Ultrasound Obstet Gynecol 2015; 46: 216–220 Published online 6 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.14755
Impact on obstetric outcome of third-trimester screening for small-for-gestational-age fetuses R. CALLEC*†‡, C. LAMY*, E. PERDRIOLLE-GALET*†‡, C. PATTE*, B. HEUDE§¶, O. MOREL*†‡ and the EDEN Mother–Child Cohort Study Group *Obstetrics and Fetal Medicine Unit, Centre Hospitalier Universitaire, Nancy, France; †Universit´e de Lorraine, Nancy, France; ‡INSERM, U947, Nancy, France; §Centre for Research in Epidemiology and Population Health (CESP), INSERM, Villejuif, France; ¶Universit´e Paris Sud, Villejuif, France
K E Y W O R D S: screening; small-for-gestational age; third trimester; ultrasound
ABSTRACT Objectives To evaluate the performance of screening for small-for-gestational-age (SGA) fetuses by ultrasound biometry at 30–35 weeks’ gestation, and to determine the impact of screening on obstetric and neonatal outcomes. Methods For this prospective cohort study, pregnant women were recruited from two French university maternity centers between 2003 and 2006. Performance measures of third-trimester biometry for the prediction of SGA, defined as estimated fetal weight < 10th centile, were analyzed. Obstetric outcomes and neonatal health status were compared, first, between SGA neonates diagnosed correctly at ultrasound examination (true positive (TP); n = 45) and SGA neonates that went undiagnosed (false negative (FN); n = 110) and, second, between non-SGA neonates identified as normal at ultrasound examination (true negative (TN); n = 1641) and non-SGA neonates diagnosed incorrectly as SGA (false positive (FP); n = 101). Results In the prediction of SGA, third-trimester ultrasound had a sensitivity of 29.0% (95% CI, 22.5–36.6%) and specificity of 94.2% (95% CI, 93.0–95.2%). Positive and negative predictive values were 30.8% (95% CI, 23.9–38.7%) and 93.7% (95% CI, 92.5–94.8%), respectively. One hundred and ten SGA neonates went undiagnosed at ultrasound. Compared to the TN neonates considered as of normal weight at ultrasound, planned preterm delivery (before 37 weeks) and elective Cesarean section for a fetal growth indication were 2.4 (P = 0.01) and 2.85 (P = 0.003) times more likely to occur, respectively, in the FP group of non-SGA neonates, diagnosed incorrectly as SGA during the antenatal period. There was no statistically significant difference in 5-min Apgar score < 7, cord blood pH at birth < 7.15 and need for
neonatal resuscitation between the two subgroups (TN vs FP and TP vs FN). Conclusions The performance of third-trimester ultrasound screening for SGA seems poor, as it misses the diagnosis of a large number of SGA neonates. The consequences of routine screening for SGA in a low-risk population may lead to unnecessary planned preterm deliveries and elective Cesarean sections in FP pregnancies, without improved neonatal outcome in the FN pregnancies. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION One of the major clinical problems in pregnancy care is the management of fetuses that are small-for-gestational age (SGA). SGA is often defined as fetal weight < 10th percentile for gestational age1 and is associated with an increased risk of perinatal morbidity and mortality2 – 5 . Undiagnosed SGA fetuses are responsible for 50% of unexplained fetal deaths at term6 – 8 . Obstetric teams need to be able to recognize a pathological fetal growth pattern in order to determine the timing of delivery that will optimize perinatal and neurodevelopmental outcomes. Ultrasound screening is a valuable tool for detecting SGA fetuses, which can lead to improved neonatal outcomes8 . Most often, abnormal fetal growth is suspected at ultrasound examination performed routinely during the second and third trimesters or in high-risk groups. In France, fetal growth is evaluated routinely at around 32 weeks’ gestation9 . The primary aim of EDEN, a prospective mother–child cohort study, is to identify prenatal and early postnatal nutritional, environmental and social determinants associated with children’s health and their normal or pathological development. Pregnant
Correspondence to: Dr R. Callec, Obstetrics and Fetal Medicine Unit, Centre Hospitalier de Nancy, Pole de la Femme, 10 Rue du Dr Heydenreich, Nancy 54000, France (e-mail: [email protected]) Accepted: 4 December 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Impact of third-trimester screening for SGA women attending a prenatal visit at the Departments of Obstetrics and Gynecology of two French University Hospitals before 24 weeks’ gestation were invited to participate. The purpose of this study was to evaluate the performance of a third-trimester ultrasound examination, at 30–35 weeks’ gestation, in screening for SGA and to determine the impact of screening on obstetric and neonatal outcomes.
METHODS This study was part of the EDEN mother–child cohort study, a prospective two-center cohort study involving the follow-up of women from the early stages of pregnancy. Between 2003 and 2006, a total of 2002 pregnant women were recruited prior to 24 weeks’ gestation from a low-risk population at two French university maternity centers (Nancy and Poitiers, France). Exclusion criteria were multiple pregnancy, known diabetes mellitus, illiteracy and intention to deliver outside the university hospital or to move outside the region within 3 years of examination. Among the women who fulfilled the inclusion criteria, 55% agreed to participate. Maternal age, socioeconomic status, parity, preconceptional weight, obstetric history and information about maternal smoking were obtained by interview or from clinical records. After delivery, information about the pregnancy, delivery and anthropometric measures (birth weight) of the infant was obtained from clinical records. Gestational age was determined from the date of the last menstrual period in women with a regular cycle, or by ultrasound assessment of crown–rump length or biparietal diameter. When there was a discrepancy of > 7 days between age deduced from the last menstrual period and sonographic age, the sonographic estimation was used. SGA was defined as an estimated fetal weight (EFW) below the 10th percentile, according to the formula of Hadlock et al.10 : log10 (EFW) = 1.3596 − (0.00386 (AC × FL)) + (0.0064 × HC) + (0.00061 (BPD × AC)) + (0.0424 × AC) + (0.0174 × FL), where AC is abdominal circumference, FL is femur length, HC is head circumference and BPD is biparietal diameter. All ultrasound examinations were performed by one of five specialists who agreed on standardized procedures before the study commenced. Furthermore, the first five measurements made by each examiner were reviewed by another examiner to check for consistency with the protocol. The study was approved by the Ethical Research Committee (Comit´e Consultatif de Protection des Personnes dans la Recherche Biom´edicale) of the hospital of Bicˆetre and by the Data Protection Authority (Commission Nationale de l’Informatique et des Libert´es). Informed written consent was obtained from the women, both for themselves at enrollment and for the newborns after delivery. Performance measures for the prediction of SGA birth by third-trimester ultrasound were analyzed by estimating the sensitivity, specificity and positive and negative predictive values. Obstetric outcomes and neonatal health
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
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status, in terms of morbidity and mortality (newborns who died within 28 days of delivery, 5-min Apgar score < 7, cord blood pH at birth < 7.15, preterm delivery before 37 weeks’ gestation, elective Cesarean section, need for neonatal resuscitation or transfer to the neonatal intensive care unit (NICU)), were compared, first, between true-positive (TP) and false-negative (FN) SGA neonates and, second, between true-negative (TN) and false-positive (FP) non-SGA neonates.
Statistical analysis Descriptive analysis of the study group was performed by estimating the mean and SD for continuous variables, and frequency and percentage for categorical ones. The chi-square test or Fisher’s exact test was used to compare qualitative variables and Student’s t-test was used to compare continuous variables. Odds ratios (ORs) with 95% CIs were calculated. Statistical analysis was carried out using SAS 9.3 (SAS Inc., Cary, NC, USA); P < 0.05 was considered to indicate statistical significance.
RESULTS Of the 2002 women originally included in the cohort, 80 were lost to follow-up, declined to continue participation or experienced fetal death. One woman who had a stillbirth was also excluded (Figure 1). Ultrasound examinations were scheduled at 32–34 weeks’ gestation; however, as several women underwent an ultrasound examination slightly later, we extended the study period to 30–35 weeks’ gestation to increase the final sample size. Twenty-four women who were scanned before 30 weeks or after 35 weeks were excluded, bringing the study total to 1897. Maternal characteristics of the study cohort are summarized in Table 1. The diagnostic performance of third-trimester ultrasound in the prediction of SGA is reported in Table 2, with a sensitivity of 29.0% (95% CI, 22.5–36.6%) and specificity of 94.2% (95% CI, 93.0–95.2%). Positive and negative predictive values were 30.8% (95% CI, 23.9–38.7%) and 93.7% (95% CI, 92.5–94.8%), respectively, and the positive and negative likelihood ratios were 5 and 0.75, respectively. Maternal and fetal outcomes for the non-SGA and SGA groups are summarized in Table 3, according to their screening result. There was no statistically significant difference in the mode of onset of labor. Elective Cesarean section for reduced fetal growth was 2.85 times more likely in the FP group than in the TN group (4.5% vs 11.9%; OR, 2.85 (95% CI, 1.36–5.53); P = 0.003). There was no difference in the rate of spontaneous preterm delivery between the TN and FP groups and between the TP and FN groups, however, a greater number of FP patients had a planned preterm delivery before 37 weeks’ gestation than did TN patients (11.9% vs 5.2%; OR, 2.44 (95% CI, 1.17–4.69); P = 0.01). However, there was no difference with regard to planned preterm delivery between TP and FN patients (8.9% vs 5.5%;
Ultrasound Obstet Gynecol 2015; 46: 216–220.
Callec et al.
218 Recruited (n = 2002) Poitiers (n = 969) Nancy (n = 1033) Lost to follow-up, declined participation or fetal death (n = 80) Third-trimester ultrasound examination at 30–35 weeks (n = 1922)
Study population (n = 1897)
DISCUSSION Excluded: Third-trimester ultrasound performed before 30 or after 35 weeks (n = 24) Stillbirth (n = 1)
Figure 1 Flowchart summarizing recruitment of study population of pregnant women who underwent screening for small-for-gestational-age fetus by third-trimester ultrasound examination. Table 1 Maternal characteristics of study population of 1897 women who underwent screening for small-for-gestational-age fetus by third-trimester ultrasound examination Maternal characteristic Age (years) Height (cm) Weight (kg) Body mass index (kg/m2 ) Chronic hypertension Gestational hypertension
Value 29.2 ± 4.9 163 ± 6 62.2 ± 12.8 23.3 ± 4.6 92 (4.8) 37 (2.0)
Data are given as mean ± SD or n (%). Table 2 Diagnostic performance of screening for small-for-gestational-age fetuses by third-trimester ultrasound at 30–35 weeks’ gestation Performance measure Prevalence (%) Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Positive likelihood ratio Negative likelihood ratio
admission to the NICU was found between the TP infants, diagnosed correctly as SGA, and the FN infants that went undiagnosed during the third-trimester ultrasound examination (17.8% vs 12.7%; OR, 0.67 (95% CI, 0.26–1.74); P = 0.45).
Value (95% CI) 8.2 29.0 (22.5–36.6) 94.2 (93.0–95.2) 30.8 (23.9–38.7) 93.7 (92.5–94.8) 5 0.75
OR, 0.59 (95% CI, 0.13–3.01); P = 0.48). In addition, a significant difference in birth weight was found between the TN and FP and between the TP and FN neonates (3359.5 g vs 3003.3 g (P < 0.01) and 2456.4 g vs 2605.6 g (P = 0.02), respectively). There was no statistically significant difference in neonatal morbidity, as shown by a 5-min Apgar score < 7, cord blood pH at birth < 7.15 and the need for neonatal resuscitation, in the two subgroups (TN vs FP and TP vs FN). Admission to the NICU was 2.2 times more likely in FP newborns, diagnosed incorrectly as SGA at screening, than in TN newborns (11.9% vs 5.7%; OR, 2.21 (95% CI, 1.07–4.26); P = 0.03), however, no significant difference regarding Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
This study focused on the detection of SGA fetuses in a low-risk population and demonstrates the limitations of predicting fetal weight. The EDEN study followed standardized ultrasound examination procedures: at the beginning of the study, all operators participated in a training session and, subsequently, the first five ultrasound scans carried out by each operator were reviewed, resulting in consistent and reliable data for estimating fetal weight on third-trimester ultrasound examination, according to the formula of Hadlock et al.10,11 . Performance rates of predicting SGA by ultrasound were low, with a sensitivity of less than 30%. In our study, the diagnostic performance of third-trimester ultrasound screening for SGA, as defined by an EFW < 10th percentile, appears to be lower than those found in other studies; some authors found a sensitivity of 50–60%12 – 14 . Indeed, some authors12,15,16 found a sensitivity and specificity of 87% when using the formula of Hadlock et al. The obstetric and neonatal outcomes were compared between TN and FP patients and between TP and FN patients. The rate of spontaneous preterm delivery was not different between either subgroup of SGA or non-SGA patients. Compared to the TN patients, a significant increase in planned preterm deliveries before 37 weeks, planned Cesarean sections for fetal growth indication and admissions to the NICU were found among FP infants, erroneously diagnosed as SGA at screening. The increased rate of planned induction of preterm delivery before 37 weeks in the FP group may help to explain the significant difference in birth weight when compared with that of the TN group. In addition, neonatal admission to the NICU was 2.2 times more likely in the FP group than in the TN group, which may be due to planned early induction of delivery (before 37 weeks) and early elective Cesarean section for fetal indication. The negative impact of SGA screening has been described previously by Ringa et al.17 in 1993, who showed that a larger number of interventions performed for SGA were related to the findings at ultrasound screening. Another study showed that screening was the source of additional unnecessary Cesarean sections performed in FP patients18 . More recently, a randomized controlled trial (RCT) showed a significant increase in the rate of induction of labor and elective Cesarean section due to suspected intrauterine growth restriction at the routine third-trimester ultrasound, compared to ultrasound performed on clinical suspicion19 . No significant differences were found for the mode of onset of labor or delivery, incidence of planned or spontaneous preterm delivery or health status of the newborns at birth between SGA newborns diagnosed
Ultrasound Obstet Gynecol 2015; 46: 216–220.
Impact of third-trimester screening for SGA
219
Table 3 Obstetric and neonatal outcomes of small-for-gestational-age (SGA) and non-SGA neonates, according to result of third-trimester ultrasound screening Non-SGA (n = 1742) TN (n = 1641)
FP (n = 101)
1189 (72.5) 344 (21.0) 108 (6.6)
72 (71.3) 16 (15.8) 13 (12.9)
74 (4.5)
12 (11.9)
0.003*
86 (5.2)
12 (11.9)
0.01*
49 (3.0)
6 (5.9)
0.06
Mode of delivery Vaginal Instrumental CS
1219 (74.3) 171 (10.4) 251 (15.3)
74 (73.3) 8 (7.9) 19 (18.8)
Birth weight (g) 5-min Apgar score < 7
3359.5 ± 480 43 (2.6)
Cord blood pH < 7.15
165 (10.1)
13 (12.9)
0.39
Neonatal resusc.
147 (9.0)
10 (9.9)
0.7
94 (5.7)
12 (11.9)
0.03*
—
—
Outcome Mode of labor onset Spontaneous Labor induction Elective CS before labor Elective CS for fetal growth indication Planned PTD† Spontaneous PTD†
Admission to NICU Neonatal death
P
SGA (n = 155) OR (95% CI)
TP (n = 45)
FN (n = 110)
27 (60.0) 14 (31.1) 4 (8.9)
79 (71.8) 22 (20.0) 9 (8.2)
4 (8.9)
7 (6.4)
0.7
4 (8.9)
6 (5.5)
0.48
2 (4.4)
4 (3.6)
1
31 (68.9) 4 (8.9) 10 (22.2)
80 (72.7) 12 (10.9) 18 (16.4)
0.49
2456.4 ± 288 1 (2.2)
2605.6 ± 323 15 (13.6)
0.02* 0.05
5 (11.1)
25 (22.7)
0.12
4 (8.9)
17 (15.5)
0.44
8 (17.8)
14 (12.7)
0.45
—
3 (2.7)
0.036
3003.3 ± 343 < 0.01* — 0.17
1
OR (95% CI)
0.3
2.85 (1.36–5.53) 2.44 (1.17–4.69) 2.05 (0.85–4.91)
0.5
0.32
P
0.69 (0.16–3.43) 0.59 (0.13–3.01) 0.81 (0.11–9.29)
0.63
0.77 (0.46–1.39) 1 1.32 (0.66–2.44) 1.11 (0.50–2.21) 2.21 (1.07–4.26)
1.45 (0.54–3.72) 0.14 (0.01–1.1) 2.35 (0.84–6.6) 1.87 (0.59–5.91) 0.67 (0.26–1.74)
1
Data are given as n (%) or mean ± SD. *P < 0.05. †Before 37 weeks’ gestation. CS, Cesarean section; FN, false negative; FP, false positive; NICU, neonatal intensive care unit; OR, odds ratio; PTD, preterm delivery; resusc., resuscitation; TN, true negative; TP, true positive.
correctly during the antenatal period and those not detected. These results confirm previously published data20 – 23 . A study by Jahn et al.21 showed that fetuses correctly detected as SGA were more frequently delivered before 38 weeks’ gestation by Cesarean section and more often admitted to the NICU without any other clinical indication (Apgar score and cord blood pH were the same in the two groups) compared with SGA fetuses that were undetected by screening. Various randomized trials have tested the clinical relevance of the use of ultrasound biometry and have shown conflicting results. The RADIUS study found no benefit in conducting systematic ultrasound scans in the second and third trimesters compared to scans performed only when clinically indicated18 . Additionally, a study in Norway, in which two routine ultrasound scans are performed, found no benefit in detecting babies of low birth weight (< 2500 g)20 . In a more recent study in 2005, the results showed that routine third-trimester ultrasound screening in an unselected population did not reduce perinatal mortality or early neonatal morbidity23 . In 2013, an RCT compared routine third-trimester ultrasound to ultrasound performed on the basis of clinical concern: although third-trimester routine ultrasound improved detection rates of SGA fetuses, from 46% to 80%, overall perinatal morbidity and mortality remained unchanged19 . Finally, a meta-analysis in 2008 concluded that routine
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
late-pregnancy ultrasound examinations in low-risk or unselected populations did not confer any benefit on the mothers or neonates and was perhaps associated with a small increase in rates of Cesarean section24 . An observational study presents obvious limitations. In this study, operators received the results of biometry after ultrasound examination. Evaluation of a diagnostic test should be performed blind, as knowledge of the result could lead to a different management strategy. In this study, however, no significant difference between the management of TP and FN neonates was found, which suggests that no such bias was introduced. In addition, although this was a prospective study, information on additional ultrasound scans during pregnancy was not collected and it was therefore not possible to assess the impact of further ultrasound monitoring on pregnancy outcomes. Finally, the number of patients per subgroup remained relatively low, leading to a possible lack of power to highlight differences between groups. The diagnostic performance of third-trimester ultrasound screening for SGA seems poor, as it misses the diagnosis of a large number of SGA newborns. The consequences of routine screening in a low-risk population may lead to unnecessary planned preterm delivery and elective Cesarean section of non-SGA neonates misdiagnosed as SGA, without improving neonatal outcome of SGA neonates that go undiagnosed prenatally. Ultrasound Obstet Gynecol 2015; 46: 216–220.
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ACKNOWLEDGMENTS The EDEN Mother–Child Cohort Study Group includes I. Annesi-Maesano, J. Botton, M. A. Charles, P. DargentMolina, B. de Lauzon-Guillain, P. Ducimeti`ere, M. de Agostini, B. Foliguet, A. Forhan, X. Fritel, A. Germa, V. Goua, R. Hankard, B. Heude, M. Kaminski, B. Larroque, N. Lelong, J. Lepeule, G. Magnin, L. Marchand, C. Nabet, R. Slama, M. J. Saurel-Cubizolles, M. Schweitzer and O. Thiebaugeorges. The authors acknowledge the funding sources for the EDEN study: Fondation pour la Recherche M´edicale (FRM), French Ministry of Research: IFR Program, INSERM Human Nutrition National Research Program, Diabetes National Research Program (via a collaboration with the Association for Diabetes Research), French Ministry of Health Perinatality Program, French Agency for Environment Security (AFFSET), French National Institute for Population Health Surveillance (INVS), Paris–Sud University, French National Institute for Health Education (INPES), Nestl´e, Mutuelle G´en´erale de l’Education Nationale (MGEN), French-Speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM), National Agency for Research (ANR nonthematic program) and the National Institute for Research in Public Health (IRESP: TGIR cohorte sant´e 2008 program).
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Impact on obstetric outcome of third-trimester screening for small-for-gestational-age fetuses R. CALLEC*†‡, C. LAMY*, E. PERDRIOLLE-GALET*†‡, C. PATTE*, B. HEUDE§¶, O. MOREL*†‡ and the EDEN Mother–Child Cohort Study Group *Obstetrics and Fetal Medicine Unit, Centre Hospitalier Universitaire, Nancy, France; †Universit´e de Lorraine, Nancy, France; ‡INSERM, U947, Nancy, France; §Centre for Research in Epidemiology and Population Health (CESP), INSERM, Villejuif, France; ¶Universit´e Paris Sud, Villejuif, France
K E Y W O R D S: screening; small-for-gestational age; third trimester; ultrasound
ABSTRACT Objectives To evaluate the performance of screening for small-for-gestational-age (SGA) fetuses by ultrasound biometry at 30–35 weeks’ gestation, and to determine the impact of screening on obstetric and neonatal outcomes. Methods For this prospective cohort study, pregnant women were recruited from two French university maternity centers between 2003 and 2006. Performance measures of third-trimester biometry for the prediction of SGA, defined as estimated fetal weight < 10th centile, were analyzed. Obstetric outcomes and neonatal health status were compared, first, between SGA neonates diagnosed correctly at ultrasound examination (true positive (TP); n = 45) and SGA neonates that went undiagnosed (false negative (FN); n = 110) and, second, between non-SGA neonates identified as normal at ultrasound examination (true negative (TN); n = 1641) and non-SGA neonates diagnosed incorrectly as SGA (false positive (FP); n = 101). Results In the prediction of SGA, third-trimester ultrasound had a sensitivity of 29.0% (95% CI, 22.5–36.6%) and specificity of 94.2% (95% CI, 93.0–95.2%). Positive and negative predictive values were 30.8% (95% CI, 23.9–38.7%) and 93.7% (95% CI, 92.5–94.8%), respectively. One hundred and ten SGA neonates went undiagnosed at ultrasound. Compared to the TN neonates considered as of normal weight at ultrasound, planned preterm delivery (before 37 weeks) and elective Cesarean section for a fetal growth indication were 2.4 (P = 0.01) and 2.85 (P = 0.003) times more likely to occur, respectively, in the FP group of non-SGA neonates, diagnosed incorrectly as SGA during the antenatal period. There was no statistically significant difference in 5-min Apgar score < 7, cord blood pH at birth < 7.15 and need for
neonatal resuscitation between the two subgroups (TN vs FP and TP vs FN). Conclusions The performance of third-trimester ultrasound screening for SGA seems poor, as it misses the diagnosis of a large number of SGA neonates. The consequences of routine screening for SGA in a low-risk population may lead to unnecessary planned preterm deliveries and elective Cesarean sections in FP pregnancies, without improved neonatal outcome in the FN pregnancies. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION One of the major clinical problems in pregnancy care is the management of fetuses that are small-for-gestational age (SGA). SGA is often defined as fetal weight < 10th percentile for gestational age1 and is associated with an increased risk of perinatal morbidity and mortality2 – 5 . Undiagnosed SGA fetuses are responsible for 50% of unexplained fetal deaths at term6 – 8 . Obstetric teams need to be able to recognize a pathological fetal growth pattern in order to determine the timing of delivery that will optimize perinatal and neurodevelopmental outcomes. Ultrasound screening is a valuable tool for detecting SGA fetuses, which can lead to improved neonatal outcomes8 . Most often, abnormal fetal growth is suspected at ultrasound examination performed routinely during the second and third trimesters or in high-risk groups. In France, fetal growth is evaluated routinely at around 32 weeks’ gestation9 . The primary aim of EDEN, a prospective mother–child cohort study, is to identify prenatal and early postnatal nutritional, environmental and social determinants associated with children’s health and their normal or pathological development. Pregnant
Correspondence to: Dr R. Callec, Obstetrics and Fetal Medicine Unit, Centre Hospitalier de Nancy, Pole de la Femme, 10 Rue du Dr Heydenreich, Nancy 54000, France (e-mail: [email protected]) Accepted: 4 December 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Impact of third-trimester screening for SGA women attending a prenatal visit at the Departments of Obstetrics and Gynecology of two French University Hospitals before 24 weeks’ gestation were invited to participate. The purpose of this study was to evaluate the performance of a third-trimester ultrasound examination, at 30–35 weeks’ gestation, in screening for SGA and to determine the impact of screening on obstetric and neonatal outcomes.
METHODS This study was part of the EDEN mother–child cohort study, a prospective two-center cohort study involving the follow-up of women from the early stages of pregnancy. Between 2003 and 2006, a total of 2002 pregnant women were recruited prior to 24 weeks’ gestation from a low-risk population at two French university maternity centers (Nancy and Poitiers, France). Exclusion criteria were multiple pregnancy, known diabetes mellitus, illiteracy and intention to deliver outside the university hospital or to move outside the region within 3 years of examination. Among the women who fulfilled the inclusion criteria, 55% agreed to participate. Maternal age, socioeconomic status, parity, preconceptional weight, obstetric history and information about maternal smoking were obtained by interview or from clinical records. After delivery, information about the pregnancy, delivery and anthropometric measures (birth weight) of the infant was obtained from clinical records. Gestational age was determined from the date of the last menstrual period in women with a regular cycle, or by ultrasound assessment of crown–rump length or biparietal diameter. When there was a discrepancy of > 7 days between age deduced from the last menstrual period and sonographic age, the sonographic estimation was used. SGA was defined as an estimated fetal weight (EFW) below the 10th percentile, according to the formula of Hadlock et al.10 : log10 (EFW) = 1.3596 − (0.00386 (AC × FL)) + (0.0064 × HC) + (0.00061 (BPD × AC)) + (0.0424 × AC) + (0.0174 × FL), where AC is abdominal circumference, FL is femur length, HC is head circumference and BPD is biparietal diameter. All ultrasound examinations were performed by one of five specialists who agreed on standardized procedures before the study commenced. Furthermore, the first five measurements made by each examiner were reviewed by another examiner to check for consistency with the protocol. The study was approved by the Ethical Research Committee (Comit´e Consultatif de Protection des Personnes dans la Recherche Biom´edicale) of the hospital of Bicˆetre and by the Data Protection Authority (Commission Nationale de l’Informatique et des Libert´es). Informed written consent was obtained from the women, both for themselves at enrollment and for the newborns after delivery. Performance measures for the prediction of SGA birth by third-trimester ultrasound were analyzed by estimating the sensitivity, specificity and positive and negative predictive values. Obstetric outcomes and neonatal health
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
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status, in terms of morbidity and mortality (newborns who died within 28 days of delivery, 5-min Apgar score < 7, cord blood pH at birth < 7.15, preterm delivery before 37 weeks’ gestation, elective Cesarean section, need for neonatal resuscitation or transfer to the neonatal intensive care unit (NICU)), were compared, first, between true-positive (TP) and false-negative (FN) SGA neonates and, second, between true-negative (TN) and false-positive (FP) non-SGA neonates.
Statistical analysis Descriptive analysis of the study group was performed by estimating the mean and SD for continuous variables, and frequency and percentage for categorical ones. The chi-square test or Fisher’s exact test was used to compare qualitative variables and Student’s t-test was used to compare continuous variables. Odds ratios (ORs) with 95% CIs were calculated. Statistical analysis was carried out using SAS 9.3 (SAS Inc., Cary, NC, USA); P < 0.05 was considered to indicate statistical significance.
RESULTS Of the 2002 women originally included in the cohort, 80 were lost to follow-up, declined to continue participation or experienced fetal death. One woman who had a stillbirth was also excluded (Figure 1). Ultrasound examinations were scheduled at 32–34 weeks’ gestation; however, as several women underwent an ultrasound examination slightly later, we extended the study period to 30–35 weeks’ gestation to increase the final sample size. Twenty-four women who were scanned before 30 weeks or after 35 weeks were excluded, bringing the study total to 1897. Maternal characteristics of the study cohort are summarized in Table 1. The diagnostic performance of third-trimester ultrasound in the prediction of SGA is reported in Table 2, with a sensitivity of 29.0% (95% CI, 22.5–36.6%) and specificity of 94.2% (95% CI, 93.0–95.2%). Positive and negative predictive values were 30.8% (95% CI, 23.9–38.7%) and 93.7% (95% CI, 92.5–94.8%), respectively, and the positive and negative likelihood ratios were 5 and 0.75, respectively. Maternal and fetal outcomes for the non-SGA and SGA groups are summarized in Table 3, according to their screening result. There was no statistically significant difference in the mode of onset of labor. Elective Cesarean section for reduced fetal growth was 2.85 times more likely in the FP group than in the TN group (4.5% vs 11.9%; OR, 2.85 (95% CI, 1.36–5.53); P = 0.003). There was no difference in the rate of spontaneous preterm delivery between the TN and FP groups and between the TP and FN groups, however, a greater number of FP patients had a planned preterm delivery before 37 weeks’ gestation than did TN patients (11.9% vs 5.2%; OR, 2.44 (95% CI, 1.17–4.69); P = 0.01). However, there was no difference with regard to planned preterm delivery between TP and FN patients (8.9% vs 5.5%;
Ultrasound Obstet Gynecol 2015; 46: 216–220.
Callec et al.
218 Recruited (n = 2002) Poitiers (n = 969) Nancy (n = 1033) Lost to follow-up, declined participation or fetal death (n = 80) Third-trimester ultrasound examination at 30–35 weeks (n = 1922)
Study population (n = 1897)
DISCUSSION Excluded: Third-trimester ultrasound performed before 30 or after 35 weeks (n = 24) Stillbirth (n = 1)
Figure 1 Flowchart summarizing recruitment of study population of pregnant women who underwent screening for small-for-gestational-age fetus by third-trimester ultrasound examination. Table 1 Maternal characteristics of study population of 1897 women who underwent screening for small-for-gestational-age fetus by third-trimester ultrasound examination Maternal characteristic Age (years) Height (cm) Weight (kg) Body mass index (kg/m2 ) Chronic hypertension Gestational hypertension
Value 29.2 ± 4.9 163 ± 6 62.2 ± 12.8 23.3 ± 4.6 92 (4.8) 37 (2.0)
Data are given as mean ± SD or n (%). Table 2 Diagnostic performance of screening for small-for-gestational-age fetuses by third-trimester ultrasound at 30–35 weeks’ gestation Performance measure Prevalence (%) Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Positive likelihood ratio Negative likelihood ratio
admission to the NICU was found between the TP infants, diagnosed correctly as SGA, and the FN infants that went undiagnosed during the third-trimester ultrasound examination (17.8% vs 12.7%; OR, 0.67 (95% CI, 0.26–1.74); P = 0.45).
Value (95% CI) 8.2 29.0 (22.5–36.6) 94.2 (93.0–95.2) 30.8 (23.9–38.7) 93.7 (92.5–94.8) 5 0.75
OR, 0.59 (95% CI, 0.13–3.01); P = 0.48). In addition, a significant difference in birth weight was found between the TN and FP and between the TP and FN neonates (3359.5 g vs 3003.3 g (P < 0.01) and 2456.4 g vs 2605.6 g (P = 0.02), respectively). There was no statistically significant difference in neonatal morbidity, as shown by a 5-min Apgar score < 7, cord blood pH at birth < 7.15 and the need for neonatal resuscitation, in the two subgroups (TN vs FP and TP vs FN). Admission to the NICU was 2.2 times more likely in FP newborns, diagnosed incorrectly as SGA at screening, than in TN newborns (11.9% vs 5.7%; OR, 2.21 (95% CI, 1.07–4.26); P = 0.03), however, no significant difference regarding Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
This study focused on the detection of SGA fetuses in a low-risk population and demonstrates the limitations of predicting fetal weight. The EDEN study followed standardized ultrasound examination procedures: at the beginning of the study, all operators participated in a training session and, subsequently, the first five ultrasound scans carried out by each operator were reviewed, resulting in consistent and reliable data for estimating fetal weight on third-trimester ultrasound examination, according to the formula of Hadlock et al.10,11 . Performance rates of predicting SGA by ultrasound were low, with a sensitivity of less than 30%. In our study, the diagnostic performance of third-trimester ultrasound screening for SGA, as defined by an EFW < 10th percentile, appears to be lower than those found in other studies; some authors found a sensitivity of 50–60%12 – 14 . Indeed, some authors12,15,16 found a sensitivity and specificity of 87% when using the formula of Hadlock et al. The obstetric and neonatal outcomes were compared between TN and FP patients and between TP and FN patients. The rate of spontaneous preterm delivery was not different between either subgroup of SGA or non-SGA patients. Compared to the TN patients, a significant increase in planned preterm deliveries before 37 weeks, planned Cesarean sections for fetal growth indication and admissions to the NICU were found among FP infants, erroneously diagnosed as SGA at screening. The increased rate of planned induction of preterm delivery before 37 weeks in the FP group may help to explain the significant difference in birth weight when compared with that of the TN group. In addition, neonatal admission to the NICU was 2.2 times more likely in the FP group than in the TN group, which may be due to planned early induction of delivery (before 37 weeks) and early elective Cesarean section for fetal indication. The negative impact of SGA screening has been described previously by Ringa et al.17 in 1993, who showed that a larger number of interventions performed for SGA were related to the findings at ultrasound screening. Another study showed that screening was the source of additional unnecessary Cesarean sections performed in FP patients18 . More recently, a randomized controlled trial (RCT) showed a significant increase in the rate of induction of labor and elective Cesarean section due to suspected intrauterine growth restriction at the routine third-trimester ultrasound, compared to ultrasound performed on clinical suspicion19 . No significant differences were found for the mode of onset of labor or delivery, incidence of planned or spontaneous preterm delivery or health status of the newborns at birth between SGA newborns diagnosed
Ultrasound Obstet Gynecol 2015; 46: 216–220.
Impact of third-trimester screening for SGA
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Table 3 Obstetric and neonatal outcomes of small-for-gestational-age (SGA) and non-SGA neonates, according to result of third-trimester ultrasound screening Non-SGA (n = 1742) TN (n = 1641)
FP (n = 101)
1189 (72.5) 344 (21.0) 108 (6.6)
72 (71.3) 16 (15.8) 13 (12.9)
74 (4.5)
12 (11.9)
0.003*
86 (5.2)
12 (11.9)
0.01*
49 (3.0)
6 (5.9)
0.06
Mode of delivery Vaginal Instrumental CS
1219 (74.3) 171 (10.4) 251 (15.3)
74 (73.3) 8 (7.9) 19 (18.8)
Birth weight (g) 5-min Apgar score < 7
3359.5 ± 480 43 (2.6)
Cord blood pH < 7.15
165 (10.1)
13 (12.9)
0.39
Neonatal resusc.
147 (9.0)
10 (9.9)
0.7
94 (5.7)
12 (11.9)
0.03*
—
—
Outcome Mode of labor onset Spontaneous Labor induction Elective CS before labor Elective CS for fetal growth indication Planned PTD† Spontaneous PTD†
Admission to NICU Neonatal death
P
SGA (n = 155) OR (95% CI)
TP (n = 45)
FN (n = 110)
27 (60.0) 14 (31.1) 4 (8.9)
79 (71.8) 22 (20.0) 9 (8.2)
4 (8.9)
7 (6.4)
0.7
4 (8.9)
6 (5.5)
0.48
2 (4.4)
4 (3.6)
1
31 (68.9) 4 (8.9) 10 (22.2)
80 (72.7) 12 (10.9) 18 (16.4)
0.49
2456.4 ± 288 1 (2.2)
2605.6 ± 323 15 (13.6)
0.02* 0.05
5 (11.1)
25 (22.7)
0.12
4 (8.9)
17 (15.5)
0.44
8 (17.8)
14 (12.7)
0.45
—
3 (2.7)
0.036
3003.3 ± 343 < 0.01* — 0.17
1
OR (95% CI)
0.3
2.85 (1.36–5.53) 2.44 (1.17–4.69) 2.05 (0.85–4.91)
0.5
0.32
P
0.69 (0.16–3.43) 0.59 (0.13–3.01) 0.81 (0.11–9.29)
0.63
0.77 (0.46–1.39) 1 1.32 (0.66–2.44) 1.11 (0.50–2.21) 2.21 (1.07–4.26)
1.45 (0.54–3.72) 0.14 (0.01–1.1) 2.35 (0.84–6.6) 1.87 (0.59–5.91) 0.67 (0.26–1.74)
1
Data are given as n (%) or mean ± SD. *P < 0.05. †Before 37 weeks’ gestation. CS, Cesarean section; FN, false negative; FP, false positive; NICU, neonatal intensive care unit; OR, odds ratio; PTD, preterm delivery; resusc., resuscitation; TN, true negative; TP, true positive.
correctly during the antenatal period and those not detected. These results confirm previously published data20 – 23 . A study by Jahn et al.21 showed that fetuses correctly detected as SGA were more frequently delivered before 38 weeks’ gestation by Cesarean section and more often admitted to the NICU without any other clinical indication (Apgar score and cord blood pH were the same in the two groups) compared with SGA fetuses that were undetected by screening. Various randomized trials have tested the clinical relevance of the use of ultrasound biometry and have shown conflicting results. The RADIUS study found no benefit in conducting systematic ultrasound scans in the second and third trimesters compared to scans performed only when clinically indicated18 . Additionally, a study in Norway, in which two routine ultrasound scans are performed, found no benefit in detecting babies of low birth weight (< 2500 g)20 . In a more recent study in 2005, the results showed that routine third-trimester ultrasound screening in an unselected population did not reduce perinatal mortality or early neonatal morbidity23 . In 2013, an RCT compared routine third-trimester ultrasound to ultrasound performed on the basis of clinical concern: although third-trimester routine ultrasound improved detection rates of SGA fetuses, from 46% to 80%, overall perinatal morbidity and mortality remained unchanged19 . Finally, a meta-analysis in 2008 concluded that routine
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
late-pregnancy ultrasound examinations in low-risk or unselected populations did not confer any benefit on the mothers or neonates and was perhaps associated with a small increase in rates of Cesarean section24 . An observational study presents obvious limitations. In this study, operators received the results of biometry after ultrasound examination. Evaluation of a diagnostic test should be performed blind, as knowledge of the result could lead to a different management strategy. In this study, however, no significant difference between the management of TP and FN neonates was found, which suggests that no such bias was introduced. In addition, although this was a prospective study, information on additional ultrasound scans during pregnancy was not collected and it was therefore not possible to assess the impact of further ultrasound monitoring on pregnancy outcomes. Finally, the number of patients per subgroup remained relatively low, leading to a possible lack of power to highlight differences between groups. The diagnostic performance of third-trimester ultrasound screening for SGA seems poor, as it misses the diagnosis of a large number of SGA newborns. The consequences of routine screening in a low-risk population may lead to unnecessary planned preterm delivery and elective Cesarean section of non-SGA neonates misdiagnosed as SGA, without improving neonatal outcome of SGA neonates that go undiagnosed prenatally. Ultrasound Obstet Gynecol 2015; 46: 216–220.
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ACKNOWLEDGMENTS The EDEN Mother–Child Cohort Study Group includes I. Annesi-Maesano, J. Botton, M. A. Charles, P. DargentMolina, B. de Lauzon-Guillain, P. Ducimeti`ere, M. de Agostini, B. Foliguet, A. Forhan, X. Fritel, A. Germa, V. Goua, R. Hankard, B. Heude, M. Kaminski, B. Larroque, N. Lelong, J. Lepeule, G. Magnin, L. Marchand, C. Nabet, R. Slama, M. J. Saurel-Cubizolles, M. Schweitzer and O. Thiebaugeorges. The authors acknowledge the funding sources for the EDEN study: Fondation pour la Recherche M´edicale (FRM), French Ministry of Research: IFR Program, INSERM Human Nutrition National Research Program, Diabetes National Research Program (via a collaboration with the Association for Diabetes Research), French Ministry of Health Perinatality Program, French Agency for Environment Security (AFFSET), French National Institute for Population Health Surveillance (INVS), Paris–Sud University, French National Institute for Health Education (INPES), Nestl´e, Mutuelle G´en´erale de l’Education Nationale (MGEN), French-Speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM), National Agency for Research (ANR nonthematic program) and the National Institute for Research in Public Health (IRESP: TGIR cohorte sant´e 2008 program).
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