NICU

NEONATAL ABSTINENCE SYNDROME Pharmacologic

Indicated for moderate to severe symptoms; only known benefit is short-term relief of signs and symptoms; NAS is self-limited.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Treatment

Maintain systemic blood pressure to overcome right-to-left shunt and decrease pulmonary vas- cular resistance to facilitate oxygenation.

Examples of Drugs That Are Contraindicated in Lactation

1. Antineoplastic agents 2. Retinoids 3. Tetracyclines: Chronic use 4. Chloramphenicol 5. Amiodarone

PATENT DUCTUS ARTERIOSUS Complications

"Ductal steal" results in a left-to-right shunt of blood that reduces blood flow to some major organs (e.g., poor kidney perfusion can result in elevated serum creatinine/acute kidney injury) and increases pulmonary blood flow excessively. Hypotension, pulmonary hemorrhage, NEC, IVH, pulmonary edema, prolonged need for mechan- ical ventilation, BPD, and heart failure are associated with the failure of ductal closure.

NECROTIZING ENTEROCOLITIS Antibiotics

The goals are to prevent ongoing GI mucosal injury, prevent translocation of enteric bacteria into the bloodstream, and reduce mortality. Common pathogens (a) Blood cultures are positive in only around 30% of neonates with NEC. (b) Enterobacteriaceae (e.g., E. coli, Klebsiella spp., and Enterobacter spp.) are the most com- mon causative organisms. (c) Staphylococcus epidermidis, Enterococcus spp., Staphylococcus aureus, Clostridium perfringens, Pseudomonas aeruginosa, and Salmonella have also been isolated from neo- nates with NEC. Possible regimens (a) There is no evidence to support the superiority of one regimen to the others. (1) Lack of well-designed studies evaluating antibiotic regimens for NEC (2) Most recent Cochrane review included only two trials from the 1980s that compared ampicillin plus gentamicin with the same regimen plus clindamycin or the same reg- imen plus enteral gentamicin. (b) Gram-positive coverage can be provided by ampicillin or vancomycin. (c) Gram-negative coverage can be provided by an aminoglycoside or a third-, or fourth- generation cephalosporin. (d) Anaerobic coverage (e.g., clindamycin, metronidazole) is added if there is evidence of bowel perforation or peritonitis (i.e., surgical NEC). Some institutions routinely add anaerobic coverage for all cases of NEC. (1) Mortality benefit of adding anaerobic coverage in medical NEC has not been shown. (2) Neonates randomized to receive ampicillin plus gentamicin and clindamycin had a statistically higher risk of strictures than those who received ampicillin plus genta- micin alone. (e) The specific antimicrobial agents used should be based on an individual unit's antibiogram. (f) Optimal duration is not known; in clinical practice, duration is generally based on Bell's staging. (1) Bell's stage I: Often 48-72 hours, "rule out" NEC (2) Bell's stage IIa: 7-10 days (3) Bell's stages IIb and III: 10-14 days

PATENT DUCTUS ARTERIOSUS Repeat courses

a. Response rate after a second course of indomethacin or ibuprofen is around 40%. b. Lowest rates of closure occur in the most premature neonates. c. It is unknown whether several courses of indomethacin/ibuprofen increase the risk of adverse effects.

NECROTIZING ENTEROCOLITIS Supportive care

i. Intravenous fluids/parenteral nutrition (a) Third spacing often increases fluid requirements to 1.5 times maintenance amounts. (b) Fluid loss from gastric output requires intravenous fluid replacement. ii. Vasopressors

APNEA OF PREMATURITY

An immature central respiratory drive, inability to maintain airway patency, and underdeveloped respi- ratory muscles cause hypoventilation resulting in apneic and cyanotic spells. Types Central: Reduced sensitivity to hypercarbia of the central respiratory center results in a lack of respiratory effort. Obstructive: A respiratory effort exists, as evidenced by chest wall movement, but the inability to maintain upper airway (i.e., larynx and pharynx) patency results in obstruction of airflow. Mixed: The most common type of apnea of prematurity, a combination of central and obstructive apnea

A 2500-g boy is born at 35 weeks' gestational age to a mother whose hepatitis B surface antigen (HBsAg) status is unknown. Which is the best recommenda- tion regarding postexposure prophylaxis for this neonate? a. Give the hepatitis B vaccine within 12 hours of birth; administer hepatitis B immune globulin (HBIG) within 7 days if the maternal HBsAg is positive. b. Give the hepatitis B vaccine and HBIG within 12 hours of life. c. Give the hepatitis B vaccine birth dose; HBIG is not indicated. d. Wait for the results of the maternal HBsAg test before giving the hepatitis B vaccine or HBIG.

Answer: A According to AAP recommendations, a neonate with a birth weight of at least 2000 g who is born to a mother with an unknown HBsAg status should receive the hep- atitis B vaccine within 12 hours of birth. Administration of HBIG can be delayed for up to 7 days after birth, awaiting the mother's test results (Answer A is correct). If, at that time, the mother's status is still unknown or is positive, HBIG should be administered (Answers C and D are incorrect). Administration of both agents within 12 hours of birth is recommended if the mother's HBsAg is positive or for neonates with a birth weight less than 2000 g who are born to mothers whose HBsAg status is unknown (Answer B is incorrect).

You are working with the neonatologists in your unit to develop a treatment protocol for NEC. Which organism is most important to cover with your recommended empiric antibiotic regimen? a. Candida albicans. b. Escherichia coli. c. Group B Streptococcus. d. Listeria monocytogenes.

Answer: B Group B Streptococcus, E. coli, and Listeria are all common pathogens causing early neonatal sepsis (Answer B is correct; Answers C and D are incorrect). C. albicans can cause late-onset neonatal sepsis, espe- cially in neonates with specific risk factors (e.g., history of abdominal surgery, long-term total parenteral nutri- tion, Candida colonization of several sites) (Answer A is incorrect). However, because E. coli is most likely to be associated with NEC, it should be covered by an empiric antibiotic regimen—most commonly with an aminoglycoside or a third- or fourth-generation cephalosporin.

DRUGS IN PREGNANCY AND LACTATION Teratogenesis

Clinical perspective: The risk of major malformations in the general population, with or without drug therapy, is about 2%-3%. Teratogenicity results from in utero exposure to a drug(s) or substance associated with irreversible structural abnormalities or functional damage. a. Can cause embryopathy or fetopathy. b. Highest risk of structural abnormalities occurs from 5 to 10 weeks' gestation; organogenesis occurs during this "embryonic" period. c. Fetotoxicity can occur any time between the late first trimester and birth. d. Teratogenicity can also occur when the male partner, rather than the mother, is taking the offending drug. Common teratogenic effects: Neural tube defects, congenital heart defects, cleft lip/palate, stillbirth

CONGENITALLY ACQUIRED INFECTIONS Herpes Simplex Virus (HSV) - Presentation

Disseminated disease: Involves several organ systems, especially the lungs and liver; may involve the CNS. i. Around 25% of neonatal HSV cases ii. Around 60% will have skin lesions. iii. Typically presents within 1-2 weeks after birth. Should be suspected in a septic-appearing neonate with negative bacteriologic cultures and severe liver dysfunction. Localized CNS disease i. 30% of neonatal HSV cases ii. Around 66% will have skin lesions. iii. Presentation may be later, between 2 and 3 weeks after birth. Suspect especially if onset of seizures is 2 weeks or more after birth. Localized skin, eyes, and mouth (SEM) disease i. 45% of neonatal HSV cases ii. Most (more than 80%) will have skin vesicles. iii. Typically presents within 1-2 weeks after birth. Associated with high morbidity and mortality rates, despite appropriate antiviral treatment.

BRONCHOPULMONARY DYSPLASIA Clinical Presentation

Tachypnea, retractions, shallow breathing, wheezing, increased oxygen requirement, and broncho- spasm may be present. Chest radiograph typically appears diffusely hazy with areas of lung hyperinflation and hypoinflation (i.e., "patchy atelectasis").

Examples of Drugs Known to Be Teratogens

Warfarin: Skeletal defects if exposed in the first trimester; CNS defects, mental retardation, and micro- hemorrhages if exposed in second or third trimester. Valproic acid: Neural tube defects; craniofacial, limb, cardiac and CNS abnormalities Phenytoin: Fetal hydantoin syndrome can include craniofacial abnormalities, hypoplasia of the nails, cleft lip/palate, microcephaly, developmental delay. Methotrexate: Embryopathy with many malformations Nonsteroidal anti-inflammatory drugs: Cardiac malformations and gastroschisis if exposed during the first trimester; premature closure of the ductus arteriosus in a fetus if exposed during the third trimester. Angiotensin-converting enzyme inhibitors: Cardiac malformations if exposed during the first trimes- ter; renal failure if exposed in the second or third trimester. Tetracycline: Staining of teeth if exposed in second or third trimester.

RESPIRATORY DISTRESS SYNDROME Antenatal corticosteroid

i. Betamethasone 12 mg intramuscularly every 24 hours for two doses administered to women in preterm labor (between 24 and 34 weeks' gestation) (a) Delivery should be delayed for at least 24 hours for improved response; benefit lasts up to 7 days. (b) Dexamethasone 6 mg intramuscularly every 12 hours for four doses is an alternative regimen. (c) If preterm delivery is delayed, the benefit of repeated courses is controversial. Promotes fetal lung maturation and surfactant production Significantly reduces mortality and incidence of RDS; effect is additive with surfactant therapy.

NEONATAL ABSTINENCE SYNDROME Clonidine

i. Central α2-adrenergic receptor agonist ii. Thought to reduce symptoms of autonomic overactivity by decreasing central catecholamine release. iii. When used in combination with morphine, shown to reduce total morphine dose and shorten treatment duration and length of stay. No significant hypotension or bradycardia reported. Requires extemporaneous preparation of an oral solution.

NEONATAL ABSTINENCE SYNDROME Phenobarbital

i. Prolonged half-life (67-115 hours) ii. May be most beneficial as an adjunctive therapy in polysubstance exposure or non-opioid withdrawal. iii. Not as effective as an opiate agent for monotherapy of opioid withdrawal; does not improve GI symptoms or prevent seizures. iv. Concerns about detrimental neurodevelopmental effects exist.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Inhaled nitric oxide

i. Treatment of choice; provides selective vasodilation of the pulmonary circulation. ii. Initiated at 20 ppm; gradual weaning of the dose before discontinuation is necessary to mini- mize the risk of rebound pulmonary hypertension. (a) Sildenafil: A single dose, 0.4 mg/kg, of enteral sildenafil given when inhaled nitric oxide has been weaned to 2 ppm was shown to prevent rebound pulmonary hypertension on inhaled nitric oxide discontinuation. (b) The use of agents other than sildenafil to facilitate weaning of inhaled nitric oxide has not been studied.

NECROTIZING ENTEROCOLITIS Clinical Presentation

1. Often non-specific signs, including apnea, bradycardia, lethargy, temperature instability 2. GI signs include feeding intolerance (e.g., gastric residuals or emesis), abdominal distension, bloody stool, discoloration of abdominal wall. 3. Radiologic findings include dilated loops of bowel, pneumatosis intestinalis (hallmark sign of NEC), portal venous gas, and pneumoperitoneum (indicates intestinal perforation). 4. Mortality is high (up to 30% overall), especially with fulminant NEC (more than 90%). In survivors, significant GI morbidities occur, including intestinal failure (e.g., short bowel syn- drome) leading to nutrient malabsorption and failure to thrive, stricture formation, and complica- tions of long-term parenteral nutrition, including cholestasis and liver failure. Survivors also have significant neurologic complications, including neurodevelopmental delay and cerebral palsy. 5. Modified Bell's staging criteria

BRONCHOPULMONARY DYSPLASIA

1. Also known as chronic lung disease 2. Significant risk of mortality and long-term morbidity 3. Definition: "Old" versus "new" BPD a. Originally described by Northway in 1967; mean gestational age of the study cohort was 33 weeks with a birth weight of 1600 g.i. "Old BPD": Oxygen dependence for longer than 28 days in the presence of characteristic chest radiograph findings ii. Radiographic findings: Heterogeneous pattern of small airway obstruction, emphysema, atel- ectasis, hyperinflation and cystic disease b. In 1999, Jobe described the "new BPD" in a cohort of neonates with a mean gestational age of 27 weeks and birth weight less than 1000 g.i. "New BPD": Initially described as the need for supplemental oxygen at or beyond 36 weeks' postmenstrual age; broken down into 3 classifications. (a) Mild: Period of oxygen requirement of at least 28 days, but on room air by 36 weeks' postmenstrual age (b) Moderate: Continued oxygen requirement with a fraction of inspired oxygen (FiO2) less than 30% (c) Severe: Continued oxygen requirement with an FiO2 of at least 30% or any form of posi- tive pressure ventilation or CPAP pressure ii. Radiographic findings: Homogeneous, diffuse lung parenchymal disease with fewer and larger alveolar spaces, decreased vascularization, and decreased surface area 4. Risk factors a. Premature birth b. Very low (less than 1500 g) and especially extremely low (less than 1000 g) birth weight c. Invasive mechanical ventilation resulting in barotrauma and volutrauma d. Others including chorioamnionitis, airway colonization with Ureaplasma urealyticum, pulmonary edema, persistent patent ductus arteriosus, poor nutrition

RESPIRATORY DISTRESS SYNDROME

1. Common cause of neonatal morbidity and mortality before the development of exogenous surfactant 2. Immaturity of type II alveolar cells results in endogenous surfactant deficiency. a. Surfactant deficiency increases alveolar surface tension and decreases lung compliance. b. Atelectasis causes pulmonary vasoconstriction, impaired gas exchange, and ischemia of lung tis- sue. The resulting lung epithelial sloughing and edema forms hyaline membranes. c. Surfactant synthesis and storage begins at about 16 weeks' gestation. Secretion of surfactant in the fetus begins later, at 30-32 weeks' gestation, and is stimulated by endogenous cortisol. By 34-36 weeks' gestation, adequate amounts of endogenous surfactant are produced to sup- port normal lung function. 3. Components of endogenous surfactant a. Phosphatidylcholine (70%) b. Surfactant proteins (SP) (8%) SP-B and SP-C facilitate adsorption and spread of phospholipids at the air/fluid interface within the alveoli, thus preventing collapse during expiration. SP-A stimulates host defense and enhances recycling of surfactant. SP-D is thought to stimulate host defense mechanisms. c. Natural lipids (8%), phospholipids (6%), and phosphatidylglycerol (8%) d. Phosphatidylcholine, SP-B, and SP-C are most crucial for surfactant function.

PATENT DUCTUS ARTERIOSUS Prevention

1. Indomethacin Regimen: 0.1 mg/kg/dose intravenously every 24 hours for three doses given within 6-12 hours of birth to neonates with birth weights less than 1000-1250 g Shown to reduce the incidence of symptomatic PDA. Not shown to increase survival or reduce long-term neurodevelopmental disability. May result in unnecessary exposure to indomethacin as up to 60% of PDAs present within 1 day of birth will close spontaneously. 2. Ibuprofen and acetaminophen have not been well studied for prevention of PDA.

Strategies for Minimizing Exposure

1. Pregnancy Counseling regarding teratogenic potential in any woman (or man) of childbearing potential i. About 50% of pregnancies in the United States are unintended.ii. Some medications require routine pregnancy testing before prescribing (e.g., bosentan). Planning for alternative, "safer" therapies before pregnancy occurs 2. Lactation a. "Pump and dump" is rarely the best solution. b. Try to breastfeed when maternal plasma concentrations are likely to be low: Difficult to do when the infant feeds every 3-4 hours. c. When possible, choose a drug with a short half-life.d. When possible, choose a drug that is highly protein bound.

CONGENITALLY ACQUIRED INFECTIONS Hepatitis B Virus

1. Presentation Most neonates with perinatally acquired hepatitis B virus are asymptomatic; some may have signs of hepatitis. Long-term complications include hepatocellular carcinoma and cirrhosis. 2. Treatment a. There is no treatment for acute hepatitis B infection.b. The risk of developing hepatitis B infection can be reduced by postexposure prophylaxis. If the mother is positive for HBsAg, the neonate should receive hepatitis B vaccine and HBIG within 12 hours of birth. If the mother's HBsAg status is unknown at delivery, she should be tested immediately AND the neonate should receive the hepatitis B vaccine within 12 hours of birth. If the mother's HBsAg is positive, HBIG should be administered to the neonate within 7 days of birth. (a) Preterm neonates with a birth weight less than 2 kg born to mothers whose HBsAg status is unknown should receive the hepatitis B vaccine within 12 hours of birth. If the mother's HBsAg status remains unknown at 12 hours after birth, the neonate should also receive HBIG within 12 hours of birth. (b) In this circumstance, the hepatitis B vaccine given to the preterm neonate should not be counted toward completion of the routine vaccine series.

CONGENITALLY ACQUIRED INFECTIONS Toxoplasmosis

1. Presentation a. Death often results if transmission occurs in the first trimester. b. "Classic triad" of hydrocephalus, intracranial calcifications, and chorioretinitis may occur if trans- mission occurs during the second trimester. c. Other complications include hepatosplenomegaly, developmental delay, hearing loss, and seizures. 2. Treatment a. Pyrimethamine plus sulfadiazine plus leucovorin for 1 year b. Optimal dosing regimen is not known.

INTRAVENTRICULAR HEMORRHAGE Clinical Presentation

1. Symptoms a. Often asymptomatic: Up to 50% of cases b. Symptoms may include rapid decline in hematocrit, acidosis, hypo- or hyperglycemia, bulging fontanel, altered consciousness, seizures, and cardiorespiratory deterioration. Diagnosed by cranial ultrasonography a. 50% occur on the first day of life. b. 90% occur within the first 4 days of life. Risk factors a. Birth weight: Lower birth weights correlate with a higher incidence of IVH. b. Premature birth

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Clinical Presentation

1. Symptoms: Evidence of respiratory distress, tachypnea, oxygen desaturation, cyanosis 2. Oxygenation index (OI): Used as an indication of disease severity. a. Relatively mild: OI of 15-25 b. Moderate: OI of 25-40c. Severe: OI greater than 40 3. OI = (mean airway pressure x FiO2 x 100)/PaO2 4. ECHO findings: Right-to-left shunt across the ductus arteriosus or foramen ovale, tricuspid valve regurgitation as a result of elevated pulmonary vascular pressure, and right ventricular hypertrophy.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Targeted therapies:

: Overall lack of well-designed studies of the neonatal population; therefore, no vali- dated treatment algorithm or clear roles for the various drug classes The treatment duration is relatively short (3-10 days) for PPHN, although neonates with underlying structural changes (e.g., BPD) may require prolonged therapy.

When comparing the literature evaluating the effi- cacy of various treatments for patent ductus arte- riosus (PDA), you find a case series of 10 patients treated with acetaminophen at an average age of 10 days and a retrospective study of 160 patients treated with indomethacin at an average age of 11 days. The reported closure rates after the first course of therapy were 100% with acetaminophen and 72% with indomethacin. Which best explains the disparity in closure rates between the two therapies? a. Heterogeneity between the two study populations. b. Inadequate statistical power. c. Publication bias. d. Superior efficacy of acetaminophen.

Answer: C Case reports and case series are known to be subject to publication bias because of the desire to report positive results and to be less likely to report inconclusive or negative results, thus, a case series reporting the 100% efficacy of acetaminophen for PDA closure (Answer C is correct). Heterogeneity between comparator groups can also lead to disparate results; however, in this example, it is not the most likely cause because most neonates treated for PDA are premature, the timing of the treatments was similar in the two publications, and both publications examined the efficacy of a first course of treatment—all major factors that could confound the results if they differed between the groups (Answer A is incorrect). An inadequate statistical power results in the failure to find a difference between treatments when a difference actually exists and often results from an inadequate sample size. This concept applies to a single study comparing two or more treatment groups, but it cannot be applied when comparing results from different studies (Answer B is incorrect). Superiority of one treatment to another can be concluded only from head-to-head comparison studies designed to detect this difference. Superiority cannot be proved in studies designed to find noninferiority, nor can it be concluded from comparing the results of separate publications (Answer D is incorrect).

The patient in cases 1-3 is now 37-3/7 weeks' postmenstrual age. After prolonged intubation and mechanical ventilation, he was extubated 10 days ago to nasal CPAP with 21% oxygen. He has received caffeine since shortly after birth but has had no apneic spells since extubation. Which is the best recommendation regarding his methylxanthine therapy? a. Discontinue caffeine, and monitor the patient for apnea recurrence. b. Taper the caffeine dose over the next 2 weeks, and discontinue it if no apnea occurs during the taper. c. Switch to theophylline because its shorter half-life will allow for a faster wean off therapy. d. Continue caffeine until discharge, and then plan to taper off over several weeks as an outpatient.

Answer: A Apnea of prematurity typically resolves by 34-36 weeks' postmenstrual age. Most institutions would not discharge an infant home on methylxanthines if he were still having apnea because the risk of sudden infant death, in the absence of a well-established home mon- itoring program, is a concern. If apnea has resolved, continuing methylxanthine therapy as an outpatient exposes the infant to possible adverse effects without benefit (Answer D is incorrect). Because this patient has been apnea free since extubation and is older than 36 weeks' postmenstrual age, methylxanthine therapy can be discontinued (Answer A is correct). There is no need to taper caffeine (Answer B is incorrect). Because caf- feine has a long half-life, the infant should be monitored for 5-7 days to ensure that he remains apnea free after the drug has been sufficiently cleared from the body. Switching to theophylline offers no advantages; rather, it has several disadvantages, most notably a narrower therapeutic index, which increases the risk of adverse effects and necessitates the monitoring of serum drug concentrations (Answer C is incorrect).

A 750-g girl born at 26 weeks' gestational age was initiated on caffeine citrate for the prevention of apnea of prematurity. Initially, an intravenous load- ing dose of 20 mg/kg/dose was given, followed by a maintenance dose of 8 mg/kg/dose every 24 hours. One week later, the neonate is having more epi- sodes of apnea. Other causes of apnea (e.g., sepsis) were ruled out, so the caffeine maintenance dose was increased to 10 mg/kg/dose every 24 hours. The physician is concerned about potential toxicity because the dose is at the higher end of the recom- mended range. Which monitoring value would be most indicative of caffeine toxicity? a. Heart rate. b. Renal function. c. Serum concentration. d. Signs of gastroesophageal reflux.

Answer: A Tachycardia is a well-known adverse effect of both the- ophylline and caffeine therapy (Answer A is correct). Unlike theophylline, caffeine has a wide therapeutic range, and serum concentrations have not been shown to correlate well with efficacy or toxicity. Therefore, rou- tine monitoring of caffeine serum concentrations is not recommended (Answer C is incorrect). Methylxanthine therapy has been associated with decreased lower esophageal sphincter tone, which, some investigators have theorized, increases episodes of gastroesophageal reflux. However, a causative relationship has not been clearly defined, and the more likely cause of reflux epi- sodes in a preterm neonate is immaturity of the lower esophageal sphincter and poor GI motility (Answer D is incorrect). Physiologic gastroesophageal reflux is com- mon in this patient population. Methylxanthine therapy is not known to be nephrotoxic (Answer B is incorrect).

A 2600-g girl was born at 36 weeks' gestational age to a mother in a methadone treatment program for heroin addiction. The mother has received methadone 80 mg daily for the past 7 months and has been adherent. The neonate is admitted to the NICU for initial respiratory distress in the delivery room and for monitoring of withdrawal symptoms. Finnegan scores have been assessed every 4 hours since birth, and the nurse indicates that she has been crying "a lot" and is very "irritable." Scores for the first 24 hours are 4, 6, 5, 8, 7, and 8. Which is the best recommendation for the treatment of this neonate at risk of abstinence syndrome? a. No pharmacologic intervention for withdrawal is currently indicated. b. Start clonidine. c. Start methadone. d. Start phenobarbital.

Answer: A This infant is at high risk of developing NAS because of in utero exposure to methadone. When using the Finnegan scoring tool to assess neonates at risk of with- drawal, three consecutive scores of 8 or higher or two consecutive scores of 12 or higher indicate the need for pharmacologic management of withdrawal (Answer A is correct). Lower scores may indicate mild withdrawal symptoms that should be managed with nonpharma- cologic interventions (e.g., swaddling; minimal han- dling; reduced environmental noise; subdued lighting; frequent, small feedings). Although this neonate is not currently showing severe signs of withdrawal requir- ing pharmacologic intervention, she should continue to be monitored because withdrawal from methadone typically manifests on days 2-6 of age (Answers B-D are incorrect). If severe withdrawal does occur, an opi- oid agent (e.g., morphine, methadone) is the treatment of choice. Clonidine is an effective adjunctive therapy with morphine. Phenobarbital is not as effective for monotherapy as an opioid agent because phenobarbital does not treat the GI symptoms or seizures.

A new drug for the treatment of hypertension was shown to be teratogenic in rat models, but there are no reports of its use in pregnant women. Which characteristic is most likely to allow the drug to cross the placental barrier into the fetal circulation? a. High molecular weight (greater than 500 Da). b. Hydrophilicity. c. Low protein binding. d. Long half-life.

Answer: C Drug characteristics associated with transport across the placenta include low molecular weight (less than 500 Da), lipophilicity, and low protein binding (Answer C is correct; Answers A and B are incorrect). A pro- longed half-life may increase the time during which the drug can cross the placenta but, without the other characteristics, does not alone promote drug transport across the placenta (Answer D is incorrect). Although transfer across the placenta does not necessarily pre- dict a drug's teratogenicity, it is required for the drug to cause fetal harm.

When benchmarking against similar NICUs, your unit finds a higher than average rate of necrotizing enterocolitis (NEC). The medical team would like to develop a protocol to standardize care of neo- nates at highest risk of developing NEC. Which intervention is most likely to be beneficial in reduc- ing the incidence of NEC in high-risk neonates? a. Initiate trophic feeding at 7 days of age. b. Administer oral probiotics until 34 weeks' postmenstrual age is reached. C. Administer oral antibiotics until full enteral feeding is achieved. D. Administer histamine-2 receptor antagonists until enteral feeds are initiated.

Answer: B Although oral probiotics are not considered the stan- dard of care for preventing NEC, many studies show their efficacy of doing so. The optimal duration is unknown, but a recent study showed a benefit in neo- nates receiving oral probiotics until 34 weeks' postmen- strual age (Answer B is correct). Other positive studies continued this intervention until the neonate reached term corrected age or until hospital discharge. Delaying enteral feeding has been theorized to reduce the inci- dence of NEC because it allows for the maturation of the GI tract, and cases of NEC rarely occur in neonates who have not been fed enterally. Overall, clinical stud- ies have not shown this benefit (Answer A is incor- rect). Administration of oral antibiotics has been shown to reduce NEC, but the benefit of this intervention is outweighed by the risk of colonization with resistant organisms, which is an outcome that has occurred in clinical trials (Answer C is incorrect). Administration of histamine-2 receptor antagonists has been associated with an increased incidence of NEC. Increasing the pH of the GI tract allows the overgrowth of bacteria, so this intervention should be avoided (Answer D is incorrect).

The patient in case 5 who was born at 26 weeks' gestational age was treated for a PDA with indomethacin at 12 days of age; a repeat ECHO confirmed closure. Trophic enteral feedings were discontinued when the PDA was diagnosed. Feedings were resumed at 14 days of age with 2 mL every 3 hours (20 mL/kg/day) of preterm formula at 24 kcal/oz. Feedings were advanced by 20 mL/kg every day. At 20 days of age, she developed abdominal distension, bloody stools, and temperature instability. Her feedings were discontinued. An urgent abdominal radiograph was ordered, which revealed dilated loops of bowel and pneumatosis intestinalis with evidence of free air. Which is the best antibiotic regimen to recommend? a. Ampicillin plus gentamicin b. Ampicillin plus gentamicin plus metronidazole c. Piperacillin/tazobactam plus metronidazole d. Vancomycin plus imipenem

Answer: B The bacterial pathogens associated with NEC include Enterobacteriaceae (e.g., E. coli, Klebsiella spp.), Enterococcus spp., Staphylococcus spp., Clostridium, and P. aeruginosa, among others. There is no evidence to support the superiority of one antibiotic regimen to others. Selection of the specific agents should be based on the most likely infecting organisms and the indi- vidual NICU's susceptibilities. Very broad-spectrum agents (e.g., imipenem) should be avoided unless sus- ceptibility patterns warrant their use (Answer D is incorrect). A combination of ampicillin and gentamicin lacks the necessary anaerobic coverage recommended for cases of NEC with intestinal perforation and/or peritonitis (Answer A is incorrect); however, adding metronidazole to this combination provides the nec- essary antibacterial coverage (Answer B is correct). Piperacillin/tazobactam provides anaerobic coverage, so adding metronidazole is unnecessary (Answer C is incorrect). Piperacillin/tazobactam is not generally rec- ommended as a first-line agent because its enterococcal coverage is not as good as that of ampicillin or vanco- mycin, and its extended gram-negative coverage may not be needed (unless dictated by an individual NICU's susceptibility patterns).

A 39 weeks' gestational age boy was born to a mother with a history of sickle cell disease treated with chronic hydrocodone plus acetaminophen. He is admitted to the NICU for monitoring for withdrawal symptoms. In the past 12 hours, his Finnegan scores are 10, 8, 9, and 11 (evaluated every 3 hours). Which recommendation would be best for managing this neonate? a. Initiate clonidine. b. Initiate morphine. c. Initiate phenobarbital. d. Treatment is not indicated because withdrawal symptoms are not severe enough

Answer: B Three consecutive scores using the Finnegan tool of 8 or higher or two consecutive scores of 12 or higher are indicative of the need for pharmacologic management of withdrawal (Answer D is incorrect). An opioid agent (e.g., morphine, methadone) is the treatment of choice for managing withdrawal symptoms from hydroco- done exposure (Answer B is correct). Clonidine is gen- erally reserved for adjunctive therapy with morphine (Answer A is incorrect). Phenobarbital monotherapy is not as effective as morphine or methadone for manag- ing opioid withdrawal because it does not treat the GI symptoms or prevent seizures (Answer C is incorrect). Phenobarbital is often used as first-line monotherapy for withdrawal from non-opioid agents.

The patient in case 1 had a modest response after two doses of surfactant, but he remains intubated and mechanically ventilated, requiring 30% oxygen 24 hours after birth. Because of his prematurity and con- tinued need for invasive respiratory support, the medical team would like to initiate a therapy to prevent the development of BPD. Which medication would be best to recommend? A. Azithromycin B. Caffeine C. Dexamethasone D. Poractant

Answer: B Very few interventions, other than preventing preterm birth, have been shown efficacious in preventing BPD. Several pharmacologic interventions theoreti- cally should prevent BPD, but clinical trials have not confirmed this benefit. Macrolide antibiotics (e.g., azithromycin) have been studied for the prevention of BPD because colonization with Ureaplasma in the neonate has been associated with the development of BPD. However, clinical trials did not show a reduced incidence of BPD when all high-risk neonates were given macrolide prophylaxis (Answer A is incorrect). A subset of neonates with a positive PCR result for Ureaplasma who were treated with azithromycin were shown to have lower rates of BPD, but this evidence is limited. Treatment of RDS with surfactant replacement therapy theoretically would prevent BPD; however, clinical trials have not shown this long-term benefit (Answer D is incorrect). Early dexamethasone therapy (within 96 hours of birth) has been shown to signifi- cantly decrease the incidence of BPD. Unfortunately, long-term follow-up studies showed an increased risk of cerebral palsy and developmental delay. Until further studies investigating lower doses and optimal timing of dexamethasone are completed, early use of systemic corticosteroids for the prevention of BPD should not be recommended (Answer C is incorrect). Caffeine ini- tiated within 3 days of age has been shown to reduce BPD without negative effects on neurodevelopmental outcomes (Answer B is correct).

A boy born at 42 weeks' gestational age has pulmo- nary hypertension secondary to meconium aspira- tion syndrome. Sedation, vasopressor therapy, and mechanical ventilation are initiated as supportive therapy. Which is the best initial intervention to lower his pulmonary pressures? a. Beractant. b. Epoprostenol. c. Inhaled nitric oxide. d. Vecuronium.

Answer: C Inhaled nitric oxide is the treatment of choice for PPHN (Answer C is correct). Beractant may be a reasonable adjunctive therapy because meconium aspiration can result in endogenous surfactant inactivation, but it is not a pulmonary vasodilator (Answer A is incorrect). Similarly, vecuronium may be added as supportive therapy if the patient does not respond adequately to sedation and pain management, but it will not pro- duce pulmonary vasodilation (Answer D is incorrect). Epoprostenol is a pulmonary vasodilator, but it is con- sidered an additive therapy if the response to nitric oxide is inadequate. Its more invasive route of admin- istration (i.e., intravenous vs. inhaled), risk of systemic hypotension, and relative lack of supporting literature compared with inhaled nitric oxide make epoprostenol a second-line therapy for PPHN (Answer B is incorrect).

A 3400-g girl is born by cesarean section at 37 weeks' gestational age to a mother with a history of genital HSV infection and visible genital lesions at delivery. The neonate appears well and begins feeding within a few hours after birth. Surface cultures for HSV are sent at 24 hours of age and are subsequently reported as positive. Intravenous acyclovir is initiated. Cerebrospinal fluid for HSV PCR and serum ALT are sent. The neonate remains asymptomatic. The HSV PCR is negative, and the ALT is 120 units/L (range 5-45 units/L). Which is the best recommendation regarding this patient's treatment? a. Discontinue acyclovir. b. Continue acyclovir 60 mg/kg/day intravenously in three divided doses to complete 14 days of treatment. c. Continue acyclovir 60 mg/kg/day intravenously in three divided doses to complete 21 days of treatment. d. Switch to oral acyclovir 300 mg/m2/dose every 8 hours to complete 10 days of treatment.

Answer: C The AAP has published a treatment algorithm for asymptomatic neonates born to mothers with visible genital HSV lesions. Because this neonate's surface cultures were positive for HSV, acyclovir cannot be discontinued (Answer A is incorrect). The neonate's CSF HSV PCR is negative, but her serum ALT is more than 2 times the upper limit of normal. This rules out CNS involvement but confirms disseminated disease. Therefore, she should receive therapy with intravenous acyclovir for proven disease. The recommended dura- tion for disseminated disease is a minimum of 21 days (Answer C is correct). If she had developed only skin lesions (SEM disease), she would be treated with intra- venous acyclovir for 14 days (Answer B is incorrect). Oral acyclovir is recommended for suppressive therapy after intravenous acyclovir treatment of SEM, CNS, or disseminated disease, but it is not indicated for the ini- tial treatment of HSV infection (Answer D is incorrect).

A 3900-g boy was born at 38 weeks' gestational age to a mother with a history of syphilis that was adequately treated 6 weeks before delivery. The mother has shown no signs of relapse or recurrence since treatment. Maternal syphilis rapid plasma reagin (RPR) is 1:16. In the delivery room, the neonate had some grunting and retractions. He was transferred to the NICU and initiated on ampicillin 100 mg/kg/dose intravenously every 8 hours and gen- tamicin 5 mg/kg/dose intravenously every 24 hours to rule out sepsis/pneumonia. Syphilis RPR was sent for the neonate, and the result was 1:16. The neonate's symptoms resolved within 6 hours after birth, and blood cultures remained negative at 48 hours. Which is the best recommendation regarding this patient's treatment? a. Continue ampicillin and gentamicin. No treatment is indicated for congenital syphilis. b. Discontinue gentamicin and continue ampicillin to complete 10 days for congenital syphilis. c. Discontinue ampicillin and gentamicin. Give benzathine penicillin G 50,000 units/kg intramuscularly x 1 dose for congenital syphilis. d. Discontinue ampicillin and gentamicin. Give aqueous penicillin G 50,000 units/kg/dose intravenously every 12 hours for 10 days for congenital syphilis.

Answer: C The AAP has published a treatment algorithm for neo- nates born to mothers with reactive serologic tests for syphilis. This neonate is at minimal risk of syphilis because the mother received adequate treatment (i.e., penicillin given more than 4 weeks before delivery), the neonate's RPR titer is not greater than 4-fold the moth- er's titer (i.e., it is the same), the mother shows no signs of relapse/reinfection, and the neonate is asymptomatic. However, because adequate maternal treatment can still result in failure to prevent congenitally acquired syphilis, treatment is indicated (Answer A is incorrect). According to the algorithm, aqueous penicillin G is the preferred treatment of syphilis, even if ampicillin was started initially for ruling out sepsis, because the efficacy of ampicillin for treating congenital syphilis is unknown (Answer B is incorrect). Benzathine penicil- lin G is the recommended treatment for neonates born to mothers treated with penicillin more than 4 weeks before delivery but during the pregnancy AND if the neonate has a normal physical examination and an RPR/ VDRL titer is the same as or less than 4-fold the moth- er's titer (Answer C is correct). Close follow-up should be ensured if a single-dose treatment option is used. Longer treatment durations (e.g., aqueous penicillin G x 10 days) are recommended if the neonate's RPR titer is greater than 4-fold the mother's titer or if the neo- nate's evaluation is abnormal (Answer D is incorrect). In this case, the neonate's initial respiratory symptoms most likely occurred because of transient tachypnea of the newborn, rather than sepsis or pneumonia, because they resolved quickly; this, in conjunction with blood cultures that are negative at 48 hours, makes it reason- able to discontinue ampicillin and gentamicin.

A 32-year-old woman is seen by her physician for symptoms of depression. She is 30 weeks pregnant and has not previously taken medication for her depression. She has chronic hypertension that is well controlled but no other significant medical history. Her current medications include a prenatal vitamin and methyldopa. The physician is considering three different drugs with which to treat her depression. Drug 1 is pregnancy category B. Drugs 2 and 3 are pregnancy category C. Which is the best assessment of the risk of these drugs when used in a pregnant woman? a. Drugs 2 and 3 have a higher risk of fetal harm than drug 1. b. Drugs 2 and 3 have the same level of risk (i.e., are equally as safe in pregnancy). c. Drugs 1, 2, and 3 may all be acceptable options for treating this mother's depression. d. This mother's depression should not be treated during pregnancy because the risks outweigh the benefit.

Answer: C The current FDA pregnancy categories do not provide a scale of risk (i.e., the risk of harm does not increase from category A to category X). These pregnancy categories only provide information on whether evi- dence that exposure to the drug during pregnancy, in animals and/or humans, has been associated with fetal harm (Answer A is incorrect). For example, the main difference between category B and category C is that animal studies have not shown fetal harm for drugs categorized as B, whereas animal studies have shown harm for drugs in category C. It is important to recog- nize that harm in animals does not always translate to the same effect in humans. Neither category contains information regarding the safety in pregnant humans. The current categories also do not consider the severity, treatability, or reversibility of fetal harm, so drugs in the same category can cause very different degrees of harm—what is the same within the category is the type of evidence supporting whether harm occurs (Answer B is incorrect). In addition, the pregnancy categories address only the potential risk to the fetus from drug exposure. They do not consider the risk to the fetus or mother if the mother's condition is untreated (Answer D is incorrect). Overall, drugs from any category, except for category X, may be reasonable treatment options for a pregnant woman (Answer C is correct). When determining which drug to use in a pregnant woman, the clinician must evaluate many factors, including the specific teratogenic/fetotoxic effects, their inci- dence (if known), and the mother's medical history (i.e., current diagnoses and medications), and must weigh the potential benefits of treatment against the risks to the fetus from drug exposure as well as the risk of not treating. For these reasons, the current pregnancy categories are not very helpful clinically, and a new system has been proposed.

A 750-g girl was delivered prematurely at 26 weeks' gestational age caused by maternal chorioamnionitis. Soon after birth, she had symptoms of RDS and subsequently received two doses of surfactant. Despite some improvement in her symptoms, she remained intubated and mechanically ventilated. Caffeine was initiated. She also received three doses of indomethacin according to the NICU's IVH prophylaxis protocol. At 12 days of age, she became tachycardic and had a widened pulse pressure; also, a systolic murmur was heard. She became hypotensive, so a dopamine continuous infusion was initiated, and the dose was titrated to 20 mcg/ kg/minute. Her total daily fluid intake was 120 mL/kg/day. Her chest radiograph revealed pulmonary edema, and her ventilator support had to be increased. An echocardiogram (ECHO) was ordered, which showed a moderate PDA with left-to-right shunting. Which is the best therapy to recommend for the management of this patient's PDA? a. Acetaminophen 15 mg/kg/dose intravenously every 6 hours for 3 days because indomethacin failed. b. Furosemide 1 mg/kg/dose intravenously every 12 hours until pulmonary edema is resolved; then recheck ECHO. c. Indomethacin 0.2 mg/kg/dose for 1 dose; then 0.25 mg/kg/dose every 12 hours for 2 doses for late symp- tomatic treatment. d. Restrict fluid intake to 100 mL/kg/day, and recheck ECHO in 2 days.

Answer: C The need for and the timing of pharmacologic closure of the PDA are somewhat controversial. Early therapy (within 3 days of life) is likely to result in overtreatment because many PDAs will spontaneously close. Most cli- nicians would agree that a PDA should be closed when it manifests with symptoms of significant respiratory deterioration or heart failure. This patient's status has worsened significantly enough to warrant PDA closure with indomethacin (Answer C is correct). Although indomethacin prophylaxis decreases the incidence of symptomatic PDA, it is not 100% effective in doing so, and it is not generally recommended for this indication. Failure of indomethacin prophylaxis to prevent a symp- tomatic PDA does not indicate the need for a different agent to treat the PDA (Answer A is incorrect). Limited evidence supports the efficacy of acetaminophen for PDA closure, but this agent is not routinely recom- mended as first-line therapy. Fluid restriction can be adequate to facilitate PDA closure, especially early on; however, it is unlikely to be effective as the sole inter- vention in an extremely premature neonate. In addition, further fluid restriction in a hypotensive patient whose fluid intake is already limited may worsen hypoten- sion and end-organ perfusion (Answer D is incorrect). Similarly, furosemide administration could worsen hypotension. Furosemide has also been shown to increase renal prostaglandin production; therefore, it is postulated that this agent can contribute to the patency of the ductus arteriosus (Answer B is incorrect).

A 3700-g boy was born at 38 weeks' gestational age by cesarean section for maternal preeclampsia. In the delivery room, he required positive pressure ventilation because of a lack of spontaneous respiratory effort. Apgar scores were 2, 5, and 7 at 1, 5, and 10 minutes, respectively. He was intubated and transferred to the NICU, where his initial blood gas shows a severe respiratory acidosis. His oxygen saturation is 87% on an FiO2 of 100%. Despite efforts to optimize his oxygenation and mechanical ventilation, he remains cyanotic with an oxygenation index of 30. An urgent ECHO revealed no structural cardiac defects other than a PDA with a right-to-left shunt, tricuspid valve regurgitation, and an elevated right-sided pressure by Doppler flow. A diag- nosis of persistent pulmonary hypertension of the newborn (PPHN) is made. Inhaled nitric oxide at 20 ppm, vasopressors, and sedation are initiated with minimal improvement in oxygenation. Systolic blood pressure remains lower than the estimated pulmonary pressures by ECHO, despite dopamine 20 mcg/kg/minute and dobutamine 20 mcg/kg/minute. A repeat ECHO confirms that the pulmonary pressures remain high, and there is significant right ventricular dysfunction. Which drug is the best therapy to add to this patient's regimen? A. Bosentan B. Treprostinil C. Milrinone D. Sildenafil

Answer: C There is no evidence-based treatment algorithm for PPHN; therefore, the place in therapy for the various available drugs is unclear. Neonates with PPHN who are treated with inhaled nitric oxide have been found to have increased PDE-3 activity. Milrinone is a PDE-3 inhibitor that augments the pulmonary vasodilation of inhaled nitric oxide. In addition, milrinone has ino- tropic and lusitropic effects that would be expected to improve right ventricular function (Answer C is correct). There is a risk of systemic hypotension with milrinone therapy, but this can be decreased by avoid- ing a loading dose. Treprostinil produces pulmonary vasodilation through the prostacyclin pathway; how- ever, it is not a pulmonary-selective vasodilator, and systemic hypotension is likely (Answer B is incorrect). Treprostinil may be given intravenously as well as sub- cutaneously or by inhalation, which would not be ideal in a neonate because of administration difficulties with these routes. Of the targeted therapies for PPHN, the prostacyclin analogs, especially epoprostenol, have the most published data in neonates, but there is minimal information about treprostinil. The absorption of oral medications (i.e., sildenafil and bosentan) is unlikely to be reliable because of the severity of this patient's ill- ness and the reduced perfusion to the GI tract (Answer A is incorrect). Sildenafil administered as an intermit- tent intravenous infusion has been reported in neonates with PPHN, but data are insufficient regarding its opti- mal dosing to recommend it routinely (Answer D is incorrect).

A 660-g boy born by vaginal delivery at 24 weeks' gestational age had a poor respiratory effort, grunting, and retractions at birth and required intubation with 100% oxygen in the delivery room. Apgar scores were 4 at 1 minute, 6 at 5 minutes, and 8 at 10 minutes. Maternal obstetric history was significant for preterm labor, tobacco smoking, and no prenatal care. Because of the lack of prenatal care and a precipitous delivery, no antenatal steroids were administered. An initial blood gas showed pH 7.1, Pco2 73, Po2 71, and base deficit 10. Ampicillin and gentamicin are ordered for possible early sepsis. A chest radiograph is ordered, and the result is pending. After transfer to the NICU at 15 minutes of life, he continues to require 100% oxygen and high peak inspiratory pressures to maintain adequate oxygen saturations. Which is the best recommendation regarding surfactant therapy for this patient? a. Surfactant therapy should be withheld pending radiographic findings confirming RDS. b. Prophylactic surfactant therapy should be administered because this neonate is at high risk of developing RDS. c. Early surfactant rescue therapy should be administered because this neonate's presentation is consistent with RDS. d. Surfactant rescue therapy should be delayed to avoid overtreatment of this neonate, whose symptoms of RDS may resolve spontaneously.

Answer: C This patient is at high risk of RDS because of extreme prematurity, lack of antenatal steroids, and male sex, so surfactant replacement therapy is indicated. Respiratory distress syndrome is usually diagnosed by clinical signs and symptoms. Although radiographic findings may be consistent with RDS, they are not required to make a diagnosis (Answer A is incorrect). Because this patient is at high risk of RDS, prophylactic surfactant admin- istration is a reasonable consideration; however, the time interval for administration (at 10-30 minutes of life, ideally before positive pressure ventilation) has been missed, and the patient already has signs of RDS (Answer B is incorrect). Prophylactic therapy for all high-risk neonates results in overtreatment because not all of these neonates will progress to RDS. Early surfac- tant rescue therapy has been shown to reduce chronic lung disease and mortality compared with delayed rescue therapy (Answer D is incorrect). Because this patient has risk factors for RDS, has signs consistent with RDS, and early rescue therapy has benefits over delaying surfactant administration, early surfactant res- cue therapy (within 2 hours of birth) should be adminis- tered (Answer C is correct).

A2-month oldboy who was born at term and has no significant medical history is being breastfed. His mother is prescribed tobramycin ophthalmic solution 2 drops in both eyes every 4 hours for 10 days for a severe con- junctivitis. Which is the best recommendation regarding breastfeeding during this mother's treatment? a. Therapy should be switched to an agent with a higher molecular weight. b. Tobramycin ophthalmic can be used, but breast milk should be discarded during therapy (i.e., "pump and dump") and formula used. c. Tobramycin ophthalmic can be used, and breastfeeding can continue without modifications. d. Tobramycin ophthalmic can be used, breastfeeding can continue, and the infant should receive probiotics.

Answer: C When assessing whether a drug is safe for administra- tion during lactation, several factors must be consid- ered: The molecular weight, protein binding, half-life, and oral bioavailability of the drug can affect the transfer of the drug into the breast milk and the sub- sequent oral absorption by the infant; the maternal serum concentration can affect the concentration in the breast milk; potential adverse effects of the drug in the infant; and the risk-benefit of continuing breastfeeding during therapy. The likelihood of significant maternal serum concentrations of tobramycin after ophthalmic administration is very low. Similarly, tobramycin's oral bioavailability is very low; therefore, the amount of drug available to the infant and the extent to which it is absorbed will not lead to a significant exposure (Answer A is incorrect; Answer C is correct). Because tobramycin exposure is likely to be low from breast- feeding, GI flora should not be altered; therefore, pro- biotics would not be of benefit (Answer D is incorrect). "Pumping and dumping," which eliminates all the ben- efits of breastfeeding, is generally not recommended (Answer B is incorrect).

As a member of your institution's pharmacy and therapeutics committee, you are asked to evaluate the available surfactant products and select one for adding to the institution's formulary. Which state- ment best justifies your selection? A. The selected product has the highest content of surfactant protein B (SP-B). B. The selected product has the most rapid onset of action. C. The selected product has been shown to reduce the need for mechanical ventilation. D. The selected product has been shown to reduce the risk of bronchopulmonary dysplasia (BPD).

Answer: D Although all of the stated properties of a surfactant product would potentially be advantageous, a product that affects long-term outcomes (e.g., reducing the inci- dence of BPD) would be the most beneficial (Answer D is correct). Surfactant protein B is known to be a critical component of endogenous surfactant; however, exoge- nous products with higher SP-B content have not been shown consistently to result in better long-term outcomes (Answer A is incorrect). A rapid onset of action may result in the ability to wean oxygen more rapidly and a shorter duration of mechanical ventilation, but these short-term improvements have not translated into long-term benefit (e.g., decreased length of hospital stay, reduced risk of BPD, reduced mortality) (Answers B and C are incor- rect). In fact, a very rapid onset may increase the risk of adverse effects (e.g., pneumothorax) if vigilant adjust- ments are not made to the patient's mechanical ventilator settings shortly after surfactant administration.

You work in a neonatal intensive care unit (NICU) that is considering implementing a protocol using indomethacin for intraventricular hemorrhage (IVH) prophylaxis. Which outcome is best sup- ported by results of clinical trials and best justifies such a protocol? a. Improved long-term neurodevelopmental outcomes. b. Reduced mortality. c. Reduced incidence of PDA. d. Reduced incidence of severe IVH.

Answer: D Clinical trials have shown that indomethacin prophy- laxis for IVH reduces the incidence of severe IVH (i.e., grades III and IV). For this reason, some NICUs have implemented an IVH prophylaxis protocol using indomethacin in premature neonates (Answer D is correct). The trials also showed a reduced incidence of PDA; however, this finding does not justify the use of indomethacin for prophylaxis. Many PDAs will close spontaneously, so the benefit of preventing them by exposing neonates to a drug that ultimately may not have been needed does not justify the risk of adverse effects from this intervention (Answer C is incorrect). The trials have not shown a reduction in mortality or improved neurodevelopmental outcome (Answers A and B are incorrect). Some clinicians would argue that this lack of long-term benefit suggests that indometha- cin prophylaxis should not be routinely used.

A breastfeeding mother presents with newly diag- nosed hypertension. The medical team asks you to suggest ways to minimize neonatal risks and exposure from the treatment while still allowing the mother to breastfeed. Which recommendation is most likely to achieve this goal? A. Choose a drug with a relatively long half-life. B. Choose a drug that is not highly protein bound. C. Advise the mother to feed when her serum concentrations of the drug are likely to be low- est during the day. D. Select the lowest effective treatment dose.

Answer: D Drugs that are not highly protein bound or that have long half-lives are more likely be transferred into and accumulate in breast milk than are those that are highly protein bound or have shorter half-lives, thus increasing the potential for neonatal exposure and adverse effects (Answers A and B are incorrect). In theory, breastfeed- ing when maternal serum concentrations are likely to be the lowest during the day would minimize exposure to the neonate. However, in reality, this is not very feasible because most neonates feed at least six to eight times a day; thus, maternal serum concentrations would not be low at most of the feeding times (Answer C is incor- rect). Maternal serum concentrations do have a signif- icant effect on the concentration of drug in the breast milk, so treating the mother with the lowest effective dose would result in a lower concentration and therefore decrease overall drug exposure to the neonate (Answer D is correct).

The patient from cases 1 and 2 is now 36 weeks' postmenstrual age. During his NICU stay, he was treated for RDS and Klebsiella sepsis. He has had several failed extubation attempts and remains intubated, requiring 30%-40% oxygen to maintain adequate oxygenation and prevent frequent desaturations. His chest radio- graph reveals diffuse haziness with lung hyperinflation consistent with chronic lung disease. Which treat- ment for his severe BPD is best supported by the literature? a. Albuterol 2 puffs by endotracheal tube every 6 hours, budesonide 0.25 mg by nebulizer every 12 hours, and furosemide 2 mg/kg/dose orally daily. b. Albuterol 2 puffs by endotracheal tube every 6 hours, budesonide 0.25 mg by nebulizer every 12 hours, and hydrochlorothiazide/spironolactone 3 mg/kg/day by mouth divided every 12 hours. c. Albuterol 2 puffs by endotracheal tube every 6 hours and fluticasone 2 puffs by endotracheal tube every 12 hours. d. Albuterol 2 puffs by endotracheal tube every 6 hours as needed for bronchospasm and furosemide 1 mg/kg/dose intravenously as needed for signs of pulmonary fluid overload.

Answer: D In clinical practice, long-term therapies for the treat- ment of BPD are often prescribed. However, there is no evidence to support the use of scheduled broncho- dilators, inhaled corticosteroids, or scheduled diuret- ics in this patient population. None of these therapies have been shown to provide a long-term benefit such as decreased need for mechanical ventilation, length of hospital stay, or mortality in infants with BPD (Answers A-C are incorrect). Symptomatic treatment with as-needed bronchodilators for acute bronchospasm or intermittent doses of diuretic for pulmonary edema provide short-term relief of symptoms without chron- ically exposing the infant to drugs that have significant potential to cause adverse effects (Answer D is correct). Trial of a short course of low-dose dexamethasone may be warranted at this time to facilitate extubation, given that extubation has failed on several previous attempts.

A 450-g boy who was born at 24 weeks' gestational age received three doses of surfactant for respiratory distress syndrome (RDS). Because of his very low birth weight and severity of RDS, the medical team would like to initiate therapy to prevent progression to BPD. According to clinical trials, which is most likely to prevent BPD in premature neonates at high- est risk? a. Azithromycin. b. Indomethacin. c. Inhaled nitric oxide. d. Vitamin A.

Answer: D There are several biologically plausible theories for the prevention of BPD by various drug therapies. Because Ureaplasma spp. have been isolated from the tracheal aspirates of neonates with BPD, it has been theorized that eliminating that organism will decrease the inci- dence of BPD. Clinical trials have not shown this benefit in all neonates at high risk of BPD (Answer A is incor- rect). When examining a specific subset of neonates proven to be colonized with Ureaplasma, azithromycin initiated within 3 days of birth did reduce the incidence of BPD. A PDA with a left-to-right shunt increases pul- monary blood flow and is a risk factor for developing BPD; therefore, theoretically preventing a PDA would decrease the risk of BPD. This has not been shown to be true with indomethacin or ibuprofen prophylaxis or with PDA treatment (Answer B is incorrect). In animal models, inhaled nitric oxide has been shown to reduce lung inflammation and promote lung growth that would theoretically decrease the risk of BPD. Clinical trials of human neonates have not shown this benefit (Answer C is incorrect). Vitamin A has been shown to reduce the incidence of BPD in clinical trials (Answer D is cor- rect). Although used in some NICUs, vitamin A has not become a standard of care within neonatology, given concerns about frequent intramuscular injections in extremely premature neonates as well as a lack of evi- dence showing a long-term benefit in improving neuro- developmental outcomes.

A 2100-g girl born at 34 weeks' gestational age devel- ops seizures 2 weeks after birth. Serum electrolytes and glucose are normal. Vesicular lesions are noted on the tongue and buccal mucosa. In addition to anticonvulsant therapy, ampicillin, ceftazidime, and acyclovir are initiated for suspected meningitis. Two days later, the herpes simplex virus (HSV) poly- merase chain reaction (PCR) from the cerebrospinal fluid (CSF) is positive and the bacterial cultures are negative, so ampicillin and cefotaxime are discon- tinued. Serum alanine aminotransferase (ALT) has remained normal. Which is the best recommenda- tion regarding this neonate's antiviral therapy? A. Continue intravenous acyclovir 20 mg/kg/dose every 8 hours for 7 days. B. Continue intravenous acyclovir 20 mg/kg/dose every 8 hours for 10 days. C. Continue intravenous acyclovir 20 mg/kg/dose every 8 hours for 14 days. D. Continue intravenous acyclovir 20 mg/kg/dose every 8 hours for 21 days.

Answer: D This neonate's presentation is consistent with dis- seminated herpes disease because she has lesions in her mouth and positive herpes PCR from the CSF. According to the AAP treatment algorithm, intravenous acyclovir should be administered for at least 21 days for disseminated or localized CNS disease (Answer D is correct; Answers A-C are incorrect). Near the end of 21 days of treatment, the CSF PCR should be repeated to confirm the clearance of HSV. If the PCR is negative, acyclovir can be discontinued after 21 days of therapy. If the PCR is positive, acyclovir should be continued for an additional 7 days, after which the CSF PCR should be rechecked; acyclovir should be continued until the PCR is negative. Shorter courses of acyclovir are rec- ommended for preemptive therapy without proven dis- ease (10 days) and for SEM disease (14 days).

BRONCHOPULMONARY DYSPLASIA Antenatal and postnatal steroids

Antenatal corticosteroids: Although shown to decrease the incidence of RDS, there is no evidence of a reduced risk of BPD, which may be owing to improved survival of very preterm neonates. Postnatal corticosteroids Early (less than 96 hours after birth) and moderately early (7-14 days of age) systemic dexameth- asone have been shown to significantly decrease the incidence of BPD; this practice was common in the 1990s. In the early 2000s, AAP advised against the use of postnatal corticosteroids for the prevention of BPD because of evidence of significant long-term neurologic complications (e.g., increased cere- bral palsy and developmental delay). Most commonly, high doses (0.5 mg/kg/day) of dexamethasone for long durations (up to 42 days) were used in these studies. A recent Cochrane Review concluded the use of dexamethasone regardless of timing of initia- tion, dose, or duration is still not supported by currently published evidence. Clinicians are still using lower-dose (less than 0.2 mg/kg/day) postnatal corticosteroids in chron- ically mechanically ventilated neonates to facilitate extubation. Adverse neurodevelopmental outcomes have not been reported for this lower-dose regimen when used after a few weeks of age. However, the optimal dosing and timing, as well as the overall safety and effectiveness in preventing BPD, of this intervention are unknown. Clinical trials to address this question are ongoing and encouraged by AAP. Hydrocortisone has also been evaluated for the prevention of BPD. i. Some evidence suggests low-dose (1 mg/kg/day) hydrocortisone tapered over the first 10 days to 2 weeks after birth reduces the incidence of BPD without affecting neurodevelopment. (a) The most benefit may be in neonates exposed to prenatal inflammation (e.g., chorioamnionitis). (b) Concurrent use of systemic corticosteroids with indomethacin/ibuprofen may increase the risk of spontaneous intestinal perforation. ii. Higher doses (3-6 mg/kg/day) after the first week of age have not been shown to decrease the incidence of BPD. e. Inhaled budesonide Initiated within 24 hours of birth; 400 mcg every 12 hours for 14 days; then, 200 mcg every 12 hours until supplemental oxygen and positive-pressure support no longer needed or 32 weeks' postmenstrual age reached regardless of ventilator status; note: 200 mcg/puff metered dose inhaler not currently available in the U.S. Statistically significant reduction in BPD in budesonide group compared with placebo (27.8% vs. 38%; p=0.004) Statistically nonsignificant increase in mortality in budesonide group compared with placebo (16.9% vs. 13.6%; p=0.17) A 2017 Cochrane review concluded that data are insufficient to recommend inhaled cortico- steroids for BPD prevention in preterm neonates.

NECROTIZING ENTEROCOLITI Prevention

Because NEC can rapidly evolve from early signs of intestinal pathology to fulminant necrosis despite medical therapy, primary prevention should be the therapeutic goal. Antenatal corticosteroids a. Shown to augment intestinal maturation. b. Conflicting results regarding effect on incidence of NEC; some studies show reduced incidence, whereas others show more NEC (may be owing to the improved survival of very preterm neonates because of decreased pulmonary morbidity). Feeding protocols that emphasize the use of early trophic feedings (to promote peristalsis) and breast milk (contains maternal IgA) may help decrease NEC. Probiotics: Augment intestinal maturation, reduce growth and colonization by potentially pathogenic organisms, increase amounts of anti-inflammatory cytokines a. Consist mainly of strains of Lactobacillus, Bifidobacterium, and Saccharomyces. b. Studies have shown at least a 30% reduction in NEC and a significantly reduced mortality. c. A few case reports of sepsis caused by probiotic bacterial strains exist; however, larger reports of probiotic use have not shown an increased risk. d. Probiotics are not yet considered standard of care because several unanswered questions remain: What is the optimal species or combination of species of probiotic? What is the optimal dosing and duration of therapy? When should probiotics be initiated and in whom? Should probiotics be U.S. Food and Drug Administration (FDA) regulated (currently classified as supplements)? Are these products safe, especially in light of reports of contamination with Rhizopus? Oral antibiotics a. Orally administered gentamicin has been shown to decrease the incidence of NEC. b. Not routinely recommended because of a higher rate of colonization with resistant organisms in neonates receiving prophylactic oral antibiotics.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Endothelin receptor antagonists

Bosentan (a) Dual endothelin receptor antagonist that blocks the vasoconstricting effect of endothelin (b) Optimal dosing not known; available only as enteral extemporaneous formulation. (c) Short-term benefit of improved oxygenation shown in small case reports/trials, but no studies of long-term safety or efficacy. (d) Adjunctive therapy for PPHN did not shorten time to wean from inhaled nitric oxide or mechanical ventilation in a small, randomized trial, possibly due to impaired enteral absorption or severity of illness in bosentan group.(e) Black box warning for hepatotoxicity in the adult labeling Ambrisentan (a) Selective endothelin-A receptor antagonist blocks vasoconstricting effect of endothelin-1 and promotes clearance of endothelin-1. (b) No black box warning for hepatotoxicity. (c) No data regarding use or pharmacokinetics in neonates. Known to have a longer half-life in adults than bosentan; may be expected to be even longer in neonates, which would not be ideal because it increases the potential risk of prolonged systemic hypotension and other adverse effects.

BRONCHOPULMONARY DYSPLASIA Prevention

Caffeine: Caffeine for Apnea of Prematurity (CAP) trial showed a reduced incidence of BPD (defined as need for supplemental oxygen at 36 weeks' postmenstrual age) in neonates receiving caffeine compared with placebo. Vitamin A a. 5000 units administered intramuscularly three times a week for 4 weeks to neonates with a birth weight less than 1000 g has been shown to decrease the risk of BPD; oral administration did not result in the same benefit. B. A long-term follow-up trial did not show a difference in neurodevelopmental outcomes between neonates who received vitamin A compared with placebo. C. A 2016 Cochrane review concluded that vitamin A supplementation modestly reduced BPD among very-low-birth-weight neonates. The authors concluded that the decision to use vitamin A should be based on the local incidence of BPD and weighed against the lack of other proven benefits (e.g., neurodevelopmental outcomes). Inhaled nitric oxide Animal models suggest that inhaled nitric oxide decreases lung inflammation, improves surfactant function, and augments lung growth. Clinical trials of preterm human neonates have failed to show a reduction in the incidence or sever- ity of BPD.

APNEA OF PREMATURITY Clinical Presentation

Cessation of breathing for at least 20 seconds or pauses in breathing of less than 20 seconds if associated with bradycardia (heart rate less than 100 beats/minute), cyanosis, or pallor Diagnosis of exclusion: Other causes of apnea must be ruled out. Risk factors a. Prematurity i. The incidence of apnea is inversely related to gestational age. ii. The incidence of apnea is significantly lower if the gestational age is older than 34 weeks. b. Extremely low birth weight (less than 1000 g)

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Characterized by elevated pulmonary pressures after birth in conjunction with a right-to-left shunt across the ductus arteriosus or foramen ovale. a. Previously called persistent fetal circulation. b. Imbalance of relative excess of endogenous vasoconstrictors (e.g., endothelin-1, thromboxane A2) to endogenous vasodilators (e.g., nitric oxide, prostacyclin) c. Usually transient; may be idiopathic or secondary to an underlying disease. d. Affects primarily term neonates. Causes of secondary pulmonary hypertension a. Congenital diaphragmatic hernia b. Meconium aspiration syndrome c. Pneumonia/sepsis d. RDS e. BPD f. Congenital heart defects g. In utero drug exposure: Can occur after in utero exposure to nonsteroidal anti-inflammatory drugs or selective serotonin reuptake inhibitors

CONGENITALLY ACQUIRED INFECTIONS Herpes Simplex Virus (HSV) - Diagnosis

Definitive diagnosis: Isolation of HSV by culturei. Scraping of skin vesicles for cultureii. "Surface cultures": Swabs of the conjunctivae, mouth, nasopharynx, and rectum performed at about 24 hours after birth PCR testing of CSF is used for confirming CNS involvement. i. Persistently positive PCR assay of the CSF after treatment is associated with poor outcomes. ii. A repeat specimen should be tested near the end of the treatment course to confirm the clear- ance of HSV from the CSF; therapy should continue until the result is negative. PCR testing of blood: Usefulness for guiding the length of therapy is unknown.

NEONATAL ABSTINENCE SYNDROME Risk factors

Gestational age i. Symptoms tend to be milder in premature neonates. ii. May be related to immaturity of CNS, lower fat deposits of drug, and decreased total time for drug exposure. Drug to which fetus was exposed i. Polysubstance exposure is associated with increased severity of NAS. ii. Variable reports related to the incidence and severity of NAS based on the drug to which the neonate was exposed in utero (e.g., there are reports of higher incidence/severity of NAS after methadone exposure compared with buprenorphine or heroin, whereas others report no differ- ence among the drugs) iii. Higher maternal methadone dose has not been shown to correlate with a greater incidence or severity of NAS.

PATENT DUCTUS ARTERIOSUS Optimal timing for initiating pharmacologic treatment of a PDA is controversial.

Early (less than 3 days old) versus late (7-14 days old) symptomatic treatment Studies from the 1980s and early 1990s suggest a reduction in the need for mechanical venti- lation, surgical ligation of the PDA and BPD with early indomethacin treatment of the PDA. (a) The lack of routine antenatal corticosteroid use and exogenous surfactant replacement during this time may have affected the results. (b) Outcomes have not been well studied since antenatal corticosteroids, surfactant, and non-invasive modes of respiratory support have become routine interventions for prema- ture neonates. Closure rates with early treatment are high; however, this practice may subject more neo- nates to unnecessary medication and adverse effects because their PDA could have closed spontaneously. More recently, a difference in long-term benefits (e.g., reduction in BPD or NEC, improved survival) has not been clearly shown when early treatment is compared with delayed treatment. Late/delayed symptomatic treatment i. Early fluid restriction may delay or negate the need for pharmacologic treatment of the PDA. ii. Sick neonates with a hemodynamically significant PDA have often been excluded from trials of late treatment, so their ability to tolerate this approach or its effects on long-term outcomes are unknown. iii. The outcome of treatment delays beyond 14 days has not been studied.

RESPIRATORY DISTRESS SYNDROME Pharmacologic Management

Exogenous surfactant replacement Has significantly reduced mortality and respiratory morbidity since use became routine in the early 1990s Adverse effects i. Apnea, bradycardia, oxygen desaturation ii. Pneumothorax may occur because of a rapid increase in lung compliance if changes to mechan- ical ventilation settings are not made quickly. iii. Pulmonary hemorrhage rarely occurs, but it is most common in extremely low-birth-weight neonates..

CONGENITALLY ACQUIRED INFECTIONS Herpes Simplex Virus (HSV)

HSV type 2 is the most common cause of neonatal herpes disease. Transmission is usually during vaginal birth by an infected maternal genital tract; may also be an ascending infection through the amniotic membranes (ruptured or intact). i. If a pregnant woman has active genital lesions, a cesarean delivery can reduce the risk of transmission to the neonate. ii. Suppressive therapy with oral acyclovir or valacyclovir given near the end of pregnancy to a woman with a history of HSV infection can reduce, but not eliminate, the risk of transmission. c. Risk of transmission to the neonate Highest (60%) in those born to mothers with first-episode primary genital infection, followed by those born to mothers with first-episode nonprimary infection (25%). Transmission from a mother with recurrent HSV infection is low (less than 2%).

CONGENITALLY ACQUIRED INFECTIONS Herpes Simplex Virus (HSV) - Management of asymptomatic neonates born to women with active genital HSV lesions

If no history of maternal genital HSV, the neonate is evaluated at 24 hours of age with surface cultures, CSF and blood HSV PCR, and liver function tests AND acyclovir is initiated; mater- nal serology should be sent to determine infection classification (i.e., recurrent, first-episode primary, first-episode nonprimary). (a) If maternal serologies reveal recurrent infection AND neonatal laboratory values remain negative at 48-72 hours, discontinue acyclovir. (b) If maternal serologies reveal recurrent infection AND neonatal PCR or cultures are pos- itive, continue acyclovir.(1) If the neonate remains asymptomatic AND CSF and blood PCR are negative and ALT is normal, complete 10 days of preemptive therapy. (2) If the neonate remains asymptomatic but the PCR is positive or ALT is more than 2 times the upper limit of normal, treat for proven disease (see "Duration" above). (c) If maternal serologies reveal first-episode primary or nonprimary, continue acyclovir. (1) If the neonate remains asymptomatic AND CSF and blood PCR are negative and ALT is normal, complete 10 days of preemptive therapy. (2) If the neonate remains asymptomatic but the PCR is positive or ALT is more than 2 times the upper limit of normal, treat for proven disease (see "Duration" above). If the mother has a history of genital HSV before pregnancy, the neonate is evaluated at 24 hours of age with surface cultures and blood PCR; acyclovir is NOT initiated. (a) If neonatal laboratory values remain negative, no therapy is needed. (b) If neonatal surface cultures or PCR results are positive, CSF PCR and liver function tests are sent AND acyclovir is initiated. (1) If the neonate remains asymptomatic AND CSF and blood PCR are negative and ALT is normal, complete 10 days of preemptive therapy. (2) If the neonate remains asymptomatic but PCR is positive or ALT is more than 2 times the upper limit of normal, treat for proven disease (see "Duration" above).

CONGENITALLY ACQUIRED INFECTIONS Congenital Syphilis - Treatment

If the maternal RPR (test)/Venereal Disease Research Laboratory [test for syphilis] (VDRL) is reactive but the maternal treponemal test is nonreactive, no treatment for the neonate is required. If the maternal RPR/VDRL and treponemal tests are reactive, determining the need to treat the neonate depends on the maternal treatment. i. If adequate maternal treatment before pregnancy with stable low titer AND examination of the neonate is normal, then congenital syphilis is unlikely and no neonatal treatment is required. If maternal treatment was during pregnancy and more than 4 weeks before delivery AND no evidence of maternal reinfection/relapse, neonatal treatment is determined by comparing the neonate with the maternal nontreponemal titers. (a) If the neonatal RPR/VDRL is NOT 4-fold or greater than the maternal titer AND the neo- nate's examination is normal, then congenital syphilis is less likely, so treat the neonate with benzathine penicillin G 50,000 units/kg/dose intramuscularly for one dose. (b) If the neonatal RPR/VDRL is NOT 4-fold or greater than the maternal titer AND the neonate's examination is abnormal, then congenital syphilis is proven or highly proba- ble, so treat the neonate with (1) aqueous penicillin G 50,000 units/kg/dose intravenously every 12 hours (if 1 week old or younger) or every 8 hours (if older than 1 week) for 10 days -OR- (2) procaine penicillin G 50,000 units/kg/dose intramuscularly every 24 hours for 10 days. (c) If the neonatal RPR/VDRL is 4-fold or greater than the maternal titer, then congenital syphilis is proven or highly probable, so treat the neonate with (1) aqueous penicillin G 50,000 units/kg/dose intravenously every 12 hours (if 1 week old or younger) or every 8 hours (if older than 1 week) for 10 days -OR - (2) procaine penicillin G 50,000 units/kg/ dose intramuscularly every 24 hours for 10 days. If maternal treatment did not occur, was undocumented, was less than 4 weeks before deliv- ery, or consisted of a nonpenicillin drug; or if there is evidence of maternal reinfection/ relapse, treat the neonate with (1) aqueous penicillin G 50,000 units/kg/dose intravenously every 12 hours (if 1 week old or younger) or every 8 hours (if older than 1 week) for 10 days - OR - (2) procaine penicillin G 50,000 units/kg/dose intramuscularly every 24 hours for 10 days. (a) If the neonate's examination is abnormal in this scenario, then congenital syphilis is proven or highly probable. (b) If the neonate's examination is normal and his or her RPR/VDRL is less than 4-fold the maternal titer, then congenital syphilis is possible, so a single dose of benzathine penicil- lin 50,000 units/kg may be adequate if follow-up is certain. 10 full days of penicillin is preferred, even if the neonate originally received ampicillin for possible sepsis. The entire course must be repeated if more than 1 day of therapy is missed.

NECROTIZING ENTEROCOLITIS Pathogenesis is multifactorial.

Immaturity of the GI tract is the most important factor. i. Immaturity results in intestinal hyperpermeability. ii. Decreased peristalsis increases the time intestinal bacteria are in contact with carbohydrate substrates from feedings and increases the time the bowel is exposed to bacterial antigens, thus increasing inflammation. iii. Decreased immunoglobulin A (IgA) production by the immature intestine compromises an important protective mechanism against pathogens. It is thought that an exaggerated inflammatory response occurs after the exposure of bacterial pathogens, which colonize the gut, to a substrate provided by enteral feedings. A perinatal hypoxic-ischemic episode preceding NEC may be the inciting event in some cases; however, this is unlikely to be the overall primary cause because the age of onset for NEC, about 21 days in preterm neonates, is remote from birth, and no such event is identifiable in many cases of NEC. Necrosis usually involves the ileum and proximal colon.

CONGENITALLY ACQUIRED INFECTIONS Herpes Simplex Virus (HSV) - Management of neonates with symptomatic/proven HSV disease

Intravenous acyclovir (a) Dose: 20 mg/kg/dose every 8 hours; recommended to prolong interval to every 12 hours in premature neonates. (b) Duration (1) SEM disease: 14 days (2) Disseminated or localized CNS disease: Minimum of 21 days (c) Monitoring: Twice-weekly neutrophil count is recommended. (d) Add topical ophthalmic drug (e.g., trifluridine) with ocular involvement. Oral acyclovir (a) Not recommended for treatment of HSV infections. (b) Used as suppressive therapy after treatment of an acute HSV infection. (1) Shown to prevent skin recurrences: Occurs in 50% of infants after neonatal HSV infection. (2) Improves neurodevelopmental outcomes after CNS disease. (3) Regimen: 300 mg/m2/dose given three times daily for 6 months.

New FDA Pregnancy and Lactation Labeling Rule

Labeling for pregnancy and lactation are similar and include: Risk summary: Describes the likelihood that the drug will increase the risk of fetal/infant harm according to available data. Clinical considerations: Describes the risk to the fetus after inadvertent exposure; risk to the pregnant woman and fetus from the disease for which the drug is prescribed; effects related to dose, timing, and duration of exposure; potential neonatal complications and potential montoring/management options; potential effect on milk production; and techniques to minimize infant drug exposure (in Lactation section). Data: Human and animal data are presented separately. Also emphasizes the importance of patient enrollment in a registry, if one exists, to collect data about the effects of the medication when used during pregnancy and lactation. All drugs submitted to the FDA after June 30, 2015, will use the new format; new labeling for drugs approved earlier will be phased in gradually.

NEONATAL ABSTINENCE SYNDROME Screening for Intrauterine Drug Exposure

Maternal characteristics (e.g., history of drug use, late or no prenatal care, many spontaneous abor- tions, severe mood swings, abruptio placentae) consistent with drug abuse may prompt screening of the neonate. Methods for screening: Natural opioids are readily detectable in urine or meconium; semisynthetic and synthetic opioids as well as "designer drugs" are not detected by routinely used laboratory tests. Urine Must be performed soon after birth. (a) Beware of false positives owing to maternal drug administration during the peripartum period. (b) False negatives may occur because of maternal drug abstinence shortly before delivery. May detect only recent drug exposure because of the rapid clearance of many drugs. (a) Opioids, cocaine metabolites, amphetamines, and short-acting benzodiazepines are typi- cally cleared within 1-3 days. (b) Long-acting barbiturates and benzodiazepines may be detectable for a longer period. Meconium: Earliest stool; contains ingested material from swallowing amniotic fluid; typically thick, sticky, and very dark green. Many drugs concentrate in meconium, especially those excreted through the fetal hepatobili- ary system or into amniotic fluid by renal elimination. The window of detection (from 20 weeks' gestation) is much longer than for urine testing. Sample must be meconium; cannot include transitional or breast milk/formula-fed stools (typically thinner and yellow). Results may be delayed because the sample often is not processed within the hospital labora- tory and must be sent to a reference laboratory. A positive result is not predictive of neonatal abstinence syndrome (NAS). Other biological samples such as umbilical cord blood and neonatal hair have also been used for screening.

Factors Affecting Drug Transport Into breast milk

Maternal plasma concentration: Most drugs enter by passive diffusion, so the higher the maternal plasma concentration, the more likely the drug will enter the breast milk. Molecular weight: Low molecular weight increases the likelihood of drug excretion into milk. Charge: Lack of ionization increases drug excretion into milk. Lipophilicity: Highly lipid-soluble substances are more likely to be excreted into milk. Protein binding: Highly protein-bound substances are less likely to be excreted into milk. Volume of distribution: Drugs with a small volume of distribution are more likely to be excreted into milk. Half-life: Drugs with long half-lives are likely to accumulate in milk.

APNEA OF PREMATURITY Methylxanthines (i.e., theophylline/aminophylline and caffeine)

Mechanism of action: Nonspecific inhibitor of adenosine receptors i. CNS stimulant ii. Increase respiratory drive iii. Increase sensitivity to hypercapnia iv. Increase diaphragmatic contractility Comparison of available agents i. Pharmacokinetics (a) Distribution: Theophylline has a higher free fraction in neonates than in older children and adults because of reduced plasma protein binding. (b) Metabolism (1) Oxidation and N-demethylation of theophylline is decreased in neonates compared with adults because of the immaturity of the hepatic enzyme system. (2) Theophylline is methylated to caffeine. (3) Demethylation of caffeine is decreased in neonates compared with adults. (c) Elimination (1) Theophylline (24-36 hours) has a relatively short half-life compared with caffeine (72-100 hours). (2) In neonates, theophylline (55%) and caffeine (85%) are primarily excreted unchanged in the urine. ii. Efficacy (a) Theophylline and caffeine have similar efficacy in treating apnea of prematurity. (b) A randomized controlled trial suggests that caffeine, but not theophylline, is beneficial for preventing apnea. (c) Dosing

NECROTIZING ENTEROCOLITIS Nonpharmacologic

a. Bowel rest and abdominal decompression with gastric tube b. Peritoneal drains and/or surgery i. Indicated if bowel perforation occurs. ii. Mortality higher if surgery is required.

INTRAVENTRICULAR HEMORRHAGE

Mechanism of hemorrhage a. Likely multifactorial b. Lack of cerebral pressure autoregulation resulting in an inability to maintain relatively steady cerebral blood flow at a range of cerebral perfusion pressures i. Factors causing low cerebral blood flow: Hypotension, perinatal asphyxia ii. Factors causing increased cerebral blood flow: Hypertension, rapid infusion of fluid bolus, vasopressor therapy, pain, handling, hypercarbia iii. Factors causing elevated cerebral venous pressure: RDS, pneumothorax, pulmonary hemor- rhage, positive pressure ventilation iv. Fluctuating cerebral blood flow is common in ventilated neonates who are out of synchrony with the ventilator. c. Excessive angiogenesis within the germinal matrix: VEGF (vascular endothelial growth factor) is a potent angiogenic factor d. Cytokines induce cyclooxygenase-2 production resulting in increased prostaglandin production, which causes vasodilatation that further affects cerebral pressure autoregulation.

"Old" FDA pregnancy risk categorization

Misconceptions The risk of severe fetal harm increases from category A to X: The categories are not a scale of harm; rather, they show the degree of evidence for fetal harm. The "risk" is only that of fetal harm: The potential harm to the mother from withholding the therapy must also be considered. All drugs within the same category have the same level of risk (e.g., oral contraceptives are primarily classified as category X because there is no benefit to trying to prevent pregnancy in a woman who is already pregnant. In contrast, warfarin is classified as category X for most indications because it is associated with known embryopathy). This classification system does not account for timing of exposure, severity of fetal harm, or potential treatability of the fetal injury.

NEONATAL ABSTINENCE SYNDROME Opioids

Morphine versus methadone (a) Morphine is the most commonly used agent. (b) Methadone has a significantly longer and more variable half-life (4-62 hours). (c) The shorter half-life of morphine necessitates more frequent dosing but allows for easier dose titration. (d) Both are available as alcohol-free products. (e) There is no difference in treatment outcomes or length of stay when comparing methadone- treated neonates with those treated with morphine. (f) Although many institutions have protocols for dose titration, no specific dose or regimen has been proven superior. Tincture of opium (a) Contains 25-fold higher concentration of morphine than does oral morphine solution. (1) Increased risk of medication error when dosing or diluting the product (2) Increased risk of morphine overdose (b) Contains alcohol Buprenorphine (a) Partial μ-opioid receptor agonist with a long, but predictable half-life (72 hours) (b) Administration to neonates requires compounding a sublingual solution that contains alcohol. Significant first-pass metabolism necessitates sublingual administration. (c) Limited evidence suggests a decreased length of treatment and hospital stay compared with morphine; however, safety and efficacy need further investigation in larger studies.

APNEA OF PREMATURITY Treatment duration

Most neonates will "outgrow" apnea of prematurity by 34-36 weeks' postmenstrual age because of maturation of the central respiratory center, so methylxanthine therapy can be discontinued at that time. Most clinicians will monitor the neonate for up to 1 week after discontinuation of methylxanthine therapy to ensure that the drug has been eliminated from the body and that apnea of prematurity has resolved before discharging the patient home.

CONGENITALLY ACQUIRED INFECTIONS Cytomegalovirus (CMV)

Most neonates with congenital CMV will be asymptomatic at birth. Manifestations include intrauterine growth restriction (i.e. birth weight below the 10th percentile), microcephaly, periventricular calcifications, jaundice, hepatosplenomegaly, retinitis, "blueberry muffin" rash, petechiae Mildly symptomatic: One or two isolated findings that are transient. Moderately to severely symptomatic: Multiple findings consistent with congenital CMV or any CNS involvement. c. Long-term complications include developmental delay and deafness. Treatment Typically, antiviral therapy is reserved for neonates with moderate to severe symptoms caused by CMV disease. Mildly symptomatic and asymptomatic infants, including those with isolated senso- rineural hearing loss, should not be treated with antivirals. Oral valganciclovir 16 mg/kg/dose twice daily for 6 months May be of benefit in reducing the risk of hearing loss and decreasing the severity of develop- mental impairment. Ganciclovir 6 mg/kg/dose intravenously every 12 hours is an alternative. Should be initiated within 1 month after birth. Monitoring: Transaminases (monthly during treatment) and absolute neutrophil count (weekly for 6 weeks then at week 8 then monthly until completion of treatment)

NEONATAL ABSTINENCE SYNDROME Agents that are not recommended for treatment of NAS:

Naloxone: Maternal opioid use is a relative contraindication to naloxone administration to the neonate for apnea/hypoventilation after birth; may precipitate acute withdrawal and seizures. Paregoric: Used commonly historically, but no longer recommended because it contains sev- eral opioids as well as toxic ingredients, including camphor, anise oil, alcohol, and benzoic acid. Benzodiazepines: Not shown to be effective for treating opioid withdrawal symptoms.

RESPIRATORY DISTRESS SYNDROME Comparison of surfactant products: Clinical outcomes

Natural versus synthetic products (a) Natural products result in improved outcomes compared with historical synthetic product (i.e., colfosceril). (b) A reduction in RDS-related deaths was observed at 14 days with lucinactant compared with beractant; a longer-term benefit has not been shown. No difference in morbidities associated with prematurity (e.g., BPD). (c) No difference in short- or long-term outcomes when comparing lucinactant with poractant Natural product comparison (a) A short-term clinical benefit (e.g., reduced oxygen requirement, faster wean of mechani- cal ventilation, decreased need for repeat doses) was observed with calfactant compared with beractant. No difference in incidence of BPD or mortality. (b) Meta-analysis comparing poractant with beractant showed that risk of death or need for oxygen at 36 weeks' postmenstrual age was reduced in group receiving higher initial poractant dose (i.e., greater than 100 mg/kg). (c) No comparison studies of calfactant with poractant (d) The American Academy of Pediatrics (AAP) concluded that it is unclear whether there is a significant difference in clinical outcomes when comparing the natural products.

INTRAVENTRICULAR HEMORRHAGE Grades based on criteria by Papile and Volpe

a. Grade I: Hemorrhage is limited to the germinal matrix. b. Grade II: Hemorrhage in the lateral ventricle, blood fills less than 50% of the ventricle. c. Grade III: Hemorrhage in the lateral ventricle causing distension, blood fills more than 50% of the ventricle. d. Grade IV: Hemorrhage into the surrounding parenchyma

NEONATAL ABSTINENCE SYNDROME Clinical Presentation

Onset of symptoms depends on drug to which fetus was exposed and timing of drug use before delivery. a. Heroin: Within 24 hours after birth b. Methadone: Within 2-6 days after birth c. Buprenorphine: Within 2-3 days after birth d. 55%-94% of neonates exposed to opioids in utero will have withdrawal. e. Non-opioid substances (e.g., alcohol, barbiturates, cocaine, caffeine, selective serotonin reuptake inhibitors) may cause symptoms consistent with withdrawal; however, the routine need for phar- macologic treatment of these neonates has not been established. Symptoms manifest in the autonomic, neurologic, and GI systems. Finnegan score: Most commonly used assessment tool a. Neonate is evaluated every 3-4 hours, after feeding. Score should include signs and symptoms present at the time of the evaluation as well as at any time since the previous evaluation. If three consecutive scores are 8 or higher or if two consecutive scores are 12 or higher, pharmaco- logic therapy should be initiated. After symptoms are controlled, scores are often used in clinical practice to gradually wean therapy.

NECROTIZING ENTEROCOLITIS Risk factors

Premature birth i. Incidence is inversely related to gestational age. ii. Unlikely in term neonates except for those with specific risk factors that decrease mesenteric blood supply (e.g., congenital heart disease, sepsis, hypotension). Very low (less than 1500 g) or extremely low (less than 1000 g) birth weight Formula feeding (as opposed to breast milk) Abnormal bacterial colonization of the intestinal tract because of prolonged antibiotic exposure or acid-suppressive therapy i. Decreased normal gut flora i. Proliferation of pathogenic bacteria

RESPIRATORY DISTRESS SYNDROME Prophylaxis versus rescue surfactant administration

Prophylaxis (a) Surfactant administration to neonates at high risk of RDS to prevent rather than treat RDS. (b) Surfactant administration occurs in the delivery room before the onset of RDS, typically within 10-30 minutes after birth; theoretically, the ideal timing would be before the neo- nate's first breath or before positive pressure ventilation is administered. (c) May result in administration to more neonates than would actually develop RDS. Rescue (a) Surfactant administration to neonates with established RDS for treatment (b) "Early" rescue surfactant therapy is administered within 1-2 hours after birth. (c) "Delayed" or "late" rescue surfactant therapy is administered 2 hours or more after birth, typically within 12 hours. Prophylactic surfactant administration does not result in clinically important benefits (e.g., reduced mortality or incidence of BPD) compared with continuous positive airway pressure (CPAP) provided in the delivery room and followed by rescue surfactant, if indicated (about one-third did not require rescue surfactant). Early rescue treatment decreases the risk of mortality and chronic lung disease compared with delayed treatment.

INTRAVENTRICULAR HEMORRHAGE Indomethacin

Proposed mechanism: Cyclooxygenase-1 and -2 inhibition reduces prostaglandin production, thus decreasing cerebral blood flow; also can stimulate vascular maturation and is an antioxidant. Regimen: 0.1 mg/kg/dose intravenously every 24 hours for 3 doses; administered within 6-12 hours of life to neonates with a birth weight less than 1000-1250 g Significantly reduces the incidence of severe (grade III and IV) IVH. i. Benefit not shown with ibuprofen prophylaxis. ii. Also shown to reduce the risk of symptomatic PDA. Not shown to improve long-term survival without neurodevelopmental sequelae.

INTRAVENTRICULAR HEMORRHAGE Recombinant human erythropoietin

Proposed mechanism: Neuroprotection after brain injury (e.g., hypoxic-ischemic encephalopa- thy, caused by premature birth) is facilitated by anti-inflammatory, anti-excitotoxic, antioxidant, and antiapoptotic effects on neurons and oligodendrocytes, which promote neurogenesis and angiogenesis. High-dose regimens (1000-30,000 units/kg/dose), much higher than those previously used for anemia of prematurity, are required to achieve measurable concentrations within the brain. A recently published study showed no difference in death or severe neurodevelopmental impair- ment at 2 years of age between high-dose erythropoietin and placebo.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Prostacyclin analogs:

Prostacyclin produces vasodilation by stimulating cyclic adenosine mono-phosphate (cAMP) production. Epoprostenol: Not a selective pulmonary vasodilator (a) Administered by continuous intravenous infusion or inhalation; risk of rebound pulmo- nary hypertension owing to the drug's extremely short half-life if infusion or inhalation is interrupted (b) Optimal dose is unclear; limited evidence suggests that neonates need higher doses than do adults with pulmonary hypertension. (c) Systemic hypotension is the primary adverse effect. Iloprost (a) Administration by nebulization through the ventilator circuit results in selective pulmo- nary vasodilation. (1) Actuated inhalation delivery device is recommended by the manufacturer, but not compatible with ventilator circuits. (2) Continuous-flow conventional nebulizers used in a ventilator circuit will result in significant drug loss. (b) Optimal dose and frequency unclear; has a relatively short half-life.

APNEA OF PREMATURITY caffine safety and monitoring

Safety (a) Theophylline is associated with increased adverse effects, including tachycardia, feeding intolerance, irritability, jitteriness, and seizures. (b) Similar adverse effects can occur with caffeine, but they are relatively uncommon because of its wider therapeutic index compared with theophylline. Monitoring (a) Clinical response (i.e., reduced number of apneic episodes) is the most useful monitoring value for efficacy. (b) The therapeutic range of theophylline serum concentrations is considered 5-12 mcg/mL; theophylline concentrations should be routinely monitored during therapy because of theophylline's narrow therapeutic index. (c) Serum concentrations of caffeine are not shown to correlate well with efficacy or toxicity, so routine monitoring is not recommended. Clinical practice: The wide therapeutic index and longer half-life allowing for once-daily administration make caffeine the therapy of choice. Association with gastroesophageal reflux Considerable controversy exists regarding whether reflux worsens apnea of prematurity and whether methylxanthine therapy worsens reflux. Most evidence suggests that treatment of gastroesophageal reflux does not reduce or resolve apneic episodes. CAP trial: Multicenter randomized placebo-controlled trial of caffeine versus placebo in neonates with apnea of prematurity Short-term outcomes in caffeine treatment group i. Decreased duration of respiratory support (i.e., positive airway pressure, supplemental oxygen) ii. Decreased rates of BPD iii. No difference in NEC or IVH iv. Temporary reduction in weight gain during first 3 weeks of treatment v. Effects most significant when caffeine is initiated within 3 days of birth. vi. These were the secondary end points of the study. Long-term neurodevelopmental outcomes Significantly lower incidence of death or survival with a neurodevelopmental disability at 18-21 months of age; there was no difference between groups at 5-year follow-up. These were the primary end points of the study.

RESPIRATORY DISTRESS SYNDROME Clinical Presentation

Signs and symptoms a. Tachypnea, grunting, nasal flaring, retractions, hypoxia, and cyanosis occurring soon after birth b. Chest radiograph reveals homogeneous opaque infiltrates and air bronchograms; classic "ground- glass" appearance.' Risk factors a. Prematurity i. Most common in neonates born before 28 weeks' gestation ii. Rare (less than 5%) in neonates born after 34 weeks' gestation iii. Lack of antenatal steroid administration further increases the risk of RDS in the premature neonate. Male sex Maternal diabetes White race

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Phosphodiesterase (PDE) inhibitors

Sildenafil (a) PDE-5 inhibition increases cyclic guanosine monophosphate, a second messenger in the nitric oxide pathway, resulting in pulmonary vasodilation. (b) Case reports and small studies used a wide range of enteral doses; showed short-term beneficial effect, but long-term safety and efficacy are unknown. (c) Small case series reported on the improvement in short-term respiratory parameters with the use of intermittent intravenous sildenafil. Optimal dosing regimen for this route is unknown. (d) Systemic hypotension, although rare, has been reported. (e) Concerns for increased mortality in older children (1-17 years) with pulmonary hyperten- sion led the FDA to caution against the use of sildenafil in children. (1) STARTS-1 and STARTS-2 trials did not include neonates.(2) Sildenafil was used as monotherapy, regardless of disease severity, in these studies. (3) The mortality rate of 16% in the high-dose group (more than 3 mg/kg/day) is lower than the historical rates of 33%-52% before the availability of targeted therapies. ii. Milrinone (a) PDE-3 inhibition increases cAMP, leading to pulmonary vasodilation. (b) May be useful in combination with inhaled nitric oxide, which has been shown to increase PDE-3 activity. (c) The optimal dose and role in the treatment of PPHN are not known

PATENT DUCTUS ARTERIOSUS Treatment - supportive

Supportive care, including fluid restriction and respiratory support, may be sufficient to manage the symptoms of PDA until spontaneous closure occurs, especially in neonates born older than 28 weeks' Surgical closure: Considered if urgent closure indicated or if there are contraindications to pharmaco- logic treatment (e.g., NEC, GI perforation, pulmonary hemorrhage).

BRONCHOPULMONARY DYSPLASIA Additional tx options

Surfactant a. Not shown to reduce BPD; may be because of increased survival of very preterm neonates. b. Late administration to preterm neonates who remain intubated at 14 days may improve pulmonary outcomes (e.g., reduced rehospitalizations) at 1 year of age. Indomethacin/ibuprofen It was theorized that preventing the PDA, a risk factor for BPD, would decrease the incidence of BPD Trials of prophylactic closure of the ductus arteriosus have not shown a decrease in the incidence of BPD. Macrolide therapy a. U. urealyticum has been isolated from the respiratory tract of neonates with BPD. b. Most studies evaluating the effect of macrolide antibiotics in neonates with Ureaplasma-positive respiratory cultures have shown clearance of the organism but no effect on incidence of BPD; one study evaluating clarithromycin found a reduction in the incidence of BPD. c. Macrolide antibiotics administered to all neonates at high risk of developing BPD did not prevent BPD; in a subset analysis of neonates with positive PCR for Ureaplasma, azithromycin initiated within 3 days of age and continued for up to 6 weeks decreased the incidence of BPD. d. The routine use of macrolides for the prevention of BPD caused by Ureaplasma colonization/ infection is not recommended because of very limited evidence of a beneficial effect.

RESPIRATORY DISTRESS SYNDROME Administration techniques

Surfactant is administered through a catheter placed in the endotracheal tube of mechanically ventilated neonates. (a) INSURE (acronym) method of surfactant administration: Intubation, surfactant admin- istration, extubation to CPAP (b) Less invasive surfactant administration (LISA) uses a thin catheter for intratracheal sur- factant administration to neonates on CPAP: Shown to reduce need for mechanical venti- lation and BPD compared to INSURE. The neonate is positioned to facilitate uniform delivery of surfactant to all lung fields. (a) For example, the surfactant dose is divided into four aliquots and delivered to the neonate in four different positions: (1) body tilted slightly downward with the head turned to the right, (2) body tilted slightly downward with the head turned to the left, (3) body tilted slightly upward with the head turned to the right, (4) body tilted slightly upward with the head turned to the left. (b) Adequate distribution may also occur with delivery in two aliquots: (1) body tilted and head turned to the right and (2) body tilted and head turned to the left.

PATENT DUCTUS ARTERIOSUS Clinical Presentation

Symptoms: Murmur, hyperactive precordium, bounding pulses, widened pulse pressure, hypotension, worsening respiratory status Diagnosis confirmed by echocardiogram. Risk factors a. Gestational age: 70%-80% of neonates born before 28 weeks' gestation will have a PDA. b. Lack of antenatal corticosteroids c. RDS

PATENT DUCTUS ARTERIOSUS

The ductus arteriosus is a vessel connecting the pulmonary artery to the aorta that allows blood flow to bypass the fetal lungs. Decreased circulating prostaglandin concentrations and increased oxygen levels promote postnatal constriction of the ductus arteriosus; therefore, the failure of circulating prostaglandin concentrations to drop results in persistent patency of the ductus arteriosus. Ductal constriction typically occurs within 72 hours of birth in term neonates and by 4 days in preterm neonates born older than 29 weeks' gestation.

RESPIRATORY DISTRESS SYNDROME Inhaled nitric oxide

Theorized role in RDS (a) Intrapulmonary shunting of blood owing to ventilation-perfusion mismatching or extrapulmonary shunting owing to pulmonary hypertension can worsen RDS. (b) Inhaled nitric oxide may improve oxygenation by vasodilating the pulmonary vascula- ture, thus lowering pulmonary vascular resistance and improving distribution of pulmo- nary blood flow. Summary of trials and meta-analysis (a) Three meta-analyses, including a Cochrane review, evaluated the use of inhaled nitric oxide in neonates with RDS. (b) No difference in mortality or incidence of BPD was shown. (c) Inhaled nitric oxide cannot be recommended for routine treatment of preterm neonates with RDS.

BRONCHOPULMONARY DYSPLASIA Diuretics

Thiazide diuretics (e.g., hydrochlorothiazide), potassium-sparing diuretics (e.g., spironolactone), and loop diuretics (e.g., furosemide) are commonly used in clinical practice to decrease pulmonary edema in patients with BPD. Short-term benefits of improved oxygenation and lung compliance have not been shown to corre- spond to improvements in long-term outcomes (e.g., decreased need for mechanical ventilation, length of hospital stay, or mortality). c. Electrolyte derangements are common and can lead to complications such as nephrocalcinosis and osteopenia caused by increased urinary calcium loss. i. Thiazides may have calciuric effects similar to loop diuretics in preterm neonates. ii. Hypochloremia may be associated with a poorer outcome in infants with BPD. iii. Various alterations to the diuretic regimen (e.g., administration by inhalation, every-other-day dosing) have been studied in an effort to minimize adverse effects. Although some have shown fewer electrolyte abnormalities, a lack of long-term clinical benefit remained. d. Chronic use of diuretics should be discouraged because of the very limited evidence with respect to meaningful benefits, together with the potential for significant adverse effects.

CONGENITALLY ACQUIRED INFECTIONS Congenital Syphilis

Transmission of Treponema pallidum usually occurs transplacentally; also can occur as a result of contact with active lesion during birth.i. Transmission rates are 60%-100% in primary and secondary syphilis.ii. Rates in early latent (40%) and late latent (8%) infections are lower. Spontaneous abortion or stillbirth is common if maternal infection is untreated. 2. Presentation a. Two-thirds of neonates will be asymptomatic at birth. b. Early signs include hepatosplenomegaly, rash, neurosyphilis, rhinitis ("snuffles"), leukocytosis, hemolytic anemia, thrombocytopenia, bony involvement, and skin lesions. c. Late manifestations include "saddle-nose deformity" (from snuffles related to nasal carti- lage destruction), frontal bossing, bowing of mid-tibia, synovial effusions, tooth abnormalities ("Hutchinson teeth," "mulberry molars"), and perforated hard palate. i. Usually occur after 2 years of age. ii. Some complications present much later. (a) Interstitial keratitis: 5-20 years of age (b) Eighth cranial nerve deafness: 10-40 years of age iii. Can be prevented if the neonate receives treatment for early infection.

Lactation risk categories

Weighing the risk-benefit of using a medication during lactation includes several factors: i. Necessity of the drug for the mother ii. Potential effect on milk production iii. Concentration of the drug in breast milk iv. Potential for oral absorption in the breastfed infant v. Possible adverse effects from the drug in the breastfed infant vi. Age of the infant: Infants younger than 2 months are reported to have the highest incidence of adverse effects from drug exposure during breastfeeding; reports are rare in infants older than 6 months. vii. Benefits of breastfeeding to the infant and mother Other factors that may affect the decision to use a drug in a lactating woman include: i. Is the drug being continued after in utero exposure or is it a newly initiated therapy? ii. Is the therapy a single-dose or short course as opposed to chronic therapy? iii. Are the risks associated with a potential adverse event higher in a preterm infant or one with underlying illness compared with a term or otherwise healthy infant? c. No formal classification system; most often cited as recommended/not recommended or compatible/ not compatible with breastfeeding. d. Dr. Thomas Hale's lactation risk categories L1 Compatible: Controlled trials of breastfeeding women did not find infant harm, or the prod- uct is not orally bioavailable. L2 Probably Compatible: Limited trials of breastfeeding women did not find infant harm, or if harm was shown, the likelihood was low. L3 Probably Compatible: No controlled trials of breastfeeding women, but a risk of adverse effects in the infant is possible; or controlled trials show only minimal, non-life-threatening adverse effects. Drug should be taken by a breastfeeding woman only if the potential benefits outweigh the potential risks to the infant. L4 Possibly Hazardous: Evidence of adverse effects to the infant exist, but the benefit to the breastfeeding mother may justify the risk to the infant. L5 Hazardous: Trials of breastfeeding women have shown a significant harm to the infant or the drug is associated with a high risk of harm to the infant. Drug is contraindicated in breast- feeding women.

INTRAVENTRICULAR HEMORRHAGE Antenatal corticosteroids

a. Betamethasone b. Although their primary indication is to promote fetal lung maturation, antenatal corticosteroids also have been shown to reduce the risk of IVH.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Supportive therapies

a. Inotropic and vasopressor agents: To support cardiac function and maintain systemic blood pressure b. Sedatives/analgesics: Agitation and pain can worsen pulmonary vasoconstriction. c. Neuromuscular blocking agents: Usually reserved for neonates who respond inadequately to appro- priate sedation/analgesia. d. Surfactant replacement Shown to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO) when persistent pulmonary hypertension of the newborn (PPHN) is secondary to RDS, pneumonia/sepsis, or meconium aspiration (i.e., disease states in which surfactant defi- ciency/inactivation occurs). Greatest benefit in those with relatively mild disease e. ECMO: May be indicated for severe pulmonary hypertension.

Factors Affecting Drug Transport Across the placenta

a. Molecular weight: Substances with a mass below 500 Da readily diffuse across the placental barrier. b. Charge: Nonionized substances are transported rapidly across the placenta by simple diffusion. c. Lipophilicity: Highly lipid-soluble substances are transported rapidly across the placenta by simple diffusion. d. Protein binding: Highly protein-bound substances are less likely to cross the placental barrier.

INTRAVENTRICULAR HEMORRHAGE Complications

a. Periventricular leukomalacia b. Posthemorrhagic hydrocephalus: Up to 40% will require a ventriculoperitoneal shunt c. Cerebral palsy and/or mental retardation The risk for neonates with grade I or II IVH is similar to that for a premature neonate with a normal cranial ultrasonography and similar NICU course (i.e., experienced similar complica- tions of prematurity). Neonates with grade III or IV IVH have a 35%-50% and 75% increased risk of neurodevelop- mental sequelae, respectively.

PATENT DUCTUS ARTERIOSUS Monitoring

a. Renal function (i.e., serum creatinine and urine output) b. Platelet count c. Liver function tests: For acetaminophen d. Gastrointestinal (GI) signs (e.g., bloody stool; distended, discolored abdomen): Risk of sponta- neous intestinal perforation may be higher if given during first week of life, with hypotension, or with concurrent corticosteroids. e. Serum concentrations i. Not routinely done at most institutions. ii. Studies from a few institutions report improved closure rates with individualized dosing based on serum concentrations of indomethacin.

APNEA OF PREMATURITY Other causes of apnea in a neonate

a. Sepsis b. Necrotizing enterocolitis c. Gastroesophageal reflux d. Seizures e. IVH f. Drugs (i.e., respiratory depressants) g. Inborn errors of metabolism h. Central nervous system (CNS) structural abnormalities

NEONATAL ABSTINENCE SYNDROME Nonpharmacologic

a. Swaddling; minimal handling; reduced environmental noise; subdued lighting; frequent, small feedings b. Nonpharmacologic interventions alone may suffice for mild withdrawal, but they should be used in all cases.

BRONCHOPULMONARY DYSPLASIA Corticosteroids

a. Systemic corticosteroids: Adverse effects outweigh potential benefits. b. Inhaled corticosteroids Inhaled corticosteroids have the theoretical advantage of decreased systemic adverse effects compared with systemic corticosteroids; however, trials have not confirmed this. There is no evidence to support long-term clinical benefits, so routine use is not recommended.

BRONCHOPULMONARY DYSPLASIA Bronchodilators

a. β-Agonists have been shown to improve lung compliance and decrease pulmonary resistance. b. They may be beneficial in the management of acute exacerbations of BPD to improve airway hyperactivity. c. Most reports of bronchodilator use in BPD are single-dose studies or short-term evaluations; long- term effects have not been well studied, and there is no evidence of reduced need for ventilator support or mortality.