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Neonatal management of the growth-restricted infant
Seminars in Fetal & Neonatal Medicine (2004) 9, 403e409
www.elsevierhealth.com/journals/siny
Neonatal management of the growth-restricted infant Victor Y.H. Yu), Amit Upadhyay Department of Paediatrics and Ritchie Centre for Baby Health Research, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia
KEYWORDS Intra-uterine growth retardation; Newborn infant; Neonatal care
Summary Close collaboration between obstetricians and neonatologists is essential for proper care of the growth-restricted fetus. A joint decision on the appropriate timing of delivery is made, based on the risk of fetal compromise compared with that of neonatal morbidity. A neonatal resuscitative team should be available at delivery. Gestational assessment, anthropological measurements and physical examination are necessary to confirm the diagnosis of intra-uterine growth retardation and establish the symmetric, asymmetric, combined or dysmorphic classification. Neonatal management requires special attention to a number of significant morbidities that growth-restricted infants are more prone to develop compared with normally grown infants, including asphyxia, meconium aspiration syndrome, respiratory distress syndrome, massive pulmonary haemorrhage, chronic lung disease, hypothermia, hypoglycaemia, hypocalcaemia, polycythaemiaehyperviscosity, intraventricular haemorrhage, sepsis, necrotizing enterocolitis, coagulation abnormalities, and congenital anatomical and genetic abnormalities. Intra-uterine growth retardation is associated with a higher stillbirth rate and infant mortality rate in preterm, term and post-term infants. ª 2004 Elsevier Ltd. All rights reserved.
Introduction Up to 20 weeks’ gestation, fetal growth is due primarily to an increase in cell number with rapid mitosis and an increase in DNA content (hyperplastic stage). Between 20 and 28 weeks’ gestation, there is declining mitosis and an increase in cell size. After 28 weeks’ gestation, there is rapid increase in cell size and accumulation of fat, muscle and connective tissue (hypertrophic stage). ) Corresponding author. Tel.: C61-3-9594-5191; fax: C61-39594-6115. E-mail address: [email protected] (V.Y.H. Yu).
Ninety-five percent of fetal weight gain occurs during the second half of pregnancy. This growth may be restricted by numerous adverse events during pregnancy, leading to intra-uterine growth retardation (IUGR). The neonatal management of these infants poses a diagnostic and therapeutic challenge.
Definitions IUGR is commonly defined as a birth weight of !10th percentile on the intra-uterine growth chart. Others have defined IUGR as a birth weight
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of less than two standard deviations below the mean, which corresponds with approximately the third percentile. Some fetuses have growth restriction and do not achieve their full genetic growth potential, but the intra-uterine insult may not be sufficient to curtail their birth weight to !10th percentile and they are therefore not labelled ‘IUGR’. The diagnosis of growth restriction in such infants can be made by careful anthropometry that demonstrates asymmetric or disproportionate growth. This may be important because it has been shown that even infants between the 10th and 25th percentile may suffer higher mortality and morbidity rates.1 Some infants are ‘normally or constitutionally small’, and these infants are generally born to small parents. These infants pose no increased obstetrical or neonatal risks.2 Ethnicity also influences birth weight,3 and the growth chart used should ideally be based on the local specific population group into which the infant is born. These scenarios may be difficult to distinguish from the small mother who was IUGR herself, a known risk factor for IUGR of her own children [adjusted odds ratio 2.0; 95% confidence interval (CI) 1.4e3.0].4
Indications of delivery in the presence of IUGR include a gestational age of O37 weeks, presence of fetal distress, cessation of fetal growth over a 2e4-week period, oligohydramnios, and absent or reversed end-diastolic flow on Doppler velocimetry. Although fetal lung maturity may be enhanced by antenatal corticosteroids, significant problems associated with very preterm delivery should deter a decision of early delivery before 32 weeks’ gestation. The guidelines for use of antenatal corticosteroids in IUGR pregnancies are the same as with other instances of preterm labour.7 An analysis of a large database of nearly 20 000 singleton infants of 501e1500 g birth weight showed similar effectiveness of antenatal corticosteroids in IUGR and normally grown infants: reduced risks of respiratory distress syndrome (RDS, odds ratio 0.51; 95% CI 0.44e0.58), intraventricular haemorrhage (IVH, odds ratio 0.67; 95% CI 0.61e0.73), severe IVH (odds ratio 0.50; 95% CI 0.43e0.57) and death (odds ratio 0.54; 95% CI 0.48e0.62).8 However, another study reported less beneficial effects of antenatal corticosteroids in IUGR infants on RDS, IVH and death.9
Timing of delivery
Early management
The frequency of IUGR is increased in preterm infants compared with term infants.5 There have been no published randomized controlled trials (RCTs) addressing the optimum timing or mode of delivery in the IUGR fetus. The timing of delivery needs to be individualized; a decision is made to deliver if the risk of fetal death exceeds that of neonatal death, although in many cases, these risks may be difficult to assess. Early delivery may lead to all the complications of prematurity, while delaying delivery may lead to worsening of the medical condition in the mother that is responsible for IUGR (such as pre-eclampsia) and worsening intra-uterine hypoxaemia in the infant that may result in stillbirth or long-term neurological sequelae. Aggressive management ( patients prepared for delivery 48 h after corticosteroids) and expectant management ( patients managed with bed rest, oral antihypertensives and intensive antenatal fetal testing until 34 weeks’ gestation) of severe pre-eclampsia at 28e32 weeks’ gestation were compared in an RCT.6 Expectant management was found to reduce neonatal complications and hospital stay without an increase in adverse consequences to the mother or infant. This RCT, however, excluded those who had severe IUGR (estimated fetal weight less than the fifth percentile).
Neonatal staff who are competent at neonatal resuscitation are required to attend deliveries. Precautions should be taken to prevent hypothermia. The umbilical cord should be double clamped and a blood specimen taken from the umbilical artery for pH and lactate determination. The placenta should be weighed, inspected on both surfaces for evidence of infarction and gross abnormalities, and sent for histopathology, especially in preterm IUGR births.10 In the stillborn fetus, karyotyping, serology for congenital infection, and detailed autopsy should be done. A maternal thrombophilia screen should be performed following delivery at !32 weeks’ gestation for severe IUGR and/or severe pre-eclampsia with haemolysiseelevated liver enzymeselow platelets (HELLP) syndrome,11 although a recent study did not find an association of thrombophilia polymorphism with IUGR.12 Indications for admission of IUGR infants to a neonatal special or intensive care unit include symptomatic infants (such as those who require resuscitation, develop early respiratory distress, look polycythaemic or are documented to have hypoglycaemia) and asymptomatic infants who appear to be severely growth restricted (birth weight less than the third percentile) or who are !1800 g birth weight or !34 weeks’ gestation.
Neonatal management of the growth-restricted infant An initial neonatal examination would probably show an infant with soft tissue wasting, diminished skinfold thickness and a relatively large head. The skin is often dry, rough, desquamated and wrinkled, and at times covered in meconium. The infant may have long fingernails, and the skin may look plethoric, although peripheral vasoconstriction can give it a pale look. Cranial sutures may be widened with large fontanelles. The umbilical cord is probably thinner than usual and can be yellow/ green stained if meconium is passed in utero. IUGR infants are often ‘‘alert-looking’’ and jittery even without hypoglycaemia or hypocalcaemia. They can be hyperexcitable with aberrations in muscle tone. The Moro reflex can be exaggerated with more extension and abduction.13 However, severe IUGR infants may be floppy as they become easily exhausted on handling. These infants (birth weight of less than the third percentile) should, especially, be examined for the presence of congenital malformations and stigmata of congenital infections (skin rash, hepatosplenomegaly and ocular abnormalities such as cloudy cornea, cataract or chorioretinitis). Those with stigmata of congenital infections should have toxoplasmosiseother infectionerubellae cytomegaloviruseherpes and syphilis testing. Due to a reduced amount of vernix caseosa in IUGR infants, their skin appears more mature. Sole creases also appear more advanced for gestational age. Conversely, their breast nodule and female genitalia appear less mature than actual gestation due to a decreased amount of fat deposition. Even the ear may be less well formed. However, neonatal reflexes are not affected by IUGR. If one is in doubt about gestational age, pupillary reaction, Moro reflex, glabellar tap, traction response, cross extensor reflex, and active and passive tone and posture can be relied on for gestational age assessment. When the gestational age has been determined and the anthropological measurements have been made after birth, IUGR infants can be classified into four types: symmetric, asymmetric, combined and dysmorphic.
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Asymmetric IUGR Asymmetric IUGR occurs when the growth restriction begins in the late second trimester or the third trimester. These infants, which comprise half of IUGR infants, are disproportionately small: birth weight !10th percentile, but length and head circumference are preserved. As a result of failure in delivery of adequate oxygen or nutrition to the fetus, there is a shortage of energy stores such as glycogen and adipose tissue. ‘Brain sparing’ occurs at the cost of growth of skeletal muscles, adrenals, liver and thymus. Their low ponderal index (birth weight in g ! 100 O crowneheel length in centimetres) is a useful objective measure of the severity of asymmetric IUGR.14 Conditions associated with asymmetric IUGR include diseases that lead to vascular or nutritional uteroplacental insufficiency and fetal constraint in utero, such as preeclampsia, maternal heart disease or anaemia, high altitude, multiple pregnancy and substance abuse late in pregnancy.
Combined IUGR Combined IUGR has features of both symmetric and asymmetric IUGR. These infants, which comprise about one-tenth of IUGR infants, have skeletal shortening and some reduction of soft tissue mass. Causes of combined IUGR include severe maternal disease from the first trimester, skeletal dysplasia and metabolic bone disease.
Dysmorphic IUGR Dysmorphic IUGR includes infants with head, trunks and limbs that appear disproportionate. They often have major and minor congenital anomalies.
Morbidity Perinatal asphyxia
Symmetric IUGR Symmetric IUGR occurs when the growth restriction begins early in gestation. These infants, which comprise one-third of IUGR infants, are proportionately small: birth weight, length and head circumference of the infant are all !10th percentile. Brain growth is compromised. Causes of symmetric IUGR include genetic and chromosomal abnormalities and syndromes, congenital infections, substance abuse and exposure to teratogens.
Even transient diminished placental blood flow during uterine contractions are tolerated poorly by IUGR fetuses. Already compromised by placental insufficiency and chronic intra-uterine hypoxia, they are more prone to asphyxia than normally grown infants. As a result, there is an increased risk of meconium aspiration syndrome in IUGR infants, who also have lower Apgar scores and umbilical artery pH, more endotracheal intubation in the delivery room, and more seizures and hypoxice ischaemic encephalopathy.15e17
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Hypothermia Although IUGR infants were reported to have a higher than normal temperature at birth,18 they are at risk of hypothermia,19 due to a greater cephalic volume and body surface area in relation to weight, and less subcutaneous fat and lower fat stores including depleted brown fat reserves that limit their non-shivering thermogenesis. Perinatal asphyxia may impair muscular activity, oxygen consumption and heat production. Therefore, prompt and complete drying of the infant after birth, wrapping in warm linen after resuscitation, and maintaining the baby under a radiant heat source are crucial. Subsequently, adequate clothing is necessary including a prewarmed hat to minimize heat loss from the head. Skin-to-skin contact nursing (kangaroo care) is also an effective measure. Body temperature should be recorded at birth and at 2 h, and then every 6e8 h for the first 48e72 h of life.
Hypoglycaemia Hypoglycaemia occurs in 12e24% of IUGR infants, seven times higher than in normally grown infants, with a higher risk found in those with severe IUGR and asymmetric IUGR.15,20 Contributing factors include diminished hepatic and skeletal muscle glycogen, reduced alternate energy substrates such as free fatty acids due to the scant adipose tissues, decreased concentration of lactate, hyperinsulinaemia or increased sensitivity to insulin or both, decreased glycogenolysis and gluconeogenesis, and deficient counter-regulatory hormones. The risk of hypoglycaemia is greatest during the first 3 days of life, but especially in the first 24 h. About 1% of IUGR infants who develop hypoglycaemia have a prolonged course requiring intravenous treatment for days. IUGR infants should be screened for hypoglycaemia at 6e12-h intervals for the first 3 days of life to enable prompt detection and treatment. To avoid intravenous therapy, the strategy in developing countries in infants with asymptomatic hypoglycaemia is to feed sugarfortified milk (addition of 1.5 g powdered sugar to 30 ml of standard milk formula) on a 2-h regime.21 Only when this fails to correct the hypoglycaemia is the infant admitted to the neonatal special care unit, where an intravenous dextrose infusion is started. All infants with symptomatic hypoglycaemia should be given a bolus of 2 ml/kg of 10% dextrose, followed by continuous infusion of dextrose at 6e8 mg/kg/min. Tapering of the intravenous dextrose infusion should be done over
V.Y.H. Yu, A. Upadhyay a 12e24-h period in order to avoid rebound hypoglycaemia.
Respiratory failure The traditionally held concept that IUGR accelerates pulmonary maturation and reduces the risk of RDS is not supported by most studies, especially when comparisons were made of IUGR infants and normally grown infants of the same gestation, sex and race.22e24 Some studies have even reported a higher incidence of RDS in IUGR infants.8,25 It is possible that the RDS risk may vary within some subgroups of IUGR infants. It has been reported that IUGR infants born at 29e32 weeks’ gestation have a significantly lower risk of RDS,9,26 while those born at !29 weeks’9 or O34 weeks’5 gestation have a significantly higher risk of RDS. Further studies are required that take other confounding variables into account. Preterm IUGR infants have been reported to have an increased risk of developing chronic lung disease ( prolonged oxygen therapy and assisted ventilation at 28 postnatal days or 36 weeks’ postconceptual age).24,27 It is uncertain whether this is due to immature lungs, abnormal lung development or both.
Hypocalcaemia Serum calcium levels have been shown to be low in IUGR infants.15,25 Contributing factors include perinatal asphyxia and prematurity; if present, these warrant screening for hypocalcaemia in the IUGR infant. However, routine measurement of serum calcium is not indicated in the healthy term IUGR infant.
Polycythaemia and hyperviscosity IUGR infants are more prone to develop polycythaemia, and the reported incidence is 15e17%.15,20 It is more common in asymmetric IUGR after 34 weeks’ gestation, as the increased red cell mass results from chronic in utero hypoxaemia that leads to an increased erythropoietin level.28 Most polycythaemic infants remain asymptomatic. Polycythaemia contributes to hypoglycaemia, hyperbilirubinaemia and necrotizing enterocolitis in IUGR infants. Plethoric IUGR infants should have their haematocrit checked. This should be re-checked if the value is over 60% or if the infant has lost O10% of birth weight. Partial exchange transfusion is performed with normal saline29,30 if the venous haematocrit is O65% in a symptomatic infant or O70% in an asymptomatic infant.
Neonatal management of the growth-restricted infant
Brain injury Some studies have reported an increased incidence of IVH in preterm IUGR infants compared with normally grown infants,5,31,32 while other studies have found no difference.9,26,33 One study showed an increased risk of IVH only in more mature preterm IUGR infants born in the third trimester.5 No increased risk for periventricular leucomalacia has been found.32 Abnormal antenatal Doppler velocimetry of the umbilical artery defines a distinct subgroup of preterm IUGR infants at three times the risk of IVH and a higher incidence of long-term neurological damage compared with those with normal velocimetry.34,35
Immune function and sepsis IUGR infants have compromised humoral and cellular immunocompetence, including a decrease in IgG concentration, phagocytic index and lysozymes.36 Studies have shown that culture-proven sepsis is more common,16,25,33 especially in those born at term with birth weight less than the third percentile.16 Neutropaenia in extremely preterm IUGR infants, which occurs frequently in those born to pre-eclamptic mothers, adds substantially to the risk of sepsis. However, there is inconclusive evidence from RCTs to support or refute the use of granulocyte transfusion or colony stimulating factors to reduce mortality and morbidity.37,38
407 countries to replace gavage feeding with cup/ spoon feeding prior to a trial of breast feeding. Breast feeding from the outset is possible in most IUGR infants O35 weeks’ gestation who can continue to be roomed-in with their mothers. They should be started on feeds within 30 min of birth and fed frequently at 2e3-h intervals to prevent hypoglycaemia.
Other morbidities IUGR infants have significantly lower levels of coagulation factors V and VII and platelet counts compared with normally grown infants.41 Massive pulmonary haemorrhage has been reported as a cause of sudden unexpected death in severe IUGR infants.42 The risk of anatomical or genetic abnormalities is increased two- to threefold (the reported incidence ranged from 9% to 27%).43,44 IUGR infants have a longer length of hospital stay and a higher cost of hospital treatment, especially in the subgroup with abnormal antenatal Doppler velocimetry.5,35 With a progressive increase in the severity of IUGR, significant linear trends were documented for increasing risks of a variety of neonatal morbidities, including perinatal asphyxia, hypoglycaemia, hypocalcaemia and polycythaemia, as well as stillbirth and neonatal death.15
Mortality Necrotizing enterocolitis Studies have reported an increased incidence of necrotizing enterocolitis in preterm IUGR infants,8,32 especially in those who are born in the third trimester5 or who have absent end-diastolic frequencies in the fetal aorta on antenatal Doppler.39 Perinatal asphyxia results in re-distribution of blood in favour of the brain leading to mesenteric ischaemia, as was documented in postnatal Doppler studies of the superior mesenteric and celiac arteries in IUGR infants.40 This factor, together with polycythaemia which IUGR infants are also prone to develop, contributes to the pathogenesis of necrotizing enterocolitis. Enteral feeding should be started cautiously, preferably using the mother’s milk, to minimize the risk of necrotizing enterocolitis. Intravenous therapy is generally required in IUGR infants !1200 g birth weight or !30 weeks’ gestation to supplement gavage feeding. In more mature IUGR infants who are otherwise healthy, exclusive gavage feeding can be tried. It is common practice in developing
Stillbirth rates are increased in preterm, term and post-term IUGR fetuses.23,45,46 Neonatal, hospital and infant mortality rates are also increased in all three gestational categories of IUGR infants.31,47 Overall, the perinatal mortality rate among IUGR infants is 8e10 times higher than among normally grown infants. Both stillbirth and neonatal mortality rates are higher among asymmetric IUGR infants.15,47 In a cohort of infants !1500 g birth weight, a two- to threefold increase in mortality was reported in IUGR infants compared with normally grown infants.8,48 A higher mortality rate was also found when IUGR and normally grown infants were stratified by gestation.23 A ‘dose effect’ was observed with higher mortality in severe IUGR infants (birth weight less than the fifth percentile) compared with IUGR infants with birth weights between the fifth and the ninth percentiles.49 A higher mortality rate was reported in singleton IUGR infants compared with IUGR twins,50 and in those with absent or reversed end-diastolic flow on antenatal Doppler velocimetry.34,39
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Practice points Close collaboration between obstetricians and neonatologists is essential for proper care of the infant with IUGR, especially with the timing of delivery. Antenatal corticosteroids remain effective and safe in preterm labour in the presence of IUGR. It is important to ascertain whether IUGR is of the symmetric or asymmetric type, as their morbidity risks and outcome differ. The popular notion that IUGR accelerates pulmonary maturation and reduces the risk of RDS in preterm infants is untrue. IUGR is associated with a significantly higher stillbirth rate and infant mortality rate in preterm, term and post-term infants.
Research directions How should neonatal hypoglycaemia and polycythaemiaehyperviscosity be defined and when is treatment warranted in these conditions? Why do infants with IUGR have a higher risk of IVH and long-term neurological sequelae, and is this preventable? Are there neonatal strategies that are effective in reducing the increased risk of sepsis and necrotizing enterocolitis in infants with IUGR?
References 1. Seeds JW, Peng T. Impaired growth and risk of fetal death: is the tenth percentile the appropriate standard? Am J Obstet Gynecol 1998;178:658e69. 2. Chard T, Yoong A, Macintosh M. The myth of fetal growth retardation at term. Br J Obstet Gynaecol 1993;100:1076e81. 3. Shiono PH, Klebanoff MA, Graubard BI, Berendes HW, Rhoads GG. Birth weight among women of different ethnic groups. JAMA 1986;255:48e52. 4. Klebanoff MA, Schulsinger C, Mednick BR, Secher NJ. Preterm and small-for-gestational-age birth across generations. Am J Obstet Gynecol 1997;176:521e6. 5. Gilbert WM, Danielsen B. Pregnancy outcomes associated with intrauterine growth restriction. Am J Obstet Gynecol 2003;188:1596e9. 6. Sibai B, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks’ gestation: a randomized controlled trial. Am J Obstet Gynecol 1994;17:818e22. 7. NIH consensus statement. Effects of corticosteroids for fetal maturation on perinatal outcomes, vol. 12. Bethesda: National Institute of Health; 1994. p. 1e24.
8. Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198e206. 9. Ley D, Wide-Swensson D, Lindroth M, Svenningsen N, Marsal K. Respiratory distress syndrome in infants with impaired intrauterine growth. Acta Paediatr 1997;86: 1090e6. 10. Burke CJ, Tannenberg AE, Payton DJ. Ischaemic cerebral injury, intrauterine growth retardation, and placental infarction. Dev Med Child Neurol 1997;39:726e30. 11. Kupferminc MJ, Peri H, Zwang E, Yaron Y, Wolman I, Eldor A. High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand 2000;79:963e7. 12. Infante-Rivard C, Rivard GE, Yotov WV, Genin E, Guiguet M, Weinberg C, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med 2002;347:19e25. 13. Fredrickson WT, Brown JV. Gripping and moro responses: differences between small-for-gestational age and normal weight term newborns. Early Hum Dev 1980;4:69e77. 14. Balcazar H, Haas J. Classification schemes of small-for-gestational age and type of intrauterine growth retardation and its implications to early neonatal mortality. Early Hum Dev 1990;24:219e30. 15. Kramer MS, Olivier M, McLean FH, Willis DM, Usher RH. Impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcome. Pediatrics 1990;86: 707e13. 16. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999;340:1234e8. 17. Bukowski R, Gurgett AD, Gei A, Saade GR, Hankins GD. Impairment of fetal growth potential and neonatal encephalopathy. Am J Obstet Gynecol 2003;188:1011e5. 18. Hawdon JM, Weddell A, Aynsley-Green A, Ward Platt MP. Hormonal and metabolic response to hypoglycaemia in small for gestational age infants. Arch Dis Child 1993;68: 269e73. 19. Doctor BA, O’Riordan MA, Kirchner HL, Shah D, Hack M. Perinatal correlates and neonatal outcomes of small for gestational age infants born at term gestation. Am J Obstet Gynecol 2001;185:652e9. 20. Deorari AK, Aggarwal R, Paul VK. Management of infants with intra-uterine growth restriction. Indian J Pediatr 2001;68: 1155e7. 21. Singhal PK, Singh M, Paul VK, Lamba IM, Malhotra AK, Deorari AK, et al. Prevention of hypoglycemia: a controlled evaluation of sugar fortified milk feeding in small-for-gestational age infants. Indian Pediatr 1992;29:1365e9. 22. Tyson JE, Kennedy K, Broyles S, Rosenfeld CR. The small for gestational age infant: accelerated or delayed pulmonary maturation? Increased or decreased survival? Pediatrics 1995;95:534e8. 23. Piper JM, Xenakis EM, McFarland M, Elliott BD, Berkus MD, Langer O. Do growth-retarded premature infants have different rates of perinatal morbidity and mortality than appropriately grown premature infants? Obstet Gynecol 1996;87:169e74. 24. Gortner L, Wauer RR, Stock GJ, Reiter HL, Reiss I, Jorch G, et al. Neonatal outcome in small for gestational age infants: do they really better? J Perinat Med 1999;27:484e9. 25. Spinillo A, Capuzzo E, Egbe TO, Fazzi E, Colonna L, Nicola S. Pregnancies complicated by idiopathic intrauterine growth retardation. Severity of growth failure, neonatal morbidity
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26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
and two-year infant neurodevelopmental outcome. J Reprod Med 1995;40:209e15. Cooper PA, Sandler DL, Simchowitz ID, Galpin JS. Effects of suboptimal intra-uterine growth on preterm infants between 30 and 32 weeks’ gestation. S Afr Med J 1997;87: 314e8. Lal MK, Manktelow BN, Draper ES, Field DJ. Chronic lung disease of prematurity and intrauterine growth retardation: a population-based study. Pediatrics 2003;111:483e7. Snijders RJ, Abbas A, Melby O, Ireland RM, Nicolaides KH. Fetal plasma erythropoietin concentration in severe growth retardation. Am J Obstet Gynecol 1993;168:615e9. Deorari AK, Paul VK, Shreshta L, Singh M. Symptomatic neonatal polycythemia: comparison of partial exchange transfusion with saline versus plasma. Indian Pediatr 1995; 32:1167e71. Wong W, Fok TF, Lee CH, Ng PC, So KW, Ou Y, et al. Randomised controlled trial: comparison of colloid or crystalloid for partial exchange transfusion for treatment of neonatal polycythaemia. Arch Dis Child Fetal Neonatal Ed 1997;77:F115e8. Heinonen K, Matilainen R, Koski H, Launiala K. Intrauterine growth retardation (IUGR) in pre-term infants. J Perinat Med 1985;13:171e8. Zaw W, Gagnon R, da Silva O. The risks of adverse neonatal outcome among preterm small for gestational age infants according to neonatal versus fetal growth standards. Pediatrics 2003;111:1273e7. Simchen MJ, Beiner ME, Strauss-Liviathan N, Dulitzky M, Kuint J, Mashiach S, et al. Neonatal outcome in growth-restricted versus appropriately grown preterm infants. Am J Perinatol 2000;17:187e92. Valcamonico A, Danti L, Frusca T, Soregaroli M, Zucca S, Abrami F, et al. Absent end-diastolic velocity in umbilical artery: risk of neonatal morbidity and brain damage. Am J Obstet Gynecol 1994;170:796e801. Gaziano EP, Knox H, Ferrera B, Brandt DG, Calvin SE, Knox GE. Is it time to reassess the risk for the growthretarded fetus with normal Doppler velocimetry of the umbilical artery? Am J Obstet Gynecol 1994;170: 1734e43. Chandra RK, Matsumara T. Ontogenic development of the immune system and effect of growth retardation. J Perinat Med 1979;7:279e90. Mohan P, Brocklehurst P. Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutro-
409
38.
39.
40.
41.
42.
43.
44. 45.
46.
47.
48.
49.
50.
paenia [Cochrane review]. In: The Cochrane library. Chichester: John Wiley & Sons, Ltd; 2003. Carr R, Modi N, Dore C. FGeCSF and GMeCSF for treating or preventing neonatal infections [Cochrane review], In: The Cochrane library, Issue 4. Chichester: John Wiley & Sons, Ltd; 2003. Hackett GA, Campbell S, Gamsu H, Cohen-Overbeek T, Pearce JM. Doppler studies in the growth retarded fetus and prediction of neonatal necrotising enterocolitis, haemorrhage, and neonatal morbidity. Br Med J 1987;294:13e6. Kempley ST, Gamsu HR, Vyas S, Nicholaides K. Effects of intrauterine growth retardation on postnatal visceral and cerebral flow velocity. Arch Dis Child 1991;66:1115e8. Salonvaara M, Riikonen P, Kekomaki R, Vahtera E, Mahlamaki E, Halonen P, et al. Effects of gestational age and prenatal and perinatal events on the coagulation status in premature infants. Arch Dis Child Fetal Neonatal Ed 2003;88:F319e23. Sly PD, Drew JH. Massive pulmonary haemorrhage: a cause of sudden unexpected deaths in severely growth retarded infants. Aust Paediatr J 1981;17:32e4. Khoury MJ, Erickson JD, Cordero JF, McCarthy BJ. Congenital malformations and intrauterine growth retardation: a population study. Pediatrics 1988;82:83e90. Spiers PS. Does growth retardation predispose the fetus to congenital malformation? Lancet 1982;1:312e4. Clausson B, Cnattingius S, Axelsson O. Outcomes of postterm births: the role of fetal growth restriction and malformations. Obstet Gynecol 1999;94:758e62. Divon MY, Haglund B, Nisell H, Otterblad PO, Westgren M. Fetal and neonatal mortality in the postterm pregnancy: the impact of gestational age and fetal growth restriction. Am J Obstet Gynecol 1998;178:726e31. Vik T, Markestad T, Ahlsten G, Gebre-Medhin M, Jacobsen G, Hoffman HJ, et al. Body proportions and early neonatal morbidity in small-for-gestational-age infants of successive births. Acta Obstet Gynecol Scand 1997;165(Suppl):76e81. Chen SJ, Vohr BR, Oh W. Effects of birth order, gender, and intrauterine growth retardation on the outcome of very low birth weight in twins. J Pediatr 1993;123:132e6. Dobson PC, Abell DA, Beischer NA. Mortality and morbidity of fetal growth retardation. Aus N Z J Obstet Gynaecol 1981; 21:69e72. Kilpatrick SJ, Jackson R, Croughan-Minihane MS. Perinatal mortality in twins and singletons matched for gestational age at delivery at O or Z 30 weeks. Am J Obstet Gynecol 1996;174:66e71.
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Neonatal management of the growth-restricted infant Victor Y.H. Yu), Amit Upadhyay Department of Paediatrics and Ritchie Centre for Baby Health Research, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia
KEYWORDS Intra-uterine growth retardation; Newborn infant; Neonatal care
Summary Close collaboration between obstetricians and neonatologists is essential for proper care of the growth-restricted fetus. A joint decision on the appropriate timing of delivery is made, based on the risk of fetal compromise compared with that of neonatal morbidity. A neonatal resuscitative team should be available at delivery. Gestational assessment, anthropological measurements and physical examination are necessary to confirm the diagnosis of intra-uterine growth retardation and establish the symmetric, asymmetric, combined or dysmorphic classification. Neonatal management requires special attention to a number of significant morbidities that growth-restricted infants are more prone to develop compared with normally grown infants, including asphyxia, meconium aspiration syndrome, respiratory distress syndrome, massive pulmonary haemorrhage, chronic lung disease, hypothermia, hypoglycaemia, hypocalcaemia, polycythaemiaehyperviscosity, intraventricular haemorrhage, sepsis, necrotizing enterocolitis, coagulation abnormalities, and congenital anatomical and genetic abnormalities. Intra-uterine growth retardation is associated with a higher stillbirth rate and infant mortality rate in preterm, term and post-term infants. ª 2004 Elsevier Ltd. All rights reserved.
Introduction Up to 20 weeks’ gestation, fetal growth is due primarily to an increase in cell number with rapid mitosis and an increase in DNA content (hyperplastic stage). Between 20 and 28 weeks’ gestation, there is declining mitosis and an increase in cell size. After 28 weeks’ gestation, there is rapid increase in cell size and accumulation of fat, muscle and connective tissue (hypertrophic stage). ) Corresponding author. Tel.: C61-3-9594-5191; fax: C61-39594-6115. E-mail address: [email protected] (V.Y.H. Yu).
Ninety-five percent of fetal weight gain occurs during the second half of pregnancy. This growth may be restricted by numerous adverse events during pregnancy, leading to intra-uterine growth retardation (IUGR). The neonatal management of these infants poses a diagnostic and therapeutic challenge.
Definitions IUGR is commonly defined as a birth weight of !10th percentile on the intra-uterine growth chart. Others have defined IUGR as a birth weight
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of less than two standard deviations below the mean, which corresponds with approximately the third percentile. Some fetuses have growth restriction and do not achieve their full genetic growth potential, but the intra-uterine insult may not be sufficient to curtail their birth weight to !10th percentile and they are therefore not labelled ‘IUGR’. The diagnosis of growth restriction in such infants can be made by careful anthropometry that demonstrates asymmetric or disproportionate growth. This may be important because it has been shown that even infants between the 10th and 25th percentile may suffer higher mortality and morbidity rates.1 Some infants are ‘normally or constitutionally small’, and these infants are generally born to small parents. These infants pose no increased obstetrical or neonatal risks.2 Ethnicity also influences birth weight,3 and the growth chart used should ideally be based on the local specific population group into which the infant is born. These scenarios may be difficult to distinguish from the small mother who was IUGR herself, a known risk factor for IUGR of her own children [adjusted odds ratio 2.0; 95% confidence interval (CI) 1.4e3.0].4
Indications of delivery in the presence of IUGR include a gestational age of O37 weeks, presence of fetal distress, cessation of fetal growth over a 2e4-week period, oligohydramnios, and absent or reversed end-diastolic flow on Doppler velocimetry. Although fetal lung maturity may be enhanced by antenatal corticosteroids, significant problems associated with very preterm delivery should deter a decision of early delivery before 32 weeks’ gestation. The guidelines for use of antenatal corticosteroids in IUGR pregnancies are the same as with other instances of preterm labour.7 An analysis of a large database of nearly 20 000 singleton infants of 501e1500 g birth weight showed similar effectiveness of antenatal corticosteroids in IUGR and normally grown infants: reduced risks of respiratory distress syndrome (RDS, odds ratio 0.51; 95% CI 0.44e0.58), intraventricular haemorrhage (IVH, odds ratio 0.67; 95% CI 0.61e0.73), severe IVH (odds ratio 0.50; 95% CI 0.43e0.57) and death (odds ratio 0.54; 95% CI 0.48e0.62).8 However, another study reported less beneficial effects of antenatal corticosteroids in IUGR infants on RDS, IVH and death.9
Timing of delivery
Early management
The frequency of IUGR is increased in preterm infants compared with term infants.5 There have been no published randomized controlled trials (RCTs) addressing the optimum timing or mode of delivery in the IUGR fetus. The timing of delivery needs to be individualized; a decision is made to deliver if the risk of fetal death exceeds that of neonatal death, although in many cases, these risks may be difficult to assess. Early delivery may lead to all the complications of prematurity, while delaying delivery may lead to worsening of the medical condition in the mother that is responsible for IUGR (such as pre-eclampsia) and worsening intra-uterine hypoxaemia in the infant that may result in stillbirth or long-term neurological sequelae. Aggressive management ( patients prepared for delivery 48 h after corticosteroids) and expectant management ( patients managed with bed rest, oral antihypertensives and intensive antenatal fetal testing until 34 weeks’ gestation) of severe pre-eclampsia at 28e32 weeks’ gestation were compared in an RCT.6 Expectant management was found to reduce neonatal complications and hospital stay without an increase in adverse consequences to the mother or infant. This RCT, however, excluded those who had severe IUGR (estimated fetal weight less than the fifth percentile).
Neonatal staff who are competent at neonatal resuscitation are required to attend deliveries. Precautions should be taken to prevent hypothermia. The umbilical cord should be double clamped and a blood specimen taken from the umbilical artery for pH and lactate determination. The placenta should be weighed, inspected on both surfaces for evidence of infarction and gross abnormalities, and sent for histopathology, especially in preterm IUGR births.10 In the stillborn fetus, karyotyping, serology for congenital infection, and detailed autopsy should be done. A maternal thrombophilia screen should be performed following delivery at !32 weeks’ gestation for severe IUGR and/or severe pre-eclampsia with haemolysiseelevated liver enzymeselow platelets (HELLP) syndrome,11 although a recent study did not find an association of thrombophilia polymorphism with IUGR.12 Indications for admission of IUGR infants to a neonatal special or intensive care unit include symptomatic infants (such as those who require resuscitation, develop early respiratory distress, look polycythaemic or are documented to have hypoglycaemia) and asymptomatic infants who appear to be severely growth restricted (birth weight less than the third percentile) or who are !1800 g birth weight or !34 weeks’ gestation.
Neonatal management of the growth-restricted infant An initial neonatal examination would probably show an infant with soft tissue wasting, diminished skinfold thickness and a relatively large head. The skin is often dry, rough, desquamated and wrinkled, and at times covered in meconium. The infant may have long fingernails, and the skin may look plethoric, although peripheral vasoconstriction can give it a pale look. Cranial sutures may be widened with large fontanelles. The umbilical cord is probably thinner than usual and can be yellow/ green stained if meconium is passed in utero. IUGR infants are often ‘‘alert-looking’’ and jittery even without hypoglycaemia or hypocalcaemia. They can be hyperexcitable with aberrations in muscle tone. The Moro reflex can be exaggerated with more extension and abduction.13 However, severe IUGR infants may be floppy as they become easily exhausted on handling. These infants (birth weight of less than the third percentile) should, especially, be examined for the presence of congenital malformations and stigmata of congenital infections (skin rash, hepatosplenomegaly and ocular abnormalities such as cloudy cornea, cataract or chorioretinitis). Those with stigmata of congenital infections should have toxoplasmosiseother infectionerubellae cytomegaloviruseherpes and syphilis testing. Due to a reduced amount of vernix caseosa in IUGR infants, their skin appears more mature. Sole creases also appear more advanced for gestational age. Conversely, their breast nodule and female genitalia appear less mature than actual gestation due to a decreased amount of fat deposition. Even the ear may be less well formed. However, neonatal reflexes are not affected by IUGR. If one is in doubt about gestational age, pupillary reaction, Moro reflex, glabellar tap, traction response, cross extensor reflex, and active and passive tone and posture can be relied on for gestational age assessment. When the gestational age has been determined and the anthropological measurements have been made after birth, IUGR infants can be classified into four types: symmetric, asymmetric, combined and dysmorphic.
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Asymmetric IUGR Asymmetric IUGR occurs when the growth restriction begins in the late second trimester or the third trimester. These infants, which comprise half of IUGR infants, are disproportionately small: birth weight !10th percentile, but length and head circumference are preserved. As a result of failure in delivery of adequate oxygen or nutrition to the fetus, there is a shortage of energy stores such as glycogen and adipose tissue. ‘Brain sparing’ occurs at the cost of growth of skeletal muscles, adrenals, liver and thymus. Their low ponderal index (birth weight in g ! 100 O crowneheel length in centimetres) is a useful objective measure of the severity of asymmetric IUGR.14 Conditions associated with asymmetric IUGR include diseases that lead to vascular or nutritional uteroplacental insufficiency and fetal constraint in utero, such as preeclampsia, maternal heart disease or anaemia, high altitude, multiple pregnancy and substance abuse late in pregnancy.
Combined IUGR Combined IUGR has features of both symmetric and asymmetric IUGR. These infants, which comprise about one-tenth of IUGR infants, have skeletal shortening and some reduction of soft tissue mass. Causes of combined IUGR include severe maternal disease from the first trimester, skeletal dysplasia and metabolic bone disease.
Dysmorphic IUGR Dysmorphic IUGR includes infants with head, trunks and limbs that appear disproportionate. They often have major and minor congenital anomalies.
Morbidity Perinatal asphyxia
Symmetric IUGR Symmetric IUGR occurs when the growth restriction begins early in gestation. These infants, which comprise one-third of IUGR infants, are proportionately small: birth weight, length and head circumference of the infant are all !10th percentile. Brain growth is compromised. Causes of symmetric IUGR include genetic and chromosomal abnormalities and syndromes, congenital infections, substance abuse and exposure to teratogens.
Even transient diminished placental blood flow during uterine contractions are tolerated poorly by IUGR fetuses. Already compromised by placental insufficiency and chronic intra-uterine hypoxia, they are more prone to asphyxia than normally grown infants. As a result, there is an increased risk of meconium aspiration syndrome in IUGR infants, who also have lower Apgar scores and umbilical artery pH, more endotracheal intubation in the delivery room, and more seizures and hypoxice ischaemic encephalopathy.15e17
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Hypothermia Although IUGR infants were reported to have a higher than normal temperature at birth,18 they are at risk of hypothermia,19 due to a greater cephalic volume and body surface area in relation to weight, and less subcutaneous fat and lower fat stores including depleted brown fat reserves that limit their non-shivering thermogenesis. Perinatal asphyxia may impair muscular activity, oxygen consumption and heat production. Therefore, prompt and complete drying of the infant after birth, wrapping in warm linen after resuscitation, and maintaining the baby under a radiant heat source are crucial. Subsequently, adequate clothing is necessary including a prewarmed hat to minimize heat loss from the head. Skin-to-skin contact nursing (kangaroo care) is also an effective measure. Body temperature should be recorded at birth and at 2 h, and then every 6e8 h for the first 48e72 h of life.
Hypoglycaemia Hypoglycaemia occurs in 12e24% of IUGR infants, seven times higher than in normally grown infants, with a higher risk found in those with severe IUGR and asymmetric IUGR.15,20 Contributing factors include diminished hepatic and skeletal muscle glycogen, reduced alternate energy substrates such as free fatty acids due to the scant adipose tissues, decreased concentration of lactate, hyperinsulinaemia or increased sensitivity to insulin or both, decreased glycogenolysis and gluconeogenesis, and deficient counter-regulatory hormones. The risk of hypoglycaemia is greatest during the first 3 days of life, but especially in the first 24 h. About 1% of IUGR infants who develop hypoglycaemia have a prolonged course requiring intravenous treatment for days. IUGR infants should be screened for hypoglycaemia at 6e12-h intervals for the first 3 days of life to enable prompt detection and treatment. To avoid intravenous therapy, the strategy in developing countries in infants with asymptomatic hypoglycaemia is to feed sugarfortified milk (addition of 1.5 g powdered sugar to 30 ml of standard milk formula) on a 2-h regime.21 Only when this fails to correct the hypoglycaemia is the infant admitted to the neonatal special care unit, where an intravenous dextrose infusion is started. All infants with symptomatic hypoglycaemia should be given a bolus of 2 ml/kg of 10% dextrose, followed by continuous infusion of dextrose at 6e8 mg/kg/min. Tapering of the intravenous dextrose infusion should be done over
V.Y.H. Yu, A. Upadhyay a 12e24-h period in order to avoid rebound hypoglycaemia.
Respiratory failure The traditionally held concept that IUGR accelerates pulmonary maturation and reduces the risk of RDS is not supported by most studies, especially when comparisons were made of IUGR infants and normally grown infants of the same gestation, sex and race.22e24 Some studies have even reported a higher incidence of RDS in IUGR infants.8,25 It is possible that the RDS risk may vary within some subgroups of IUGR infants. It has been reported that IUGR infants born at 29e32 weeks’ gestation have a significantly lower risk of RDS,9,26 while those born at !29 weeks’9 or O34 weeks’5 gestation have a significantly higher risk of RDS. Further studies are required that take other confounding variables into account. Preterm IUGR infants have been reported to have an increased risk of developing chronic lung disease ( prolonged oxygen therapy and assisted ventilation at 28 postnatal days or 36 weeks’ postconceptual age).24,27 It is uncertain whether this is due to immature lungs, abnormal lung development or both.
Hypocalcaemia Serum calcium levels have been shown to be low in IUGR infants.15,25 Contributing factors include perinatal asphyxia and prematurity; if present, these warrant screening for hypocalcaemia in the IUGR infant. However, routine measurement of serum calcium is not indicated in the healthy term IUGR infant.
Polycythaemia and hyperviscosity IUGR infants are more prone to develop polycythaemia, and the reported incidence is 15e17%.15,20 It is more common in asymmetric IUGR after 34 weeks’ gestation, as the increased red cell mass results from chronic in utero hypoxaemia that leads to an increased erythropoietin level.28 Most polycythaemic infants remain asymptomatic. Polycythaemia contributes to hypoglycaemia, hyperbilirubinaemia and necrotizing enterocolitis in IUGR infants. Plethoric IUGR infants should have their haematocrit checked. This should be re-checked if the value is over 60% or if the infant has lost O10% of birth weight. Partial exchange transfusion is performed with normal saline29,30 if the venous haematocrit is O65% in a symptomatic infant or O70% in an asymptomatic infant.
Neonatal management of the growth-restricted infant
Brain injury Some studies have reported an increased incidence of IVH in preterm IUGR infants compared with normally grown infants,5,31,32 while other studies have found no difference.9,26,33 One study showed an increased risk of IVH only in more mature preterm IUGR infants born in the third trimester.5 No increased risk for periventricular leucomalacia has been found.32 Abnormal antenatal Doppler velocimetry of the umbilical artery defines a distinct subgroup of preterm IUGR infants at three times the risk of IVH and a higher incidence of long-term neurological damage compared with those with normal velocimetry.34,35
Immune function and sepsis IUGR infants have compromised humoral and cellular immunocompetence, including a decrease in IgG concentration, phagocytic index and lysozymes.36 Studies have shown that culture-proven sepsis is more common,16,25,33 especially in those born at term with birth weight less than the third percentile.16 Neutropaenia in extremely preterm IUGR infants, which occurs frequently in those born to pre-eclamptic mothers, adds substantially to the risk of sepsis. However, there is inconclusive evidence from RCTs to support or refute the use of granulocyte transfusion or colony stimulating factors to reduce mortality and morbidity.37,38
407 countries to replace gavage feeding with cup/ spoon feeding prior to a trial of breast feeding. Breast feeding from the outset is possible in most IUGR infants O35 weeks’ gestation who can continue to be roomed-in with their mothers. They should be started on feeds within 30 min of birth and fed frequently at 2e3-h intervals to prevent hypoglycaemia.
Other morbidities IUGR infants have significantly lower levels of coagulation factors V and VII and platelet counts compared with normally grown infants.41 Massive pulmonary haemorrhage has been reported as a cause of sudden unexpected death in severe IUGR infants.42 The risk of anatomical or genetic abnormalities is increased two- to threefold (the reported incidence ranged from 9% to 27%).43,44 IUGR infants have a longer length of hospital stay and a higher cost of hospital treatment, especially in the subgroup with abnormal antenatal Doppler velocimetry.5,35 With a progressive increase in the severity of IUGR, significant linear trends were documented for increasing risks of a variety of neonatal morbidities, including perinatal asphyxia, hypoglycaemia, hypocalcaemia and polycythaemia, as well as stillbirth and neonatal death.15
Mortality Necrotizing enterocolitis Studies have reported an increased incidence of necrotizing enterocolitis in preterm IUGR infants,8,32 especially in those who are born in the third trimester5 or who have absent end-diastolic frequencies in the fetal aorta on antenatal Doppler.39 Perinatal asphyxia results in re-distribution of blood in favour of the brain leading to mesenteric ischaemia, as was documented in postnatal Doppler studies of the superior mesenteric and celiac arteries in IUGR infants.40 This factor, together with polycythaemia which IUGR infants are also prone to develop, contributes to the pathogenesis of necrotizing enterocolitis. Enteral feeding should be started cautiously, preferably using the mother’s milk, to minimize the risk of necrotizing enterocolitis. Intravenous therapy is generally required in IUGR infants !1200 g birth weight or !30 weeks’ gestation to supplement gavage feeding. In more mature IUGR infants who are otherwise healthy, exclusive gavage feeding can be tried. It is common practice in developing
Stillbirth rates are increased in preterm, term and post-term IUGR fetuses.23,45,46 Neonatal, hospital and infant mortality rates are also increased in all three gestational categories of IUGR infants.31,47 Overall, the perinatal mortality rate among IUGR infants is 8e10 times higher than among normally grown infants. Both stillbirth and neonatal mortality rates are higher among asymmetric IUGR infants.15,47 In a cohort of infants !1500 g birth weight, a two- to threefold increase in mortality was reported in IUGR infants compared with normally grown infants.8,48 A higher mortality rate was also found when IUGR and normally grown infants were stratified by gestation.23 A ‘dose effect’ was observed with higher mortality in severe IUGR infants (birth weight less than the fifth percentile) compared with IUGR infants with birth weights between the fifth and the ninth percentiles.49 A higher mortality rate was reported in singleton IUGR infants compared with IUGR twins,50 and in those with absent or reversed end-diastolic flow on antenatal Doppler velocimetry.34,39
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Practice points Close collaboration between obstetricians and neonatologists is essential for proper care of the infant with IUGR, especially with the timing of delivery. Antenatal corticosteroids remain effective and safe in preterm labour in the presence of IUGR. It is important to ascertain whether IUGR is of the symmetric or asymmetric type, as their morbidity risks and outcome differ. The popular notion that IUGR accelerates pulmonary maturation and reduces the risk of RDS in preterm infants is untrue. IUGR is associated with a significantly higher stillbirth rate and infant mortality rate in preterm, term and post-term infants.
Research directions How should neonatal hypoglycaemia and polycythaemiaehyperviscosity be defined and when is treatment warranted in these conditions? Why do infants with IUGR have a higher risk of IVH and long-term neurological sequelae, and is this preventable? Are there neonatal strategies that are effective in reducing the increased risk of sepsis and necrotizing enterocolitis in infants with IUGR?
References 1. Seeds JW, Peng T. Impaired growth and risk of fetal death: is the tenth percentile the appropriate standard? Am J Obstet Gynecol 1998;178:658e69. 2. Chard T, Yoong A, Macintosh M. The myth of fetal growth retardation at term. Br J Obstet Gynaecol 1993;100:1076e81. 3. Shiono PH, Klebanoff MA, Graubard BI, Berendes HW, Rhoads GG. Birth weight among women of different ethnic groups. JAMA 1986;255:48e52. 4. Klebanoff MA, Schulsinger C, Mednick BR, Secher NJ. Preterm and small-for-gestational-age birth across generations. Am J Obstet Gynecol 1997;176:521e6. 5. Gilbert WM, Danielsen B. Pregnancy outcomes associated with intrauterine growth restriction. Am J Obstet Gynecol 2003;188:1596e9. 6. Sibai B, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks’ gestation: a randomized controlled trial. Am J Obstet Gynecol 1994;17:818e22. 7. NIH consensus statement. Effects of corticosteroids for fetal maturation on perinatal outcomes, vol. 12. Bethesda: National Institute of Health; 1994. p. 1e24.
8. Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198e206. 9. Ley D, Wide-Swensson D, Lindroth M, Svenningsen N, Marsal K. Respiratory distress syndrome in infants with impaired intrauterine growth. Acta Paediatr 1997;86: 1090e6. 10. Burke CJ, Tannenberg AE, Payton DJ. Ischaemic cerebral injury, intrauterine growth retardation, and placental infarction. Dev Med Child Neurol 1997;39:726e30. 11. Kupferminc MJ, Peri H, Zwang E, Yaron Y, Wolman I, Eldor A. High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand 2000;79:963e7. 12. Infante-Rivard C, Rivard GE, Yotov WV, Genin E, Guiguet M, Weinberg C, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med 2002;347:19e25. 13. Fredrickson WT, Brown JV. Gripping and moro responses: differences between small-for-gestational age and normal weight term newborns. Early Hum Dev 1980;4:69e77. 14. Balcazar H, Haas J. Classification schemes of small-for-gestational age and type of intrauterine growth retardation and its implications to early neonatal mortality. Early Hum Dev 1990;24:219e30. 15. Kramer MS, Olivier M, McLean FH, Willis DM, Usher RH. Impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcome. Pediatrics 1990;86: 707e13. 16. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999;340:1234e8. 17. Bukowski R, Gurgett AD, Gei A, Saade GR, Hankins GD. Impairment of fetal growth potential and neonatal encephalopathy. Am J Obstet Gynecol 2003;188:1011e5. 18. Hawdon JM, Weddell A, Aynsley-Green A, Ward Platt MP. Hormonal and metabolic response to hypoglycaemia in small for gestational age infants. Arch Dis Child 1993;68: 269e73. 19. Doctor BA, O’Riordan MA, Kirchner HL, Shah D, Hack M. Perinatal correlates and neonatal outcomes of small for gestational age infants born at term gestation. Am J Obstet Gynecol 2001;185:652e9. 20. Deorari AK, Aggarwal R, Paul VK. Management of infants with intra-uterine growth restriction. Indian J Pediatr 2001;68: 1155e7. 21. Singhal PK, Singh M, Paul VK, Lamba IM, Malhotra AK, Deorari AK, et al. Prevention of hypoglycemia: a controlled evaluation of sugar fortified milk feeding in small-for-gestational age infants. Indian Pediatr 1992;29:1365e9. 22. Tyson JE, Kennedy K, Broyles S, Rosenfeld CR. The small for gestational age infant: accelerated or delayed pulmonary maturation? Increased or decreased survival? Pediatrics 1995;95:534e8. 23. Piper JM, Xenakis EM, McFarland M, Elliott BD, Berkus MD, Langer O. Do growth-retarded premature infants have different rates of perinatal morbidity and mortality than appropriately grown premature infants? Obstet Gynecol 1996;87:169e74. 24. Gortner L, Wauer RR, Stock GJ, Reiter HL, Reiss I, Jorch G, et al. Neonatal outcome in small for gestational age infants: do they really better? J Perinat Med 1999;27:484e9. 25. Spinillo A, Capuzzo E, Egbe TO, Fazzi E, Colonna L, Nicola S. Pregnancies complicated by idiopathic intrauterine growth retardation. Severity of growth failure, neonatal morbidity
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26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
and two-year infant neurodevelopmental outcome. J Reprod Med 1995;40:209e15. Cooper PA, Sandler DL, Simchowitz ID, Galpin JS. Effects of suboptimal intra-uterine growth on preterm infants between 30 and 32 weeks’ gestation. S Afr Med J 1997;87: 314e8. Lal MK, Manktelow BN, Draper ES, Field DJ. Chronic lung disease of prematurity and intrauterine growth retardation: a population-based study. Pediatrics 2003;111:483e7. Snijders RJ, Abbas A, Melby O, Ireland RM, Nicolaides KH. Fetal plasma erythropoietin concentration in severe growth retardation. Am J Obstet Gynecol 1993;168:615e9. Deorari AK, Paul VK, Shreshta L, Singh M. Symptomatic neonatal polycythemia: comparison of partial exchange transfusion with saline versus plasma. Indian Pediatr 1995; 32:1167e71. Wong W, Fok TF, Lee CH, Ng PC, So KW, Ou Y, et al. Randomised controlled trial: comparison of colloid or crystalloid for partial exchange transfusion for treatment of neonatal polycythaemia. Arch Dis Child Fetal Neonatal Ed 1997;77:F115e8. Heinonen K, Matilainen R, Koski H, Launiala K. Intrauterine growth retardation (IUGR) in pre-term infants. J Perinat Med 1985;13:171e8. Zaw W, Gagnon R, da Silva O. The risks of adverse neonatal outcome among preterm small for gestational age infants according to neonatal versus fetal growth standards. Pediatrics 2003;111:1273e7. Simchen MJ, Beiner ME, Strauss-Liviathan N, Dulitzky M, Kuint J, Mashiach S, et al. Neonatal outcome in growth-restricted versus appropriately grown preterm infants. Am J Perinatol 2000;17:187e92. Valcamonico A, Danti L, Frusca T, Soregaroli M, Zucca S, Abrami F, et al. Absent end-diastolic velocity in umbilical artery: risk of neonatal morbidity and brain damage. Am J Obstet Gynecol 1994;170:796e801. Gaziano EP, Knox H, Ferrera B, Brandt DG, Calvin SE, Knox GE. Is it time to reassess the risk for the growthretarded fetus with normal Doppler velocimetry of the umbilical artery? Am J Obstet Gynecol 1994;170: 1734e43. Chandra RK, Matsumara T. Ontogenic development of the immune system and effect of growth retardation. J Perinat Med 1979;7:279e90. Mohan P, Brocklehurst P. Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutro-
409
38.
39.
40.
41.
42.
43.
44. 45.
46.
47.
48.
49.
50.
paenia [Cochrane review]. In: The Cochrane library. Chichester: John Wiley & Sons, Ltd; 2003. Carr R, Modi N, Dore C. FGeCSF and GMeCSF for treating or preventing neonatal infections [Cochrane review], In: The Cochrane library, Issue 4. Chichester: John Wiley & Sons, Ltd; 2003. Hackett GA, Campbell S, Gamsu H, Cohen-Overbeek T, Pearce JM. Doppler studies in the growth retarded fetus and prediction of neonatal necrotising enterocolitis, haemorrhage, and neonatal morbidity. Br Med J 1987;294:13e6. Kempley ST, Gamsu HR, Vyas S, Nicholaides K. Effects of intrauterine growth retardation on postnatal visceral and cerebral flow velocity. Arch Dis Child 1991;66:1115e8. Salonvaara M, Riikonen P, Kekomaki R, Vahtera E, Mahlamaki E, Halonen P, et al. Effects of gestational age and prenatal and perinatal events on the coagulation status in premature infants. Arch Dis Child Fetal Neonatal Ed 2003;88:F319e23. Sly PD, Drew JH. Massive pulmonary haemorrhage: a cause of sudden unexpected deaths in severely growth retarded infants. Aust Paediatr J 1981;17:32e4. Khoury MJ, Erickson JD, Cordero JF, McCarthy BJ. Congenital malformations and intrauterine growth retardation: a population study. Pediatrics 1988;82:83e90. Spiers PS. Does growth retardation predispose the fetus to congenital malformation? Lancet 1982;1:312e4. Clausson B, Cnattingius S, Axelsson O. Outcomes of postterm births: the role of fetal growth restriction and malformations. Obstet Gynecol 1999;94:758e62. Divon MY, Haglund B, Nisell H, Otterblad PO, Westgren M. Fetal and neonatal mortality in the postterm pregnancy: the impact of gestational age and fetal growth restriction. Am J Obstet Gynecol 1998;178:726e31. Vik T, Markestad T, Ahlsten G, Gebre-Medhin M, Jacobsen G, Hoffman HJ, et al. Body proportions and early neonatal morbidity in small-for-gestational-age infants of successive births. Acta Obstet Gynecol Scand 1997;165(Suppl):76e81. Chen SJ, Vohr BR, Oh W. Effects of birth order, gender, and intrauterine growth retardation on the outcome of very low birth weight in twins. J Pediatr 1993;123:132e6. Dobson PC, Abell DA, Beischer NA. Mortality and morbidity of fetal growth retardation. Aus N Z J Obstet Gynaecol 1981; 21:69e72. Kilpatrick SJ, Jackson R, Croughan-Minihane MS. Perinatal mortality in twins and singletons matched for gestational age at delivery at O or Z 30 weeks. Am J Obstet Gynecol 1996;174:66e71.