Infants born with intrauterine growth restriction (IUGR) are considered at increased risk of perinatal morbidity and mortality.1–3 Despite the importance of making the diagnosis of IUGR correctly, the recognition of low birth weight often remains based upon population-based norms, which use neonatal birth weight data without taking into account the characteristics of intrauterine growth, of physiologic determinants of individual growth, and of potentially inaccurate dating. As a matter of fact, most studies evaluating the perinatal outcome in preterm neonates compare appropriate compared with small for gestational age infants or report outcomes based upon birth weight based on gestational-age–based categories with no information about fetal growth. Most studies use the analysis of large databases in which the assessment of gestational age and/or growth are made retrospectively.1–3 However, it has already been pointed out that population-based standards that use neonatal birth weights are limited by the fact that inclusion of premature growth-restricted infants incorrectly lowers the norms, resulting in a high rate of misclassification of newborns, with some IUGR infants inappropriately considered to have normal fetal growth.4 In the past, we have shown that there are significant differences in oxygenation and acid base balance5,6 as well in glucose7 and amino acid metabolism8,9 for IUGR fetuses compared with appropriately grown fetuses and that the magnitude of these changes tracks with the clinical severity of IUGR. More recently we have shown that severity of IUGR determines differences in perinatal outcome (Marconi AM, Ronzoni S, Vailati S, Bozzetti P, Pardi G, Battaglia FC. Neonatal morbidity and mortality in intrauterine growth restricted (IUGR) pregnancies according to clinical severity [meeting abstract]. Pediatr Res 2004;55:476A), as have others.10 In previous studies, we included only antenatally diagnosed IUGR who were also small for gestational age at birth. The present study was suggested by the observation of discrepancies between the diagnosis of growth restriction made in utero and the neonatal classification of birth weight based upon population-based standards. Thus, the aim of this study was to evaluate the obstetric and neonatal outcome of infants with a clear-cut diagnosis of IUGR both by reduced fetal size and by the presence of abnormal fetal velocimetry of the umbilical artery.
The study was performed in the Department of Obstetrics and Gynecology of the University of Milano, Department of Medicine, Surgery, and Dentistry, San Paolo, Italy. The study was exempt from institutional review board approval because obstetric and neonatal outcomes were collected as part of the clinical management. The privacy of all patients was warranted.
We collected maternal and neonatal outcomes in 53 consecutive singleton pregnancies complicated by IUGR and abnormal pulsatility index who delivered between 28/0 and 33/6 weeks of pregnancy and were followed prospectively until discharge from the High Risk Pregnancy Unit of the Department of Obstetrics and Gynecology of the San Paolo Hospital between 1996 and 2002. Gestational age at delivery was calculated by the last menstrual period and confirmed by an ultrasound examination performed within 20 weeks. We used a classification of clinical severity previously proposed,5 which was based upon pulsatility index of the umbilical artery and on the fetal heart rate (FHR) recording. Only severe IUGR cases were included, ie, cases with pulsatility index of the umbilical artery measured by Doppler velocimetry 2 standard deviations (SD) or more of reference normal values. Twenty-two IUGR pregnancies were classified as group 2, with abnormal pulsatility index and normal FHR, and 31 were classified as group 3, with abnormal pulsatility index and FHR.
The diagnosis of IUGR was determined by ultrasound measurement of the abdominal circumference according to standards previously published for this population11: the criteria were an abdominal circumference less than 10th percentile or a reduction of 40 percentiles in two consecutive measurements.12 Only live births without malformations or abnormal karyotypes were included.
Umbilical arterial pulsatility index was measured within 24 hours from delivery according to the simplified Gosling formula (systolic velocity minus diastolic velocity divided by mean velocity); the mean velocity was calculated by dividing the area of the maximal velocity by the length of the cycle. The reference values were those obtained in our laboratory from a cross-sectional study of 440 normal fetuses.13
The fetal heart rate was recorded within 24 hours from birth. The tracings were examined independently by two investigators who did not know the results of Doppler velocimetry. A tracing was considered abnormal if at least one of the following patterns was present: less than two accelerations of the heart rate to an amplitude of 10 or more beats per minute (bpm) lasting 15 seconds or more during a period of at least 30 minutes, variability of 5 bpm or less during a period of at least 60 minutes, and U-shaped (late) decelerations in the heart rate after Braxton Hicks contractions.5
We analyzed maternal data, including age, height, weight, body mass index (BMI) parity, preexisting medical or obstetric problems, and complications of pregnancy (such as gestational hypertension/preeclampsia, gestational diabetes mellitus, placenta previa/placental abruption, previous stillbirth, or IUGR).
Neonatal outcome was analyzed immediately after birth in terms of Apgar score at 1 minute and 5 minutes, and the requirement for mechanical ventilation and admission to the neonatal intensive care unit (NICU). At the time of discharge, data were collected on neonatal morbidity and mortality. Major morbidity included respiratory distress syndrome, intraventricular hemorrhage, retinopathy of prematurity, sepsis, necrotizing enterocolitis, and disseminated intravascular coagulopathy. Minor morbidity included hypoglycemia, jaundice, and anemia. The presence of pulmonary dysplasia, retinopathy stage 3 or greater, and neurologic sequelae at the time of discharge were recorded. Neonatal mortality was defined as the death rate within the first 28 days of life.
In addition, neonatal ponderal index and body mass index (BMI) were calculated as follows: neonatal ponderal index=100×[birth weight (g)/length (cm)3]; BMI=birth weight (kg)/length (m)2. The brain–body weight ratio was defined as 100 times the ratio of the infant’s estimated brain weight to its birth weight. Brain weight was estimated from the formula brain weight in grams equals 0.037 times the head circumference in centimeters to the 2.57 power, which is derived from the National Institute of Neurological and Communicative Disorders and Stroke’s Collaborative Perinatal Project.14 Thus, brain–body weight ratio was calculated as 100×[0.037×head circumference (cm)2.57]/birth weight (g).
The data collected in IUGR pregnancies were compared with those collected in 79 singleton pregnancies, similarly selected with normal intrauterine fetal growth and pulsatility index matched for gestational age (range 28–33.6), whose birth weight was appropriate for gestational age (AGA group).
Results are reported as mean±standard deviation. The χ2 test and, when appropriate, the Student t test, were used to evaluate differences in maternal and fetal/neonatal characteristics. Analysis of covariance was performed to assess differences between means corrected for gestational age in the different groups (AGA, IUGR as a whole, IUGRAGA and small for gestational age IUGR [IUGRSGA]). P<.05 were considered significant. Data were analyzed using Stata 9 (Stata Corp., College Station, TX).
Table 1 shows that at the time of delivery, when using the Italian birth weight/gestational age neonatal standards,15 25 of 53 (47%) IUGR showed a birth weight above the 10th percentile and were classified appropriate for gestational age (IUGRAGA), whereas in the remaining 28, birth weight was less than 10th percentile (IUGRSGA). In other words, 9 of 22 newborns of group 2 and 16 of 31 of group 3 exhibited a birth weight more than 10th percentile (IUGRAGA), whereas 13 of 22 in group 2 and 15 of 31 in group 3 had a birth weight below the 10th percentile (IUGRSGA). The mean (±SD) percent reduction in birth weight from the 50th percentile was 47.6±9.6% in IUGRSGA and 23.6±6.4% in IUGRAGA (P<.001).
Figure 1 presents the distribution of birth weight in IUGR fetuses plotted on the reference standards for intrauterine growth.11 It is important to note that all of these infants had a birth weight less than 10th percentile and 70% (37 of 53) were less than third percentile, when plotted on the intrauterine growth charts. The selection criteria required that all of these infants also had abnormal umbilical artery velocimetry findings. The same data are plotted in Figure 2, which incorporates the reference male and female neonatal birth weight/gestational age standards for the Italian population.15
The abdominal circumference was the principal fetal measurement upon which the diagnosis of IUGR was made. The diagnosis in utero received additional confirmation by the fact that all infants in the study also had abnormal umbilical artery velocimetry findings.
Figure 3 presents the abdominal circumference data measured by ultrasonography within 7 days from delivery. All IUGR infants were below the 10th percentile. The mean±SD percent reduction of the abdominal circumference compared with the 10th percentile of the reference values11 was significantly higher in the IUGRSGA (21.1±5.8%) when compared with the IUGRAGA (11.3±2.8%; P<.001).
Table 2 presents maternal age, height, prepregnancy weight, BMI, and weight increase in pregnancy of AGA and IUGR mothers. No differences were present in any of these variables. It is worth noting that all IUGRAGA mothers were primigravid (P<.001 both compared with AGA and IUGRSGA).
The number of women who started their pregnancy as low risk (absence of familial, personal, or obstetric pathologies) was 47 of 79 in the AGA group, 14 of 25 in the IUGRAGA group, and 16 of 28 in the IUGRSGA group (P=.8). During pregnancy, 50 of 79 control AGA mothers had no pathology other than premature labor or preterm premature rupture of the membranes compared with 10 of 53 IUGR mothers (five IUGRAGA and five IUGRSGA; P<.001).
On the contrary, the incidence of hypertensive disorders was significantly higher in IUGR (35 of 53) than in AGA (13 of 79; P<.001) mothers, a difference that persisted when the individual IUGR groups were considered (19 of 25 IUGRAGA; 16 of 28 IUGRSGA). Among multiparas, a previous stillbirth or IUGR was present in 6 of 19 IUGR compared with 3 of 28 AGA pregnancies (P=.1).
Table 3 presents the gestational age, birth weight, placental weight, fetal/placental weight ratio, neonatal length, head circumference, ponderal index, body mass index, and brain body weight ratio in AGA and IUGR for the IUGR group as a whole and subdivided into the birth weight–related groups. Gestational age was significantly higher in controls (P<.003): when corrected for gestational age, brain–body weight ratio, and fetal/placental ratio, were significantly lower in AGA compared with IUGR, whereas all other measures were significantly higher in AGA compared with IUGR. Similarly, all body size measurements were also greater for AGA compared with the IUGR groups separately. These measurements included birth weight, placental weight, neonatal length, head circumference, neonatal pulsatility index, and BMI, which were significantly higher in AGA than in IUGRAGA and IUGRSGA, whereas, again, brain–body weight ratio and fetal/placental weight ratio were significantly lower in AGA.
Among IUGR, birth weight, placental weight, neonatal length, and neonatal BMI were significantly higher in IUGRAGA than in IUGRSGA, whereas brain–body weight ratio was significantly increased in IUGRSGA, although we found no differences in placental weight, fetal/placental weight ratio, head circumference, and neonatal ponderal index.
Forty-seven of 79 AGA mothers had cesarean deliveries compared with 53 of 53 IUGR (P<.001). In most IUGR pregnancies (85%), cesarean delivery was performed for fetal indication.
Twenty-nine of 79 AGA newborns had a 5-minute Apgar score of 7 or less when compared with 35 of 53 IUGR (P<.001); no differences were present between IUGR groups (16 of 25 IUGRAGA and 19 of 28 IUGRSGA; P=.8). The number of newborns requiring assisted ventilation was significantly higher in the IUGR group when compared with the AGA (75.5% compared with 40.5%; P<.001), with no differences between IUGRs (Fig. 4). The number of fetuses receiving antenatal corticosteroids was significantly higher in IUGR (51 of 53 compared with 23 of 79; P<.001) as was the number of neonates receiving surfactant after delivery (49 of 53 compared with 50 of 79; P<.001).
Forty-nine of 79 AGA and 49 of 53 IUGR were admitted to the NICU (P<.001). One of 79 AGA and 6 of 53 IUGR newborns (one IUGRAGA and five IUGRSGA) died within 28 days after delivery (P<.02). Neonatal major and minor morbidity is presented in Figure 4. More than one third of the control AGA and 23 of 53 IUGR newborns had major complications, whereas 68.4% of AGA had minor complications when compared with 85% IUGR newborns; none of these differences was significant when corrected for gestational age. Similarly, no differences were present in the individual IUGR groups. Only 6 of 53 IUGR had no postnatal complications when compared with 23 of 79 AGA. Pulmonary dysplasia, retinopathy of prematurity stage 3 or more, and neurologic sequelae at the time of discharge were present in 5 of 79 AGA and 7 of 53 IUGR (ns).
This article presents the obstetric and neonatal outcome in IUGR pregnancies diagnosed using intrauterine fetal growth curves and velocimetry without regard to the neonatal growth curves. The study clearly demonstrates that neonatal morbidity and mortality are similar in IUGR of the same clinical severity, whether or not they could be defined appropriate or small for gestational age according to the neonatal growth standards.
The issue of whether fetal or neonatal growth curves should be used when assessing weight at birth has been addressed by other authors.16,17 Zaw et al18 showed that fetal growth standards are better in identifying infants at increased risk of respiratory morbidity and intraventricular hemorrhage among preterm SGA infants compared with neonatal standards. Similarly, Clausson et al19 showed that the use of customized birth weight standards increases identification of fetuses at risk of stillbirth, neonatal death, and Apgar score less than 4 at 5 minutes when compared with population-based birth weight standards.
However, we have reviewed the literature using PubMed restricted to English language from 1970 to May 2008, using the key words intrauterine growth charts, neonatal growth charts, abnormal doppler, fetal growth restriction, and fetal biometry and were unable to find any other studies that had the dual characteristics of 1) a prospective study of IUGR and 2) met the stringent requirements of diagnosis of IUGR made in utero based upon both fetal growth and the presence of abnormal velocimetry and related these cases to neonatal outcome. Furthermore, to avoid growth restriction based solely upon biometry, which could have included “normal small” neonates, we have included in our study only fetuses with abnormal pulsatility index of the umbilical artery, ie, the more severe, as we have shown previously (Marconi AM, Ronzoni S, Vailati S, Bozzetti P, Pardi G, Battaglia FC. Neonatal morbidity and mortality in intrauterine growth restricted (IUGR) pregnancies according to clinical severity [meeting abstract]. Pediatr Res 2004;55:476A).5,20 These dual criteria should have avoided the interference of potential confounding factors such as maternal height, weight, ethnicity, parity, and newborn’s gender.4 In our study, as in Zaw’s,18 there was a large birth weight difference between fetal and neonatal growth standards. This finding is strengthened by the fact that we have used standards developed for our population both for intrauterine growth11 and for neonatal growth.15
It is well recognized that the assessment of fetal growth is a fundamental component of good antenatal as well as postnatal care due to its consequences for perinatal outcome1 and adult health.21 It is now acknowledged that there are ethnic differences that should be taken into account when analyzing perinatal outcomes.4 Also, the issue of whether customized compared with population-based growth curves should be used16 has been debated. The customized growth standards are useful in taking into account all known constitutional factors affecting growth in individual fetuses. But both of these effects are minor when one uses both fetal biometry and fetal velocimetry data.
This study highlighted several facts. First, there were no relevant prepregnancy differences for mothers in the control AGA group compared with those in the IUGR groups; more than one half in each group started pregnancy considered at low risk. On the other hand, most IUGR mothers developed hypertension in pregnancy, with no differences between IUGRAGA and IUGRSGA mothers.
The second observation is that we did not find significant differences in neonatal outcome between AGA and IUGR infants, most likely due to two factors: 1) that IUGR fetuses were followed prospectively and delivered to minimize morbidity and mortality22 and 2) that AGA infants were gestational age–matched and thus were preterm infants with significant morbidity and mortality. The differences in morbidity and mortality are mainly due to IUGRSGA. All IUGR fetuses of group 2 and 3 exhibited abnormal umbilical pulsatility index measurements of the umbilical artery. In addition, as shown in Table 3, they had birth weights, placental weights, neonatal lengths, head circumferences, ponderal indexes, and body mass indexes that were significantly lower and fetal/placental weight ratios and brain–body weight ratios that were significantly higher than AGA fetuses whose intrauterine growth was normal. Also, they required NICU admission more frequently than fetuses with normal intrauterine growth.
The issue of whether perinatal outcome is different in preterm AGA when compared with SGA has been debated for many years. However, as reported above, only recently the question of the growth standards to be used in comparing different populations and the criteria for diagnosis of intrauterine growth restriction prenatally has begun to be addressed. The results of the present prospective study are in agreement with the results of larger retrospective studies3,18 in showing not only that IUGR increases perinatal morbidity and mortality, but also that perinatal outcome is correlated with the degree of clinical severity (Marconi AM, Ronzoni S, Vailati S, Bozzetti P, Pardi G, Battaglia FC. Neonatal morbidity and mortality in intrauterine growth restricted (IUGR) pregnancies according to clinical severity [meeting abstract]. Pediatr Res 2004;55:476A). They also reinforce the conclusion that neonatal birth weight/gestational age percentile curves are misleading in detecting low birth weight infants and should be used only when obstetric data are unavailable. The results of the present study also point out the need of a truly perinatal approach (ie, joint obstetric and neonatal approach) in the clinical management of these patients if optimal medical care is to be provided.
1. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999;340:1234–8.
2. 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;87:169–74.
3. Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction increases morbidity and mortality among premature neonates. Am J Obstet Gynecol 2004;191:481–7.
4. Bukowski R. Fetal growth potential and pregnancy outcome. Semin Perinatol 2004;28:51–8.
5. Pardi G, Marconi AM, Cetin I, Lanfranchi A, Bozzetti P, Ferrazzi E, et al. Diagnostic value of blood sampling in fetuses with growth retardation. N Engl J Med 1993;328:692–6.
6. Marconi AM, Paolini CL, Zerbe G, Battaglia FC. Lactacidemia in intrauterine growth restricted (IUGR) pregnancies: relationship to clinical severity, oxygenation and placental weight. Pediatr Res 2006;59:570–4.
7. Marconi AM, Paolini CL, Buscaglia M, Zerbe G, Battaglia FC, Pardi G. The impact of gestational age and of fetal growth on the maternal–fetal glucose concentration difference. Obstet Gynecol 1996;87:937–42.
8. Marconi AM, Paolini CL, Stramare L, Cetin I, Fennessey PV, Pardi G, et al. Steady state maternal–fetal leucine enrichments in normal and intrauterine growth-restricted pregnancies. Pediatr Res 1999;46:114–9.
9. Paolini CL, Marconi AM, Ronzoni S, Di Noio M, Fennessey PV, Pardi G, et al. Placental transport of leucine, phenylalanine, glycine, and proline in intrauterine growth–restricted pregnancies. J Clin Endocrinol Metab 2001;86:5427–32.
10. Baschat AA, Cosmi E, Bilardo CM, Wolf H, Berg C, Rigano S, et al. Predictors of neonatal outcome in early-onset placental dysfunction. Obstet Gynecol 2007;109:253–61.
11. Todros T, Ferrazzi E, Groli C, Nicolini U, Parodi L, Pavoni M, et al. Fitting growth curves to head and abdomen measurements of the fetus: a multicentric study. J Clin Ultrasound 1987;15:95–105.
12. American College of Obstetricians and Gynecologists. Intrauterine growth restriction. ACOG Practice Bulletin 12. Washington (DC): ACOG; 2000.
13. Ferrazzi E, Gementi P, Bellotti M, Rodolfi M, Della Peruta S, Barbera A, et al. Doppler velocimetry: critical analysis of umbilical, cerebral and aortic reference values. Eur J Obstet Gynecol Reprod Biol 1991;38:189–96.
14. McLennan JE, Gilles FH, Neff RK. A model of growth of the human fetal brain. In: Gilles, FH, Leviton A, Dooling EC, editors. The developing human brain: growth and epidemiologic neuropathy. Boston (MA): Wright PSG; 1983:43–58.
15. Parazzini F, Cortinovis I, Bortolus R, Fedele L.. Standards of birth weight in Italy [in Italian]. Ann Ostet Ginecol Med Perinat 1991;112:203–46.
16. Gardosi J. Ethnic differences in fetal growth. Ultrasound Obstet Gynecol 1995;6:73–4.
17. Cooke RW. Conventional birth weight standards obscure fetal growth restriction in preterm infants. Arch Dis Child Fetal Neonatal Ed 2007;92:F189–92.
18. 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;111:1273–7.
19. Clausson B, Gardosi J, Francis A, Cnattingius S. Perinatal outcome in SGA births defined by customised versus population-based birthweight standards. BJOG 2001;108:830–4.
20. Ferrazzi E, Bozzo M, Rigano S, Bellotti M, Morabito A, Pardi G, et al. Temporal sequence of abnormal doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 2002;19:140–6.
21. Barker DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol 2006;49:270–83.
22. Thornton JG, Hornbuckle J, Vail A, Spiegelhalter DJ, Levene M; GRIT study group. Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial. Lancet 2004;364:513–20.
Figure. No caption available.