Macrosomia

Etiology

The following underlying factors have been associated with fetal macrosomia, which can be categorized as maternal or fetal etiologies:

• Maternal factors
  • Diabetes: Diabetes in pregnancy includes gestational diabetes (GDM), insulin-dependent, or drug-induced diabetes. Jordan Pederson, in 1920, hypothesized that maternal hyperglycemia is associated with fetal hyperinsulinemia and fetal hyperglycemia, which ultimately leads to the overutilization of glucose by the fetus and, hence, the abnormal increase in growth.[5]
  • Obesity: Globally, there is a current epidemic of obesity. Obesity constitutes a significant risk for diabetes in all demographics. Precisely, maternal obesity is linked to a 4- to 12-fold increase in the prospect of fetal macrosomia. The standard metabolic basis of macrosomia is believed to be increased insulin resistance and hyperinsulinemia. Abnormalities in maternal lipid levels may also play an essential role in the development of macrosomia.[6]
  • Multiparity: Compared to other maternal risk factors, multiparity is not a major risk factor for macrosomia. Still, it can contribute to maternal diabetes and obesity, which are more important causes. Women with parity greater than 3 are prone to have macrosomic babies.[7] An associated 100 to 150-g weight gain can be observed with each pregnancy, thus increasing the risk of macrosomia in the long term in this group of patients.
  • Previous LGA infants: women with previous macrocosmic babies are at a 5- to 10-fold increased risk of another macrosomic baby.
  • Postterm pregnancy: prolonged gestation of more than 42 weeks is more likely linked with an increased chance of macrosomia due to the continuous supply of nutrients and oxygen-rich blood to the developing fetus.
•  Fetal factors 
  • Fetal gender: Male fetal sex is commonly cited as a fetal risk factor for macrosomia. In a retrospective study including nearly 11,000 newborns of mothers with gestational diabetes, male newborns were at a 2-fold increased risk of developing macrosomia compared to female newborns. However, this data seems to be conflicting. In another more extensive retrospective study of 105,000 newborns of mothers with gestational diabetes, the risk of macrosomia was noted to be higher among female newborns.[8]
  • Genetic and congenital disorders: Some congenital disorders have been shown to have associations with macrosomia and LGA fetuses.
    • Beckwith-Weiderman syndrome
    • Sotos syndrome
    • Fragile X syndrome
    • Weaver syndrome

Epidemiology

In 2017, the United States Vital Statistics reported that 7.8% of infants were born weighing >4,000 g, 1% exceeded 4,500 g, and 0.1% had birth weights >5,000 g. Globally, approximately 9% of newborns weigh at least 4,000 g, with 0.1% surpassing 5,000 g, though prevalence varies significantly between regions.[3] Factors, eg, age, race, genetics, and ethnicity, contribute to macrosomia, with Hispanic women being at higher risk compared to other racial groups.[9] Northern European countries report the highest rates, with around 20% of infants born weighing ≥4,000 g, while developing countries report prevalence rates ranging from 1% to 5%, with some variability between 0.5% and 14.9%.[3] 

Pathophysiology

An interplay of physiologic and endocrine changes occurs in pregnancy, aiming to nurture the developing fetus adequately. The primary underlying pathophysiology of macrosomia could be broadly divided into maternal and fetal risk factors. However, maternal hyperglycemia appears to be the most significant factor in the pathogenesis of macrosomia. In the second trimester of pregnancy, an increase in the levels of stress hormones, eg, cortisol, human placenta lactogen (HPL), and prolactin, leads to modest degrees of maternal insulin resistance. This insulin resistance, however, is countered by physiologic postprandial hyperinsulinemia. Patients with metabolic syndrome or other existing risk factors may be unable to mount an adequate hyperinsulinemic response, leading to the development of hyperglycemia. Glucose transfer through the placenta occurs through facilitated diffusion, which results in fetal hyperglycemia. Fetal hyperglycemia, in turn, brings about the hyperplasia of the β-islet cells of the fetal pancreas, leading to overutilization of glucose by the fetus and, hence, an abnormal increase in fetal growth.

Findings from the hyperglycemia and adverse pregnancy outcomes study show a strong linear relationship between maternal glucose concentration and LGA fetuses, fetal adiposity, and fetal hyperinsulinemia.[10] A subsequent meta-analysis of the relationship between macrosomia (weight >4,000 g) and maternal glucose levels in women without diabetes demonstrates that a fasting blood glucose level or any abnormal value on oral glucose tolerance testing is associated with macrosomia. However, the fasting glucose level is more strongly associated with macrosomia. In women with GDM, the risk of macrosomia increases 2- to 3-fold, even with treatment. In a cohort of nearly 13,000 women, LGA newborns occurred in 29% of women with GDM type A1, 30% of women with GDM type A2, and 38% of women with preexisting diabetes.[2] Patients with type A1 GDM typically have an abnormal glucose tolerance test but can keep blood glucose levels in the normal range with dietary changes alone. Patients with type A2 GDM usually have an abnormal glucose tolerance test and abnormal glucose levels during fasting and after meals.

History and Physical

Pregnancy is a physiologic state that requires close monitoring and evaluation from the time of initial diagnosis to the expulsion of all products of conception. High-risk pregnancies require close monitoring, with varied management when indicated. Therefore, antenatal care involves continued assessment for the timely identification of risk factors.

History

 A detailed history should be taken at the initial visit as well as in subsequent prenatal follow-up visits. Please see StatPearls' companion resources, "Initial Antepartum Care" and "Antepartum Care in the Second and Third Trimester," for more detailed information. In general, an obstetric history should include:

•  The first day of the last menstrual period (LMP) and current estimated gestational age
•  Parity
•  Prepregnancy weight
•  Immunization history
•  Previous or preexisting medical conditions, including diabetes, obesity, polyhydramnios, Rh incompatibility
•  Past pregnancies, including previous macrosomic infants' mode of delivery, associated complications, child gender

Additionally, recognizing early indicators of this condition is essential because GDM is a significant risk factor for macrosomia. Because early screening is indicated by clinical history and assessment, documenting past medical history, obstetric outcomes, and family history of type 2 diabetes are essential components of GDM assessment. The clinical features of GDM can be varied. The disproportionate weight gain, obesity, and elevated body mass index (BMI) can be suggestive features.[11] 

ACOG recommends targeted evaluation for type 2 diabetes early in pregnancy with a 75-g or 50-g oral glucose tolerance test at the initial prenatal visit in patients who have a BMI of 30 kg/m² or more and 1 of the following risk factors:

• History of GDM 
• Hemoglobin A1C ≥5.7% on previous testing
• Immediate family member with diabetes
• High-risk race (eg, African American, Latin American, Native American, Asian American, Pacific Islander)
• Cardiovascular disease history
• Hypertension 
• High-density lipoprotein (HDL) cholesterol level <35 mg/dL or a triglyceride level >250 mg/dL
• Polycystic ovary syndrome
• Physical inactivity [12][11]

Physical Examination

 A detailed physical examination should include monitoring of patient weight at each prenatal visit that should be correlated with suggested United States Institute of Medicine guidelines (IOM) as follows:

• A weight gain of 28 to 40 lbs (12-18 kg) for patients with a BMI of <18 kg/m² 
• A weight gain of 25 to 35 lbs (11.5-16 kg) for patients with a BMI between 18.5 to 24.9 kg/m²
• A weight gain of 15 to 25 lbs (7-11.5 kg) for patients with a BMI between 25.0 to 29.9 kg/m²
• A weight gain of 11 to 20 lbs (5-9 kg) for patients with a BMI >30 kg/m²

Any aberrations of the patient's weight should prompt a repeat abdominal examination with fundal height measurement correlated with the patient's gestational age and the obstetric clinician's subsequent performance of the Leopold maneuver. Please see StatPearls' companion resource, "Leopold Maneuvers," for further information. According to ACOG, weighting the newborn after delivery is the most accurate way to diagnose macrosomia, and no singular modality such as the Leopold maneuver, fundal height measurement, or an ultrasound scan can effectively diagnose macrosomia. On the other hand, a combination of these factors should warrant a very high suspicion index.[2]

Evaluation

Maternal Gestational Diabetes Screening and Diagnostic Testing

Maternal hyperglycemia is a significant cause of fetal macrosomia. Several laboratory and aneuploid screening studies are performed during the second trimester to provide optimal time for potential interventions. ACOG and the United States Preventive Services Task Force (USPSTF), as well as other professional societies, recommend that laboratory studies for gestational diabetes be performed in all pregnant individuals between 24 and 28 weeks gestation. However, the screening method and cut-off thresholds vary among experts.[11]

The 2-step screening approach, recommended by the ACOG, starts with a nonfasting 1-hour 50-g glucose challenge test. This initial test can be conveniently integrated into routine prenatal visits and is more straightforward to implement. Most women who undergo the 1-hour glucose challenge test do not require further testing, as they do not meet the threshold for abnormal glucose levels. However, approximately 20% of women fail this initial screening and subsequently undergo a 3-hour fasting diagnostic oral glucose tolerance test (OGTT) to confirm GDM diagnosis. This additional step aims to reduce unnecessary testing and intervention for those who do not have GDM. Different cut-off thresholds are used for the 50-g glucose tolerance screening to be considered an abnormal result, including ≥135 mg/dL (7.5 mmol/L), ≥130 mg/dL (7.22 mmol/L), and ≥140 mg/dL (7.8 mmol/L). Because studies have not demonstrated an optimal cut-off threshold, clinicians should determine which cut-off to implement based on the prevalence of community gestational diabetes risk factors and clinical preference for test sensitivity and specificity.[13]

In patients with a positive 50-g glucose screen, a diagnostic test using a 100-g 3-hour OGTT is necessary.[11] The following values are used as parameters for abnormal results for a 3-hour OGTT:

• Fasting: ≥95 mg/dL
• First hour: ≥180 mg/dL
• Second hour: ≥155 mg/dL
• Third hour: ≥140 mg/dL [11]

The presence of ≥2 abnormal results establishes the diagnosis of gestational diabetes.[11] Please see StatPearls' companion resource, "Gestational Diabetes," for further information on GDM diagnostic studies and management. Other maternal evaluations should include:

•  Blood pressure monitoring to rule out preeclampsia
•  Complete blood count (CBC)
•  Urinalysis
•  BUN
•  Creatinine
•  Lipid profile
•  Liver function tests (LFT)

Additionally, in patients who are identified as having high-risk pregnancies or clinical suspicion of a pregnancy complication (eg, fundal height greater than gestational age), ultrasound imaging may be performed for diagnostic evaluation or as part of antenatal surveillance. Typically, fetal growth assessments require serial ultrasounds performed at at least 4-week intervals.[14] See StatPearls' companion reference, "Sonography 3rd Trimester and Placenta Assessment, Protocols, and Interpretation," for further information. Furthermore, antenatal fetal surveillance may be indicated in patients with medication-controlled or uncontrolled diabetes.[15] 

Neonatal Evaluation 

Macrosomic neonates are at risk of various metabolic derangements and should be monitored closely. Laboratory measurements of the following electrolytes should be taken immediately after delivery:

• Glucose: With the sudden withdrawal of the glucose-rich in-utero environment, neonates born to mothers with GDM are prone to hypoglycemia.
• Calcium: In macrosomic neonates, hypocalcemia and tetany can occur.
• Magnesium levels: hypomagnesemia can also occur
• Bilirubin: Elevated bilirubin levels may occur due to inefficient enterohepatic circulation and increased hemolysis if polycythemia also exists.
• Complete blood count: This study should be performed in macrosomic neonates to check for polycythemia.

Clinical evaluation of the neonate's respiratory effort after birth is also essential as meconium aspiration due to fetal distress and transient tachypnea of the newborn (TTN) are common and tend to occur 2 to 3 times more frequently in macrocosmic babies, especially if secondary to GDM.

Treatment / Management

Dietary and Weight Management Approaches

The ADA and ACOG also recommend nutritional counseling by a registered dietitian and the development of a personalized plan based on the patient's BMI to ensure that the patient's caloric demand is met while avoiding excessive weight gain. Clinicians can also advise patients regarding general dietary modifications, including consuming 3 small to moderate-sized meals and 2 to 3 snacks daily comprised of whole-grain carbohydrates, protein, and unsaturated fats with less carbohydrate at breakfast due to increased carbohydrate intolerance during that time. ACOG recommends a diet lower in carbohydrates; however, the optimal ratio of specific macronutrients in patients with GDM has not been determined. Some studies have also found that combining carbohydrates with lean proteins can help reduce postprandial hypoglycemia. To prevent ketosis at night, which can have adverse effects on fetal neurodevelopment, a bedtime snack is often recommended.[16]

Gestational weight gain may also affect pregnancies complicated by GDM. Maternal obesity and excessive weight gain have been associated with an increased risk of fetal macrosomia, gestational diabetes, gestational hypertension, preeclampsia, and Cesarean section.[17][18] Obese women also have an increased risk of antepartum cardiac dysfunction, proteinuria, nonalcoholic fatty liver disease, and sleep apnea, as well as intrapartum complications, including endometritis, labor induction failure, venous thrombosis, and wound dehiscence. Macrosomia, which has a higher incidence in those who are obese, is also associated with maternal complications (eg, protracted or arrest of labor, uterine rupture, genital tract lacerations, and postpartum hemorrhage). Additionally, macrosomic neonates have an increased risk of shoulder dystocia, clavicular fractures, brachial plexus injuries, and nerve palsies. A recent meta-analysis showed the highest risk of adverse outcomes occurred in women with a BMI of over 40 and a high total gestational weight gain.[19] The same meta-analysis recommended the following range for gestational weight gain for each prepregnancy weight class:

• Underweight (BMI <18.5): 14 to <16 kg
• Normal weight (BMI 18.5 to 24.9): 10 to <18 kg
• Overweight (BMI 25 to 29.9): 2 to <16 kg
• Obesity grade 1 (BMI 30 to 34.9): 2 to <6 kg
• Obesity grade 2 (BMI 35 to 39.9): weight loss or gain of 0 to <4 kg
• Obesity grade 3 (BMI ≥40): 0 to <6 kg [19]

These gestational weight gain ranges for patients with obesity grades 1, 2, or 3 were lower than those recommended by the US National Academy of Medicine guidelines, which recommend 5 to 9 kg in this population.[17] Obese individuals are more prevalent than underweight patients and continue to increase, with a reported prevalence in the US of approximately 34%.[20] Antepartum weight loss is not recommended due to an associated risk of small for gestational age infants. Therefore, in obese pregnant women, the primary management involves diet and behavioral modifications and increased exercise.[20] 

Preventative measures such as exercise during pregnancy, a low-glycemic diet for women with gestational diabetes, and prepregnancy bariatric surgery for individuals with severe obesity have shown promise in reducing macrosomia risk. Exercise interventions during pregnancy, particularly those combining aerobic and resistance training, have been associated with lower rates of macrosomia, fewer large-for-gestational-age newborns, and reduced weight gain without increasing risks of preterm delivery or small-for-gestational-age newborns.[2][4] The amount of exercise recommended in patients with GDM is 30 minutes of moderate-intensity aerobic exercise at least 5 days a week or a minimum of 150 minutes per week. Additionally, postprandial exercise is often recommended as this has been shown to help control glucose levels for up to 3 hours after eating.[16][2](A1)

Obstetrical Management Approaches

Pregnancies complicated by fetal macrosomia in patients with preexisting or gestational diabetes and improved glycemic control via recommended pharmacologic and other interventions will lead to a reduction in the risk of perinatal complications. Induction of labor (IOL), which was widely recommended until recently, has been discouraged due to the lack of clear evidence on its significance in the management of macrosomia. Inducing labor for suspected fetal macrosomia has not been conclusively shown to reduce the risk of brachial plexus injury, though the rarity of such injuries limits the statistical power of studies to detect a significant effect.[4] However, ACOG states that patients with fetal macrosomia or an LGA fetus are not indications for IOL before 39 0/7 weeks gestation.[2](A1)

Additionally, prenatal weight estimates are often imprecise, leading to potentially unnecessary anxiety and inductions. Despite this, labor induction for suspected macrosomia has been linked to lower average birth weights, fewer occurrences of birth fractures, and reduced shoulder dystocia rates, though it is associated with an increased need for phototherapy in some cases. A recent Cochran review suggested that preventing 1 birth fracture may require inducing labor in approximately 60 women.[4] However, this review also demonstrated that induction did not appear to increase cesarean or instrumental delivery rates. Therefore, patients and clinicians may prefer IOL due to the potential complications of macrosomia. Decisions regarding induction should involve thorough discussions with parents and shared decision-making.[4](A1)

The role of cesarean delivery for suspected macrosomia remains controversial. While cesarean birth may reduce the risk of severe birth trauma in cases of extreme macrosomia, its use for estimated fetal weights below specific thresholds, particularly in women without diabetes, is not supported by current evidence due to the inaccuracy of prenatal weight estimates and the associated maternal risks. ACOG recommends an elective cesarean delivery may be considered in women with pregnancies complicated by macrosomia if the estimated fetal weight is above 5000 g with no underlying GDM or 4500 g in women with GDM.[21][2][21] Assisted vaginal delivery, such as forceps or vacuum-assisted deliveries, should be performed with significant caution in women with macrosomic pregnancies. Individualized counseling is critical, emphasizing the challenges in predicting shoulder dystocia, the low overall risk of brachial plexus injury, and the limitations of cesarean birth in eliminating such risks. Ultimately, for pregnancies complicated by suspected macrosomia, management decisions should balance maternal and neonatal risks, consider the limitations of diagnostic tools, and prioritize patient-centered discussions to guide choices regarding induction, vaginal delivery, or cesarean birth.[2]

Differential Diagnosis

 Differential diagnoses that should also be considered when evaluating macrosomia include:

• Polyhydramnios
• Inaccurate estimation of gestational age
• Multiple gestations
• Uterine anatomic lesions, eg, uterine myoma, adenomyosis
• Pelvic masses (eg, ovarian masses)
• Morbid obesity
• Postterm pregnancies

Treatment Planning

The ACOG recommends against delivery before 39 0/7 weeks of gestation unless medically indicated. At this time, and until additional studies are reported, suspected macrosomia or LGA fetus is not an indication for induction of labor before 39 0/7 weeks of gestation because of insufficient evidence that the benefits of reducing shoulder dystocia risk would outweigh the harms of early delivery.[10]

Prognosis

A patient who delivers a macrosomic infant should be screened very carefully for previously undiagnosed diabetes. If such screening is negative, they should be monitored carefully in subsequent pregnancies. The goal of scheduled cesarean birth for suspected macrosomia is to reduce fetal morbidity or maternal morbidity, or both. Although fetal and maternal morbidity increases with birth weights >4,000 g, most births of macrosomic newborns are uncomplicated.[10]

Complications

Pregnancies complicated by macrosomia are inherently at an increased risk of adverse outcomes depending on the degree of macrosomia. At ≥5000g, an increased risk of stillbirth or neonatal death is present.[22][10] Macrosomia and its complications can be subdivided into the following broad categories:

•  Maternal complications
  • Postpartum hemorrhage (PPH): PPH typically refers to excessive blood loss (>500 mL) with vaginal delivery or loss of 1000 mL of blood or greater with the cesarean section. PPH is the leading cause of maternal mortality worldwide, as well as in industrialized nations, and is one of the top 3 causes of maternal mortality. One of the most significant contributors to PPH is uterine atony, which arises from the over-distention of the pregnant uterus and can be further complicated by macrosomic pregnancies.
  • Perineal trauma of various degrees: this arises from the prolongation of the second phase of labor and operative vaginal deliveries, both of which are associated with the delivery of macrosomic babies.
  • Prolongation of the second phase of labor [23][24]
•  Fetal complications
  • Shoulder dystocia: This is the mechanical inability to deliver the anterior fetal shoulder after delivery of the fetal head and is also associated with injury to the clavicle and brachial plexus. The occurrence of shoulder dystocia after vaginal deliveries varies with the weight of the newborn. A 1% chance of shoulder dystocia in newborns with a birth weight <4000 g and about a 5% to 10% chance for newborns with a birth weight of 4000 to 4500 g is present.[25]
  • Fetal distress
  • Congenital anomalies associated with infants of diabetic mothers, including congenital heart diseases, caudal regression syndrome, small left colon syndrome, spinal bifida
  • Metabolic and electrolyte imbalance, eg, hypocalcemia, hypomagnesemia, hyperinsulinemia, hypoglycemia
  • Polycythemia
  • Hyperbilirubinemia