Fetal Growth Restriction (FGR) - Full Theory

Based primarily on Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice and Robbins Pathology, with supporting pathophysiology from the fetal circulation chapters.

1. Definition and Terminology

• Low birth weight (LBW): weight <2500 g (WHO) - regardless of gestational age
• Small for gestational age (SGA): birth weight <10th percentile for gestational age - a statistical, population-based definition
• FGR: a fetus that has not achieved its growth potential - a pathophysiologic concept
• Appropriate for gestational age (AGA): birth weight between the 10th and 90th percentile
• Large for gestational age (LGA): birth weight >90th percentile

2. Normal Fetal Growth - Phases

• Peak mean weekly weight gain: 230-285 g at 32-34 weeks' gestation
• Weight gain then decreases, potentially reaching zero at 41-42 weeks
• If expressed as % increase per week, the maximum is in the first trimester, declining steadily thereafter

3. Classification of FGR

3a. Symmetric vs. Asymmetric FGR

• In asymmetric FGR: a decrease in interval AC growth is one of the earliest ultrasound findings. The liver is reduced in size and subcutaneous fat is diminished ("brain-sparing")
• These patterns can overlap - long-standing placental disorders may eventually produce symmetric patterns, and asymmetric FGR identified in the late 2nd trimester may become more symmetric over time

3b. By Gestational Age at Delivery

• Early FGR: diagnosed <32 weeks - usually more severe, more often associated with preeclampsia
• Late FGR: diagnosed ≥32 weeks - often milder, frequently idiopathic

3c. Staging System (Mari et al.)

4. Etiology and Risk Factors

4a. Fetal Factors

• Trisomy 18 (83.7% with FGR), trisomy 13, trisomy 21 (less pronounced)
• In isolated FGR + structural defect: karyotype recommended
• Chromosomal microarray provides ~4% incremental yield over standard karyotyping in isolated FGR with normal karyotype; in FGR with a structural defect, microarray identified abnormalities in 18.8% vs. 9.3% with standard karyotype

• 22.3% of malformed infants have FGR (RR = 2.6)
• Congenital heart defects are particularly associated
• Fetuses with gastroschisis are also at increased risk

• Rubella and CMV have a well-established causal relationship with FGR
• Parvovirus B19 can also cause FGR
• Malaria, toxoplasmosis, syphilis are implicated in certain populations
• Fetal infection should be considered in all growth-restricted neonates
• SMFM recommends against routine TORCH serology for isolated FGR; recommends CMV PCR via amniocentesis in women who elect diagnostic testing for unexplained FGR

4b. Maternal Factors

• Vascular disease: Preeclampsia, chronic hypertension (most common maternal causes)
• Hypercoagulability: Acquired (antiphospholipid syndrome) or inherited thrombophilias - increasingly recognized contributors
• Substance use: Narcotic use, heavy cigarette smoking, alcohol intake
• Medications: Phenytoin and other teratogenic drugs; some non-teratogenic drugs
• Malnutrition: Prolonged hypoglycemia
• Maternal size: Low pre-pregnancy weight, low BMI
• Other: Anemia, high altitude, uterine anomalies

4c. Placental Factors

• Placenta previa (low implantation)
• Placental abruption (separation from decidua by hematoma)
• Abnormal placentation / impaired trophoblast invasion
• Placental infarcts - limit trophoblastic surface area for substrate transfer
• Umbilical cord abnormalities (velamentous insertion, single umbilical artery)
• Multiple gestation - inadequate placental perfusion

5. Pathophysiology

5a. Placental Mechanisms

1. Reduced umbilical blood flow per kg fetal weight - because decreased terminal villi growth reduces expansion of the umbilical capillary bed. Umbilical pulsatility index (PI) is elevated.
2. Reduced vasosyncytial membrane production - a greater fraction of umbilical oxygen uptake must occur by diffusion across thick, oxygen-consuming placental barrier segments. Placental oxygen permeability is abnormally low.
3. Reduced transplacental glucose diffusion - glucose permeability to fetal blood is also decreased.

5b. Fetal Hypoxemia and Cardiovascular Adaptation

1. Enlarges the transplacental PO2 gradient, partly compensating for decreased permeability
2. Slows fetal growth, thereby reducing total oxygen demand

5c. Brain-Sparing (Asymmetric Redistribution)

• Vasodilation of cerebral, coronary, and adrenal vessels
• Vasoconstriction of splanchnic, renal, and peripheral vessels
• Result: HC and FL are relatively preserved; AC is reduced (decreased liver size + subcutaneous fat)
• This is detected on Doppler as decreased middle cerebral artery (MCA) PI (increased cerebral diastolic flow) and increased umbilical artery (UA) PI

6. Diagnosis

6a. Clinical Assessment

• Symphysis-fundal height (SFH): Serial measurements; a lag of >3 cm below expected warrants ultrasound evaluation. Poor sensitivity (~27%) but simple screening tool.
• Risk factor assessment: History of prior FGR, hypertension, smoking, multiple gestation, prior SGA neonate (2 SD below mean) - all increase surveillance intensity

6b. Ultrasound Biometry

• Biparietal diameter (BPD): Head size
• Head circumference (HC): More accurate than BPD alone
• Abdominal circumference (AC): Most sensitive single parameter for FGR; reflects liver glycogen stores and subcutaneous fat. A normal AC virtually excludes FGR.
• Femur length (FL): Reflects skeletal growth
• Estimated fetal weight (EFW): Composite formula

• EFW or AC <10th percentile: SGA (possible FGR)
• EFW <3rd percentile: Strongly suggestive of FGR with increased risk of adverse outcome
• Serial measurements: Growth velocity is important - an interval growth deceleration is highly significant even if absolute values remain above 10th percentile

• Oligohydramnios (AFI <5 cm or MVP <2 cm) frequently accompanies FGR due to reduced fetal renal perfusion (redistribution of cardiac output away from splanchnic/renal)

6c. First-Trimester Screening

• Crown-rump length (CRL): Suboptimal growth in the first trimester (below expected CRL) is associated with subsequent FGR
• Uterine artery Doppler at 11-14 or 23 weeks: Elevated PI and "notching" predict subsequent FGR, but predictive value is low as a standalone test
• PAPP-A: Low first-trimester PAPP-A combined with elevated uterine artery PI increases prediction of FGR (though did not reach statistical significance in some studies)
• PlGF (placental growth factor): Low serum PlGF in first/second trimester is associated with risk of subsequent FGR and preeclampsia

7. Doppler Surveillance - Sequential Changes

Sequential Doppler Changes in FGR:

Stage 1: Umbilical Artery (UA) - Elevated PI (reduced diastolic flow)
           ↓
Stage 2: Middle Cerebral Artery (MCA) - Decreased PI (brain-sparing; increased diastolic flow)
         [Note: Abnormal MCA PI may occasionally precede UA changes]
           ↓
Stage 3: Umbilical Artery - Absent End-Diastolic Flow (AEDF)
           ↓
Stage 4: Umbilical Artery - Reversed End-Diastolic Flow (REDF)
           ↓
Stage 5: Ductus Venosus (DV) - Absent or reversed a-wave
         Umbilical Vein (UV) - Pulsatile flow

Cerebroplacental Ratio (CPR)

• CPR = MCA PI / UA PI
• CPR <1.0 is associated with adverse neonatal outcome (18% adverse outcome vs. 2% when CPR >1)
• Low CPR also predicts poorer neurodevelopmental outcome at 3 years
• However, a recent meta-analysis (individual participant data) found CPR added no predictive value beyond UA PI alone for adverse perinatal outcome - its routine clinical role in FGR management requires further study

Uterine Artery Doppler

• Bilateral notching + elevated PI: indicator of impaired trophoblast invasion
• Useful in predicting FGR at 11-14 weeks and 23 weeks, but alone has low sensitivity

8. Antenatal Surveillance

• A prior non-anomalous SGA neonate (birth weight ≥2 SD below mean) in the first pregnancy is associated with increased stillbirth risk in the subsequent pregnancy, even if the second pregnancy is AGA - antenatal surveillance from 32 weeks is recommended.

9. Management

9a. General Principles

• Identify etiology: Maternal labs, genetic testing (karyotype + microarray if structural defect), CMV PCR if elected
• Optimize modifiable factors: Treat hypertension, stop smoking, treat infections
• Correct placental blood flow where possible
• Plan delivery timing balancing risks of prematurity vs. fetal compromise

9b. Antepartum Therapy

• 100 mg/day initiated before 16 weeks significantly reduces FGR in at-risk women (RR = 0.56; 95% CI 0.44-0.70; P <0.001) in a meta-analysis of 20,909 women
• Lower doses and initiation >16 weeks do not show significant benefit
• Aspirin before 16 weeks is now standard for women at high risk of preeclampsia/FGR

• Increases umbilical artery PO2 and pH in hypoxemic, acidotic FGR fetuses
• Improves mean aortic blood flow velocity
• Evidence is inconclusive for long-term benefit - differences in outcome may reflect more advanced gestational age in oxygen-treated groups

• Antioxidants (vitamins C and E) - not effective in reducing FGR risk
• Low-molecular-weight heparin - meta-analysis showed no significant reduction in FGR/preeclampsia (RR = 0.64; CI 0.36-1.11) - cannot be recommended
• Pomegranate juice - one study suggested reduced brain injury, but not replicated

• Standard corticosteroids for fetal lung maturity if preterm delivery anticipated

9c. Timing of Delivery

• Trial of labor is reasonable in FGR with meticulous fetal monitoring
• Persistent UA reversed flow: offer cesarean section as these fetuses may not tolerate labor

10. Neonatal Consequences of FGR

Immediate (Perinatal):

• Perinatal asphyxia and meconium aspiration
• Hypothermia (decreased subcutaneous fat)
• Hypoglycemia (decreased glycogen stores, poor gluconeogenesis)
• Polycythemia (chronic hypoxemia stimulates erythropoiesis)
• Thrombocytopenia and leukopenia
• Necrotizing enterocolitis (NEC) - particularly in preterm FGR
• Pulmonary hemorrhage

Long-term (Barker / Developmental Origins of Disease):

• Cardiovascular disease: Hypertension, ischemic heart disease, stroke
• Type 2 diabetes mellitus and insulin resistance
• Metabolic syndrome
• Obesity (paradoxically - "thrifty phenotype")
• Neurodevelopmental disorders: Lower IQ, learning difficulties, cerebral palsy risk
• Chronic kidney disease

11. Special Considerations

FGR in Multiple Gestation

• Discordant growth (>20-25% weight difference between twins) indicates selective FGR
• In monochorionic twins, consider twin-to-twin transfusion syndrome (TTTS) or selective FGR
• Placental insufficiency is more common due to shared and unequal placentation

FGR vs. Preeclampsia

• In preeclampsia-associated FGR, the full sequence of Doppler changes is often not seen because most fetuses are delivered before deterioration progresses
• These cases behave distinctly from idiopathic FGR

Recurrence Risk

• Prior FGR or SGA neonate increases risk in subsequent pregnancy
• Women with prior preterm FGR should undergo weekly antenatal testing in subsequent pregnancy (ACOG recommendation)

12. Summary Flowchart

Suspected FGR (SFH lag / risk factors)
         ↓
Ultrasound biometry + Doppler
         ↓
EFW < 10th percentile?
    ├── Yes → Confirm with serial scans (2-4 weekly)
    │          Check UA Doppler
    │          Genetic evaluation if structural anomaly
    │          Infectious screen if indicated (CMV PCR)
    │
    └── No → Consider customized growth curves
              Rule out AGA fetus with low CPR
         ↓
UA Doppler
    ├── Normal PI → Serial monitoring; deliver ~39 weeks
    ├── Elevated PI → Increase surveillance frequency
    ├── AEDF → Consider delivery 33-34 weeks; DV Doppler
    └── REDF → Deliver 30-32 weeks; consider cesarean
         ↓
DV Doppler (if AEDF/REDF present)
    ├── Normal → Continue close monitoring
    └── Absent/reversed a-wave → Deliver (NICU)

Sources

• Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice, Chapter 44 (FGR Definition, Classification, Etiology, Doppler, Management) and Chapter 14 (Fetal Circulation & Pathophysiology)
• Robbins & Kumar Basic Pathology - Prematurity and Fetal Growth Restriction
• DIGITAT trial (induction vs expectant monitoring in FGR >36 weeks)
• Mari et al. staging system for IUGR (J Ultrasound Med, 2007)
• Aspirin meta-analysis: 100 mg before 16 weeks reduces FGR (RR 0.56; Creasy Ch. 44, ref. 203)
• Barker DJ & Osmond C, Lancet 1986 (fetal origins of adult disease)
• Recent PubMed: prediction model meta-analysis for FGR and birthweight (PMID 39252507, Health Technol Assess, 2024)