INTRODUCTION — Infants who are born large for gestational age (LGA), especially full-term or post-term infants, are at risk for perinatal morbidity and potentially long-term metabolic complications.
The pathogenesis, epidemiology, risk factors, complications, and management of infants born LGA will be reviewed here.
DEFINITION — In general, LGA is defined as a birth weight (BW) greater than the 90th percentile for age. However, it has been suggested that the definition be restricted to infants with BW greater than the 97th percentile (2 standard deviations above the mean), as this more accurately describes infants who are at greatest risk for perinatal morbidity and mortality (figure 1) [1,2]. Using a national reference based on single live births in the United States, infants born at 40 weeks gestation at the 90th percentile had BW greater than 4000 g, and those at the 97th percentile had BW greater than 4400 g [3].
Macrosomia refers to excessive intrauterine growth beyond a specific threshold regardless of gestational age (GA). This condition is usually defined as a BW greater than 4000 or 4500 g. The American College of Obstetricians and Gynecologists (ACOG) supports use of the 4500 g threshold for diagnosis of macrosomia because morbidity increases sharply beyond this weight.
A grading system for macrosomia has been proposed based on BW (see "Fetal macrosomia", section on 'Definition'):
●Grade 1 – 4000 to 4499 g
●Grade 2 – 4500 to 4999 g
●Grade 3 – >5000 g
Term infants who are appropriate for gestational age have BW between 2500 and 3999 g.
INCIDENCE — Among term liveborn infants in the United States born in 2008, the incidence of LGA based on the above grades of macrosomia is 6.6, 0.9, and 0.1 percent for BW of 4000 to 4499 g, 4500 to 4999 g, and >5000 g, respectively [4]. The birth rates for all three grades of LGA have declined in the United States from 1990 to 2008 [4]. However, in other countries (eg, Sweden and Australia), the reported incidence of LGA births has increased [5,6]. In these countries, the rise in proportion of neonates born LGA was thought to be due to a decreased exposure to prenatal smoking, increases in maternal age and weight, and gestational diabetes.
RISK FACTORS AND ETIOLOGY — Although the mechanisms that control fetal weight gain and growth are poorly understood, excessive fetal growth appears to be due to increased delivery of nutrients to the fetus, which is influenced/caused by genetic factors and intrauterine environmental factors, or a combination of the two.
●Genetic factors – In a number of genetic syndromes, macrosomia is a characteristic feature [2].
•There is ethnic variability in the incidence of LGA infants.
•Familial trait – Mothers who were LGA are more likely to deliver an LGA infant than mothers who were appropriate for gestational age.
●Intrauterine environmental factors – LGA infants are more likely to be delivered to mothers who are obese, who have diabetes, and those with excessive gestational weight gain [7]. These maternal conditions result in excessive delivery of nutrients to the fetus, which contributes to increased fetal growth.
●Epigenetic factors – Limited data suggest that placental epigenetic alterations may contribute to increased fetal growth [8-11].
Genetic factors
Genetic syndromes — Several genetic disorders are characterized by early excessive growth resulting in an LGA infant. They include Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, Sotos syndrome, Weaver syndrome, and Berardinelli lipodystrophy (table 1).
Race and ethnicity — Racial and ethnic factors influence birth weight (BW). In a study from the United States that included all term, singleton live births from 1995 to 1997, mothers who were White, American Indian, or Samoan were disproportionately overrepresented in the group with LGA offspring [2]. In another report of mothers with gestational diabetes, macrosomia occurred significantly more often in Latino than in Black infants (50 versus 19 percent) [12].
Maternal factors
Maternal diabetes — Macrosomia is common in infants of diabetic mothers (IDMs), especially when maternal diabetes is poorly controlled. Excessive delivery of nutrients to the fetus results in fetal hyperglycemia, hyperinsulinemia, and increased growth. In IDMs, macrosomia is also associated with disproportionate growth with an increased ponderal index that results in higher chest-to-head and shoulder-to-head ratios, higher body fat, and thicker upper extremity skinfolds compared with LGA offspring of nondiabetic mothers (picture 1). This disproportionate macrosomia increases the risk of birth injuries, especially shoulder dystocia. (See "Infants of women with diabetes", section on 'Macrosomia' and "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management".)
Maternal prepregnancy weight — The risk of an LGA offspring increases in a linear fashion as the prepregnancy maternal weight rises. As a result, the highest risk of delivering an LGA infant occurs in obese mothers. This relationship is independent of the increased prevalence of gestational diabetes in obese women. The evidence for the effect of maternal prepregnancy weight on BW is presented separately. (See "Obesity in pregnancy: Complications and maternal management", section on 'Large for gestational age'.)
Excessive maternal weight gain — Excessive maternal weight gain during pregnancy is associated with macrosomia. Women with normal prepregnancy body mass index who gained more than 35 lbs (15.9 kg) had an almost 2.5 times greater risk of delivering an LGA infant compared with mothers who gained between 25 and 35 lbs (11.3 and 15.9 kg) [13]. The amount of weight gain associated with an LGA birth is lower in women who are overweight or obese, as discussed separately. (See "Obesity in pregnancy: Complications and maternal management", section on 'Large for gestational age' and "Gestational weight gain", section on 'Recommendations for gestational weight gain' and "Gestational weight gain", section on 'Overweight and obese pregnant people'.)
Other factors — Other factors that are associated with the birth of LGA infants include multiparity, advanced maternal age, post-term pregnancy, male infant, birth of a previous LGA infant, and maternal BW greater than 4000 g.
NEONATAL MORBIDITY
Overview — Neonatal morbidity for term infants is greater in LGA infants (birth weights [BWs] above 4000 g) compared with appropriate for gestational age (AGA) infants (BW between 2500 and 3999 g) [2,14]. In addition, morbidity increases as the BW increases above 4000 g.
This was best illustrated in a study that analyzed data that included all singleton live births in the United States from 1995 to 1997 with a gestational age between 37 and 44 weeks of gestation [2]. Logistic regression analysis demonstrated that the risk of several neonatal complications was greater in LGA infants compared with infants who were AGA (BW 3000 to 3999 g), and the frequency increased with increasing severity of macrosomia as follows:
●Compared with AGA infants, the risk of birth injuries was twofold, threefold, and fourfold greater for infants with grade 1 (BW between 4000 and 4499 g), grade 2 (BW between 4500 and 4999 g), and grade 3 (BW >5000 g) macrosomia, respectively.
●Mechanical ventilation for more than 30 minutes duration was 1.19 (95% CI 1.14-1.23), 1.85 (95% CI 1.73-1.99), and 3.96 (95% CI 3.45-4.55) times greater for infants with grades 1, 2, and 3 macrosomia, respectively.
●The risk of a five-minute Apgar score lower than 3 was 1.3 (95% CI 1.21-1.39), 2 (95% CI 1.76-2.29), and 5.2 (95% CI 4.09-6.62) times greater for infants with grades 1, 2, and 3 macrosomia, respectively.
●The risk of respiratory distress syndrome (RDS; referred to as hyaline membrane disease) was 1.15 (95% CI 1.1-1.22), 1.84 (95% CI 1.68-2.01), and 3.7 (95% CI 3.11-4.4) times greater for infants with grades 1, 2, and 3 macrosomia, respectively.
●The risk of meconium aspiration was 1.28 (95% CI 1.23-1.34), 1.65 (95% CI 1.52-1.79), and 2.61 (95% CI 2.15-3.16) times greater for infants with grades 1, 2, and 3 macrosomia, respectively.
●Neonatal mortality was only increased in infants with grade 3 macrosomia and was 2.69 (95% CI 1.91-3.8) times greater than the mortality rate in AGA infants.
Macrosomia is also associated with significant maternal morbidity, including an increased likelihood of cesarean delivery, severe postpartum hemorrhage, and vaginal lacerations. (See "Fetal macrosomia" and "Shoulder dystocia: Intrapartum diagnosis, management, and outcome", section on 'Maternal'.)
The increased morbidity seen in LGA infants results in a higher utilization of neonatal intensive care compared with AGA infants, as illustrated by a study from the Arizona Neonatal Intensive Care Program (NICP) of infants born between 1994 and 1998 [15]. In this study, LGA infants with BW >4000 g were more likely to be enrolled in the NICP (criteria included admission to a neonatal intensive care unit [NICU] for a prolonged stay [>72 hours], readmission to a NICU, or transport to a NICU) compared with AGA infants with BWs between 2500 and 3999 g (2.7 versus 2.1 percent). The four most common diagnoses in LGA infants, which accounted for 53 percent of the admission diagnoses, were respiratory distress (19 percent), transient tachypnea of the newborn infant (16 percent), hypoglycemia (9 percent), and meconium aspiration (9 percent).
Birth injury — Macrosomia predisposes to shoulder dystocia and birth injury, including brachial plexus injury and clavicular fracture [2,16,17]. As previously noted, the risk of birth injury increases with the severity of macrosomia [2]. In addition, the rate of birth injury for LGA infants is greater in vaginal compared with cesarean deliveries. In one large case series, birth injury was three times more likely when LGA infants (BW 4500 to 5000 g) were the product of vaginal compared with cesarean delivery (9.3 versus 2.6 percent) [16].
The neonatal complications of shoulder dystocia are discussed in greater detail separately. (See "Shoulder dystocia: Intrapartum diagnosis, management, and outcome", section on 'Infant'.)
Respiratory distress — As noted above, LGA infants are more likely to develop respiratory distress than AGA infants [2,15]. This is primarily due to the increased risk of RDS, especially in infants of diabetic mothers (IDMs), who are more likely to be delivered prematurely. The higher incidence of cesarean deliveries in LGA infants appears to increase the risk of transient tachypnea of the newborn. In addition, meconium aspiration is a common respiratory complication in LGA infants, perhaps due to the increased risk of perinatal depression. (See "Infants of women with diabetes", section on 'Respiratory distress' and "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis" and "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis", section on 'Pathophysiology' and "Transient tachypnea of the newborn".)
Preterm birth — There may be an increased risk of preterm birth, as illustrated in a study from the Dutch perinatal registry of singleton birth in nulliparous women from 1999 to 2010 [18]. In this large cohort, the risk of preterm birth between 25 and <37 weeks gestation was greater in LGA (BW >97th percentile for age) compared with those born AGA (11.3 versus 7.3 percent, odds ratio [OR] 1.8, 85% CI 1.7-1.9).
Other abnormalities — LGA infants have increased intrauterine exposure to excessive nutrients, especially glucose, which may result in hyperinsulinemia, increased utilization of oxygen and glucose, and oxidative stress [19,20]. These abnormalities may lead to perinatal complications, including hypoglycemia, polycythemia, and asphyxia.
Hypoglycemia — LGA infants can develop hypoglycemia when the placental supply of glucose is interrupted at birth. In a report based upon data from the Netherlands Perinatal Registry from 1997 to 2002, the incidence of hypoglycemia was approximately 19 and 15 percent in all LGA infants and in LGA infants of nondiabetic mothers, respectively [21]. Seizures due to hypoglycemia occurred in 0.3 percent of all LGA infants and in 0.2 percent of LGA infants without maternal diabetes. In another large case series of 887 German LGA infants (defined as a BW >90th percentile) who were tested for hypoglycemia, 16 percent had hypoglycemia (blood glucose level <40 mg/dL) during the first 24 hours of life [22]. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Increased glucose utilization' and "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Who should be screened?'.)
Polycythemia — Polycythemia occurs more frequently in LGA infants of both diabetic and nondiabetic mothers compared with AGA infants [23]. The mechanism of polycythemia is thought to be due to an increased production of erythropoietin, which results from fetal hypoxia caused by the increased oxidative demands associated with hyperglycemia and hyperinsulinemia. (See "Neonatal polycythemia".)
Perinatal asphyxia — Macrosomic infants are at increased risk for perinatal asphyxia, especially IDMs. Indirect evidence of the increased risk of perinatal asphyxia in LGA infants is the higher frequency of low Apgar scores in LGA compared with AGA infants [1,2,16,24]. Contributing factors are thought to be increased intrauterine oxygen utilization due to fetal hyperglycemia and hyperinsulinemia, especially in IDMs, and complications of delivery related to shoulder dystocia. (See "Infants of women with diabetes", section on 'Perinatal asphyxia' and "Shoulder dystocia: Intrapartum diagnosis, management, and outcome", section on 'Infant'.)
Congenital anomalies — Minor congenital anomalies are more common in LGA than AGA infants. This was evaluated in a retrospective case-control study of more than two million births in Latin America, of which 1800, out of 31,897 infants with congenital anomalies, were LGA [25]. The most common anomalies associated with macrosomia included:
●Talipes calcaneovalgus and hip subluxation caused by intrauterine deformation
●Hydrocephaly and combined angiomatoses reflect increased body mass and fluid, and thus increased BW
●Non-brown pigmented nevi
NEONATAL MORTALITY — Increased mortality is associated with LGA and may only occur in the most severe grade of macrosomia. As noted above, in a study of all singleton, term live births between 1995 and 1997, the neonatal mortality rate was only higher in infants born with grade 3 macrosomia (BW >5000 g) compared with AGA infants (adjusted odds ratio [aOR] 2.69, 95% CI 1.91-3.8) [2]. Similar results were noted in a Canadian study that reported more than a twofold increased risk of deaths in term infants with BW greater than the 97th percentile compared with AGA term infants [24].
Neonatal mortality is also higher in LGA preterm infants compared with AGA infants born at the same gestation. In a retrospective cohort study of preterm infants (gestational age <29 weeks) from the Canadian Neonatal Network and Canadian Neonatal Follow-Up Network databases, LGA infants compared with AGA infants had a higher risk of death (26 versus 18 percent, aOR, 1.6, 95% CI 1.0-2.54) [26].
PRETERM INFANTS — Unlike term infants, preterm infants who are LGA may have lower mortality and morbidity than appropriate for gestational age (AGA) infants with the same gestational age (GA). This was illustrated by a retrospective review of data from the Vermont Oxford Network of preterm infants (GA 22 to 29 weeks) born between 2006 and 2014 [27]. Compared with AGA infants, LGA preterm infants had decreased risks of mortality, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, late-onset sepsis, severe retinopathy of prematurity, and chronic lung disease. However, LGA infants were more likely to have early-onset sepsis and severe intraventricular hemorrhage, but these findings were not consistent across GA range. These data suggest that for preterm infants, large birth weight may be a protective factor resulting in better outcomes. These findings are limited, as they were based on a review of the medical record without validation of GA and need to be confirmed in other cohorts, preferably in a prospective study with validation of GA.
NEONATAL MANAGEMENT — Neonatal management of LGA infants includes screening and treating complications associated with macrosomia; determining, if possible, the etiology of increased growth; and providing routine newborn care.
●Prior to delivery, an assessment of the need for neonatal resuscitation is made based on the gestational age, anticipated birth weight, presence of a congenital anomaly or labor complications, mode of delivery (eg, cesarean delivery), and maternal history. (See "Neonatal resuscitation in the delivery room", section on 'Anticipation of resuscitation need'.)
●Immediately after delivery, routine neonatal care is provided that includes drying, clearing the airway of secretions, maintaining warmth, and a rapid assessment of the infant's clinical status based on respiratory effort, tone, heart rate, and an examination to identify any major congenital anomaly or genetic syndrome. The need for further intervention is based on this initial evaluation. If the infant does not require additional resuscitation, the infant should be given to the mother for skin-to-skin care and initiation of breastfeeding in the delivery room. LGA infants should be fed as quickly as possible after delivery to avoid hypoglycemia. (See "Neonatal resuscitation in the delivery room", section on 'Resuscitation' and "Overview of the routine management of the healthy newborn infant", section on 'Delivery room care'.)
●Further evaluation following transition from the delivery room includes a comprehensive examination to identify any underlying genetic syndrome (table 1), any evidence of birth trauma (eg, perinatal depression, brachial plexus injury, or clavicular fracture), or congenital defects. (See 'Genetic syndromes' above and 'Birth injury' above and 'Congenital anomalies' above.)
●Laboratory screening for hypoglycemia and polycythemia should be performed within the first hours following birth. (See 'Hypoglycemia' above and 'Polycythemia' above and "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Screening' and "Neonatal polycythemia", section on 'Diagnosis'.)
●If there are no significant complications that require further intervention, routine newborn care should be provided. (See "Overview of the routine management of the healthy newborn infant".)
POTENTIAL LONG-TERM EFFECTS — Individuals of both diabetic and nondiabetic mothers who were born LGA may have long-term metabolic effects that increase the risk of obesity [28,29] and insulin resistance [30-33]. Ongoing studies will be needed to see whether effects increase the incidence of adult diseases, such as obesity, diabetes, and cardiovascular disease.
Limited data suggest neurodevelopmental outcome is similar for LGA and AGA infants.
●In a study of 2930 children from the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B), the cognitive function of 271 children with birth weights (BWs) ≥90th percentile did not differ from that of children with normal BW (defined as between the 5th and 89th percentile) at 9 months, and 2, 3.5, and 5.5 years of age [34]. By contrast, there are small observational studies that suggest infants born to mothers with poorly controlled diabetes may be at risk for developmental abnormalities, but the quality of evidence is poor. (See "Infants of women with diabetes", section on 'Neurodevelopmental outcome'.)
●In the previously described Canadian retrospective cohort study of preterm survivors born (gestational age <29 weeks), the risk of significant neurodevelopmental outcome (defined as severe cerebral palsy; Bayley III cognitive, language, and motor scores of <70; need for hearing aids or cochlear implant; and bilateral visual impairment) at 18 to 21 months corrected age were similar for those born LGA compared with those born AGA (15.3 versus 16.7 percent, adjusted odds ratio 0.97, 95% CI 0.55-1.72) [26].
SUMMARY AND RECOMMENDATIONS — Infants who are born large for gestational age (LGA), especially full-term or post-term infants, are at risk for perinatal morbidity and potentially long-term metabolic complications.
●Although LGA has been defined as a birth weight (BW) greater than the 90th percentile, it has been proposed that a higher threshold of at least the 97th percentile be used because this more accurately describes infants who are at greatest risk for perinatal morbidity and mortality (figure 1). At 40 weeks gestation, infants at the 90th and 97th percentile weigh more than 4000 or 4400 g. The American College of Obstetricians and Gynecologists (ACOG) uses a 4500 g threshold for the diagnosis of macrosomia (ie, excessive fetal growth). (See 'Definition' above.)
●In the United States, the incidence of LGA for infants born at 40 weeks gestation is 6.6, 0.9, and 0.1 percent based on BWs of 4000 to 4499 g, 4500 to 4999 g, and >5000 g, respectively. Although the incidence of LGA has declined in the United States, it appears to be increasing in other countries due to increases in maternal age and weight, gestational diabetes, and decreases in maternal smoking. (See 'Incidence' above.)
●Excessive fetal growth (macrosomia) resulting in LGA is associated with genetic factors (eg, syndromes such as Beckwith-Wiedemann (table 1)), intrauterine environmental factors (eg, maternal diabetes and obesity, excessive maternal weight gain), and other maternal factors, such as advanced maternal age and multiparity. (See 'Risk factors and etiology' above.)
●Neonatal complications are more frequent in infants who are LGA compared with those who are born appropriate for gestational age (AGA). Complications associated with LGA include:
•Birth injuries (eg, brachial plexus injury, perinatal asphyxia, and clavicular injury) primarily due to shoulder dystocia (see 'Birth injury' above)
•Respiratory distress generally due to respiratory distress syndrome, transient tachypnea of the newborn, or meconium aspiration (see 'Respiratory distress' above)
•Hypoglycemia (see 'Hypoglycemia' above)
•Polycythemia (see 'Polycythemia' above)
●Neonatal mortality appears to be increased only in LGA term infants with BWs >5000 g compared with AGA term infants. (See 'Neonatal mortality' above.)
●The management of an LGA infant includes screening and treating any complication associated with macrosomia; determining, if possible, the etiology of macrosomia; and providing routine newborn care. We recommend that in the first few hours following delivery, laboratory evaluation includes measurement of blood glucose and hematocrit (Grade 1B).
●Individuals of both diabetic and nondiabetic mothers who were born LGA may have long-term metabolic effects that increase the risk of obesity and insulin resistance. (See 'Potential long-term effects' above.)
