INTRAUTERINE GROWTH RESTRICTION

Intrauterine growth retardation (IUGR ? also known as intrauterine growth restriction or small for gestational age - SGA) occurs when the fetus is less than 10 percent of predicted fetal weight for gestational age. It can result in significant fetal morbidity and mortality1998-01 if not properly diagnosed and managed. The reason that studies on SGA fetuses have shown poor perinatal outcome is likely to be the high incidence of true Fetal Growth Retardation in this group.1998-02 The condition is most commonly caused by inadequate maternal-fetal circulation. Less common causes include intrauterine infections such as cytomegalovirus and rubella, and congenital anomalies such as trisomy 21 and trisomy 18. When IUGR is recognized, it is important to attempt to correct reversible causes, although many of the conditions responsible for IUGR are not correctable. Close fetal surveillance with delivery before 38 weeks of gestation is usually recommended. Some infants born with IUGR have reduced mental ability and medical problems, although for most infants the long-term prognosis is good.However, the vast majority of term SGA infants have no appreciable morbidity or mortality.1986-01

At one time, all babies born weighing less than 2,500 g (5 lb 8oz) were classified as ?premature?. In 1961 the World Health Organization (WHO) acknowledged that many infants defined as "premature" were not born early but were simply of "low birth weight." The current WHO criterion for low birth weight is a weight less than 2,500 g (5 lb, 8 oz) or below the 10th percentile for gestational age.

Low birth weight includes two pathologic conditions and one normal condition. The normal condition refers to the healthy but constitutionally small baby. The pathologic conditions include preterm delivery and intrauterine growth retardation (IUGR). Synonymous terms found in the literature to describe infants with IUGR include intrauterine growth restriction and fetal growth retardation. IUGR is linked to an increase of six to 10 times in perinatal mortality.

Epidemiology of

According to the common definition of IUGR as a birth weight under the 10th percentile, the expected incidence of IUGR should be 10 percent. The actual incidence, however, is only about 6 percent. About a quarter of infants who are below the 10th percentile have a normalized birth weight when it is corrected for low maternal weight, paternal phenotype or residence at higher altitudes.1992-01

The approximately 3.5 million annual births in the United States result in 350,000 infants who are born weighing less than 2,500 g (5 lb, 8 oz). Approximately one third of these infants (about 100,000) have true IUGR, and the remaining two thirds (about 250,000) are constitutionally small.

Etiology

Many different factors cause IUGR, but they may be divided into two large categories, based on etiology. These categories include fetoplacental factors and maternal factors. Within the categories of maternal and fetoplacental factors are many specific causes.

Historically, IUGR has been categorized as symmetric or asymmetric. Symmetric IUGR refers to fetuses with equally poor growth velocity of the head, the abdomen and the long bones. Asymmetric IUGR refers to infants whose head and long bones are spared compared with their abdomen and viscera. It is now believed that most IUGR is a continuum from asymmetry (early stages) to symmetry (late stages).

Maternal causes of IUGR account for most uteroplacental cases. Chronic hypertension is the most common cause of IUGR. Moreover, the infants of hypertensive mothers have a three-fold increase in perinatal mortality compared with infants with IUGR who are born of normotensive mothers.

Pre-eclampsia causes placental damage that result in uteroplacental insufficiency. The pathogenic mechanism is thought to be a failure of trophoblastic invasion by maternal spiral arterioles by 20 to 22 weeks of gestation. This failure causes luminal narrowing and medial degeneration, leading to diminished blood flow to the developing infant. Consequently, these infants fail to grow normally.

Infectious causes of fetal growth delay account for about 10 percent of all cases of IUGR. These causes include the "TORCH" group: Toxoplasma, rubella, cytomegalovirus and herpes simplex virus types 1 and 2. Other potential pathogens include hepatitis A and hepatitis B, parvovirus B19, human immunodeficiency virus (HIV) and Treponema pallidum (syphilis). Maternal pre-pregnancy weight and weight gain during pregnancy are considered strong indicators of birth weight. The current consensus is that a maternal weight gain of less than 10 kg (22 lb) by 40 weeks of gestation is clearly a risk factor for IUGR.

Maternal smoking may be the cause of IUGR.2008-02

Early use of alcohol by the pregnant mother may lead to fetal alcohol syndrome, while second- or third-trimester use may result in IUGR. As little as one to two drinks per day have been shown to result in a growth-delayed child.1984-01 Maternal cocaine use has been linked to IUGR, as well as to reduced head circumference.2002-01 Other drugs associated with IUGR include steroids, warfarin and phenytoin.

Intrauterine growth retardation occurs more frequently in twin deliveries than in single gestations.2005-01 Decreased birth weight is second only to respiratory distress syndrome as a cause of infant mortality in twins. Reasons for IUGR in twin pregnancies include poor placental implantation, placental crowding and twin-to-twin transfusion.

Diagnosis

Methods employed to detect SGA fetuses include abdominal palpation, measurement of symphyseal fundal height, ultrasound biometry, ultrasound estimated fetal weight and ultrasound Doppler flow velocimetry. Four important issues need to be considered with the use of these tests:


most measurements require an accurate estimation of gestation as a prerequisite
most tests attempt to diagnose SGA fetuses rather than growth-restricted fetuses
most studies use a one-off measurement (size) to predict SGA while there is evidence that it is the trend (growth) that is of more value in predicting poor fetal outcome.1993-01, 1994-01
in most situations no allowance is made for important prognostic factors for SGA, such as maternal height, weight, ethnicity, parity and fetal gender.1995-01, 1998-03

The main prerequisite for determining IUGR is precise dating. The most accurate dating method uses ultrasound examination at eight to 13 weeks. Later ultrasound examinations are helpful, but the margin of error is increased. The date of the last menstrual period, early uterine sizing and detection of fetal heart tones are helpful ways to accurately date the pregnancy. Most cases of IUGR present during the third trimester, which makes them difficult to accurately diagnose. This is especially true if the patient has presented for prenatal care at a late stage. The physician must determine if the dating is incorrect and the fetal size is actually normal or if the mother truly needs further evaluation for IUGR.

Before the development of ultrasonography, indicators of possible delayed fetal growth were low maternal weight gain and fundal height measurement.

Physical examination of the abdomen by inspection and palpation detects as few as 30% SGA fetuses.1982-01 Therefore, if SGA is suspected, it is necessary to supplement abdominal palpation with ultrasound biometric tests.

Currently, IUGR is still often suspected on the basis of fundal height measurements. A significant lag in fundal height is a 4-cm or greater difference than expected for gestational age.Although early studies reported sensitivities of 56?86%26?29 and specificities of 80?93% 1985-02, 1987-02, 1986-02 for fundal height to predict SGA neonates, a large study1986-03 of 2941 women found the sensitivity and specificity to be 27% and 88%, respectively. Serial measurements may improve sensitivity and specificity.1987-03 The impact on perinatal outcomes of measuring fundal height is uncertain. A systematic review found only one controlled trial with 1639 patients and showed that SFH measurement did not improve any of the perinatal outcomes measured.2000-01 Low sensitivity, high false positive rates, significant intra- and inter-observer variation1989-03 make this test alone unsuitable for diagnosis. Therefore, if SGA is suspected, it is necessary to supplement fundal height measurement with ultrasound biometric tests.

A customised SFH chart is adjusted for physiological variables such as maternal height, weight, parity and ethnic group. Use of such charts was found to result in improvement in sensitivity (29% and 48% using non-customised and customised charts, respectively), resulting in increased antenatal detection of SGA babies with a
reduction in unnecessary hospital investigations for fetal growth.1999-01 Calculation of customised centiles (both for fundal height and ultrasound growth) requires computer software that can be downloaded from the Internet (www.gestation.net), free of charge, for personal or institutional use. These charts can then be printed and incorporated into patient-held records at the time of booking.

IUGR is frequently detected in a pregnancy with a less-than-expected third-trimester weight gain or as an incidental finding on ultrasound examination when fetal measurements are smaller than expected for gestational age.

When the suspicion of IUGR is strong, a complete assessment of maternal risk factors should be undertaken. This includes past medical and obstetric history, medication use, recent infections, occupational or toxic exposures, and a history of tobacco, alcohol or illicit drug use.

Ultrasonography is normally the first study done to assess IUGR. This test loses its accuracy as the pregnancy progresses, but the sensitivity and positive predictive value can be improved if several variables are combined including estimated fetal weight, head circumference and abdominal circumference.

Estimated fetal weight is the most common screen. It is based on the measurements of head circumference, abdominal circumference and femur length. These measurements are plotted on a preexisting standardized chart. In about 95 percent of cases, ultrasound examination allows an estimation of fetal weight with a 15 to 18 percent variance. An estimated fetal weight of less than the sixth percentile strongly correlates with growth retardation, and an estimated fetal weight of greater than the 20th percentile virtually rules out IUGR.

In all growth-retarded fetuses, the abdominal circumference is the first biometric measure to change. The ratio of head circumference to abdominal circumference is normally one at 32 to 34 weeks and falls below one after 34 weeks. A ratio of greater than one detects about 85 percent of growth-restricted fetuses.

Serial measurements of AC and EFW (growth velocities) are superior to single estimates of AC or EFW in the prediction of FGR (abnormal neonatal ponderal index and skinfold thickness)18 and predicting poor perinatal outcome.1994-01, 1999-02However, use of fetal growth alone to diagnose growth restriction (especially when the interval between the scan is less than two weeks) can lead to high numbers of false positives.1998-04 The first radiographic sign of IUGR may be decreased amniotic fluid volume. About 85 percent of IUGR infants have oligohydramnios. This condition occurs because blood flow from peripheral organs (kidneys) is diverted to the brain. Renal perfusion and urinary flow rates are commonly reduced in infants with IUGR.1989-01 An amniotic fluid index of less than 5 cm increases the risk of IUGR. A vertical pocket of amniotic fluid less than 1 cm, regardless of gestational age, is found in about 39 percent of cases of IUGR. A systematic review in the Cochrane Database of Systematic Reviews has shown that routine ultrasound after 24 weeks in low-risk pregnancy does not improve perinatal poutcome.2007-01

Maternal arterial umbilical blood flow increases from 50 mL per minute early in pregnancy to about 700 mL per minute at term. The increase is secondary to a gradual decrease in vessel resistance to blood flow throughout the pregnancy. Doppler velocimetry uses ultrasound to measure peak-systolic and end-diastolic blood flow through the umbilical artery. Three measurements are averaged as the systolic/ diastolic ratio. As the pregnancy progresses, diastolic flow increases, and the systolic/diastolic ratio should gradually decrease. In a large number of IUGR pregnancies, an alteration in placental blood flow occurs. As a result, researchers have correlated an increased systolic/diastolic ratio with IUGR. The ratio is increased in about 80 percent of cases of IUGR diagnosed by ultrasound examination.1989-02 An average systolic/ diastolic ratio greater than three at 30 or more weeks of gestation has a sensitivity of 78 percent and a specificity of 85 percent in predicting IUGR.1985-01 A systematic review with meta-analysis2000-02 found that uterine artery Doppler had limited accuracy in predicting FGR and perinatal death. In the low-risk population the pooled LR to predict FGR was 3.6 for a positive test and 0.8 for a negative test. Even in the high-risk population the pooled LRs were 2.7 and 0.7 for positive and negative tests, respectively.

Ultrasonographic placental grading has been studied with respect to IUGR. Normally, a grade 3, or mature, placenta would not be detected before 36 weeks of gestation. The presence of a grade 3 placenta before 36 weeks, along with an estimated fetal weight of less than 2,700 g (5 lb, 14 oz), carries a four-fold risk of IUGR.1983-01

A distinction needs to be made between biometric tests (tests to measure size) and biophysical tests (tests to assess fetal wellbeing). Biometric tests are designed to predict size and, if performed longitudinally, growth, but not wellbeing. Biophysical tests, on the other hand, are not designed to predict size but fetal wellbeing. The presence of fetal wellbeing implies the absence of fetal acidaemia. This distinction implies that the diagnosis of SGA would rely on biometric tests while abnormal
biophysical tests are more indicative of FGR than SGA.

Antenatal Surveillance

When the diagnosis of IUGR has been established, it is helpful to determine a specific etiology. Therapy may be nonspecific but should try to address the underlying cause. Many infants thought to be growth-retarded are, in retrospect, found to be constitutionally small. The key management issues are the gestational age of the pregnancy at the time of diagnosis and the urgency to expedite delivery. Most fetal deaths involving IUGR occur after 36 weeks of gestation and before labour begins. The clinician must balance the risk of delivering a premature infant against the potential for intrauterine demise.

Ultrasonography at three- to four-week intervals is recommended to assess fetal growth. Third-trimester fetal weight gain should be 100 to 200 g per week. Head circumference that does not change over a four-week period is worrisome and may be an indication for prompt delivery.

Twice-weekly non-stress testing (NST) is an appropriate surveillance method in following a fetus with IUGR. A reactive NST (two accelerations in fetal heart rate of more than 15 beats per minute lasting for more than 15 seconds in a 20-minute span) has been shown to correlate with fetal well-being. Spontaneous variable decelerations in fetal heart rate on the NST may indicate oligohydramnios and an increased risk of perinatal mortality. A nonreactive The biophysical profile includes an NST, fetal breathing movements, gross body movements, fetal tone and amniotic fluid index. Two large studies1987-01 found the biophysical profile to be predictive of fetal well-being, fetal distress and ultimate perinatal mortality.

Doppler velocimetry, previously discussed as a diagnostic technique for IUGR, has not found a place in routine antenatal surveillance. It has helped physicians understand the pathophysiology of IUGR with regard to diminished blood flow. Results of this procedure correlate with increased fetal morbidity and mortality: an absent or reversed end-diastolic umbilical flow is an ominous finding and necessitates aggressive intervention. As a screening test, however, the procedure appears to be lacking in benefit; some studies have shown that 40 to 60 percent of infants with IUGR had normal Doppler velocimetry results just before birth.

The biophysical profile has not been shown to improve perinatal outcome but sufficient data do not exist to rule out its value: a systematic review2000-05 found only four poor-quality studies with fewer than 3000 patients. Authors of the systematic review concede that to make a meaningful conclusion about the impact of biophysical profile on perinatal mortality, in excess of 10 000 women would need to be studied. However, there is evidence from uncontrolled observational studies that biophysical profile in high-risk women has good negative predictive value, i.e. fetal death is rare in women with a normal biophysical profile.1993-03 Given the absence of benefit from randomised trials and that biophysical profile is a time-consuming test, it cannot be recommended for routine monitoring in lowrisk/ unselected pregnancies or for primary surveillance in SGA fetuses. However, when primary surveillance with umbilical artery Doppler is found to be abnormal, biophysical profile is likely to be useful given its good negative predictive value in high-risk populations.

Use of cardiotocography (CTG) antepartum to assess fetal condition is not associated with better perinatal outcome; in fact, a systematic review of randomised trials showed that there was a trend towards increased mortality in the group receiving CTG compared with those who did not.2000-06 Computer systems for interpretation of CTG have better accuracy than clinical experts in predicting umbilical acidosis and depressed Apgar scores.1988-02 However, further evaluation of this technology is required before clinical recommendations could be made regarding its widespread use.

Treatment

Treatment of the mother and the growth-restricted fetus is, when possible, dictated by the aetiology of the condition.Up to 19% of fetuses with an AC and EFW less than the fifth centile may have chromosomal defects.60 The risk is higher when growth restriction is associated with structural abnormalities,60 a normal
liquor volume or a normal uterine or umbilical artery Doppler.1993-02 Therefore, all growth-restricted fetuses need an ultrasound anatomical survey as a minimum. It may also be appropriate to offer karyotyping.

A systematic review with meta-analysis has provided compelling evidence that the use of umbilical artery Doppler to monitor high-risk fetuses reduces perinatal morbidity and mortality.1995-02 Furthermore, there was a significant reduction in the number of antenatal admissions and inductions of labour. Use of Doppler does not lead to increased interventions as the rates of positive test are low (2.7% of all umbilical artery tests in high-risk women).1990-01 There is evidence that use of Doppler ultrasound to manage SGA fetuses reduces the use of resources compared with cardiotocography.1997-01

When an anomaly scan and umbilical artery Doppler are normal, the small fetus is likely to be a ?normal small fetus?.1993-03 Evidence suggests that outpatient management of such fetuses is safe.1997-02 In addition, a randomised controlled trial2003-01 of two regimens of fetal surveillance for SGA fetuses with normal umbilical artery Doppler found that twice-weekly compared with fortnightly monitoring resulted in earlier deliveries and more inductions of labour with no difference in neonatal morbidity. This suggests frequency of monitoring in SGA fetuses with normal Doppler need not generally be more than once every fortnight.

Abnormal liquor volume has been variously defined as single cord-free 1-cm, 2-cm, 1-x-1-cm, 2-x-1- cm and 2-x-2-cm pockets or an AFI below the fifth centile for the gestation or ≤ 5 cm.2004-04 Other large studies1984-02,1986-04 have shown that a reduction in liquor volume is associated with increased perinatal mortality compared with controls with normal liquor volume.

Management

Maternal hyperoxygenation has been evaluated in several studies, but only limited data prove its efficacy. In one study,1991-01 nasal oxygen at 2.5 L per minute administered to mothers at 27 to 28 weeks of gestation improved neonatal blood gas measurements but resulted in an increased incidence of hypoglycemia and thrombocytopenia in the infants.

Low-dose aspirin (150 mg per day) as a treatment for IUGR has been studied over the past several years. One study1998-011991-02 aspirin, given in a dosage of 150 mg per day with dipyridamole in a dosage of 225 mg per day and administered at 15 to 18 weeks of gestation in high-risk patients, resulted in a lower incidence of still-birth, placental abruption and IUGR. Birth weight was improved, and no excess of maternal or fetal aspirin-related side effects occurred. It would seem prudent to consider low-dose aspirin therapy in selected patients with risk factors for IUGR.

Approximately one half of infants with IUGR have intrapartum asphyxia and lower Apgar scores than control subjects. A higher incidence of meconium aspiration has also been noted in these infants. Continuous monitoring of fetal heart rate throughout labour is , therefore, recommended in cases of IUGR. Late decelerations are more predictive of fetal hypoxia and a resultant adverse outcome in this group of high-risk infants. A lower threshold for the choice of caesarean section is therefore recommended. Neonatal resuscitation and subsequent care of the growth-restricted infant should follow in the same manner used with other newborns. Problems to closely watch out for in infants with IUGR include hypoglycemia, hypocalcemia, polycythemia secondary to intrauterine hypoxia and hypothermia due to decreased body fat.

There is wide variation in practice in the timing of delivery of growth restricted fetuses.1996-02  But thus far there is no evidence from GRIT that early delivery to pre-empt severe hypoxia and acidosis reduces any adverse outcome.2004-01

Absent or reversed end diastolic flow is associated with increased perinatal mortality and morbidity.1994-03, 1994-04 1996-03

When end diastolic flow is absent or reversed, admission, close surveillance and administration of steroids are required. If other surveillance results (biophysical profile, venous Doppler) are abnormal, delivery is indicated. If gestation is over 34 weeks, even if other results are normal, delivery may be considered.

Most prenatal interventions do not show any significant effects on perinatal outcome. Smoking cessation programmes, particularly behavioural strategies, can be effective for a small minority of smokers in increasing birthweight but there are no data to suggest that this intervention improves perinatal outcome.2001-01  Although a meta-analysis102 of 13 trials evaluated the use of aspirin in the prevention of growth restriction and found that it reduced the incidence of FGR, only a few studies have used aspirin in the treatment of FGR. These trials are small and have shown conflicting results.1999-04, 1995-03 Further trials are needed to assess the value of aspirin in the treatment of FGR. There is not enough evidence to assess the value of oxygen therapy,2003-01 hospitalisation and bedrest,2000-07 betamimetics,2001-02 hormonal therapy2003-02 and plasma volume expansion2000-08 in treating growth restriction.

Neonatal Outcomes

In most cases, infants with IUGR ultimately have good outcomes. These infants often exhibit fast catch-up growth in the first three months of life and attain normal growth curves by one year of age. Some studies have found a variety of long-term complications in infants with IUGR including hyperactivity, clumsiness and poor concentration.

In a recent British study,1996-01 records of 1,576 men and women born between 1920 and 1943 for whom birth weight and anthropomorphic measurements were recorded in detail after birth were examined. No definite association was found between cognitive function (intelligence quotient and vocabulary) and birth weight, head circumference or ratio of head circumference to abdominal circumference. Collectively, developmental studies demonstrate that many factors contribute to the ultimate intellectual development of infants with IUGR, including birth weight, time of onset of IUGR, head circumference, gestational age at delivery, etiology of the IUGR and postnatal environment. Most infants with IUGR have an excellent long-term prognosis.

 

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