Continuing Education Activity

Small for gestational age (SGA) is defined as a birth weight of less than 10th percentile for gestational age. The burden of fetal growth-restricted (FGR) SGA is higher in resource-poor countries, and children born FGR SGA have a higher risk of mortality and morbidity during the neonatal period and beyond. This activity highlights the role of the interprofessional team in the evaluation and management of FGR SGA infants.

Objectives:

• Describe the etiology of fetal growth-restricted, small for gestational age newborns.
• Describe the evaluation of fetal growth-restricted, small for gestational age newborns.
• Outline the principles of management of fetal growth-restricted, small for gestational age newborns

Introduction

Small for gestational age (SGA) is defined as a birth weight of less than 10th percentile for gestational age.[1] SGA infants are categorized into two major groups: constitutionally normal infants who are SGA and infants who are SGA because of growth restriction with a birth weight lower than expected optimal birth weight. The constitutionally normal infants have normal birth weight less than 10th percentile because of inherent factors such as maternal height, weight, ethnicity, parity, and in these infants, there is no increased risk of perinatal mortality and morbidity.[1] SGA and fetal growth restriction (FGR) are used interchangeably but are not synonymous. Many infants who are SGA have FGR, and many infants with FGR are SGA as well. However, SGA cannot be used as a marker for FGR because some infants with FGR will have a birth weight greater than the 10th percentile. Therefore, in making a distinction between SGA and FGR, it is important to use fetal growth curves customized based on constitutional factors to distinguish normal SGA infants from those with FGR.[2] In this article, we focused on infants with SGA secondary to FGR (FGR SGA)

The prevalence of FGR SGA in high-income countries such as the United States and Australia is approximately 11%, however in low and middle-income countries, an estimated 32.5 million infants were born FGR SGA, and the majority of these infants, an estimated 53% (16.8 million), were born in South Asia.[3][4][5] The causes of FGR SGA are diverse and range from fetal, maternal, uterine/placental to demographic factors. Recent studies have shown that catch-up growth is possible and normal size can be reached at nine months in about 80% of newborns with FGR SGA.[6][7] However, newborns with FGR SGA are at increased risk for other complications such as prematurity, neonatal asphyxia, hypothermia, hypoglycemia, hypocalcemia, polycythemia, sepsis, and death.[8] The purpose of this review is to highlight the current trends in the management of children born with FGR SGA.

Etiology

The causes of FGR SGA are diverse, with maternal and placental factors the most common underlying etiologies. Maternal factors such as chronic medical conditions (hypertension, renal disease, collagen vascular diseases), infections (toxoplasmosis, rubella, Cytomegalovirus, malaria, trypanosomiasis, HIV), nutritional status (low pre-pregnancy weight, low pregnancy weight), and substance use (cigarette smoking, alcohol, illicit drugs, medications) are all implicated in FGR SGA. Other factors contributing to FGR SGA include placental factors such as a single umbilical artery, placental hemangiomas, placenta previa, low-lying placenta, and chronic placental abruption.[9]

Finally, genetic disorders have been found to be responsible for FGR SGA in 1/3 of infants.[10] Syndromes such as achondroplasia and Bloom syndrome and chromosomal anomalies such as trisomy 21 and trisomy 18 are all examples of genetic conditions that could result in FGR SGA infants.

Epidemiology

The prevalence of FGR SGA varies across different populations.[11][12][13] The prevalent rate for FGR SGA is higher in resource-poor countries with the highest-burden in South Asia, where up to 34% of infants were born FGR SGA.[11][14] In comparison, approximately 11% of infants in rich and developed countries were born FGR SGA.[4][5] Children born FGR SGA have a higher risk of mortality and morbidity during the neonatal period and beyond. An estimated 22% of neonatal death are attributed to being born FGR SGA, with the highest number reported in South Asia.[11]

The incidence rates of FGR SGA in preterm infants vary according to whether data collection was based on birth weight or gestational age. In a cohort of 4438 infants with birthweight from 500 to 1500g, 22% are reported as FGR SGA, according to the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network database.[15] In other cohorts of 20,000 infants with very low birth of < 1500g and gestational age between 25 to 30 weeks, an estimated 9% of these infants were born SGA.

Pathophysiology

There is a compromise in the supply of nutrients reaching the fetus in FGR SGA. In an attempt to maximize the survival chance, the fetus responds to the reduction in its nutrient supply by reducing its overall size but preserving certain functions like brain growth, lung maturation, and increasing red blood cell production.[16] The fetus prioritizes blood supply to more vital organs such as the brain, heart, adrenals, and placenta. There is a decrease in the total body fat, lean mass, and mineral contents in infants with severe FGR SGA, giving the neonate a wasted appearance.[17]

FGR SGA is divided into symmetric and asymmetric growth restriction. Infants with symmetric FGR SGA have a proportionate reduction in all organ systems, and the growth restriction typically begins early in the gestation. The incidence of symmetric FGR SGA ranges from 38% to 45%, and factors such as first-trimester congenital infection and chromosomal abnormalities have been implicated. In asymmetric FGR SGA, which constitutes about 55% to 61% of FGR SGA cases, the growth in head circumference is preserved while the length and weight are affected.[18][19][20] 

The growth restriction in asymmetric FGR SGA begins in the late 2nd or 3rd trimesters and usually results from a reduction in fetal nutrients due to placental or maternal factors. Continued brain growth is prioritized. Ponderal index (PI), which is a ratio of body weight to length (PI=[weight (g) x 100]/[length (cm)]), is an important tool to detect FGR SGA, especially in infants with asymmetric FGR SGA.[21]

History and Physical

History starts from pre-conception through the antenatal and neonatal periods. Important points in the medical history include reviewing any chronic maternal conditions such as hypertension, renal disease, diabetes mellitus; if the mother has an acute or chronic infection such as HIV, toxoplasmosis, rubella, malaria; the mother’s nutritional status; and if substance use/abuse was present. Vaccination history and screening for antibody titers to ensure immunity to infections such as rubella and Cytomegalovirus should be determined. It is important to ask for a history of FGR SGA in prior pregnancies or in the family history. Discussing the antenatal care and social stressors are important as well.

Neonates with FGR SGA are usually thin, with loose peeling skin, decrease muscle mass, and loss of subcutaneous fat tissues. The face in these newborns is usually shrunken and wrinkled, and the umbilical cord is thin. The membranous bone formation in these infants is decreased, resulting in widened cranial sutures and larger than normal anterior fontanelle. The head appears relatively larger than the rest of the body in neonates with asymmetric FGR SGA.

Evaluation

Evaluation begins during the antenatal period. Maternal medical history and history of the index pregnancy are very important in directing the prenatal diagnosis of FGR SGA.

Antenatal Diagnosis: During antenatal care, symphysis-fundal height measurement using a measuring tape is a simple, affordable, and common ways of detecting FGR SGA or other conditions that can cause size/date discrepancy. Suspicion for FGR SGA is raised when there is a discordance between the measured fundal length and the expected size for gestational age. The measurement is said to be discordant when the fundal height is at least 3 cm less than the gestational age in weeks.[22] However, there are controversies on the use of symphysis-fundal height measurement for the diagnosis of FGR SGA, as many studies have reported a wide range of sensitivities between 13% to 86%.[22][23][24][25][26][27][28][29][30]

The routine ultrasound examination is another method of screening for FGR SGA, but there is no agreement on the timing and number of screening required. When two screening is obtained, the exams are usually performed at 32 and 36 weeks of gestation, while for a single screening, the exam is performed between 32 to 36 weeks of gestation.[31][32]

In many countries, including the United States, serial fundal height measurement, and risk assessment for impaired fetal growth such as the history of maternal chronic disease, substance use disorder, smoking, placental insufficiency are recommended for each antenatal visit.[4] In pregnancy with a high risk for FGR SGA, ultrasound is performed once or twice in the 3rd trimester or when a lag in fundal height is detected. However, in FGR SGA, low-risk pregnancies, ultrasound is only performed in any of the following: a lag in fundal height, inability to palpate fundal height, or fundal height not reliable as in the case of a uterine mass.[33][34]

Postnatal Diagnosis: FGR SGA is diagnosed in postnatal life when the birth weight is less than the 10th percentile for gestational age. Other features in support of FGR SGA include physical evidence of malnutrition, such as decreased skeletal muscles, subcutaneous fat tissues, and loose peeling skin.

Accurate determination of gestational age is important in making a reliable diagnosis of FGR SGA. The two reliable methods used in assessing the gestational age of the fetus are calculated using the date of the last menstrual period or from the measurement from a prenatal ultrasound performed before a gestational age of 20 weeks.[35] In situations where either the correct menstrual date and prenatal ultrasound are not obtainable, gestational age can be determined after birth using the physical and neuromuscular assessments of the neonate using the Ballard exam.[36]

Treatment / Management

Management of FGR SGA starts before birth. Prenatal fetal surveillance is performed using a biophysical profile (BPP) to monitor fetal well-being and determine the timing of delivery.[37][38] BPP variables include nonstress test heart rate monitoring, fetal breathing movement, gross fetal movement, fetal tone, and amniotic fluid volume, which are monitored using ultrasound. A score of 2 is assigned to a normal variable and zero for an abnormal variable, and the total score ranges between 0 and 10.[37][38] The lower the total score, the higher the risk of fetal compromise and vice versa. In other studies, serial umbilical artery Doppler studies have been recommended for monitoring and can be used for the timing of delivery, as are cerebral Doppler studies and cardiotocography.[4] 

If delivery is felt to be indicated prematurely, administration of maternal corticosteroids for fetal lung maturation before birth is indicated at <34 weeks’ gestation and should be considered for pregnancies between 34 to 36 6/7 weeks gestation in some cases.[4][39] The majority of the studies recommend magnesium sulfate for neuroprotection before preterm delivery as well, generally < 32-week gestation. There are variations in the surveillance approach and timing of birth in late-onset FGR SGA (gestational age > or =32 weeks) neonates across different countries. In addition, late-onset FGR SGA newborns with abnormal Doppler studies or estimated fetal weight of < 3rd percentiles, delivery is recommended at 37-38 weeks gestational age. While with normal doppler studies, delivery is recommended between 37-40 weeks gestational age.

As per the Neonatal Resuscitation Program, in preparation for delivery, every birth should be attended by a dedicated, qualified individual whose only responsibility is the assessment and care of the newborn.  In the case of a delivery with suspected risk factors such as FGR, two qualified individuals should be present with a full team equipped for extensive resuscitation, including intubation and CPR, immediately available if called.  Care of the FGR SGA infant after birth should begin as it does for any infant with a quick assessment of the infant’s gestational age, tone, and breathing. If the infant appears term with good tone and adequate breathing, initial steps of warming and drying, positioning the airway, and clearing any secretions can be done on the mother’s chest or abdomen; otherwise, the infant should be moved to the warmer for more extensive assessment and resuscitation.  Following stabilization, newborn care for the term FGR SGA infant can typically be done in the mother’s room or newborn nursery per institutional policy. However, preterm infants will need admission and continuing care for issues related to their prematurity in the neonatal intensive care unit.[40]

Following initial stabilization of the term FGR SGA infant, a thorough physical exam should be performed, and measurements of head circumference, length, and weight should be obtained with care to note if the FGR is symmetric or asymmetric.  Special attention should be paid to thermoregulation and feeding.  Given their low-fat stores and increased area-to-body mass ratio, these infants are at risk of hypothermia and subsequent poor feeding, increased calorie expenditure, and slow weight gain.  Keeping the mother’s room warm, encouraging skin-to-skin, and appropriate clothing and swaddling are effective techniques to maintain euthermia, but additional support with an incubator or radiant warmer may be needed if euthermia (36.5 to 37.5 degrees C) cannot be sustained. 

Early establishment of enteral feeding should be a priority to avoid hypoglycemia.  Exclusive breastfeeding from birth until six months of age should be encouraged of all infants, including preterm and term FGR SGA infants, as per the American Academy of Pediatrics and the World Health Organization.[41] In the SGA population, glucose should be checked every 3 hours until stable with a pre-prandial goal of >25 mg/dL for asymptomatic infants in the first 4 hours of life, >35 mg/dL in hours 4 to 24 of life, and >45 mg/dL after 24 hours.[42] Supplementation with formula or dextrose-containing intravenous fluid may be needed while breastfeeding or milk supply is established. Fortification of breastmilk or formula for increased calories may be needed in the newborn period or into the first year of life for adequate growth in the FGR SGA population as well.  

Finally, an investigation into the etiology of fetal growth restriction should be undertaken if it remains unknown.  Serum and urine testing for congenital infections such as toxoplasmosis and Cytomegalovirus should be considered. Placental pathology is often helpful for signs of prenatal infection or vasculopathy.  If the infant presents with dysmorphology, genetic testing should be considered as well.

Differential Diagnosis

A constitutionally normal SGA infant must be distinguished from an FGR SGA patient.  The former does not have an increased risk of morbidity and mortality compared to that seen in the latter.  These constitutionally normal SGA infants do not have wasted features of intrauterine malnourishment. The constitutionally normal SGA infants can be differentiated from FGR SGA infants by taking into consideration the height, weight, and ethnicity of the mother.

Prognosis

Perinatal morbidity and mortality are increased in infants with FGR SGA compared to those appropriate for gestational age (AGA) both in term and preterm newborns.[4][43][44][45][46][47][48][49][50] The increase in perinatal mortality reported in a population-based study showed the highest rate in infants with severe FGR SGA (birth weight < 5 percentile of gestational age.)[51]

FGR SGA is a risk factor for death in term infants, as reported in many studies. The death rate has been shown to increase with decreasing birthweight percentiles.[49][50] In one study of preterm live births, the death rates for children born between 24 and 28 weeks’ gestation age were 62%, 42%, and 30% for those who were SGA ( birth weight <10th percentile), mildly FGR SGA (birth weight between 10th and <20th percentile) and appropriate for gestational age (AGA) (birth weight > or =20th percentile). On the other hand, children born FGR SGA between 29- and 32-weeks’ gestation had not only higher mortality, but also minor cognitive difficulties, inattention-hyperactivity symptoms, and school difficulties compared to AGA infants.[52]

Complications

The risk of complications is high in infants with FGR SGA in the neonatal period, throughout childhood and beyond.  Complications in the perinatal period include prematurity, perinatal asphyxia, impaired thermoregulation, hypoglycemia, polycythemia and hyperviscosity, impaired immune function, and hypocalcemia. Infants with FGR SGA are at increased risk of premature delivery and those with FGR SGA who are born preterm have increased risk for death and prematurity-related complications such as necrotizing enterocolitis, respiratory distress syndrome, retinopathy of prematurity, and bronchopulmonary dysplasia.[53][54][55][56][57] 

Infants with FGR SGA are prone to additional hypoxic stress of uterine contraction during delivery and, with impaired placenta function, there is an increased risk of hypoxic-ischemic encephalopathy, ischemic heart failure, meconium aspiration, pulmonary hypertension, and kidney and gastrointestinal injury.[58][59][60][61] Early-onset hypoglycemia is common and the risk of hypoglycemia increases with increasing severity of FGR SGA due to depleted fat, protein, and glycogen storage.[62] 

Immunity is impaired for FGR SGA infants as both T and B peripheral lymphocytes are found to be decreased at birth in patients with FGR SGA due to stress-induced erythropoiesis, although the number of T lymphocyte normalized later in childhood but not its proliferative potential.[63]

Infants born FGR SGA are at higher risk of long-term complications including chronic kidney disease, coronary heart disease, hyperlipidemia, and hypertension.[64][65][66][67] 

Deterrence and Patient Education

Infants born with fetal growth restriction small for gestational age (FGR SGA) are at increased risk of short- and long-term complications and death. Conditions such as maternal hypertension, kidney disease, infections, malnutrition, smoking, and substance abuse increase the risk of having an FGR SGA infant.

The evaluation of FGR SGA begins during the antenatal period. Pregnancies with FGR SGA fetuses can be detected with fundal height measurement and routine ultrasound exams during antenatal clinic visits. The early detection of fetuses at risk of FGR SGA will help in planning delivery and initial treatment. At birth, infants born FGR SGA are thin with loose peeling skin and decreased muscle mass and may appear shrunken with wrinkled faces. In some, the head is larger than the rest of the body.

Treatment of FGR SGA newborns is primarily focused on preventing and managing complications. Special attention is paid to the newborn’s temperature, and blood glucose is monitored and managed as appropriate. Newborns needing more extensive care are admitted into the neonatal intensive care unit, while those with less need for monitoring can be kept in a mother’s room or a normal newborn nursery.

The rate of death and disability is more in infants born with lower gestational age and birth weight percentile.

Pearls and Other Issues

Small for gestational age (SGA) infants can be constitutionally normal with birth weight consistent with the expected optimal birth weight or from fetal growth restriction (FGR) with features of in utero malnourishment. Constitutionally normal SGA infants are not at increased risk of mortality and morbidity compared to the increased risk of mortality and morbidity in infants with FGR SGA.

The evaluation of FGR SGA begins during the antenatal period with routine obstetric physical exam and ultrasound. Also important are preconception histories such as the history of prior FGR SGA birth, maternal chronic medical conditions, infections, and substance abuse. These are helpful for early diagnosis and facilitate monitoring and delivery planning.

After birth, the newborn is stabilized with special attention paid to temperature and glucose management.  The infant should undergo further evaluation to determine the cause of FGR SGA, and treatment is directed at the underlying causes. In a large proportion of cases, there is no underlying cause prenatally identified. In these cases, further evaluation is required through detailed maternal and pregnancy history, pathological examination of the placenta, comprehensive physical examination of the newborn, prenatal drug or toxin exposure history or meconium testing, and congenital infection work-up.

Enhancing Healthcare Team Outcomes

Fetal growth-restricted small for gestational age (FGR SGA) infants are at increased risk of mortality and morbidity compared to constitutional SGA and the appropriate for gestational age (AGA) infants. Maternal medical conditions, pregnancy history, as well as fetal genetic conditions, are contributory risk factors for FGR SGA. The evaluation for FGR SGA begins during the antenatal period with routine ultrasound and obstetric exams.

The management of FGR SGA begins during pregnancy with close monitoring of fetal conditions, and the decision on the timing and approach of delivery are made by obstetricians. In preparation for delivery, a Neonatal Resuscitation Program trained professional should be present for initial resuscitation.  In cases of severe FGR, a perinatal center with an experienced neonatal interprofessional team may be selected. This interprofessional team consists of neonatologists, delivery room nurses, neonatal intensive care unit nurses, respiratory therapists, and pharmacists.

The nurses will ensure that patient’s vital signs are monitored and also will assist in providing education to the parents and family members. The pharmacists will ensure that the newborns are placed on appropriate medication and correct dosing. Infants needing extensive monitoring are admitted to the neonatal intensive care units and are managed by the neonatologist. Other consultants are involved based on the need of the individual patient. Endocrinologists are involved in patients with difficult-to-control hypoglycemia. Pediatric cardiac surgeons are involved in patients with congenital cardiac diseases. Pediatric general surgeons are involved in patients with conditions such as intestinal atresia or necrotizing enterocolitis. Genetic counselors are involved with patients born with underlying genetic diseases.