluation and management plans and to ensure appropriate communication and counseling. Based on the investigation for the causes of the problem at hand, the evaluation of the degree of cervical dilatation, the condition of the membranes, the presence or absence of chorioamnionitis, and the most recent evaluation of fetal well-being by ultrasonography, the MFM specialist can decide on the best course to be taken, ideally in consultation with the neonatologist, including an estimation of the likelihood of controlling labor with tocolysis to allow adequate time for antenatal corticosteroid therapy (21) and magnesium sulfate for neuroprotection (22).

The prospective parents need to receive accurate information regarding all facets of the proposed management, including the possible need for cesarean delivery, and information regarding the subsequent management of the newborn infant, including the potential risks related to both the degree of prematurity and the therapeutic interventions that may be necessary to keep the infant alive. Ideally, this information should be provided conjointly by both the MFM specialist and the neonatologist and should be based not only on general statistical information but also on the specific institutional experience with outcomes of newborn infants of similar gestational age. In our center, the neonatologist provides a written consultation on all patients admitted to the obstetric high-risk unit. We meet with the family, offer an extensive review of our experience with similar cases, and answer their questions regarding risks and outcomes. The father and mother are invited to visit the NICU and to familiarize themselves with the environment and the personnel.

The lowest gestational age at which resuscitation should be initiated has long been the subject of debate (see also Chapter 8). Guidelines are available from both the American and the Canadian Fetus and Newborn Committees (3,23,24). Based on our experience, we offer an optimistic opinion in terms of survival and potential morbidity for pregnancies of 25 weeks of gestation and over. Between 24 and 25 weeks, although we underline that the chances of survival are quite good, we also emphasize the increased risk of potential complications, such as intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of
prematurity (ROP), chronic lung disease (CLD), neurosensory impairments, and later school and behavioral difficulties. For pregnancies between 23 and 24 weeks of gestation, we describe the higher incidence of complications previously mentioned, and the lower survival rate; however, we also mention the possibility of intact survival or survival with minimal handicaps. Finally, for pregnancies below 23 weeks of gestation, we do not recommend intervention. For parents who request full intervention, we strongly advise that resuscitation will be undertaken only if the newborn has at least the degree of maturity predicted by dates and/or ultrasonography and if, in the judgment of the neonatologist present in the delivery room, the newborn has reasonable chances of responding to resuscitation. We always make it clear to the parents that initiation of resuscitation and subsequent treatments in the NICU do not preclude discontinuation of therapy if a major complication such as severe IVH is detected in the hours or days following birth. The presence of a staff neonatologist in the delivery room is an integral part of our protocol for the management of ELBW infants.

One of the most difficult questions that parents ask, and which our obstetrical colleagues continuously debate, is the safest route of delivery in the presence of either a breech presentation or evidence of fetal distress (25). In our institution, based on our own results, and as also recommended by the Canadian Pediatric Society (3), we advise cesarean delivery in such situations as of 25 weeks of gestation. Between 24 and 25 weeks, the decision is more delicate, and many factors have to be taken into consideration, particularly in view of the fact that many may require a classical incision. The decision to proceed with such an intervention is taken with a clear understanding by the parents of all the medical implications for both the mother and the infant. Finally, at less than 24 weeks of gestation, cesarean delivery is performed strictly for maternal indications, such as severe maternal blood loss or preeclampsia.

Another difficult management situation relates to ruptured membranes between 18 and 22 weeks of gestation, resulting in severe oligohydramnios, with the inherent risk of lung underdevelopment (26). Serial ultrasound studies can evaluate the degree of reaccumulation of amniotic fluid and allow for a better-educated decision regarding the advisability of continuing the pregnancy (27). However, in the vast majority of these cases, the outcome is very poor, and termination of pregnancy constitutes reasonable advice, particularly if rupture of membranes occurred before 20 weeks of gestation with poor reaccumulation of amniotic fluid.

The management of a patient with impending premature delivery should include the following: evaluation of gestational age by dates and/or early ultrasound, fetal size and position, condition of the fetal membranes, amniotic fluid volume, and evidence of chorioamnionitis and other obstetrical complications such as bleeding or preeclampsia. Vaginorectal cultures for the detection of group B
streptococcal colonization and initiation of therapy with penicillin or an appropriate alternative are also in order (28). In all patients from 23 weeks of gestation, we propose tocolysis, magnesium sulfate for neuroprotection, and the administration of two doses of 12 mg of betamethasone, given intramuscularly, 24 hours apart (21). We also monitor body temperature and changes in leukocyte count, keeping in mind the possible transient leukocytosis after the administration of betamethasone.

If a patient has fever or demonstrates other signs of chorioamnionitis, broad-spectrum antibiotics are initiated. In the presence of ruptured membranes, we use a combination of ampicillin and erythromycin and attempt to temporarily stop labor and administer steroids (29).

The successful management of the ELBW infant begins in the delivery room (Table 22.7). A well-organized and equipped delivery room and the presence of a competent team headed by an experienced neonatologist are essential ingredients to the proper reception of these very fragile newborns. The basic principle guiding successful management is directed toward prevention of any physiologic deviation from normality, such as hypothermia, acidosis, or hypoxia. At the same time, it is important that each intervention during the resuscitation process be carefully adapted to the size and to the needs of the tiny infant. Brisk maneuvers, excessive positive pressure with bagging, or inappropriate administration of drugs and fluids may induce permanent central nervous system (CNS) or lung injuries.

It seems particularly inappropriate when high-risk mothers are referred to a tertiary care center for specialized perinatal care, to have their premature newborn infants cared for in the delivery room and during the critical first hours of their lives by unsupervised and inexperienced in-training personnel. Major decisions, such as whether to initiate resuscitation and for how long, often need to be made in extremely short periods of time and under heavy pressure for infants at the limit of viability. This can be done only by experienced personnel (3).

In our center, the birth of an ELBW infant is always attended by a neonatologist in addition to the pediatric house staff, an NICU nurse, and a respiratory therapist. Appropriate equipment is used according to the American Heart Association and American Academy of Pediatrics (AAP) guidelines for neonatal resuscitation, with particular emphasis on temperature control, that is, radiant heater set at maximum temperature and prewarmed blankets (30).

During the initial steps of stabilization, the infant is immediately placed under a radiant warmer and in a polyethylene bag. After positioning and suctioning, most ELBW infants require immediate initiation of either continuous distending airway pressure or initiation of positive pressure ventilation with either a bag and mask or a T-piece resuscitator. Resuscitation is initiated using an inspired oxygen concentration of 30% to 40%, which is rapidly adapted to the infant’s condition and preductal oxygen saturation readings. We found that, for ELBW infants, ventilation is more effective if performed at a higher ventilatory rate than for the term infant. We use anesthesia bags and ventilate at a rate of 60 to 80 breaths per minute, adjusting the pressure to provide adequate bilateral air entry and chest wall excursion. For EP infants with poor chest expansion or persistent bradycardia, intubation in the delivery room may rapidly follow.

With proper ventilation, in our experience, rarely will an infant require chest compressions or epinephrine. The prognosis of ELBW infants requiring this extent of resuscitation is very guarded, particularly if their birth weight is below 750 g. Fluid resuscitation is reserved only for those infants in whom significant blood loss is suspected.

Even following optimal resuscitation, the Apgar scores of ELBW infants rarely exceed 6 or 7 in view of their decreased tone and reactivity, poor respiratory effort, and initially poor peripheral perfusion (31). The infant’s heart rate and oxygen saturation are thus the best measures of the effectiveness of resuscitation efforts.

The topic of delivery room management would not be complete without mentioning the ethical dilemmas faced by the neonatologist when parental and medical opinions regarding resuscitation differ, or when an ELBW infant is severely asphyxiated and requires prolonged resuscitation (see also Chapters 8 and 17). It is our view that reasonable parental opinions must be respected after full and honest discussion of the infant’s chances of meaningful survival.

Care of ELBW and EP infants is best delivered by tertiary/quaternary level NICUs having the necessary expertise, personnel, resources, and environment. Medical and technologic advances in neonatal care require specialized expertise that is best provided by a well-coordinated and dedicated multidisciplinary NICU team. Professionals constituting the NICU team can be grouped as follows: (a) medical, such as physicians, nurse practitioners, nurses, pharmacists, nutritionists, and respiratory therapists; (b) developmental, such as social workers, occupational therapists, physical therapists, and lactation consultants; and (c) support, such as clerical staff, biomedical engineering, and environmental services. Experienced personnel with advanced knowledge and skills are the most competent to give the complex care required by ELBW and EP infants, to understand the vulnerable emotional state of the families, and to navigate the intricate medical and social interface experienced by the families and NICU team through the course of the prolonged and often challenging hospitalization of such fragile infants. The parents are crucial members of this NICU team, being the most important and constant influences on their infants’ lives in the NICU and after discharge. Collaborative partnerships empower families to become competent caregivers for their infants, with confidence and effective parenting skills, and embody the commitment to family-centered care in the NICU (32).

In the last decade, it has been recognized that the physical environment of the NICU is an essential component in the optimal delivery of the complex, intensive, and developmentally supportive care needed by fragile infants and their vulnerable families and, at the same time, in the support of the activities and well-being of the NICU staff (see also Chapter 2). Safe care with adequate space and lighting, noise control, infection control, as well as promotion
of staff interaction, communication, and appropriate workload are medical imperatives. Provision of comfort, privacy, and individualized care are important considerations for families (33).

Expert management in the delivery room and during the first hours after admission to the NICU is of paramount importance in order to prevent immediate and long-term complications in the ELBW infant. It is well established that the majority of cerebral injuries occur around the time of delivery or in the immediate postnatal period. Acute changes in cerebral blood flow may predispose the very fragile network of periventricular vessels to rupture. Hence, it is essential to handle these very fragile infants with extreme care, avoiding unnecessary disturbances, and preventing, rather than correcting physiologic deviations in acid-base balance, blood gases, blood pressure, or body temperature. Also, overly aggressive ventilation either in the delivery room or in the NICU may predispose to significant acute or chronic pulmonary problems such as hyperinflation and loss of elasticity of the alveoli, pulmonary interstitial emphysema (PIE), pneumothorax, and eventually CLD. The initiation of continuous positive airway pressure (CPAP) or high-flow nasal cannula is the first approach. These are initiated in the delivery room and continued in the NICU.

The vast majority of our ELBW infants who require assisted ventilation are intubated in the NICU. Only in exceptional situations, when the infant does not respond to bag and mask ventilation, is intubation performed in the delivery room. We use the nasotracheal route and an endotracheal tube (ETT) of 2.5 mm diameter for ELBW infants. We believe that it is important to use a low-caliber ETT, even at the price of some leak around the ETT, in order to avoid subglottic trauma, strictures, and eventual stenosis.

In the vast majority of these infants, the umbilical vessels are cannulated. The arterial catheter is used for blood sampling or for invasive blood pressure monitoring. We favor the “high” position of the tip of the catheter, just above the level of the diaphragm. After each blood sampling, the catheter is flushed with a heparinized solution of 0.45% saline. We use the venous catheter to initiate parenteral alimentation pending the early planned insertion of a percutaneously inserted central venous catheter (PCVC), thus avoiding excessive handling and disturbance to the newborn infant during the first 24 to 48 hours of life. The tip of the catheter is positioned at the junction of the inferior vena cava and the right atrium, hence avoiding the liver.

Blood is analyzed for glucose, blood gases, hemoglobin, and leukocyte count. Intravenous alimentation is initiated at a rate of 65 to 85 mL/kg/d, and the infant is placed in a high-humidity incubator. Serum glucose levels are closely monitored, and the concentration of dextrose administered is adjusted accordingly. In very tiny babies, when more than 10% of the baby’s blood volume has been removed, we replace it with a transfusion of packed red blood cells. We attempt to minimize the number of donor exposures by collecting the blood in small packs, which may be used for up to several weeks (34). Parents who wish to donate blood to their infants may do so, as long as they are of a compatible blood group and are free of viral and other infections. Very sick infants receive 1:1 nursing care until their condition is stabilized, at which point the ratio of nurse to baby becomes 1:2.

A PCVC is inserted as soon as the baby’s condition has stabilized (35). As portal of entry, we favor the upper extremities of the infant, and we aim for the tip of the catheter to be in the superior vena cava, being careful to avoid intracardiac positioning, with its attendant risks of erosion into the pericardial space (36). In case of failure to properly position a central line, peripheral venous access is maintained. Parenteral nutrition (TPN) is introduced within the first hours of life. Electrolytes are measured between 12 and 18 hours of age. During the first 72 hours, the body weight is recorded every 8 hours, and fluid intake is adjusted accordingly. Incubators have incorporated scales, thus allowing recordings without excessive handling and disturbance of the newborn infant. They also provide a high level of humidity, hence substantially reducing fluid requirements.

In order to assist in prognostication, it is important to obtain a cranial ultrasound in the first 24 hours of life (37). This ultrasound needs to be repeated at least 1 week later, or as often as necessary, depending on the pathology detected on admission or deterioration of the infant’s condition compatible with CNS involvement. It is also important, before discharge from the hospital, to repeat the cranial ultrasound to evaluate the presence or absence of PVL (38). Ideally, this last ultrasound should be performed at 35 to 36 weeks of postmenstrual age.

The vast majority of ELBW infants will require some form of respiratory assistance in order to survive (see also Chapter 28). For vigorous infants, nasal CPAP, nasal ventilation, and high-flow nasal cannula are the preferred modes of support (39). Some controversy surrounds the timing and criteria for the initiation of assisted ventilation. Generally, infants requiring an Fio₂ > 0.35-0.40 in the early hours of life, or those having a significantly elevated partial pressure of CO₂ (Pco₂), are considered good candidates for mechanical ventilation. With an increasing number of infants requiring only CPAP after birth, as supported by the most recent policy statement by the American Academy of Pediatrics (40), the number of infants receiving exogenous surfactant has declined.

The introduction of exogenous surfactant therapy has reduced significantly the mortality of all newborns suffering from respiratory failure secondary to respiratory distress syndrome (RDS), but its impact has been particularly important among the most premature infants (41). Administration of surfactant in these very tiny infants requires extra care, as rapid changes in lung compliance may not only damage the lungs by increasing the risk of overinflation and overdistention but also predispose to acute changes in ductal circulation that, in turn, could lead to both cerebral and/or pulmonary hemorrhage. With rapid improvement in oxygenation, persistent hyperoxia also may be detrimental to the eyes. Hence, the administration of surfactant should be performed by an experienced person, with close monitoring of ventilatory parameters and with rapid reduction of peak inspiratory pressures (PIP) and inspired oxygen concentrations. If necessary, a second dose of surfactant may be administered as soon as 6 hours after the first. In our experience, if the response to the second dose is not satisfactory, it is highly unlikely that the condition will improve with additional administration of surfactant. Most infants improve rapidly after the first dose, such that a second dose of surfactant is rarely ever administered. Natural surfactant preparations are practically the only ones used (42), although some of the newer synthetic surfactant preparations containing artificial peptides may be a good alternative (43). There have also been recent descriptions of nonintubated infants successfully receiving surfactant therapy using minimally invasive techniques, such as by instilling it via a small feeding catheter inserted into the trachea under direct visualization, followed by the administration of continuous distending airway pressure (44).

In initiating mechanical ventilation, it is imperative that minimal effective settings be used (45). Studies have shown that hyperventilation and overinflation of the lungs increase the loss of surfaceactive phospholipids (46). Also, overinflation predisposes to air leaks and particularly to PIE. The latter is a serious complication in the tiny infant and is a relatively frequent one. It is probably related to structural immaturity of the lungs, particularly to the relative lack of elastic tissue, which normally increases progressively throughout gestation (47). Also, the interstitium is larger in the more immature infant as a result of poor alveolarization. Although drainage of a pneumothorax may lead to rapid improvement, management of PIE is far more complicated. As lung compliance is reduced, there
is a need for increased PIPs to maintain adequate ventilation. This results in increased barotrauma to the small airways. Chorioamnionitis has been reported as a risk factor predisposing to PIE (48). The highest incidence of PIE in tiny infants has been observed when intrauterine pneumonia complicates RDS. Strategies to manage PIE include acceptance of higher levels of Pco₂ and lower levels of pH, reduction of the positive end-expiratory pressure (PEEP), increasing the expiratory time, positioning the infant on the affected side, selective intubation of the contralateral lung, and systemic corticosteroid therapy. The use of high-frequency ventilation appears to be the most effective therapy (49).

A variety of ventilatory strategies have been promoted to maintain satisfactory ventilation and to reduce the risk of complications, such as high PIP-low rates, low PIP-high rates, variation in the I:E ratio, variations in the flow, permissive hypercapnia, tolerance of lower pH, and, more recently, high-frequency ventilation and even ventilation via nasal prongs. In recent years, however, the general trend is to use the lowest possible PIP to achieve acceptable ventilation and oxygenation (50). Of course, the question is what is considered “acceptable.” Some neonatologists will tolerate a pH as low as 7.20 and a Pco₂ as high as 65 mm Hg. Most centers also aim for PaO₂ values between 50 and 70 mm Hg. Our PIPs rarely exceed 14 to 15 cm H₂O, and we set the PEEP at 5 cm H₂O, with initial rates of 65 to 70 per minute. We aim for oxygen saturation values between 85% and 93%, which is enough to abolish production of lactic acid and, at the same time, remains relatively close to intrauterine values. We believe that this modest degree of oxygenation offers the advantage of reducing the need for administration of elevated oxygen concentrations, thus minimizing lung toxicity, and may help to avoid retinal damage. Our incidence of CLD and ROP is shown in Table 22.6. We believe that by using the lowest possible PIP and, initially, a relatively rapid respiratory rate, we reduce overdistention and barotrauma and minimize the risk of lung injury. We also have observed that with initially higher respiratory rates, the tiny infant very rapidly stops fighting the mechanical ventilator, thus making the gas exchange smoother and possibly decreasing the incidence of air leaks. Relatively high respiratory rates also seem to be more physiologic for the very immature infant, as observed by Greenough et al. (51). For toilet of the airways, we use the Ballard closed suction circuit, thus avoiding disconnecting the infant from the ventilator (52). We suction sparingly during the first few days of life, when the volume of secretions is minimal. Analgesia/sedation is administered prior to nonemergent intubation and, in rare cases, may be required for infants who remain agitated while on mechanical ventilation, particularly for those on high-frequency ventilatory support.

As soon as the procedures of intubation and catheterization of the umbilical vessels are completed, we perform chest and abdominal radiography to assess the position of the ETT and the umbilical catheters and, at the same time, to evaluate the severity of lung pathology. Thirty minutes after the initiation of ventilation, we obtain an arterial blood gas and adjust the ventilatory parameters accordingly. We use the principle of “permissive hypercapnia,” aiming for a pH above 7.25 and a Pco₂ between 45 and 55 mm Hg, but when the PIPs are elevated or in the presence of PIE, we tolerate Pco₂ values up to 65 mm Hg as long as the pH is at least 7.20. Our ETTs are secured with tape to a NeoBar ETT holder (Neotech Products, Inc., Valencia, CA). We record the level at which the ETT was secured, thus avoiding the need to repeat a chest radiograph to evaluate the tube position when reintubation is required. Actually, we take very few radiographs, and we rely extensively on clinical assessment, blood gases, transcutaneous capnometry, and pulse oximetry. However, a chest radiograph will be taken if there is significant clinical deterioration or if there are concerns about the position of the ETT or the development of any form of air leak.

Avery et al. (53) reported in 1987 that the incidence of CLD varied between neonatal units (see also Chapter 27). The unit with the lowest incidence used CPAP much more frequently than did the other units. Epidemiologic data from 36 units in the Vermont-Oxford Trial Network also indicate large differences in the incidence of CLD, from 16% to 70% for infants weighing between 501 and 1,500 g (54). The incidence of BPD was lower in units allowing higher Pco₂ values. More evidence of the association of CLD and Pco₂ was provided by Kraybil et al. (55). Garland et al. (56) reported the highest incidence of CLD among infants with the lowest Pco₂ before the administration of surfactant.

The concept of permissive hypercapnia for patients requiring mechanical ventilation gives priority to the prevention or limitation of severe pulmonary hyperinflation over the maintenance of normal ventilation. The principle consists of allowing the Pco₂ to rise by minimizing ventilator pressures and tidal volume (57). Potential risks of high Pco₂ values include increased cerebral perfusion, increased retinal perfusion, increased pulmonary vascular resistance, and reduction of pH. Based on epidemiologic observations, it appears that respiratory acidosis, unlike metabolic acidosis, is not associated with poor neurologic outcomes. Vannucci et al. (58) demonstrated similar findings in animal studies involving rats.

Several reports in the literature have expressed concern regarding potential side effects of low Pco₂ values (59). Graziani et al. (60) reported that, along with other factors, marked hypocarbia during the first 3 postnatal days was associated with an increased risk of periventricular white matter injury in premature infants. The theoretical model of ischemic brain injury has been described by Wigglesworth and Pape (61). These authors hypothesize that cerebral blood flow could be decreased by several factors, including hypotension, hyperoxia, hypocarbia, and increased venous pressures. Concern also has been expressed in the literature about high-frequency ventilation, which may lead to low Pco₂ values as a result of effective alveolar ventilation (62). However, the data regarding the development of PVL among infants managed with these devices remain controversial. Most authors agree, however, that for hypocarbia to be dangerous for the brain, it has to reach levels below 30 mm Hg. Our policy is to avoid Pco₂ values below 40 mm Hg by first reducing PIP before reducing respiratory rates.

High-frequency oscillatory ventilation (HFOV) has been used in recent years in an attempt to reduce the incidence of early ventilatory complications and to prevent CLD. Published reports are often contradictory and, so far, there is no clear evidence that HFOV offers an advantage over conventional ventilation (63). HFOV, however, offers an advantage when treating infants with PIE or severe pulmonary hypertension (64).

More recently, the effects of patient-triggered ventilation with volume guarantee have been explored in the management of preterm infants (65). This technique calls for an automatic adjustment of the peak inspiratory pressure to ensure a minimum set mechanical tidal volume.

The timing of extubation of ELBW infants is very important, because they are prone to develop severe apnea, with the potential risk of cerebral injury. Nowadays, with early administration of surfactant and improvement in lung compliance and the early introduction of caffeine, rapid extubation and placement on nasal CPAP or nasal ventilation is possible in the majority of ELBW infants. However, some EP infants develop severe episodes of apnea and desaturation, frequently requiring reintubation. For this reason, for infants less than 750 g, we often favor a more progressive weaning process by maintaining them for a few extra days at a very low PIP of 10 to 12 mm Hg and rates of 20 to 25 per minute, while providing maximum intravenous and oral alimentation (66). Following extubation, the infant is placed on nasal CPAP or high-flow nasal cannula support, the latter of which has been used with increasing success in the last few years (67). This support is discontinued when the infant can maintain good oxygenation without significant apnea, bradycardia, and desaturations. If an infant on nasal CPAP shows signs of fatigue, manifested by recurrent apnea and retention of CO₂, nasal ventilation is instituted prior to reintubation. In many circumstances, this approach provides the extra help that these tiny infants require to avoid reintubation (68).

Attention to clinical signs of cardiovascular stability is critically important; these include poor skin perfusion, with pallor and mottling, tachycardia, and low blood pressure. Continuous monitoring of the central blood pressure via an arterial catheter may provide better tracking of changes over time in the first days of life. As a rule of thumb, we aim for a mean blood pressure that is numerically slightly above the gestational age of the infant in weeks. We prudently observe a stable baby who is well perfused despite low initial measurements of blood pressure. In symptomatic infants, we cautiously use volume expansion with isotonic saline boluses and/or a continuous infusion of dopamine. The addition of hydrocortisone has also been found to be helpful in cases of persistent hypotension (69). If acute perinatal blood loss is suspected, a transfusion of packed red blood cells is given, avoiding rapid infusions to further curtail the risk of intracranial hemorrhage in these already at-risk ELBW infants. The use of point-of-care functional echocardiography may have potential benefits in clarifying the pathophysiology of a baby with cardiovascular instability at the bedside, thus offering more specific intervention and monitoring of the effectiveness of treatment (70).