International Journal of Gynecology and Obstetrics (2006) 93, 5 12

www.elsevier.com/locate/ijgo

REVIEW ARTICLE

Intrauterine growth restriction

K. Haram a,*, E. Sfteland b, R. Bukowski c
a

Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway Department of Anesthesia and Intensive Care, Haukeland University Hospital, and Department of Biomedicine, University of Bergen, Bergen, Norway c Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, USA
b

Received 18 October 2005; received in revised form 23 November 2005; accepted 30 November 2005

KEYWORDS
Intrauterine growth restriction; Small for gestational age; Diagnosis; Treatment

Abstract This study reviewed the screening, diagnosis, prophylaxis, and treatment of intrauterine growth restriction using the PubMed database for key words and the Cochrane database for systematic reviews. Identification of risk factors and measurement of symphysisfundus height are currently the screening standards. Diagnosis is verified by ultrasonography. Accuracy of diagnosis may be improved by using customized fetal growth curves symphysisfundus height charts, and 3dimensional ultrasonographic evaluation and measuring umbilical artery Doppler dimensional ultrasonographic evaluation measuring umbilical artery Doppler impedance. Prophylaxis with acetylsalicylic acid, started in the first or second trimester or combined with heparin before conception, may reduce the incidence of growth restriction in specific groups at high risk. Active management may reduce incidence in patients with mild to moderate asthma, and targeted treatment of infections may also be beneficial. Antenatal corticosteroid treatment also reduces the perinatal morbidity and mortality associated with IUGR. Bed rest has no demonstrated beneficial effects. D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction
As intrauterine growth restriction (IUGR) has serious short- and long-term fetal consequences, it is important to distinguish between a fetus small for gestational age (SGA) and a fetus with IUGR.
* Corresponding author. Fax: +47 55 97 49 68. E-mail address: kjell.haram@broadpark.no (K. Haram).

Whereas the estimated weight of the former is merely less than a cut-off weight for a given population, often because of constitutional factors, the latter has not reached its growth potential. Traditionally, IUGR screening is based on clinical examination and identification of risk factors. Maternal risk factors for IUGR include a prior pregnancy with IUGR, pre-eclampsia, a low prepregnancy weight, or a low weight gain during the

0020-7292/$ - see front matter D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2005.11.011

6 index pregnancy. Screening include abdominal palpation, symphysisfundal (SF) height measurement, and ultrasonographic examination. When a small fetus is detected, diagnostic signs include decreased amniotic fluid volume, abnormal umbilical artery Doppler impedance indexes, decreased fetal growth rate, and an abnormal fetal karyotype. The cause of IUGR should be treated whenever possible. Women with an IUGR pregnancy need appropriate surveillance and concurrent treatment of underlying disorders, e.g., hypertension or infection. The aim of this study was to assess current screening, diagnosis, prophylaxis, and therapy of fetal growth restriction.

K. Haram et al. [3]. Up to 30 weeks (60 mm), dating based on BPD measurement virtually coincided with dating obtained by Hadlock et al. using a multiparameter method [4]. New Norwegian reference norms for BPD and HC are also similar to those in the British charts [5]. A study of 152 singleton pregnancies conceived in vitro showed that HC was most accurate when only a single parameter was used to determine gestational age [6].

4. Diagnosis of IUGR
4.1. Determination of suspected IUGR

2. Method
The PubMed database was searched for the following: small for gestational age or intrauterine growth restriction combined with gestational age determination , risk factors , diagnosis , abdominal palpation , symphysisfundal height , ultrasound examination , estimated fetal weight , customized fetal weight , amniotic fluid volume , biochemical markers , cardiotocography, Doppler investigation , infection , treatment , beta agonists , anti-asthmatics , corticosteroids , nitric oxide , oxygen , acetyl salicylic acid (ASA), heparin , or bed rest , specifically seeking randomized trials. The Cochrane library was also searched for appropriate systematic reviews.

When a small fetus is detected by ultrasonographic examination, it is important to attempt to distinguish SGA from IUGR. This can be facilitated by ultrasonographic examination focused on the detection of markers for chromosomal abnormality, amniotic fluid volume evaluation and serial examinations monitoring fetal growth and growth symmetry as well as amniotic fluid volume changes [7]. Periodic fetal assessments using Doppler velocimetry, contraction stress tests, biophysical profiles, or nonstress tests are all accepted monitoring techniques [8].

4.2. Abdominal palpation (Leopold maneuvers)

The oldest of the clinical methods, abdominal palpation, is accomplished using the Leopold maneuvers [9], but its ability to predict fetal weight is limited [10]. Abdominal palpation should only be regarded as a tool to raise suspicion of low birth weight.

3. Determination of gestational age

Since the vast majority of measurements obtained during pregnancy depend strongly on gestational age, the precise estimate of gestational age is paramount in the screening and diagnosis of IUGR [1]. Even a bcertainQ menstrual history is uncertain and early ultrasonographic dating should be used instead of the date of the last menstrual period, unless ultrasonographic equipment is not available [2]. Measurement of the crownrump length gives the best estimate of gestational age during the first trimester; measurements of biparietal diameter (BPD); femur length (FL); and head circumference (HC), head area, and transcerebellar diameter are also standards for gestational age determination in the second trimester [2]. Charts for ultrasonographic dating by BPD, HC, head area, transcerebellar diameter, and FL measurements are derived from cross-sectional studies

4.3. Symphysisfundal height

The sensitivity of SF height measurement in predicting SGA ranges from 17% to 86%, its specificity from 64% to 88% [11], and positive predictive value from 29% to about 79% [12]. One Cochrane review concluded that there is not enough evidence to evaluate the usefulness of SF height measurements during antenatal care [13]. Yet, SF height measurement is still the most commonly used screening tool for IUGR [1]. All older studies of SF height measurements based their estimates of gestational age on the last menstrual period to derive normal curves [14]. A new SF reference curve for normal pregnancies has been established from a cross-sectional study of

Intrauterine growth restriction 1650 Swedish women between 20 and 41 weeks of pregnancy using ultrasound-based dating. Ultrasonographic dating resulted in curves more linear than those obtained using last menstrual period [15]. Mongelli et al. and Gardosi and Francis created a SF height norm customized for pregnancy characteristics. The authors suggested that using individually adjusted SF height growth charts might improve precision when screening for IUGR [14, 16]. Adjusting SF height measurements for physiological variables appears to be cost-effective and may substantially improve antenatal assessment of fetal growth (Figs. 1 and 2) [16].
44 42 40 38
90 percentile

4.2 50 percentile 4.0

36 34 32 30 28 26

3.2 3.0 2.8 2.6 2.4 2.2 2.0

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Gestational weeks

4.4. Ultrasonographically estimated fetal weight

Parameters most commonly used for ultrasonographically estimated fetal weight include BPD, FL, HC, mean abdominal diameter, and AC. Dudley has recently given a thorough review of ultrasonographic fetal weight estimation and concluded that this method is inaccurate, with a poor sensitivity for the prediction of fetal compromise. However, no consistently superior method emerged from this analysis [17].
44 42 40 38 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 10 percentile 2.6 2.4 2.2 2.0 90 percentile 50 percentile

Figure 2 Example of a customized growth chart using symphysisfundal (SF) height (left y axis) and gestational age (x axis) for the evaluation of fetal weight (right y axis). The vertical line through the 37th week denotes a fetus at term. The lines represent the median, 90th, and 10th percentile for the individually adjusted limits of SF height and fetal weight growth. The mother was European, her height was 178 cm and booking weight 90 kg; serial measurements at weeks 34 and 38 are plotted, suggesting the possibility of fetal growth restriction [16] (modified from Fig. 1, p. 311, with permission from the authors and the Royal College of Obstetricians and Gynaecologists; reprinted with permission of Jason Gardosi).

36 34 32 30 28 26

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Gestational weeks

Figure 1 Example of a customized growth chart using symphysisfundal (SF) height (left y axis) and gestational age (x axis) for the evaluation of fetal weight (right y axis). The vertical line through the 37th week denotes a fetus at term. The lines represent the median, 90th, and 10th percentile for the individually adjusted limits of SF height and fetal weight growth. The mother was of Pakistani origin, her height was 150 cm and booking weight 49 kg; serial measurements at weeks 34 and 38 are plotted, showing satisfactory fetal growth [16] (modified from Fig. 1, p. 311, with permission from the authors and the Royal College of Obstetricians and Gynaecologists; reprinted with permission of Jason Gardosi).

A reduced AC on ultrasonographic evaluation is reported to be the most sensitive biometric measurement in predicting IUGR. An AC within the normal range reliably excludes IUGR, with a falsenegative rate of less than 10% [18]. Since growth is a dynamic process, serial measurements improve prediction of SGA and IUGR. Cross-sectional data give information only on size, whereas longitudinal data may be used to produce rates of growth (changes over time in size) [19]. Thus, serial fetal biometry is essential to provide an estimated growth rate [8]. Findings of a low AC (b 10th percentile), together with an elevated umbilical artery systolic / diastolic ratio (N 90th percentile), make IUGR diagnosis more likely. When combined with quantitative assessments of amniotic fluid volume, such findings increase the accuracy of IUGR detection from a positive predictive value of 38.1% to one of 66.7% [20].

Fetal weight kg

SF-height cm

4.5. Amniotic fluid volume estimate

The first sign of IUGR may be decreased amniotic fluid volume [21]. Oligohydramnion is considered to be present when the largest vertical pocket of amniotic fluid is less than 2 cm or the amniotic fluid index (AFI) is less than 5 cm. This index is the sum

Fetal weight kg

SF-height cm

10 3.4 percentile

3.8 3.6

8 of the vertical amniotic fluid pocket depths in the 4 abdominal quadrants [22,23]. In one study, a borderline AFI index (between 5 and 10 cm) was associated with a 4-fold increase in the incidence of IUGR [24].
4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6

K. Haram et al.

Fetal weight/ Birth weight (kg)

Maternal Height cm= 150.0 Booking Weight kg= 49.0 Ethnic Origin= Indian Subcoat Parity= 0

90 percentile 50 percentile 10 percentile

4.6. Customized fetal growth charts

Physiological variables (fetal sex and age as well as maternal height, weight in early pregnancy, parity, and ethnic group) have been included in a prediction model to calculate individually adjusted or customized optimal weight [25,26]. Such customized standard charts reduce the false-positive rate of IUGR diagnosis in a normal population (Figs. 3 and 4) [25,27]. If physiological variables are not taken into account, approximately a quarter of all SGA fetuses are false-positively diagnosed as having IUGR [28].

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Gestational weeks

4.7. Three-dimensional ultrasonography

The use of 3-dimensional computer-aided ultrasonography may increase diagnostic precision in the estimation and detection of fetal malformations, although probably only marginally [17].

Figure 4 Example of customized fetal weight percentiles using symphysisfundal (SF) height (left y axis) and gestational age (x axis) for the evaluation of fetal weight (right y axis). The vertical line through the 37th week denotes a fetus at term. The chart is adjusted for a small nulliparous woman of Indian origin; her height was 150 cm and booking weight 49 kg. Serial fetal weight estimations (solid circles) led to anticipate a birth weight of 3 kg (open circle), as in Fig. 3. In this case, weights stay within normal limits as the mean, 10th, and 90th percentile lines have been adjusted downward (i.e., customized) to allow for maternal characteristics [27] (modified from Fig. 2, p. 847, with permission from the authors and the Royal College of Obstetricians and Lippincott, Williams and Wilkins; reprinted with permission of Jason Gardosi).

90 percentile 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 Maternal Height cm= 163.0 Booking Weight kg= 64.5 Ethnic Origin= European Parity= 1 50 percentile 10 percentile

Fetal weight/ Birth weight (kg)

4.8. Umbilical artery Doppler impedance measurements

Umbilical artery Doppler impedance measurement is well suited to be a pivotal test in the management of the SGA fetus. Umbilical artery Doppler impedance measurements in the management of high-risk pregnancies (especially those associated with presumed IUGR or hypertension) were associated with a trend toward a reduction in perinatal mortality (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.501.01), with fewer inductions of labor (OR, 0.83; 95% CI, 0.74 0.93) and fewer hospitalizations (OR, 0.56; 95% CI, 0.430.72) [29]. Thus, umbilical artery Doppler impedance measurements is the only surveillance method that, when used in a population at high risk, is associated with a trend toward improvement of perinatal mortality. The benefit of umbilical artery impedance testing lies mainly in the identification of SGA fetuses at high risk, those that will require intensive surveillance. Fetuses with end-diastolic flow can be safely managed on an outpatient basis [30], and testing can performed every 2 weeks [31]. Conversely, an absent or reversed end-diastolic

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Gestational weeks

Figure 3 Example of customized fetal weight percentiles using symphysisfundal (SF) height (left y axis) and gestational age (x axis) for the evaluation of fetal weight (right y axis). The vertical line through the 37th week denotes a fetus at term. The chart represents the expected average fetal growth for a given population. The mother was European and para 1, her height was 163 cm and booking weight 64.5 kg. Serial fetal weight estimations (solid circles) lead to anticipate a birth weight of 3 kg (open circle) [27] (modified from Fig. 1, p. 846, with permission from the authors and the Royal College of Obstetricians and Lippingcott, Williams and Wilkins; reprinted with permission of Jason Gardosi).

Intrauterine growth restriction flow of the umbilical artery requires maternal hospitalization and daily fetal monitoring.

9 95% CI, 0.610.73), severe intraventricular hemorrhage (OR, 0.50; 95% CI, 0.430.57), and death (OR, 0.54; 95% CI, 0.480.62). These were risks similar to those among appropriately grown infants [41]. A 2year follow-up study of babies born with IUGR between 26 and 32 weeks of gestation to women who had received betamethasone for 1 to 7 days before cesarean section showed increased survival without disability or handicap compared to controls (OR, 3.2; 95% CI, 1.111.2) [42]. Several studies have raised concerns about adverse effects of multiple doses of corticosteroids, e.g., delayed somatic growth, increased risk of fetal brain damage, perinatal infections, sepsis-related neonatal deaths, and maternal infections [43,44]. Pregnancies of a duration less than 34-week and complicated by severe pre-eclampsia and IUGR may not benefit from expectant management beyond the 48 h needed for corticosteroids to act. If delivery is indicated prior to the 34th week, corticosteroids should always be administered [45]. Betamethasone is the probably the best choice [46]. Antenatal administration of vitamin K in combination with corticosteroid therapy was proposed to reduce the incidence of fetal intracerebral bleeding [47,48]. A recent Cochrane meta-analysis concluded, however, that antenatal vitamin K therapy did not seem to have any beneficial effect [49].

4.9. Asymmetric growth (increased HC / AC ratio)

In IUGR Asymmetric growth is defined as increased HC / AC ratio [32]. When a diagnosis of IUGR is made before 24 weeks of gestation, there is often asymmetry [33]. Asymmetric IUGR early in the second trimester strongly suggests triploidy [34]. Doppler velocimetry findings may be normal in asymmetric IUGR fetuses with chromosomal or other structural etiologies [35].

4.10. Infections
A search for viral infections is often proposed when IUGR is suspected [7]. However, a study conducted in the United States showed that none of 75 growthretarded infants evaluated had positive IgM titers for bTORCHQ infections (toxoplasma, rubella, and cytomegalovirus or herpes simplex virus). Only 1 had a positive urine culture for CMV. In light of these findings, the yield of laboratory studies for TORCH infections in infants with IUGR is poor and does not seem to justify the incurred costs [36]. However, this important question requires further evaluation by additional studies. A preliminary study provided evidence that maternal periodontal disease may contribute to IUGR [37], as well as Helicobacter pylori infection [38]. Some infections with protozoans such as Toxoplasma gondii as well as syphilis are associated with IUGR [8]. It is not clear whether low birth weight associated with malaria is due to growth impairment or preterm delivery, but chemoprophylaxis seems to have beneficial effects on birth weight in primigravidae who have malaria [39].

5.2. Heparin and acetylsalicylic acid

A recent Cochrane review indicated that no completed randomized or quasi-randomized trials of heparin in women with thrombophilia allowed an evaluation of heparin treatment on pregnancy outcome [50]. Nonrandomized studies of thrombophilia suggest that prophylaxis with unfractionated heparin lowers the incidence of IUGR. Trials are in progress to determine whether low-molecularweight heparin has preventive effects on pregnancy loss or gestational vascular complications in thrombophilic women with previous fetal wastage [51]. A meta-analysis including 13,234 women concluded that early prophylaxis with acetylsalicylic acid (ASA) reduced risk of IUGR in high-risk pregnancies. The effect seemed greater with daily doses between 100 and 150 mg than between 50 and 80 mg, especially if prophylaxis was started before 17 weeks of pregnancy [52]. A more recent meta-analysis of 14 trials including 12,416 women with predisposing risk factors (a previous history of preeclampsia, hypertension, diabetes, or renal disease) concluded that prophylaxis with ASA reduced subsequent risks of preeclampsia, spontaneous preterm birth, and perinatal death, with a

5. Treatment of IUGR
5.1. Antenatal corticosteroids
Elimian et al. detected no reduction in neonatal morbidity from antenatal corticosteroid therapy in pregnancies associated with maternal hypertension or fetal IUGR [40]. In a recent controlled randomized study of 19,759 very-low-birth-weight neonates born between 25 and 30 weeks of gestation, maternal prenatal glucocorticoid administration was associated with significantly lower risks of respiratory distress syndrome (OR, 0.51; 95% CI, 0.440.58), intraventricular hemorrhage (OR, 0.67;

10 mean birth weight increase of 215 g (OR, 0.86; 95% CI, 0.790.94) [53]. In a controlled study, a daily dose of 0.5 mg/kg of ASA taken from the 12th to 14th week of pregnancy onward reduced the incidence of pregnancy-induced hypertension and pre-eclampsia in 90 women at high risk for pre-eclampsia. The differences in IUGR incidence (2.3% vs. 7%) were not statistically significant, probably in part because of the small sample size [54]. Smaller single randomized studies in high-risk pregnancies have also showed that prophylaxis with ASA reduces the incidence of IUGR, pre-eclampsia, and pregnancy-induced hypertension [55]. Pregnancies with previous histories of or risk factors for IUGR or pre-eclampsia have been reported to benefit from daily doses of 100 to 150 mg of ASA, beginning in the first or second trimester [5658]. Kupferminc et al. reported an uncontrolled trial of prophylaxis with low-molecular-weight heparin (enoxaparin 40 mg daily) and ASA (80 mg daily) in thrombophilic women with previous pre-eclampsia, abruptio placentae, IUGR, or fetal death. Those who were homozygote for a methylenetetrahydrofolate reductase gene (MTHR ) mutation also received folic acid. The mean birth weight for the second (i.e., treated) pregnancies was 2719 g compared with 1175 g for the first pregnancies [59]. However, these results need to be verified in randomized controlled trials. Acetylsalicylic acid may inhibit antiphospholipid antibody-mediated hypercoaguability in the intervillous space and heparin may prevent antiphospholipid antibodies from interfering with cytotrophoblast migration [60,61]. The latter has been demonstrated in vitro [62]. Combined prednisone and ASA prophylaxis in women with antiphospholipid autoantibodies (lupus anticoagulant or anticardiolipin) and histories of recurrent fetal losses, however, was not effective in promoting live births and seemed associated with increased risk of premature birth [63]. In a randomized controlled trial of nearly 100 women with antiphospholipid syndrome the incidence of live births in those treated with combined low doses of ASA and heparin was 71% (32 of 45 pregnancies) compared with 42% (19 of 45 pregnancies) in women treated with ASA alone (OR, 3.37; 95% CI, 1.408.10) [64].

K. Haram et al. reported that there is not enough evidence to evaluate such supplementation when impaired fetal growth is suspected [65].

5.4. Asthma
In patients with asthma IUGR incidence appears to be associated with disease severity. Preventing acute asthma attacks with steroid and theophylline use seemed to result in the normalization of low-birth-weight rates among the offspring of women with asthma [66]. A prospective study of 2205 pregnancies showed that although oral steroid and theophylline use was associated with increased risk of prematurity, the incidence of IUGR was clearly associated with asthma severity during pregnancy. Women with asthma symptoms, but without confirmed diagnosis, were at particularly high risk for IUGR pregnancies [67]. A prospective cohort study showed that the fetuses of pregnant women with asthma seemed to be at no increased risk for IUGR if the disease was actively managed and treated (with oral steroids if necessary) [68].

5.5. Oxygen therapy

A recent Cochrane analysis concluded that there is not enough evidence to conclude that continuous oxygen therapy in women with a suspected IUGR pregnancy benefits the fetus [69].

5.6. Nitric oxide (transdermal glyceryl trinitrate)

A randomized study in women at risk for preeclampsia concluded that prophylaxis with a lowdose (5 mg/day) of transdermal glyceryl trinitrate commenced late in the second trimester did not reduce the incidence of pre-eclampsia, preterm delivery, or fetal growth restriction but, in time to event analysis, was associated with decreased incidence of pregnancy complications. Treatment with transdermal glyceryl trinitrate did not affect maternal cardiovascular, uterine artery, or fetal arterial Doppler impedance indexes [70].

5.7. Bed rest

Bed rest has been used extensively to treat a wide variety of pregnancy complications at substantial cost but with little proof of effectiveness. Among the disadvantages of bed rest are increased risks of thrombosis, bone demineralization, stress, and weight loss. Bed rest should probably be curtailed

5.3. Hormone supplementation

It has been suggested that estrogen supplementation may result in a greater uterine blood flow, thereby allowing an increased nutritional supply to improve fetal growth. A recent Cochrane analysis

Intrauterine growth restriction unless randomized trials demonstrate improvement of a specific outcome [71].

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[15] Steingrimsdottir T, Cnattingius S, Lindmark G. Symphysis fundus height: construction of a new Swedish reference curve, based on ultrasonically dated pregnancies. Acta Obstet Gynecol Scand 1995;74:346 51. [16] Gardosi J, Francis A. Controlled trial of fundal height measurement plotted on customised antenatal growth charts. Br J Obstet Gynaecol 1999;106:309 17. [17] Dudley NJ. A systematic review of the ultrasound estimation of fetal weight. Ultrasound Obstet Gynecol 2005;25: 80 9. [18] Warsof SL, Cooper DJ, Little D, Campbell S. Routine ultrasound screening for antenatal detection of intrauterine growth retardation. Obstet Gynecol 1986;67:33 9. [19] Royston P, Wright EM. How to construct dnormal rangesT for fetal variables. Ultrasound Obstet Gynecol 1998;11:30 8. [20] Lin CC, Sheikh Z, Lopata R. The association between oligohydramnios and intrauterine growth retardation. Obstet Gynecol 1990;76:1100 4. [21] Vandenbosche RC, Kirchner JT. Intrauterine growth retardation. Am Fam Physician 1998;58:1384 90. [22] Chauhan SP, Doherty DD, Magann EF, Cahanding F, Moreno F, Klausen JH. Amniotic fluid index vs. single deepest pocket technique during modified biophysical profile: a randomized clinical trial. Am J Obstet Gynecol 2004;191: 661 7. [23] Ott WJ. Reevaluation of the relationship between amniotic fluid volume and perinatal outcome. Am J Obstet Gynecol 2005;192:1803 9. [24] Banks EH, Miller DA. Perinatal risks associated with borderline amniotic fluid index. Am J Obstet Gynecol 1999;180:1461 3. [25] Gardosi J. The application of individualised fetal growth curves. J Perinat Med 1998;26:333 8. [26] Gardosi J. Customized fetal growth standards: rationale and clinical application. Semin Perinatol 2004;28:33 40. [27] Mongelli M, Gardosi J. Reduction of false-positive diagnosis of fetal growth restriction by application of customized fetal growth standards. Obstet Gynecol 1996;88:844 8. [28] Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM. Customised antenatal growth charts. Lancet 1992;339:283 7. [29] Alfirevic Z, Neilson JP. Doppler ultrasonography in high-risk pregnancies: systematic review with meta-analysis. Am J Obstet Gynecol 1995;172:1379 87. [30] Nienhuis SJ, Vles JS, Gerver WJ, Hoogland HJ. Doppler ultrasonography in suspected intrauterine growth retardation: a randomized clinical trial. Ultrasound Obstet Gynecol 1997;9:6 13. [31] McCowan LM, Harding JE, Roberts AB, Barker SE, Ford C, Stewart AW. A pilot randomized controlled trial of two regimens of fetal surveillance for small-for-gestational-age fetuses with normal results of umbilical artery Doppler velocimetry. Am J Obstet Gynecol 2000;182:81 6. [32] Dashe JS, McIntire DD, Lucas MJ, Leveno KJ. Effects of symmetric and asymmetric fetal growth on pregnancy outcomes. Obstet Gynecol 2000;96:321 7. [33] Pearce JM, Robinson G. Fetal growth and intrauterine growth retardation. In: Chamberlain G, editor. Turnbulls Obstetrics, second ed. Edinburgh7 Churchill Livingstone; 1995. p. 299 312. [34] Snijders RJ, Sherrod C, Gosden CM, Nicolaides KH. Fetal growth retardation: associated malformations and chromosomal abnormalities. Am J Obstet Gynecol 1993;168: 547 55. [35] Wladimiroff JW, vd Wijngaard JA, Degani S, Noordam MJ, van Eyck J, Tonge HM. Cerebral and umbilical arterial blood flow velocity waveforms in normal and growth-retarded pregnancies. Obstet Gynecol 1987;69:705 9.

6. Preconceptional care
Uteroplacental insufficiency in IUGR is probably caused by abnormal trophoblast invasion during implantation. This is regulated by residual natural killer cells, which secrete cytokines stimulating trophoblast growth, differentiation, and migration. The complexity and precise timing of these events underscore the potential benefit of preconceptional care in preventing low birth weight [12]. This benefit most likely would be related to timely screening, diagnosis, and prophylaxis.

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