INTRODUCTION — Complications of the preterm infant (gestational age <37 weeks) are divided into short-term complications that occur in the neonatal period, and long-term sequelae in patients who survive and are discharged from the neonatal intensive care unit (NICU).
Short-term complications of prematurity will be reviewed here. The long-term complications and the long-term healthcare needs of preterm survivors are discussed separately. (See "Long-term outcome of the preterm infant".)
DEFINITIONS — Different degrees of prematurity are defined by gestational age (GA) or birth weight (BW) (table 1).
The classification based upon GA is as follows:
●Late preterm birth – GA between 34 and less than 37 weeks
●Moderate preterm birth – GA between 32 and <34 weeks
●Very preterm (VPT) birth – GA less than 32 weeks
●Extremely preterm (EPT) birth – GA at or below 28 weeks
Preterm infants are also classified by BW :
●Low birth weight (LBW) – BW less than 2500 g
●Very low birth weight (VLBW) – BW less than 1500 g
●Extremely low birth weight (ELBW) – BW less than 1000 g
Birth weights by percentile for the appropriate GA have been established (table 2). The above definitions are used throughout this review.
OVERVIEW — Prematurity is defined as a birth that occurs before 37 completed weeks (less than 259 days) of gestation. It is associated with approximately one-third of all infant deaths in the United States and accounts for approximately 45 percent of children with cerebral palsy, 35 percent of children with vision impairment, and 25 percent of children with cognitive or hearing impairment.
Complications of prematurity are the underlying reasons for the higher rate of infant mortality and morbidity in preterm infants compared with full-term infants. The risk of complications increases with increasing immaturity [1]. Thus, infants who are extremely preterm (EPT) (born at or before 25 weeks of gestation) have the highest mortality rate (approximately 50 percent) and if they survive, are at the greatest risk for severe impairment. (See "Periviable birth (limit of viability)".)
Complications of the preterm infant are divided into short-term complications (eg, respiratory and cardiovascular complications), which occur in the neonatal period, and long-term sequelae (eg, neurodevelopmental disabilities such as cerebral palsy) in patients who survive and are discharged from the neonatal intensive care unit (NICU) [2]. Short-term complications increase the risk of long-term sequelae. (See "Long-term outcome of the preterm infant".)
EPIDEMIOLOGY
●Gestational age (GA) and birth weight (BW) ‒ Complications and their frequencies vary depending on GA and BW. For very preterm/very low birth weight infants (GA <32 weeks and BW <1500 g) and extremely preterm infants (GA<28 weeks), common complications include bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and brain defects (eg, intraventricular hemorrhage [IVH]) as illustrated by the following studies.
•Very low birth weight infants (BW <1500 g) ‒ In a report from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, the following complications and their frequencies were seen in 8515 very low birth weight (VLBW) infants [3]:
-Respiratory distress – 93 percent
-ROP – 59 percent
-Patent ductus arteriosus – 46 percent
-BPD – 42 percent
-Late-onset sepsis – 36 percent
-NEC – 11 percent
-Grade III intraventricular hemorrhage (IVH) and Grade IV IVH – 7 and 9 percent
-Periventricular leukomalacia – 3 percent
•Extremely preterm infants ‒ In a population-based British study (EPICure 2 study), the survival and morbidity of 3378 births of extremely preterm infants (GA between 22 and 26 weeks) born in 2006 were reported [1]. In this cohort, there were 2034 live births (60 percent of total cohort), of which 1668 (83 percent of live births) were admitted to an intensive care unit (ICU), and, in 189 cases (9 percent of live births), active stabilization was withheld in the delivery room. The survival to discharge for all live births was 51 percent, and the survival for infants admitted to ICU was 62 percent. Among the 1041 patients who survived to discharge, the following major morbidities, including their incidences, were reported:
-BPD (defined as supplementary oxygen at 36 weeks postmenstrual age) ‒ 68 percent
-Abnormal cerebral ultrasound ‒ 13 percent
-Laser treatment for ROP ‒ 16 percent
-Laparotomies for NEC ‒ 8 percent; there were no data on medical treatment for NEC
-No major morbidity was reported in 41 percent of survivors to discharge
•Moderately preterm infants (GA between 32 and <34 weeks) ‒ Even moderately preterm infants are at risk for significant morbidity, as illustrated by a Swedish population-based study of 6674 preterm infants with a GA between 30 and 34 weeks born from 2004 to 2008 [4]. The following complications and their frequencies were as follows:
-Hyperbilirubinemia ‒ 59 percent
-Acute respiratory disease ‒ 28 percent
-Hypoglycemia ‒ 16 percent
-Bacterial infection ‒ 15 percent
●Ethnicity ‒ Black and Hispanic preterm infants appear to have a greater risk of complications than White preterm infants. This was illustrated in a population-based cohort study of very preterm infants (GA <32 weeks) that reported on a fetuses-at-risk analysis (based on the date of conception) and found higher rates of BPD, NEC, IVH, and ROP for Black and Hispanic infants compared with White infants, even after adjusting for sociodemographic factors (eg, maternal age and education, insurance status) and maternal morbidities (eg, pregestational hypertension and diabetes, gestational diabetes, obesity) [5]. Asian American infants had comparable rates of BPD, NEC, and IVH to White infants but were at greater risk for ROP. Using a conventional analysis for a subcohort of infants based on GA between 24 and 31 weeks, compared with White infants: Black infants alone had an increased risk for BPD; Black and Hispanic infants had a borderline increased risk of NEC; and Asian American infants continued to have an increased risk for ROP.
●Initial stabilization ‒ Initial stabilization of a preterm infant in the delivery room is important because proper management can reduce the risk of short-term complications. l As an example, initiation of continuous positive airway pressure or the early administration of surfactant in very preterm (VPT) infants can reduce the risk of respiratory distress syndrome. (See "Management of respiratory distress syndrome in preterm infants" and "Periviable birth (limit of viability)".)
Most VLBW infants need resuscitation at birth. Among VLBW infants born in centers of the NICHD Neonatal Research Network between 1995 and 1996, 60 percent required endotracheal intubation, and 7 percent received resuscitation medications [6]. The smallest infants were most likely to be depressed and require intervention. Apgar scores ≤3 at five minutes occurred in 27 percent of infants with birth weight (BW) 501 to 750 g, compared with 3 percent of infants weighing 1251 to 1500 g.
For these reasons, anticipated delivery of a preterm infant should be attended by a clinician experienced in neonatal resuscitation. Facilities for assessment and stabilization should be close to the delivery area, and monitors and resuscitation equipment must be readily available. Resuscitation should follow established guidelines, including special considerations for prematurity [7]. (See "Neonatal resuscitation in the delivery room", section on 'Preterm infants'.)
COMPLICATIONS — Preterm infants are at risk for developing short-term complications that result from anatomic or functional immaturity during the neonatal period. The risk of developing complications increases with decreasing gestational age (GA) and birth weight (BW) [8]. Thus, knowledge of the GA enables an assessment of the chance of survival and the likelihood of developing short-term complications. (See 'Definitions' above and "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality".)
The short-term complications are summarized in the following sections. Many of these complications are also discussed as individual topics in greater detail elsewhere in the program.
Hypothermia
Clinical features and risk factors — Rapid heat loss occurs in preterm infants because of their relatively large body surface area and inability to produce enough heat. Heat is lost by conduction, convection, radiation, and evaporation.
In preterm infants especially extremely preterm infants, hypothermia is associated with increased mortality and, in survivors, intraventricular hemorrhage (IVH), and pulmonary insufficiency and hemorrhage [9-15]. Hypothermia may contribute to metabolic disorders such as hypoglycemia or acidosis.
Preterm infants are at greatest risk for hypothermia immediately after birth in the delivery room and on admission to NICU. This was illustrated in a multicenter study from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network that reviewed the body temperature of moderate (gestational age 29 to 33 weeks) and extremely preterm (EPT) infants (gestational age <29 weeks) admitted to between 2012 to 2013 [12]. The following distribution of admission temperatures was noted for moderate and EPT infants:
●Less than 36.5°C – 39 and 41 percent
●36.5 to 37.5°C – 57 and 53 percent
●Greater than 37.5°C – 4 and 6 percent
For EPT infants, there was improvement of admission temperatures as the percentage of temperature between 36.5 to 37.5°C more than doubled in this cohort of infants compared with those born in a previous cohort born between 2002 and 2003. There also was a threefold increase in the percentage of EPT infants with admission temperatures >37.5°C (6 versus 2 percent), likely due to the implementation of preventive hypothermic measures. For the birth cohort for 2012 and 2013, there was an inverse relationship between admission temperature and in-hospital mortality for infants born between 22 and 33 weeks gestation.
Reported risk factors for hypothermia include [13,14]:
●Delivery room temperature <25°C
●Maternal temperature <36°C
●Lack of heat loss preventive measures (eg, plastic bag/wrap, head covering)
●Decreasing BW
●Cesarean delivery
●Use of respiratory support with cold air
Prevention — Standard care in the delivery room to prevent hypothermia includes:
●Maintaining the delivery room temperature at a minimum of 26°C [16]
●Drying the baby thoroughly immediately after birth
●Removal of any wet blankets
●Use of prewarmed radiant heaters if resuscitation is necessary
In preterm infants, additional interventions have been used to reduce hypothermia, such as barriers to heat loss (ie, polyethylene/polyurethane body wrap or bags, and polyethylene or stockinet caps) or external heat sources (ie, skin to skin care and transwarmer mattress), or the use of heated humidified air for initial respiratory support [9,10,17-23].
●Polyurethane bags – A systematic review of the literature reported that the use of polyurethane bags led to less hypothermia and higher temperatures on admission to NICUs [24]. In one of the largest trials (88 infants with a GA <28 weeks) included in the systematic review, infants randomized to placement within a polyurethane bag immediately after birth were less likely than control infants to be hypothermic (<36.4°C) on admission to the NICU (44 versus 70 percent) and had higher mean temperature (36.5 versus 36°C) [19]. There appears to be no difference in outcome (mean temperature and incidence of hypothermia) between the conventional polyurethane bags (body wrapped to the shoulder without including the head) and total body wrap bags (both the body and head covered with the face uncovered) [25]. A subsequently published trial of very low birth weight (VLBW) infants reported that the use of polyethylene plastic bags during transport to a tertiary NICU reduced the occurrence of hypothermia [26].
●Body wraps – In a large multicenter trial, the use of occlusive wrap immediately after birth in very preterm (VPT) infants (GA 24 to 27 6/7 weeks) resulted in an increased baseline temperature on admission to the NICU (36.2 versus 35.7°C) [27]. However, there was no difference in mortality between the wrap group and controls (odds ratio [OR] 1.0, 95% CI 0.7-1.5).
●Caps – Higher temperatures on admission to the NICU were observed when polyethylene caps were used in the delivery room [22].
●Transwarmer mattresses – The use of transwarmer mattress during transport from the delivery room to the NICU resulted in higher admission temperature versus standard care [28].
●Heated humidified air for initial respiratory support – Two trials have reported reduced rates of hypothermia on admission to the NICU when heated and humidified gas was used for respiratory support during the stabilization and transport of infants [23,29]. However, the reductions were small and there was no change in mortality or other morbidities.
It is unclear whether a combination of interventions results in excess hyperthermia.
●In one trial of 72 preterm infants (GA <31 weeks), the combination of both polyethylene bags and exothermic mattresses resulted in a greater likelihood of hyperthermia (defined as a rectal temperature >37.5°C) [30].
●In another study, a combination of interventions (increased temperature in the delivery room, use of occlusive warp, transwarmer mattress, and cap) reduced the number of infants with hypothermia (defined as an axillary temperature <36°C) and the intubation rate at 24 hours after delivery [31]. There was no increase in the number of patients with an axillary temperature >37.5°C.
Further investigation is needed to determine the optimal interventions to prevent hypothermia without causing hyperthermia.
Once in the NICU, preterm infants should be cared for in an incubator or radiant warmer to avoid hypothermia.
Resource-limited settings — In resource-limited countries, the use of polyethylene bags for preterm infants with GA between 26 and 36 weeks of age decreased the rate of hypothermia [10,32]. In addition, skin-to-skin contact or kangaroo mother care may be used. However, an observational study reported that the addition of a woolen cap during kangaroo care did not provide any additional benefit to low BW infants (BW <2500 g). Additional efforts are being made to develop alternatives for thermoregulation control in resource-limited settings, including conductive thermal mattresses [33].
Treatment — Although, slow warming (increase <0.5° C per hour) has been the traditional approach to warming infants [9,10]; data are insufficient to recommend either slow or more rapid warming. Environmental temperatures in the delivery or operating rooms are maintained to keep neonatal axillary temperature in a normal range. For infants with hypothermia, we use a radiant warmer to rapidly correct body temperature.
Respiratory abnormalities — Respiratory complications of prematurity include the following:
●Respiratory distress syndrome (RDS) is caused by surfactant deficiency. The incidence and severity of RDS increase with decreasing GA. (See "Clinical features and diagnosis of respiratory distress syndrome in the newborn".)
●Bronchopulmonary dysplasia, also known as chronic lung disease, is a late respiratory complication that commonly occurs in VLBW infants. It is defined as oxygen dependency at 36 weeks postmenstrual age (PMA). (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features".)
●Apnea of prematurity occurs in approximately 25 percent of preterm infants. The incidence of this disorder increases with decreasing GA. (See "Management of apnea of prematurity".)
●Pulmonary hemorrhage occurs most commonly in EPT infants and is associated with increased mortality. This was illustrated in a large retrospective review of data from the multicenter Pediatrix United States Neonatal Intensive Care Units that reported an overall incidence of 0.5 percent and a peak incidence of 9 percent for infants born at 24 weeks gestation [34]. In this cohort, infants with pulmonary hemorrhage had a higher mortality rate than those without pulmonary hemorrhage at seven days of age (41 versus 19 percent), 30 days of age (54 versus 29 percent), and prior to discharge (57 versus 34 percent).
Preterm infants should have continuous monitoring of heart rate and respiration beginning immediately after birth. Oxygenation also should be monitored to avoid the consequences of hypoxia or hyperoxia. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn".)
Cardiovascular abnormalities — Cardiovascular complications in the preterm infant include patent ductus arteriosus (PDA) and systemic hypotension.
Patent ductus arteriosus — Symptomatic patent ductus arteriosus (PDA) is common in preterm neonates, occurring in approximately 30 percent of VLBW infants [8]. The PDA shunts blood flow from left-to-right resulting in increased flow through the pulmonary circulation and decreased perfusion of the systemic circulation. The physiologic consequences of the PDA depend upon the size of the shunt and the response of the heart and lungs to the shunt. Significant shunting may present with a variety of symptoms including apnea, respiratory distress, or heart failure. PDA in the preterm infant is discussed in greater detail separately. (See "Patent ductus arteriosus in preterm infants: Pathophysiology, clinical manifestations, and diagnosis".)
Low blood pressure — Although low blood pressure (BP), without evidence of shock, is commonly observed in neonates, especially in extremely preterm infants, several issues remain unresolved including: do infants with low BP without shock have worse outcomes, is intervention for such low BP beneficial, and if intervention is used, what BP threshold should be used, and what is the optimal choice of therapy [35-37]? These issues and the controversy around management are discussed in greater detail separately. (See "Assessment and management of low blood pressure in extremely preterm infants".)
In contrast, treatment is always initiated for preterm infants with low BP (hypotension) and shock. Evaluation and management of these infants are discussed in greater detail separately. (See "Neonatal shock: Etiology, clinical manifestations, and evaluation" and "Neonatal shock: Management".)
Intraventricular hemorrhage — Intraventricular hemorrhage (IVH) usually occurs in the fragile germinal matrix and increases in frequency with decreasing BW. The incidence of severe IVH (Grades III and IV) is approximately 12 to 15 percent in VLBW infants [3,8].
General preventive measures include prompt and appropriate resuscitation. In addition, efforts should be made to avoid hemodynamic instability and conditions that impair cerebral autoregulation (eg, hypoxia, hypercarbia, hyperoxia, and hypocarbia). (See "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Pathogenesis, clinical presentation, and diagnosis" and "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Prevention, management, and complications".)
Glucose abnormalities — Disorders in glucose supply or metabolism can result in hypoglycemia or hyperglycemia. Blood glucose concentration should be monitored routinely starting within one to two hours after birth and continued until feedings are well established and glucose values have normalized. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia" and "Neonatal hyperglycemia".)
Necrotizing enterocolitis — Necrotizing enterocolitis (NEC) occurs in 2 to 10 percent of VLBW infants. NEC is associated with an increase in mortality. Survivors are at increased risk for growth delay and neurodevelopmental disabilities. In addition, 10 percent of preterm infants with NEC will have long-term gastrointestinal difficulties with persistent loose stools or frequent bowel movements.
The clinical features and treatment of NEC are discussed in detail separately. (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis" and "Neonatal necrotizing enterocolitis: Management".)
Infection — Late-onset sepsis, defined as occurring after three days of age, is a common complication among preterm infants. As an example, in a study from the NICHD Neonatal Research Network, one or more episodes of sepsis (defined as a positive blood culture associated with clinical signs suggestive of infection) occurred in 21 percent of VLBW infants who survived more than three days [38]. Gram-positive organisms caused infection in 70 percent of cases, and coagulase-negative Staphylococcus accounted for 48 percent. Patients who developed late-onset sepsis were more likely to die than those who were uninfected, and survivors had longer hospital stays (79 versus 60 days). Other complications associated with an increased risk of infection included prolonged intubation, bronchopulmonary dysplasia, prolonged intravascular access, PDA, and NEC. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation" and "Group B streptococcal infection in neonates and young infants", section on 'Clinical manifestations'.)
In addition, fungal infection, primarily candidiasis, accounted for 9 percent of cases of late-onset sepsis and was associated with a high mortality rate of 28 percent [39]. (See "Clinical manifestations and diagnosis of Candida infection in neonates".)
Neonatal sepsis is associated with increased likelihood of poor neurodevelopmental outcome and growth impairment. In another report from the NICHD Neonatal Research Network, ELBW survivors who had one episode of neonatal infection compared with those who were uninfected were more likely to have adverse neurodevelopmental outcome and poor growth [40].
Retinopathy of prematurity — Retinopathy of prematurity (ROP) is a developmental vascular proliferative disorder that occurs in the incompletely vascularized retina of preterm infants. The incidence and severity of ROP increase with decreasing GA or BW. The condition typically begins at approximately 34 weeks PMA, although it may be seen as early as 30 to 32 weeks. ROP advances irregularly until 40 to 45 weeks PMA and resolves spontaneously in the majority of infants. However, patients with severe untreated ROP are at increased risk for poor ocular outcome with vision impairment.
ROP and its management are discussed in detail separately. (See "Retinopathy of prematurity: Pathogenesis, epidemiology, classification, and screening".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: What to expect in the NICU (The Basics)" and "Patient education: Retinopathy of prematurity (ROP) (The Basics)" and "Patient education: When a baby is born premature (The Basics)")
SUMMARY
●Overview ‒ Prematurity is defined as a birth that occurs before 37 completed weeks (less than 259 days) of gestation. It is associated with approximately one-third of all infant deaths in the United States and accounts for approximately 45 percent of children with cerebral palsy, 35 percent of children with vision impairment, and 25 percent of children with cognitive or hearing impairment. (See 'Overview' above.)
●Epidemiology ‒ (See 'Epidemiology' above.)
•Complications are divided into short-term complications (eg, respiratory and cardiovascular complications), which occur in the neonatal period, and long-term sequelae (eg, neurodevelopmental disabilities such as cerebral palsy). (See "Long-term outcome of the preterm infant".)
•The risk of complications increases with decreasing gestational age (GA) and birth weight (BW). For very preterm and extremely preterm infants, common complications include bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and brain defects (eg, intraventricular hemorrhage [IVH]).
•In the United States, Black and Hispanic preterm infants have a greater risk of complications than White preterm infants. Asian American preterm infants have comparable rates of BPD, NEC, and IVH compared with White infants but were at greater risk for ROP.
•Initial delivery management may decrease the risk of short-term complications in very preterm infants (GA <32 weeks).
●Short-term complications – The short-term complications most commonly seen include:
•Hypothermia occurs due to rapid heat loss in preterm infants because of their relatively large body surface area and inability to produce enough heat. Hypothermia is associated with increased mortality and, in survivors, intraventricular hemorrhage (IVH), pulmonary insufficiency, hemorrhage, and metabolic disorders (eg, hypoglycemia or acidosis). (See 'Clinical features and risk factors' above.)
Prevention of hypothermia includes standard care measures in the delivery room (ie, maintaining delivery room temperature at a minimum of 26°C, thorough drying of the neonate after delivery, use of prewarmed radiant heaters if resuscitation is needed), and additional measures to reduce heat loss (ie, polyethylene/polyurethane body wrap or bags, and polyethylene or stockinet caps), external heat sources (ie, skin-to-skin care and transwarmer mattress), or the use of heated humidified air for initial respiratory support. (See 'Prevention' above.)
•Respiratory complications of prematurity include respiratory distress syndrome, BPD, apnea of prematurity, and pulmonary hemorrhage. (See "Clinical features and diagnosis of respiratory distress syndrome in the newborn" and "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features" and "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity".)
•Cardiovascular abnormalities include patent ductus arteriosus, low blood pressure, and shock. (See "Patent ductus arteriosus in preterm infants: Pathophysiology, clinical manifestations, and diagnosis" and "Assessment and management of low blood pressure in extremely preterm infants" and "Neonatal shock: Etiology, clinical manifestations, and evaluation".)
•Intracranial hemorrhage – (See "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Pathogenesis, clinical presentation, and diagnosis".)
•Glucose abnormalities include hypoglycemia and hyperglycemia – (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia" and "Neonatal hyperglycemia".)
•Necrotizing enterocolitis – (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)
•Infections in preterm infants include late-onset bacterial and fungal infections. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation".)
•Retinopathy of prematurity – (See "Retinopathy of prematurity: Pathogenesis, epidemiology, classification, and screening".)
