Definition
The term small fetus refers to a fetus whose estimated fetal weight on ultrasound examination is below the 10th percentile. Fetuses classified in this group represent 10% of all fetuses. This group includes 40% of fetuses at increased risk of intrauterine death or perinatal asphyxia, 40% of fetuses that are constitutionally small, and 20% of fetuses that are small due to chromosomal abnormalities or environmental influences.
The first and last subgroups include fetuses with an estimated weight below the 3rd percentile, as well as those between the 3rd and 10th percentiles who have abnormal blood flow on Doppler ultrasound assessment. These fetuses have growth restriction or intrauterine growth restriction, since their weight gain during pregnancy does not follow their fetal biological growth potential for their gestational age.
However, it must be made clear that the calculation of fetal weight is subject to many parameters, which often make it differ from the final birth weight. For this reason, except in extreme cases, we must be cautious when counselling parents about the final possible outcome of the pregnancy.
Neonatal birth weight percentiles and perinatal mortality rate per 1,000 births
Of course, the increased risk of mortality is not limited only to fetuses with a weight below the 10th percentile. A study from the Netherlands involving 1.2 million pregnancies reported that the risk of intrauterine death increases as birth weight decreases below the 80th percentile, becomes greater between the 50th and 20th percentiles, and rises markedly as weight becomes even lower, especially below the 2.3rd percentile.
In general, when birth weight is below the 10th percentile, the risk of intrauterine death is five times higher. The risk of low scores in neurodevelopmental tests is also increased, as is the risk of developing diabetes mellitus in adult life.
The DIGITAT study reports that birth weight below the 2.3rd percentile is the strongest prognostic factor for poor neurodevelopment of the infant during the first two years of life. For all these reasons, it is believed that if a threshold is to be set beyond which a fetus should be considered highly suspicious for growth restriction, the 3rd percentile is probably preferable. However, for diagnostic purposes, the 10th percentile has been widely established.
Growth rate of fetuses with growth restriction
In addition to the above, and given that 60–70% of intrauterine deaths occur in fetuses whose weight during pregnancy was above the 10th percentile, an important role in suspecting possible growth restriction is played by a reduction in the growth rate during pregnancy between successive fetal biometric measurements.
Classification
Fetuses with growth restriction are divided into two major categories: those in which growth restriction is accompanied by an anatomical abnormality, and those in which it is isolated.
The latter category includes fetuses in which unexpected growth is due to poor placental function, namely placental insufficiency; congenital fetal infections transmitted from the mother, most commonly cytomegalovirus infection; very young or advanced maternal age; toxic factors or substance use by the mother; and finally fetal genetic abnormalities, which include chromosomal, monogenic, and submicroscopic abnormalities.
Taking the above into account, the physician investigating a small fetus should assess the most likely cause of the growth restriction in order to counsel the couple correctly regarding the outcome of the pregnancy.
First of all, the gestational age at which growth restriction first appears is of great importance. When it occurs before 26 weeks of gestation, it is considered very early. When it occurs between 26 and 32 weeks, it is considered early, and when it occurs after 32 weeks, it is called late.
As a rule, the earlier growth restriction appears and the more severe it is, the more dangerous it is for the outcome of the pregnancy.
The timing of onset of fetal growth restriction, apart from being associated with its cause, is also related to findings from Doppler ultrasound of the maternal and fetal vessels. Thus, abnormal flow in the maternal uterine arteries and in the fetal umbilical arteries is associated with early growth restriction, whereas abnormal redistribution of fetal blood flow in the middle cerebral artery is associated with late growth restriction.
Etiology
Chromosomal abnormalities
Chromosomal abnormalities account for 19% of fetuses with growth restriction, with triploidy being the most common before 26 weeks of gestation and trisomy 18 being the most common after 26 weeks.
In isolated growth restriction, without ultrasound findings, the frequency of chromosomal abnormalities is 6.4%. In another study, the frequency of chromosomal abnormalities was 7% before 32 weeks and 1.8% after 32 weeks. It is also related to the severity of growth restriction: when fetal weight is below the 10th percentile, the frequency is 7.8%, increasing to 10% and 18% below the 5th and 3rd percentiles, respectively.
Conventional fetal karyotype showing an extra chromosome 21 in metaphase
Comparative genomic hybridization with microarrays – array CGH
However, it should be noted that sometimes the chromosomal abnormality involves the placenta, while the fetus is normal. This is known as confined placental mosaicism, with a frequency of 9–16%, and it may nevertheless cause fetal growth restriction.
It is found in 1–2% of cases when chorionic villus sampling is performed as a method of obtaining fetal genetic material, or during NIPT: trisomy 21 in 2%, trisomy 18 in 4%, and trisomy 13 in 33%.
The differential diagnosis from true fetal mosaicism can only be made by amniocentesis, and in such cases the frequency is 13.5%.
Confined placental mosaicism usually involves specific chromosomes, namely 2, 7–10, 13–18, 21, and 22, and leads to a poor pregnancy outcome.
In cases of growth restriction due to chromosomal abnormalities accompanied by increased resistance in the umbilical artery, this mainly involves trisomy 21 and less commonly trisomy 13, trisomy 18, and triploidy.
Growth restriction begins in the middle of the second trimester and becomes more pronounced as gestational age advances.
Special mention is required when confined placental mosaicism involves chromosome 16, which occurs in 1% of all pregnancies regardless of outcome. In these cases, 20–36% of pregnancies have a normal outcome, 43–58% involve constitutionally small fetuses, 20–22% have anatomical abnormalities, 16–24% are complicated by pre-eclampsia, and 32–37% by prematurity.
Submicroscopic Chromosomal Abnormalities
Submicroscopic chromosomal abnormalities can only be detected through chromosomal microarray analysis and are referred to as pathogenic copy number variants (CNVs).
In a recent study, their prevalence in fetuses with a normal conventional karyotype was 5.7%, highlighting the importance of performing chromosomal microarray analysis together with conventional karyotyping.
A meta-analysis demonstrated that this approach provides an additional diagnostic yield of 4% in fetuses with isolated growth restriction and 10% when anatomical abnormalities are also present.
Monogenic Disorders
In growth-restricted fetuses, particularly in cases of severe growth restriction (<1st percentile), several genes have been identified that are responsible for short stature after birth, while others are associated with skeletal abnormalities.
In general, fetuses with growth restriction due to monogenic disorders can be divided into:
- Those in which growth restriction affects all biometric parameters (head circumference, abdominal circumference, and long bones).
- Those in which growth restriction affects only the long bones (<3 SD below the mean), suggesting an underlying skeletal disorder that requires thorough investigation.
Types of fetal genomic testing
WES (Whole Exome Sequencing): analysis of all coding regions of the genome.
Targeted Sequencing: analysis of selected regions or genes within the genome.
Epigenetic Factors
Epigenetics is a field of genetics that has developed significantly over the last two decades. It studies how an organism’s environment affects its genome and how external factors influence development and behavior.
Such factors include toxic exposures, nutrition, psychological state, physical activity, and many others.
This means that an individual may inherit normal genes yet eventually develop a pathological condition, or may carry abnormal genes while functioning normally.
Therefore, genes are not static entities as previously believed; rather, they are dynamic units that modify their expression according to environmental conditions.
Examples of such environmental influences include smoking and environmental pollution, both of which may affect fetal development.
Monitoring Fetuses with Growth Restriction
In early-onset fetal growth restriction, significant placental insufficiency is usually present. As a result, Doppler ultrasound parameters of the fetal circulation (umbilical artery, middle cerebral artery, and ductus venosus) are abnormal in approximately 80% of cases delivered before 32 weeks of gestation.
These cases are frequently accompanied by:
- Oligohydramnios
- Fetal heart rate decelerations on cardiotocography (CTG)
- Abnormal biophysical profile
The risk of intrauterine fetal death ranges from 0% to 4%.
Gestational age at delivery is critically important for neonatal survival. Only about 50% of neonates survive when delivered before 26 weeks of gestation, provided that birth weight exceeds 500 g. Thereafter, survival increases by approximately 2% per week, while the risk of neurodevelopmental impairment decreases.
Survival rates and neurodevelopmental outcomes of extremely preterm neonates
In late-onset growth restriction occurring during the third trimester, placental insufficiency is generally milder. Consequently:
- Only 5% show abnormal umbilical artery Doppler findings.
- Only 0.1% show abnormal ductus venosus Doppler findings.
Abnormal amniotic fluid volume, biophysical profile disturbances, and cardiotocographic decelerations occur in approximately 40% of cases.
The risk of intrauterine fetal death is approximately 11 per 10,000 pregnancies at 37 weeks, but doubles with each additional week of gestation, reaching approximately 8% at the end of pregnancy.
Doppler findings in normal and growth-restricted fetuses
In early growth restriction, fetal deterioration is monitored using Doppler ultrasound.
Resistance in the fetal umbilical artery increases several weeks before cardiovascular and metabolic deterioration, which represent the final stage preceding intrauterine death.
Typically:
- Increased umbilical artery pulsatility index (PI).
- Absence of end-diastolic flow (AEDF).
- Reversed end-diastolic flow (REDF).
- Progressive abnormalities in the ductus venosus.
- Absence or reversal of the ductus venosus a-wave.
- Severe fetal hypoxia with CTG decelerations and abnormal biophysical profile.
- Intrauterine fetal death within approximately one week (40–70% risk).
In late-onset growth restriction, fetal deterioration is generally less severe and is characterized by:
- Mild increase in umbilical artery PI.
- Reduction in middle cerebral artery PI.
- Decrease in the cerebroplacental ratio (CPR).
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Timing of Delivery in Growth-Restricted Fetuses
The TRUFFLE study, conducted in 20 European centers between 2005 and 2010, recommended timing delivery according to Doppler ultrasound and cardiotocography findings in early-onset growth restriction.
Based on these findings, both the Society for Maternal-Fetal Medicine (SMFM) and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) recommend the following:
Early-Onset Growth Restriction
Reversed End-Diastolic Flow (REDF)
Delivery should occur no later than 30–32 weeks of gestation.
Prior administration of:
- Corticosteroids, which reduce:
- Respiratory distress syndrome by 29%
- Intraventricular hemorrhage by 42%
- Intrauterine death by 22%
- Magnesium sulfate, which reduces the risk of cerebral palsy by 32%
Monitoring should be performed in hospital with:
- Daily Doppler assessment
- CTG once or twice daily
Absent End-Diastolic Flow (AEDF)
Delivery should occur no later than 33–34 weeks.
Management includes:
- Antenatal corticosteroids
- Doppler surveillance 2–3 times weekly
- CTG twice weekly
Absent or Reversed Ductus Venosus a-Wave
Delivery should occur between 26 and 32 weeks, provided the estimated fetal weight exceeds 500 g and corticosteroids and magnesium sulfate have been administered.
Increased Umbilical Artery PI
Delivery may be planned at 37 weeks.
Monitoring includes:
- Weekly Doppler assessment
- CTG 1–2 times weekly
Different types fetal growth restriction in comparison to normal
Late-Onset Growth Restriction and Small-for-Gestational-Age (SGA) Fetuses
Estimated Fetal Weight Between the 3rd and 10th Percentiles with Normal Doppler Findings (SGA)
Monitoring:
- Doppler every 1–2 weeks
- If stable, every 2–4 weeks
- Weekly CTG
- Estimated fetal weight every 3–4 weeks
Delivery:
- Between 38 and 39 weeks
Estimated Fetal Weight Below the 3rd Percentile with Normal Doppler Findings, or Between the 3rd and 10th Percentiles with Abnormal Doppler Findings
Examples:
- CPR below the 5th percentile
- Uterine artery PI above the 95th percentile
Monitoring:
- Weekly Doppler ultrasound
- Weekly CTG
- Estimated fetal weight every two weeks
Delivery:
- At 37 weeks
Conclusions
The following conclusions can be drawn:
- Fetuses whose estimated weight remains between the 3rd and 10th percentiles on serial ultrasound examinations, with normal fetal Doppler findings and no anatomical abnormalities, are classified as constitutionally small (SGA). These fetuses generally have a favorable prognosis but require regular surveillance.
- Fetuses whose estimated weight is below the 3rd percentile, or whose weight is between the 3rd and 10th percentiles with abnormal fetal Doppler findings, are classified as having fetal growth restriction (FGR) and are considered at risk.
- If growth restriction develops early (<24 weeks) without anatomical abnormalities, fetal chromosomal abnormalities should be investigated by amniocentesis.
- If growth restriction develops between 24 and 32 weeks, invasive genetic testing is recommended when anatomical abnormalities are present, even if they are mild (e.g., polyhydramnios).
- In neonates born with growth restriction, if prenatal investigations have not been performed, a postnatal evaluation should include:
- Autopsy in cases of fetal or neonatal death
- Detailed phenotypic assessment
- Clinical genetic evaluation
for determination of the underlying cause and for counselling regarding future pregnancies.
Bibliography:
- Grati FR, Malvestiti F, Branca L, et al. Chromosomal mosaicism in thefetoplacental unit. Best Pract Res Clin Obstet Gynaecol. 2017 Jul;42:39-52
- Peng R, Yang J, Xie HN, et al. Chromosomal and subchromosomal anomalies associated to small for gestational age fetuses with no additional structural anomalies. Prenat Diagn. 2017 Dec;37(12):1219-1224
- Zhu H, Lin S, Huang L, et al. Application of chromosomal microarray analysis in prenatal diagnosis of fetal growth restriction. Prenat Diagn. 2016 Jul;36(7):686-692
- van Wyk L, Boers KE, van der Post JA, et al. Effects on (neuro) developmental and behavioral outcome at 2 years of age of induced labor compared with expectant management in intrauterine growth-restricted infants: long-term outcomes of the DIGITAT trial. Am J Obstet Gynecol 2012;206:406.e1–7.
- Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction: (Replaces Clinical Guideline Number 3, April 2012)Am J Obstet Gynecol. 2020 Oct;223(4):B2-B17. Epub 2020 May 12.