Complications
Respiratory distress syndrome (RDS) is secondary to pulmonary immaturity and surfactant deficiency and occurs with increasing frequency as gestational age decreases. Administration of prenatal corticosteroids and postnatal surfactant reduces the impact of RDS.[83][123][124] Long-term consequences of RDS, such as bronchopulmonary dysplasia or chronic lung disease (CLD), remain a significant health problem.[125]
Infection is one of the common causes of preterm birth and is a cause of neonatal morbidity. The incidence is highest (approximately 25%) in the most premature infants. Likelihood of postnatal sepsis increases with decreasing gestational age and need for invasive procedures such as central vascular access or intubation.[126][127]
Immature neonatal immune function contributes to the increased risk of fulminant infection. The association of sepsis with white matter injury (WMI) and neurodevelopmental impairment (NDI) places those infants at increased risk beyond their degree of prematurity. Antimicrobials can be used to treat infection, but the sustained activation of the immune system can result in poor outcome with an increased risk for WMI and NDI.[128]
This is a very common problem and is observed in >50% of infants below 32 weeks' gestational age. Causes include iatrogenic blood sampling, shortened red blood cell (RBC) life (approximately 50% to 60% of adult RBC life), and decreased RBC production. Provision of adequate nutrition and iron supplementation, and the consideration of blood transfusion, is therefore warranted.[129] Note that preterm infants should be screened for thyroid dysfunction within the first 48 to 72 hours of life, before transfusion of any blood products.[130]
The use of early erythropoietin (EPO), at less than ages 8 days, compared to late EPO, at ages 8 to 28 days, has not been shown to significantly reduce the use or number of transfusions per infant, but has been shown to increase the risk of retinopathy of prematurity and is therefore not recommended.[131]
The use of restrictive transfusion practices for anemia does not appear to have a significant impact on death or major morbidities at first hospital discharge or at follow‐up.[132]
Because premature infants miss a significant portion of nutrient and mineral transfer during the last trimester, in addition to experiencing critical illness and poor nutrition in the form of total parenteral nutrition (TPN), they are at significant risk for nutritional deficiency.
Early institution of fortified breast milk feeds or the use of a premature formula may improve bone mineralization, longitudinal growth, and myelination. Premature infants have different nutritional requirements compared with term infants and should receive preterm formulas if breast milk is not available, in order to maximize nutrition and prevent faltering growth.[133]
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Infants with severe necrotizing enterocolitis requiring partial bowel resection are at a greater risk of faltering growth and chronic cholestasis associated with prolonged TPN. Maximizing nutrition, and frequent assessments of weight gain and growth, are therefore essential.[134]
Jaundice is nearly universal in premature infants due to inadequate gastrointestinal losses of bilirubin, compounded by the slow advancement of enteral nutrition. Treatment of jaundice involves phototherapy, which is instituted when levels are deemed high, to avoid the possibility of kernicterus. Because of immaturity in the premature brain, the levels at which kernicterus is possible is variable. For this reason, and because phototherapy has shown few to no adverse effects in infants, a conservative approach of treatment when concerning levels are reached is practiced. Decisions regarding management are guided by the gestational age, the hour-specific total serum bilirubin (TSB), and the presence of risk factors for bilirubin neurotoxicity (gestational age <38 weeks, albumin <30 g/L [<3.0 g/dL], serious sickness in the newborn infant, [e.g., sepsis or significant clinical instability in the previous 24 hours], or isoimmune hemolytic disease, glucose-6-phosphate deficiency or other hemolytic conditions).[135]
Intraventricular hemorrhage (IVH) is attributed to immature blood vessels in the germinal matrix and occurs most commonly in extremely premature infants. Mortality from severe IVH is 25% to 50%, and for mild IVH is 5%. Sequelae of IVH include white matter injury such as periventricular leukomalacia and encephalopathy of prematurity, with subsequent neurodevelopmental impairment in both motor and cognitive function. IVH rarely occurs after 32 weeks' gestational age.[146]
Cerebellar hemorrhage is a frequent but serious medical condition characterized by bleeding within the cerebellum of premature infants typically before 28 weeks’ gestation.[147] The pathophysiology of this condition is complex and often related to the fragility of blood vessels in the underdeveloped cerebellum, which can rupture due to fluctuations in blood pressure and oxygen levels. The prognosis for affected neonates varies depending on the extent of hemorrhage and associated complications. Mild cases may resolve with minimal long-term effects, while severe hemorrhages can lead to significant neurologic deficits, such as motor and cognitive impairments, cerebral palsy, or death.[148] Early diagnosis through imaging and prompt medical intervention are crucial in improving outcomes. Close monitoring and multidisciplinary care are essential for optimizing the prognosis.
Gastrointestinal immaturity associated with prematurity increases the risk for necrotizing enterocolitis (NEC). The risk is inversely proportional to the gestational age.
Prenatal corticosteroids and human breast milk feeding reduce the incidence of NEC.[95]
Meta-analysis has shown that probiotics may reduce the risk of NEC and mortality in infants <32 weeks’ gestation or with birth weight <1500 g. The certainty of evidence was rated low to moderate, and data for infants <28 weeks’ gestation or birth weight <1000 g are lacking.[149]
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Newer probiotics and synbiotics that serve to stimulate the developing gut in the same manner as human breast milk are currently being evaluated.[150] Pentoxifylline treatment directed at reducing the inflammatory response associated with NEC may decrease the length of hospital stay and mortality, but the certainty of current evidence is low.[151] Enteral supplementation of bovine lactoferrin decreases late-onset sepsis but not NEC ≥stage 2 or all-cause mortality without adverse effects, though this evidence is also of low certainty.[152]
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Another trial found that lactoferrin did not reduce the incidence of infection, mortality, or other morbidity in infants born <32 weeks.[153] A Cochrane review considered the findings to be uncertain.
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Long-term sequelae of severe NEC requiring surgical resection include short gut syndrome, total parenteral nutrition dependence, and chronic cholestasis.
Delayed closure of the ductus arteriosus occurs in 65% of extremely premature infants and is associated with development of chronic lung disease. Ductal patency that leads to an increased need for supplemental oxygen or ventilatory support may be treated with indomethacin or with surgical ligation of the ductus. A systematic review of pharmacologic interventions found that high-dose oral ibuprofen was more effective in closing the ductus arteriosus compared with standard-dose intravenous indomethacin or ibuprofen without increasing mortality or necrotizing enterocolitis.[154] If pharmacotherapy fails (after two courses) or is contraindicated, closure by catheterization or surgical ligation may be considered for infants with a hemodynamically significant patent ductus arteriosus.[155]
Proliferative neovascularization of the retina in extremely premature infants is an important cause of long-term blindness and is associated with excessive oxygen exposure. Reducing postductal target peripheral oxygen saturation (SpO₂) to between 85% and 93% until 32 weeks' postmenstrual age (gestational age plus postpartum age) reduces the incidence of severe retinopathy of prematurity (ROP). However saturation targeting <90% in preterm infants is associated with increased mortality. One Cochrane review assessed the effects of oxygen saturation (SpO₂) targeted to ranges of either 85% to 89% (low) or 91% to 95% (high) in randomized trials of babies born at less than 28 weeks' gestation. Results showed a trade-off between mortality and severe retinopathy of prematurity.[77]
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Therefore, attempts to reduce oxygen exposure to the minimum necessary are recommended.[156]
Ophthalmologic screening should be performed for ROP in infants born at ≤30 weeks' gestational age or those born at ≤1500 g, and selected infants born >30 weeks or born between 1500 and 2000 g.[157] The timing of the first eye examination is recommended from 4 to 9 weeks based on gestational age, and follow-up examinations should be informed by the ophthalmologist's retinal findings.[157]
Vascular endothelial growth factor (VEGF) blockade for ROP prevention (using a VEGF-directed monoclonal antibody such as bevacizumab) may be effective in zone 1, stage 3+ ROP.[157] Evaluations are under way to assess the benefits of vitamin A administration (as premature infants have very low vitamin A stores) on ROP prevention.
Low- to very low-quality evidence in a systematic review of six trials including 383 infants who were <37 weeks’ gestation and had type 1 ROP suggests that in preterm infants anti-VEGF drugs used in the treatment of retinopathy of prematurity do not decrease retinal detachment.[158] However, one randomized, open-label, superiority multicenter trial in 225 infants with birth weight less than 1500 grams who met criteria for treatment for retinopathy found ranibizumab to be at least as effective as laser therapy for survival with no active retinopathy, no unfavourable structural outcomes, and no need for a different treatment modality at or before 24 weeks.[159] The long-term effects of anti-VEGF drugs on neurodevelopment are subject to investigation.[160]
Postdischarge rehospitalization rates for premature infants are greater than those for term infants, due to the increased risk of comorbidities. Near-term infants are almost twice as likely to be readmitted as term infants. They have the highest risk when they are not admitted to, or remain for <4 days in, a neonatal intensive care unit.
Important causes for rehospitalization are respiratory illness, poor feeding and dehydration, jaundice requiring phototherapy, and infection.[161][162][163] The excess risk of hospitalization in children born prematurely decreases with age, but remains elevated, compared with children born at term, until age 7-10 years.[164]
Neurodevelopmental impairment (NDI) is a significant risk and is inversely associated with gestational age at delivery.
NDI includes cerebral palsy, cognitive and motor defects, and mild hearing loss. At least 40% of extremely premature infants have some form of NDI.[137]
Between 10% and 20% of infants born premature have some form of behavioral sequelae as compared with <10% of term infants. These disorders are more common in extremely premature infants and include hyperactivity and ADHD, as well as conduct, emotional, and/or peer problems. Other behavioral traits such as shyness, unassertiveness, social maladaptation, withdrawal, and anxiety may also be present.[137]
Bronchopulmonary dysplasia (BPD) is the most common and most studied complication of prematurity.[138] It is defined as the need for supplemental oxygen for at least 28 days after birth.[139] The incidence is inversely proportional to gestational age. Two-thirds of infants with chronic lung disease (CLD) or BPD are born before completion of 28 weeks' gestation.
In addition to acute pulmonary problems, long-term conditions such as asthma, neurodevelopmental delay, and rate of rehospitalization during the first year of life are increased in those with CLD. Hypocapnia, as a result of excessive ventilatory tidal volumes, is associated with development of BPD; this highlights the importance of gentle effective ventilation in the delivery room and beyond.
Interventions directed at successful early extubation (using nasal positive pressure ventilation and biphasic or continuous positive airway pressure) and pharmacologic interventions to reduce CLD (such as azithromycin, montelukast, early hydrocortisone, late surfactant and nitric oxide, cysteine, and citrulline) are currently under investigation.
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Caffeine therapy for apnea of prematurity is associated with reduced BPD and improved survival without neurodevelopmental impairment.[140][141] However, higher caffeine doses have not been shown to improve mortality prior to hospital discharge or neurodevelopment outcomes.[85]
Systemic or inhaled corticosteroids given to preterm infants <28 weeks at birth, for prevention of BPD in the first 2 weeks of life, are not associated with any significant difference in the composite outcome of death or neurodisability in survivors.[142][143][144][145]
Former extremely premature infants are at an increased likelihood of facing polypharmacy challenges as they progress into toddlerhood and childhood, often due to their complex medical histories, extended stays in neonatal intensive care units, and exposure to interventions.[122][166] This increases the risk of potential drug interactions and adverse effects; vigilant monitoring is required.
The risk of mortality is inversely related to gestational age.[120] Survival in extremely premature infants is 20% to 90% and is >90% in those born at >28 weeks' gestation. The risk of death is slightly greater in black infants compared with those of other races.
Common causes of death include infection, intrinsic lung immaturity, pulmonary or intraventricular hemorrhage, and necrotizing enterocolitis. However, in some cases of extreme prematurity (23 weeks' gestation or less), resuscitation is not desired by the parents, is not initiated, or is not successful, and the cause of death is reported as "extreme prematurity."[121]
Premature infants are at greater risk for abuse and neglect than those born at term. Assessment of family support and transition to home care are critical in reducing the risk of harm in this vulnerable population.[136]
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