Neonatal Morbidities of Prenatal and Perinatal Origin

Planning for Delivery

Ideally, discussion between physicians and parents should begin prior to birth in a nonemergency situation and should include obstetric and neonatal providers. If simultaneous presence is not possible, it is imperative that obstetric and neonatal providers communicate directly prior to delivery to ensure clarity and consistency of intent. Even during active labor, communication with the family should be initiated as a prelude to postdelivery discussions. The family should understand that plans for delivery management are based upon maternal and fetal considerations. Outcome data are typically very limited and are based upon populations of similar individuals (e.g., cohorts of 23-week gestation infants, rather than an individual). Finally, it should be emphasized that additional information available only after delivery, such as actual birth weight and neonatal physical findings, may modify a previously predicted predelivery prognosis.

Neonatal Resuscitation at the Threshold of Viability

As emphasized earlier, a birth plan developed by the parents in collaboration with obstetrical and pediatric/neonatology providers should be established. The neonatologist will provide information about planned interventions in the delivery room, transfer to the neonatal intensive care unit, anticipated initial hospital course, and the significance of potential complications in the context of prior experience with neonates of similar gestational age, weight, and clinical circumstances. Even when time does not permit such discussions, the neonatologist should carefully assess gestational age at delivery and the response to initial resuscitation. This information can be instrumental in assisting families regarding viability or nonviability of an extremely premature infant. Even though resuscitation measures for extremely preterm neonates follow standard Neonatal Resuscitation Program (NRP) protocols, every effort should be made to engage the participation of the most clinically experienced neonatal provider to evaluate gestational age, estimate weight, assess response to resuscitative efforts, and provide medical leadership for the delivery room care team to support decision making. In cases when a precipitous delivery occurs and no family communication is possible, the physician/provider should employ their best judgment to initiate resuscitation until a parent can be brought into the discussion, erring on the side of resuscitative measures if the appropriate course is initially uncertain.

Who Decides?

It is generally recognized that parents are the surrogate decision makers who should determine the goals of care for their newborn child. Decisions regarding lifesaving treatment should emphasize what is believed to be best for the newborn and are greatly impacted by the provided expertise of knowledgeable health care providers. Some recent legislative dictums have emphasized an imperative toward resuscitation for any liveborn infant. Such imperatives are likely to evolve over time. Providers should be proactive in knowledge of current institutional, local, and national regulatory norms. Every effort should be made to utilize up-to-date locally relevant outcome data. It is important to note that health care providers tend to be pessimistic about outcomes based solely on recollections of their experience and subjective reasoning.

Clinicians can assist parents by providing (1) technical information (evidence-based outcome data, prognostic information), (2) individual clinical information (specific data regarding their newborn), and (3) theoretical background (ethical guidelines, local experience). It is crucially important to remember that parents bring profound emotional and psychological investment to their comprehension and decision-making processes. They also often lack technical expertise needed to evaluate outcome data and convert that into a risk/benefit framework that is consistent with their values. Finally, parents typically bring powerful instincts to advocate for treatment, no matter how futile. The phenomenon of selective listening is common. If possible, written documentation of key concepts for future reference and discussion may be helpful. In rare circumstances when clinical providers and parents come into conflict about resuscitation, involvement of an institutional ethics committee may be helpful. Legal remedies should be a last resort.

Ethics and Moral Distress

Though decisions about resuscitation should ideally be individualized to each circumstance and family, ethical frameworks can provide an important foundation. The Nuffield Council on Bioethics report “Critical Care Decisions in Fetal and Neonatal Medicine: Ethical Issues” published in 2006 remains one of the most comprehensive, although some evolution of thought regarding the precise threshold of viability has ensued since the time of publication. The cornerstone ethical principles of medical care, autonomy, beneficence, nonmaleficence, and justice remain relevant and should be a starting point.

We have already emphasized the importance of collaboration between neonatal and obstetric providers. Nonetheless, moral distress, the ethical confrontation between a plan of care and one’s own ethical principles, can occur despite best efforts to achieve consensus. This is most likely to occur when providers on the same care team have differing personal values and moral principles. Education and communication in the form of debriefing sessions, workshops, and ethics training are important tools to ensure that the resilience and optimal functionality of the health care team. There is no formula or guideline that can be consistently applied to each clinical situation. Clinicians will benefit their patients and families by taking time to consider the large body of literature focused on care of the periviable infant, while listening carefully to each family. It is also important to emphasize that clinical decision making regarding care for the periviable infant does not end in the delivery room. Several complications of prematurity listed in Table 73.4 may present in devastating fashion during the hours and days following delivery, most notably severe IVH, bowel perforation, and respiratory failure with air leak. For an extreme preterm infant, transitioning from delivery room to NICU is the beginning of a long medical journey taking from months to years.

Definition

Transient tachypnea of the newborn (TTN), commonly known as “wet lungs,” is a mild condition affecting term and late preterm infants. This is the most common “respiratory cause” of admission to the special care nursery. Transient tachypnea of the newborn is self-limiting, with no risk of recurrence or residual pulmonary dysfunction. It rarely causes hypoxic respiratory failure secondary to persistent pulmonary hypertension of the newborn.

Pathophysiology

During the last trimester, a series of physiological events lead to changes in the hormonal milieu of the fetus and its mother to facilitate neonatal transition. Rapid clearance of fetal lung fluid is essential for successful transition to air breathing. The bulk of this fluid clearance is mediated by transepithelial sodium reabsorption through amiloride-sensitive sodium channels in the respiratory epithelial cells. The mechanisms for such an effective “self-resuscitation” soon after birth are not completely understood. Traditional explanations based on Starling forces and vaginal squeeze for fluid clearance account only for a fraction of the fluid absorbed.

Risk Factors

This condition is classically seen in infants delivered late preterm/early term, especially after cesarean birth before the onset of spontaneous labor. Absence of labor is accompanied by impaired surge of endogenous steroids and catecholamines necessary for a successful transition. Additional risk factors such as multiple gestations, excessive maternal sedation, prolonged labor, and complications resulting from excessive maternal fluid administration have been less consistently observed.

Clinical Presentation

The clinical features of TTN include a combination of grunting, tachypnea, nasal flaring, and mild intercostal and subcostal retractions along with mild central cyanosis. The grunting can be prominent and sometimes misdiagnosed as respiratory distress syndrome secondary to surfactant deficiency. The chest x-ray usually shows prominent perihilar streaking that represents engorged pulmonary lymphatics and blood vessels. The presence of fluid in the fissures is a common nonspecific finding. Clinical symptoms rapidly improve in the first 24–48 hours after birth. TTN is a diagnosis of exclusion, and it is important that other potential causes of respiratory distress in the newborn be excluded. The differential diagnosis of TTN includes pneumonia/sepsis, air leaks, surfactant deficiency, and congenital heart disease. Other rare diagnoses are pulmonary hypertension, meconium aspiration, and polycythemia.

Diagnosis

This is primarily a clinical diagnosis. Chest x-rays typically demonstrate mild pulmonary congestion, with hazy lung fields. The pulmonary vasculature may be prominent. Small accumulations of extrapleural fluid, especially in the minor fissure on the right side, may be seen. Ultrasound of the lung is increasingly used to diagnose TTN.

Management

Prenatal prevention strategies include antenatal betamethasone prior to late preterm infant birth and elective cesarean birth between 37 and 39 weeks. This intervention decreases all common causes of neonatal respiratory morbidities; however, potential long-term adverse effects of this intervention need to be closely monitored. ^, Current American Academy of Pediatrics (AAP) guidelines recommending scheduling of elective cesarean births after 39 completed weeks of gestation should significantly reduce the incidence of TTN. Postnatal management is mainly supportive. Supplemental oxygen is provided to keep the O ₂ saturations greater than 90%. Infants are usually given IV fluids and not fed orally until their tachypnea resolves. Rarely, infants may need continuous positive airway pressure to relieve symptoms. Diuretic therapy is not effective; fluid restriction and inhaled beta-agonists (salbutamol) have been tried with limited success. ^,

Neonatal Implications

TTN can contribute to significant morbidity related to delayed initiation of oral feeding, which may in turn interfere with parental bonding and establishment of successful breastfeeding. The hospital stay is prolonged for mother and infant. Recently, studies have found an association between TTN and wheezing/asthma in later childhood ( Fig. 73.2 ).

Perinatal Risk Factors

The classic risk factors for RDS are prematurity and low birth weight. In 2017, according to Vermont Oxford Network the incidence of RDS was around 80% at 28 weeks increasing up to 90% at 24 weeks. Factors that negatively affect surfactant synthesis include maternal diabetes, perinatal asphyxia, cesarean delivery without labor, and genetic factors (Caucasian race, history of RDS in siblings, male sex, and surfactant protein B deficiency). Congenital malformations that lead to lung hypoplasia such as CDH or giant omphalocele are also associated with significant surfactant deficiency.

Prenatal Assessment of Fetal Lung Maturity and Treatment

The need for assessing fetal lung maturity was considered critical in timing delivery of high-risk pregnancies to minimize respiratory morbidity associated with immature lungs. There were a number of biochemical, functional, and physical lung maturity tests performed on amniotic fluid obtained by amniocentesis or from pooled vaginal secretions after rupture of the membranes; however, none of them individually or collectively had a clinically significant sensitivity or specificity to detect lung maturity. The most widely used tests were lamellar body count (LBC), the L/S ratio, and PG test (phosphatidylglycerol). The less commonly used tests were surfactant/albumin ratio (TDx FLM), foam stability test, and lung profile. Studies found that neonates delivered late preterm despite mature fetal lung testing were at increased risk for RDS, hyperbilirubinemia, and hypoglycemia; hence, recent American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM) guidelines cite the unreliability of these tests and advised clinicians to discontinue the practice of performing routine amniocentesis for fetal lung maturity testing in suboptimally dated and medically indicated or nonmedically indicated early deliveries. ^,

Quantitative ultrasound (quantusFLM) is a new technique increasingly used to detect fetal lung texture to predict lung maturity. The fetal lung is visualized at the level of the four-chamber cardiac view and images uploaded to a cloud-based database where it is quickly analyzed, and results are transmitted back. This technique has been validated in a large prospective multicenter study to have reliable (reproducible) and accurate results comparable to prior invasive methods. Magnetic resonance imaging and MRI spectroscopy are being investigated to measure lipid content of amniotic fluid but not clinically used due to high cost and maternal discomfort while obtaining images.

Antenatal steroids (ANS) are the most effective prenatal intervention to mature fetal lungs and reduce associated neonatal morbidity and mortality. The most popular treatment is to use a 1:1 mixture of betamethasone phosphate and betamethasone acetate (Celestone) in pregnant women between 24 and 34 weeks’ gestation with a high risk for preterm delivery within 7 days. A single rescue course is recommended for threatened preterm birth if >7 days after a previous full course of steroids. The use of ANS has now expanded to threatened late preterm births (34–37 weeks) and to elective cesarean delivery without labor at term to reduce respiratory morbidity. Betamethasone and dexamethasone have been compared in well-designed large trials and found to be equally effective with no difference in neurosensory impairment at 2 years. ^,

More recently, potential long-term adverse effects of ANS have been shown in both animals and human epidemiological studies. Large cohort studies from Finland and Canada have shown an increase in behavioral-emotional and psychological development effects, anxiety, and depression in long-term follow-up studies of infants who received ANS. To reduce ANS exposure, investigations are currently ongoing to examine a lower dose of betamethasone (full dose versus half dose) and to evaluate betamethasone acetate alone to reduce the peak concentrations obtained when combined with betamethasone phosphate.

Clinical Presentation of RDS

Symptoms are typically evident in the delivery room, or shortly thereafter, including tachypnea, nasal flaring, subcostal and intercostal retractions, cyanosis, and expiratory grunting. The characteristic expiratory grunt is secondary to expiration through a partially closed glottis, providing continuous distending airway pressure to maintain functional residual capacity (thereby preventing alveolar collapse). These signs of respiratory difficulty are not specific to RDS and can occur from a variety of pulmonary and nonpulmonary causes such as transient tachypnea, air leaks, congenital malformations, hypothermia, hypoglycemia, anemia, polycythemia, or metabolic acidosis. Progressive worsening of symptoms in the first 2–3 days followed by recovery characterizes the typical clinical course. This timeline (curve) is modified by administration of exogenous surfactant with a more rapid recovery. Classic radiographic findings include low-volume lungs with a diffuse reticulo-granular pattern and air bronchograms. Point-of-care lung ultrasound is being increasingly used in Europe to diagnose and determine severity of RDS. ^, The diagnosis can be established chemically by measuring surfactant activity in tracheal or gastric aspirates, but this is not routinely done. ^,

Management Principles

Complications of RDS

Acute complications include pneumothorax, pneumomediastinum, pneumopericardium, and pulmonary interstitial emphysema. The incidence of these complications has decreased significantly with surfactant treatment. Infection, intracranial hemorrhage, and patent ductus arteriosus occur more frequently in very-low-birth-weight infants with RDS. Long-term complications and comorbidities include BPD, poor neurodevelopmental outcomes, and retinopathy of prematurity. Incidence of these complications is inversely related to decreasing birth weight and gestation. Studies of early inhaled nitric oxide and supplementary inositol for prevention of long-term BPD failed to demonstrate significant effectiveness. ^,

Pathophysiology

Risk factors predisposing preterm infants to BPD include extreme prematurity, oxygen toxicity, mechanical ventilation, and inflammation (prenatal and postnatal). The pathological findings characterized by severe airway injury and fibrosis in the old BPD have been replaced in the new BPD with large simplified alveolar structures, impaired capillary configuration, and variable degrees of interstitial cellularity and/or fibroproliferation. Airway and vascular abnormalities tend to be associated with more severe disease.

Oxygen-induced lung injury is an important contributing factor. Exposure to oxygen in the first two weeks of life and as chronic therapy has been associated in clinical studies with the severity of BPD. ^, Similarly, in animal models, hyperoxia has been shown to mimic many of the pathological findings of BPD. As there are potential benefits and harm of hyperoxemia and hypoxemia, effects of targeting two different saturation ranges from birth have been studied in multiple clinical trials. Meta-analysis revealed no difference in BPD rates; however, assignment to a higher target range reduced the risk of death and severe necrotizing enterocolitis but increased the risk of treated retinopathy.

Concerns regarding oxygen toxicity are reflected in the most recent update of the neonatal resuscitation guidelines. Blended oxygen (30%) or, if not available, room air is now recommended for initial resuscitation of preterm infants in the delivery room, along with continuous monitoring via pulse oximetry.

Barotrauma and volutrauma associated with mechanical ventilation have been identified as major factors causing lung injury in preterm infants. Surfactant replacement therapy is beneficial in decreasing symptoms of RDS and improving survival. The efficacy of surfactant to decrease the incidence of subsequent BPD is less well established. Chronic inflammation and edema associated with positive-pressure ventilation cause surfactant protein inactivation leading to decreased lung compliance and need for higher positive pressures. Newer ventilation strategies have been developed to reduce lung injury and optimize repair and lung growth. As intrauterine inflammation is increasingly recognized as a cause of preterm parturition, antenatal inflammation is gaining more attention in the pathogenesis of BPD and other morbidities of prematurity. Chorioamnionitis has been shown to be strongly associated with impaired pulmonary and vascular growth, a typical finding in the new BPD.

Most deliveries before 30 weeks’ gestation are associated with histological chorioamnionitis, which except for preterm initiation of labor is otherwise clinically silent. The more preterm the delivery, the more often histological chorioamnionitis is detected. Increased levels of proinflammatory mediators in amniotic fluid, placental tissues, tracheal aspirates, lung, and serum of extremely-low-birth-weight preterm infants support an important role for both intrauterine and extrauterine inflammation in the development and severity of BPD. The proposed interaction between the proinflammatory and antiinflammatory influences on the developing fetal and preterm lung is detailed in Fig. 73.3 . Several animal models and preterm studies demonstrate that mediators of inflammation including endotoxins, tumor necrosis factor, interleukin (IL)-1, IL-6, IL-8, and transforming growth factor alpha can enhance lung maturation but concurrently impede alveolar septation and vasculogenesis, contributing to the development of BPD. Chorioamnionitis alone is associated with BPD, but the probability is increased when these babies receive a second insult such as mechanical ventilation or postnatal infection. ^{, , ,}

Maternal genital mycoplasma infection, particularly with M ycoplasma hominus and U reaplasma urealyticum , is associated with preterm delivery and BPD. The pulmonary microbiome is emerging as an important factor in the pathophysiology of BPD as studies reveal differences in airway microbiome in preterm infants with and without BPD. Numerous studies have isolated these organisms from amniotic fluid and placentas in women with spontaneous preterm birth (preterm birth due to preterm labor or pPROM). Following birth, these organisms are known to colonize and elicit a proinflammatory response in the respiratory tract leading to BPD. Preliminary evidence suggests azithromycin therapy in preterm infants colonized with ureaplasma reduces a combined outcome of BPD and death. Additional, more rigorous study is needed before broadly recommending this as an established practice.

The unpredictable variation in the incidence of BPD, despite adjusting for low birth weight and prematurity, suggests a genetic predisposition to the occurrence and the severity of BPD. Expression of genes critical to surfactant synthesis, vascular development, and inflammatory regulation are likely to play a role in the pathogenesis of BPD. Twin studies have recently shown that the BPD status of one twin, even after correcting for contributing factors, is a highly significant predictor of BPD in the second twin. In this cohort, after controlling for covariates, genetic factors accounted for 53% of the variance in the liability for BPD. Genetic polymorphisms in the inflammatory response are increasingly recognized as important in the pathogenesis of preterm parturition (see Chapter 7 ) and may be similarly important in the genesis of inflammatory morbidities in the preterm neonate as well.