What are the causes and risk factors for a large for gestational age (LGA) newborn in pregnant women, particularly those with gestational diabetes, obesity, and a history of delivering LGA babies?

Causes of Large for Gestational Age (LGA)

The primary modifiable causes of LGA are maternal pre-pregnancy obesity, excessive gestational weight gain, and poorly controlled gestational diabetes, while non-modifiable risk factors include multiparity, prior history of LGA delivery, maternal height, and genetic predisposition. 1

Maternal Metabolic Factors

Diabetes and Hyperglycemia

• Gestational diabetes mellitus (GDM) is the single most common risk factor for LGA, with maternal glucose concentration showing a continuum relationship with birth weight 1, 2
• Maternal hyperglycemia creates an adverse intrauterine environment where excess glucose crosses the placenta, stimulating fetal insulin production and promoting excessive fetal growth and adiposity 1
• Pre-existing Type 1 diabetes mellitus significantly increases LGA risk, with undiagnosed and untreated GDM carrying up to 20% macrosomia risk 1, 3
• Delivery past 38 weeks in GDM pregnancies leads to progressive macrosomia without reducing cesarean delivery rates 1, 3

Maternal Weight and Weight Gain

• Pre-pregnancy overweight and obesity independently increase LGA risk, with very heavy women (>+2 SD) being nine times more likely to deliver LGA babies compared to average-weight women 4, 1
• Excessive gestational weight gain (exceeding IOM guidelines) is independently associated with higher LGA risk, particularly in obese women with GDM (adjusted risk ratio 2.62) 1, 5
• Among women with GDM, exceeding IOM weight gain guidelines significantly increases birth weight (3,703g vs 3,490g in those meeting guidelines) 5
• The effect of maternal weight is dose-dependent, with relative risk rising sharply as weight increases 4

Obstetric History Factors

Parity and Prior Pregnancy Outcomes

• In multiparous women, the most important predictor is fast fetal growth rate demonstrated in previous pregnancies, with birth-weight Z-score in prior pregnancy being a strong predictor 1, 6, 4
• Relative risk for LGA rises sharply with increasing parity, though 27.5% of LGA babies are born to primiparous women 4
• Prior history of gestational diabetes increases risk in subsequent pregnancies 6
• Shorter interpregnancy intervals are associated with decreased LGA risk 6

Maternal Physical Characteristics

Height and Body Habitus

• Maternal height shows a steady increase in relative risk with increasing stature 6, 4
• The combination of maternal prepregnancy BMI and height represents independent risk factors for large size at birth 1
• Maternal prepregnancy BMI operates through both genetic determinants and environmental components in utero 1

Genetic and Ethnic Factors

Genetic Predisposition

• Size at birth represents a complex interaction between maternal environment and fetal genes 1
• Genetic predisposition for type 2 diabetes and obesity may be inherited from one or both parents by offspring of GDM mothers 1
• Maternal restraint of fetal growth (especially during first pregnancy) is inherited through the maternal line related to mitochondrial DNA or maternally expressed genes 1
• Common genetic variants (fetal and maternal genetic scores for birth weight) strongly influence LGA probability, with higher scores associated with increased LGA odds (OR 1.32 and 1.17 per decile, respectively) 7

Racial and Ethnic Variations

• LGA likelihood is lower in women of Afro-Caribbean and South Asian racial origins compared to other ethnic groups 6
• Significant differences in screening eligibility exist between ethnic groups 1

Protective or Negative Associations

Factors That Decrease LGA Risk

• Cigarette smoking is associated with lower LGA risk (though smoking carries other serious risks and should never be recommended) 6, 4
• Nulliparity is associated with lower LGA risk compared to multiparity 6
• Chronic hypertension decreases LGA risk 6
• Higher maternal systolic blood pressure genetic score is associated with lower odds of LGA (though associated with higher SGA risk) 7

Pathophysiologic Mechanisms

Intrauterine Environment

• The intrauterine environment establishes programming of fetal development with lifelong health consequences through multiple mechanisms 1
• Proposed mechanisms include alterations of placental function, epigenetic modifications, increased inflammation, altered mitochondrial function, and maternal OWO-related dyslipidemia 1
• Reduced energy expenditure and metabolic adaptation during pregnancy (rather than excessive energy intake) appear to drive gestational weight gain 1

Fetal Adiposity

• Newborn infants of women with GDM have increased adiposity and reduced fat-free mass even when not macrosomic 1
• Measures of adiposity at birth may be more appropriate markers than traditional macrosomia definitions 1

Clinical Risk Stratification

A practical approach to identifying high-risk pregnancies combines:

• Maternal pre-pregnancy BMI assessment (very heavy women carry 9-fold increased risk) 4
• Screening for GDM with attention to first-trimester HbA1c ≥5.2% (OR 1.63 for neonatal complications) 2
• Obstetric history review focusing on prior LGA deliveries and birth-weight Z-scores 6
• Monitoring gestational weight gain against IOM guidelines, particularly in obese women 1, 5
• Serial fetal biometry, which improves detection rates to 60%, 73%, and 85% at 35-37 weeks (at 5%, 10%, and 20% false-positive rates) 6